register interest

Emeritus Professor John Stradling

Research Area: Integrative Physiology (Systems Biology)
Scientific Themes: Physiology, Cellular & Molecular Biology and Clinical Trials & Epidemiology
Keywords: sleep apnoea, cardiovascular disease, sleepiness, vascular reactivity, vascular imaging and clinical trial

Obstructive sleep apnoea (OSA):-

  • Epidemiology
  • Cardiovascular consequences of OSA
  • Diabetes/retinopathy
  • Symptoms
  • Clinical mangement

Current main project is a multicentre trial of CPAP in patients with OSA and diabetic macular oedema, funded by the ResMed foundation. In addition we have used a CPAP withdrawal model to look at oxidative stress in OSA, funded by British Heart Foundation. A cross-sectional study of ventilatory failure in obesity has been recently completed. The CPAP withdrawal model is being used to look at vascular reactivity in the eye and the relevance of intermittent hypoxia to the cardiovascular effects in OSA.

Name Department Institution Country
Professor Malcolm Kohler Zurich University Switzerland
Prof Charalambos Antoniades (RDM) Cardiovascular Medicine Oxford University, West Wing, John Radcliffe Hospital United Kingdom
Professor Julian C Knight Wellcome Trust Centre for Human Genetics Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Prof Stefan Neubauer FMedSci FRCP (RDM) Cardiovascular Medicine Oxford University, John Radcliffe Hospital United Kingdom
Prof Fredrik Karpe (RDM) OCDEM Oxford University, Oxford Centre for Diabetes, Endocrinology & Metabolism United Kingdom
Professor Mary Morrell Brompton Hospital, Imperial College, London United Kingdom
Dr Sophie West Respiratory Medicine Newcastle University United Kingdom
Professor Najib Rahman Experimental Medicine Division Oxford University, Churchill Hospital United Kingdom
Turnbull C, Pattenden S, Gaisl T, Rossi V, Thiel S, Kohler M, Stradling J. 2019. Return of sleep apnoea and sleep fragmentation following CPAP withdrawal in patients with obstructive sleep apnoea. Eur Respir J, 53 (5), | Read more

Turnbull CD, Petousi N, Stradling JR. 2019. Reply to Jin et al.: Supplemental Oxygen in Obstructive Sleep Apnea: Much to Be Done. Am J Respir Crit Care Med, 199 (1), pp. 127. | Read more

Thiel S, Lettau F, Rejmer P, Rossi C, Haile SR, Schwarz EI, Stöberl AS, Sievi NA, Boss A, Becker AS et al. 2019. Effects of short-term continuous positive airway pressure withdrawal on cerebral vascular reactivity measured by blood oxygen level-dependent magnetic resonance imaging in obstructive sleep apnoea: a randomised controlled trial. Eur Respir J, 53 (2), pp. 1801854-1801854. | Show Abstract | Read more

Impaired cerebral vascular reactivity (CVR) increases long-term stroke risk. Obstructive sleep apnoea (OSA) is associated with peripheral vascular dysfunction and vascular events. The aim of this trial was to evaluate the effect of continuous positive airway pressure (CPAP) withdrawal on CVR.41 OSA patients (88% male, mean age 57±10 years) were randomised to either subtherapeutic or continuation of therapeutic CPAP. At baseline and after 2 weeks, patients underwent a sleep study and magnetic resonance imaging (MRI). CVR was estimated by quantifying the blood oxygen level-dependent (BOLD) MRI response to breathing stimuli.OSA did recur in the subtherapeutic CPAP group (mean treatment effect apnoea-hypopnoea index +38.0 events·h-1, 95% CI 24.2-52.0; p<0.001) but remained controlled in the therapeutic group. Although there was a significant increase in blood pressure upon CPAP withdrawal (mean treatment effect +9.37 mmHg, 95% CI 1.36-17.39; p=0.023), there was no significant effect of CPAP withdrawal on CVR assessed via BOLD MRI under either hyperoxic or hypercapnic conditions.Short-term CPAP withdrawal did not result in statistically significant changes in CVR as assessed by functional MRI, despite the recurrence of OSA. We thus conclude that, unlike peripheral endothelial function, CVR is not affected by short-term CPAP withdrawal.

West SD, Prudon B, Hughes J, Gupta R, Mohammed SB, Gerry S, Stradling JR, ROSA trial investigators. 2018. Continuous positive airway pressure effect on visual acuity in patients with type 2 diabetes and obstructive sleep apnoea: a multicentre randomised controlled trial. Eur Respir J, 52 (4), pp. 1801177-1801177. | Show Abstract | Read more

We sought to establish whether continuous positive airway pressure (CPAP) for obstructive sleep apnoea (OSA) in people with type 2 diabetes and diabetic macular oedema (DMO) improved visual acuity.We randomly assigned 131 eligible patients aged 30-85 years from 23 UK centres with significant DMO causing visual impairment (LogMAR letters identified ≥39 and ≤78, score 0.92-0.14) plus severe OSA on screening to either usual ophthalmology care (n=67) or usual ophthalmology care plus CPAP (n=64) for 12 months.Mean age of participants was 64 years, 73% male, mean body mass index 35.0 kg·m-2 Mean 4% oxygen desaturation index was 36 events·h-1 There was no significant difference in the visual acuity at 12 months between the CPAP group and the control group (mean LogMAR 0.33 (95% CI 0.29-0.37) versus 0.31 (95% CI 0.27-0.35); p=0.39), and no significant correlation between change in LogMAR and average CPAP use. The median±sd (range) daily CPAP use was 3.33±2.25 (0-7.93) h at 3 months, 3.19±2.54 (0-8.07) h at 6 months and 3.21±2.70 (0-7.98) h at 12 months.CPAP therapy for OSA did not improve visual acuity in people with type 2 diabetes and DMO compared with usual care alone over 12 months.

Crook S, Sievi NA, Bloch KE, Stradling JR, Frei A, Puhan MA, Kohler M. 2019. Minimum important difference of the Epworth Sleepiness Scale in obstructive sleep apnoea: estimation from three randomised controlled trials. Thorax, 74 (4), pp. 390-396. | Show Abstract | Read more

BACKGROUND: The Epworth Sleepiness Scale (ESS) is a widely used tool for assessing sleepiness in patients with obstructive sleep apnoea (OSA). We aimed to estimate the minimal important difference (MID) in patients with OSA. METHODS: We used individual data from three randomised controlled trials (RCTs) in patients with OSA where the preintervention to postintervention change in ESS was used as a primary outcome. We used anchor-based linear regression and responder analysis approaches to estimate the MID. For anchors, we used the change in domains of the Functional Outcomes of Sleep Questionnaire and 36-Item Short Form Health Survey. We also used the distribution-based approaches Cohen's effect size, SE of measurement and empirical rule effect size to support the anchor-based estimates. The final MID was determined by triangulating all estimates to a single MID. FINDINGS: A total of 639 patients with OSA were included in our analyses across the three RCTs with a median (IQR) baseline ESS score of 10 (6-13). The median (IQR) ESS change score overall was -2 (-5 to 1). The anchor-based estimates of the MID were between -1.74 and -4.21 points and estimates from the responder analysis were between -1 and -3 points. Distribution-based estimates were smaller, ranging from -1.46 to -2.36. INTERPRETATION: We propose an MID for the ESS of 2 points in patients with OSA with a disease severity from mild to severe. This estimate provides the means to plan trials and interpret the clinical relevance of changes in ESS. TRIAL REGISTRATION NUMBER: Provent, NCT01332175; autoCPAP trial, NCT00280800; MOSAIC,ISRCTN (3416388).

Schwarz EI, Turnbull CD, Stradling JR, Kohler M. 2018. Understanding effects of obstructive sleep apnoea and its treatment on the brain and autonomic regulation needs further research. J Thorac Dis, 10 (8), pp. E664-E665. | Read more

Schlatzer C, Bratton DJ, Schwarz EI, Gaisl T, Pepperell JCT, Stradling JR, Kohler M. 2018. Effect of continuous positive airway pressure therapy on circadian patterns of cardiac repolarization in patients with obstructive sleep apnoea: data from a randomized trial. J Thorac Dis, 10 (8), pp. 4940-4948. | Show Abstract | Read more

Background: Obstructive sleep apnoea (OSA) has been proposed as an independent risk factor for sudden cardiac death (SCD). This study takes advantage of a previous randomized trial and seeks to evaluate circadian patterns of the QTc-interval, a marker of cardiac repolarization and biomarker for SCD, in patients with OSA. We hypothesized that patients with OSA would exhibit longest QTc during the night-time and that continuous positive airway pressure (CPAP) therapy would reverse this. Methods: One hundred eighteen patients diagnosed with moderate-to-severe OSA were randomized to receive therapeutic or subtherapeutic CPAP for 4 weeks. Of these, 84 had full 24 h-Holter monitoring data at baseline and follow-up. Weighted means of all QTc-intervals were analysed over 24 h, during four time-periods (12 pm-6 am, 6 am-12 am, 12 am-6 pm, 6 pm-12 pm) as well as during each individual hour. A two-sided P value <0.05 was considered to be of statistical significance. Results: QTc-intervals at baseline [mean (SD) over 24 h: 407.8 ms (36.6)] were highest from 6 pm-12 pm [411.7 ms (42.0)] and shortest from 6 am-12 am [405.4 ms (39.5)]. Overall 24 h CPAP treatment effect on QTc was -11.3 ms [95% confidence interval (CI), -22.1 to -0.6; P=0.039] and was estimated to be greater from 6 pm-12 pm than from 12 pm-6 am (P=0.068). The CPAP treatment effect on QTc was driven by those patients in the highest QTc decile at baseline (all >430 ms). In these patients, CPAP led to reductions in QTc, allowing reclassification into lower risk-associated values of QTc (<430 ms). Conclusions: In this exploratory study, CPAP treatment led to an overall reduction in the QTc-interval compared with subtherapeutic CPAP. This reduction seems more pronounced during evening hours and in patients with a QTc above 430 ms.

Turnbull CD, Sen D, Kohler M, Petousi N, Stradling JR. 2019. Effect of Supplemental Oxygen on Blood Pressure in Obstructive Sleep Apnea (SOX). A Randomized Continuous Positive Airway Pressure Withdrawal Trial. Am J Respir Crit Care Med, 199 (2), pp. 211-219. | Show Abstract | Read more

RATIONALE: Obstructive sleep apnea (OSA) is associated with systemic hypertension. Either overnight intermittent hypoxia, or the recurrent arousals that occur in OSA, could cause the daytime increases in blood pressure (BP). OBJECTIVES: To establish the role of intermittent hypoxia in the increased morning BP in patients with OSA. METHODS: Randomized, double-blinded, crossover trial assessing the effects of overnight supplemental oxygen versus air (sham) on morning BP, after continuous positive airway pressure (CPAP) withdrawal in patients with moderate to severe OSA. The primary outcome was the change in home morning BP after CPAP withdrawal for 14 nights, oxygen versus air. Secondary outcomes included oxygen desaturation index (ODI), apnea-hypopnea index (AHI), subjective sleepiness (Epworth Sleepiness Scale score), and objective sleepiness (Oxford Sleep Resistance Test). MEASUREMENTS AND MAIN RESULTS: Supplemental oxygen virtually abolished the BP rise after CPAP withdrawal and, compared with air, significantly reduced the rise in mean systolic BP (-6.6 mm Hg; 95% confidence interval [CI], -11.3 to -1.9; P = 0.008), mean diastolic BP (-4.6 mm Hg; 95% CI, -7.8 to -1.5; P = 0.006), and median ODI (-23.8/h; interquartile range, -31.0 to -16.3; P < 0.001) after CPAP withdrawal. There was no significant difference, oxygen versus air, in AHI, subjective sleepiness, or objective sleepiness. CONCLUSIONS: Supplemental oxygen virtually abolished the rise in morning BP during CPAP withdrawal. Supplemental oxygen substantially reduced intermittent hypoxia, but had a minimal effect on markers of arousal (including AHI), subjective sleepiness, or objective sleepiness. Therefore intermittent hypoxia, and not recurrent arousals, appears to be the dominant cause of daytime increases in BP in OSA.

Schwarz EI, Furian M, Schlatzer C, Stradling JR, Kohler M, Bloch KE. 2018. Nocturnal cerebral hypoxia in obstructive sleep apnoea: a randomised controlled trial. Eur Respir J, 51 (5), pp. 1800032-1800032. | Show Abstract | Read more

Cerebral hypoxia may promote cerebral damage in patients with obstructive sleep apnoea (OSA). We investigated whether OSA patients experience nocturnal cerebral hypoxia that is prevented by continuous positive airway pressure (CPAP).OSA patients using CPAP underwent sleep studies including pulse oximetry (arterial oxygen saturation (SpO2 )) and near-infrared spectroscopy to monitor cerebral tissue oxygenation (CTO) at baseline and after 2 weeks on either subtherapeutic or therapeutic CPAP according to randomised allocation. Changes in oxygenation at end of the 2-week intervention were compared between groups.Among 21 patients (mean apnoea/hypopnoea index 50.3 events·h-1), OSA recurred in all nine patients using subtherapeutic CPAP and in none of the patients using therapeutic CPAP: mean (95% CI) between-group differences in changes of oxygen desaturation index from baseline to 2 weeks +40.7 (31.1-50.4) events·h-1 for SpO2 and +37.0 (25.3-48.7) events·h-1 for CTO (both p<0.001). Mean nocturnal SpO2 and CTO decreased more in patients using subtherapeutic versus therapeutic CPAP: -2.4 (-3.4--1.1)% and -3.8 (-7.4--0.1)%, respectively; both p<0.03. Severe CTO drops ≥13% associated with cerebral dysfunction in previous studies occurred in four out of nine patients using subtherapeutic CPAP, but in none out of 12 patients using therapeutic CPAP (p=0.01).In patients with OSA, CPAP withdrawal resulted in nocturnal cerebral deoxygenation, suggesting a role of cerebral hypoxia in predisposing untreated OSA patients to cerebral damage.

Schwarz EI, Stradling JR, Kohler M. 2018. Physiological consequences of CPAP therapy withdrawal in patients with obstructive sleep apnoea-an opportunity for an efficient experimental model. J Thorac Dis, 10 (Suppl 1), pp. S24-S32. | Show Abstract | Read more

Randomised controlled trials (RCTs) of continuous positive airway pressure (CPAP) in obstructive sleep apnoea (OSA) are time consuming, and their findings often inconclusive or limited due to suboptimal CPAP adherence in CPAP-naïve patients with OSA. Short-term CPAP withdrawal in patients with prior optimal CPAP adherence results in recurrence of OSA and its consequences. Thus, this experimental model serves as an efficient tool to investigate both the consequences of untreated OSA, and potential treatment alternatives to CPAP. The CPAP withdrawal protocol has been thoroughly validated, and applied in several RCTs focusing on cardiovascular and metabolic consequences of untreated OSA, as well as the assessment of treatment alternatives to CPAP.

Turnbull CD, Wang SH, Manuel AR, Keenan BT, McIntyre AG, Schwab RJ, Stradling JR. 2018. Relationships between MRI fat distributions and sleep apnea and obesity hypoventilation syndrome in very obese patients. Sleep Breath, 22 (3), pp. 673-681. | Show Abstract | Read more

PURPOSE: Obesity is associated with both obstructive sleep apnea (OSA) and obesity hypoventilation. Differences in adipose tissue distribution are thought to underlie the development of both OSA and hypoventilation. We explored the relationships between the distribution of upper airway, neck, chest, abdominal and muscle fat in very obese individuals. METHODS: We conducted a cross-sectional cohort study of individuals presenting to a tertiary sleep clinic or for assessment for bariatric surgery. Individuals underwent magnetic resonance (MR) imaging of their upper airway, neck, chest, abdomen and thighs; respiratory polygraphy; 1 week of autotitrating CPAP; and morning arterial blood gas to determine carbon dioxide partial pressure and base excess. RESULTS: Fifty-three individuals were included, with mean age of 51.6 ± 8.4 years and mean BMI of 44.3 ± 7.9 kg/m2; there were 27 males (51%). Soft palate, tongue and lateral wall volumes were significantly associated with the AHI in univariable analyses (p < 0.001). Gender was a significant confounder in these associations. No significant associations were found between MRI measures of adiposity and hypoventilation. CONCLUSIONS: In very obese individuals, our results indicate that increased volumes of upper airway structures are associated with increased severity of OSA, as previously reported in less obese individuals. Increasingly large upper airway structures that reduce pharyngeal lumen size are likely to lead to OSA by increasing the collapsibility of the upper airway. However, we did not show any significant association between regional fat distribution and propensity for hypoventilation, in this population.

Stöberl AS, Schwarz EI, Haile SR, Turnbull CD, Rossi VA, Stradling JR, Kohler M. 2017. Night-to-night variability of obstructive sleep apnea. J Sleep Res, 26 (6), pp. 782-788. | Show Abstract | Read more

One night of a sleep study is the standard for diagnosis and exclusion of obstructive sleep apnea. Single testing requires high sensitivity of the test method and a stable disease of interest to warrant a low rate of false-negative tests. Obstructive sleep apnea is diagnosed and graded by conventional thresholds of apneas and hypopneas per hour of sleep, and treatment is usually initiated in the presence of symptoms. The aim of this study was to assess night-to-night variability of obstructive sleep apnea to reassess the current practice. Seventy-seven patients previously diagnosed with obstructive sleep apnea, randomised to continuous positive airway pressure withdrawal within four trials, performed nightly pulse-oximetry over 2 weeks while off continuous positive airway pressure. The main outcome of interest was the coefficient of variation of the oxygen desaturation index marking night-to-night variability in obstructive sleep apnea. Obstructive sleep apnea was categorised according to conventional thresholds using oxygen desaturation index (no obstructive sleep apnea: <5 per h; mild: 5-15 per h; moderate: 15-30 per h; and severe: >30 per h). High night-to-night variability of obstructive sleep apnea was evidenced by a coefficient of variation of oxygen desaturation index of 31.1% (SD 16.5). Differences in oxygen desaturation index of >10 per h between nights were found in 84.4% and shifts in obstructive sleep apnea severity category in 77.9% of patients. The probability of missing moderate obstructive sleep apnea was up to 60%. Variability was higher in less severe obstructive sleep apnea. Obstructive sleep apnea shows a considerable night-to-night variability. Single-night diagnostic sleep studies are prone to miscategorise obstructive sleep apnea if arbitrary thresholds are used. Thus, treatment decisions should be based less on the conventional derivatives from sleep studies, especially in patients with less severe obstructive sleep apnea. CLINICAL TRIAL REGISTRATION: www.controlled-trials.com (ISRCTN 93153804, ISRCTN 73047833) and www.clinicaltrials.gov (NCT01332175 & NCT02050425).

Turnbull CD, Stradling JR. 2017. To screen or not to screen for obstructive sleep apnea, that is the question. Sleep Med Rev, 36 pp. 125-127. | Read more

Johar A, Turnbull CD, Stradling JR. 2017. Can postural OSA be usefully identified from its severity alone? BMJ Open Respir Res, 4 (1), pp. e000259. | Show Abstract | Read more

Introduction: When obstructive sleep apnoea (OSA) does not occur throughout sleep, there must be factors influencing its presence or absence. These are most likely to be sleep stage, posture and presleep alcohol, among others. We hypothesised that as OSA severity increases, the likelihood of postural OSA (POSA) would also decrease. Methods: Laboratory sleep studies of 39 patients with OSA were manually reviewed to calculate supine and non-supine oxygen desaturation indices (ODI). The usual definition for POSA was used, a ratio of supine to non-supine ODI of ≥2. Results: The mean age was 53.2 (SD 12.4) years, the body mass index was 35.0 (SD 8.9) kg/m2 and 74% were male. The median supine ODI was 54.3 (IQR 25.7-73.5) and non-supine ODI was 18.7 (IQR 8.6-38.4). The overall prevalence of POSA was 56%. The prevalence of POSA for ODIs of <40 was 68%, and 35% if ≥40. Conclusions: An ODI ≥40, compared with <40, halved the likelihood of POSA from 68% to 35%. Although there is clearly a relationship between overall ODI and POSA, it is not strong enough to diagnose an individual with POSA. However the relationship provides a useful way to prescreen trial subjects to enrich for POSA.

Murphy PB, Rehal S, Arbane G, Bourke S, Calverley PMA, Crook AM, Dowson L, Duffy N, Gibson GJ, Hughes PD et al. 2017. Effect of Home Noninvasive Ventilation With Oxygen Therapy vs Oxygen Therapy Alone on Hospital Readmission or Death After an Acute COPD Exacerbation: A Randomized Clinical Trial. JAMA, 317 (21), pp. 2177-2186. | Show Abstract | Read more

Importance: Outcomes after exacerbations of chronic obstructive pulmonary disease (COPD) requiring acute noninvasive ventilation (NIV) are poor and there are few treatments to prevent hospital readmission and death. Objective: To investigate the effect of home NIV plus oxygen on time to readmission or death in patients with persistent hypercapnia after an acute COPD exacerbation. Design, Setting, and Participants: A randomized clinical trial of patients with persistent hypercapnia (Paco2 >53 mm Hg) 2 weeks to 4 weeks after resolution of respiratory acidemia, who were recruited from 13 UK centers between 2010 and 2015. Exclusion criteria included obesity (body mass index [BMI] >35), obstructive sleep apnea syndrome, or other causes of respiratory failure. Of 2021 patients screened, 124 were eligible. Interventions: There were 59 patients randomized to home oxygen alone (median oxygen flow rate, 1.0 L/min [interquartile range {IQR}, 0.5-2.0 L/min]) and 57 patients to home oxygen plus home NIV (median oxygen flow rate, 1.0 L/min [IQR, 0.5-1.5 L/min]). The median home ventilator settings were an inspiratory positive airway pressure of 24 (IQR, 22-26) cm H2O, an expiratory positive airway pressure of 4 (IQR, 4-5) cm H2O, and a backup rate of 14 (IQR, 14-16) breaths/minute. Main Outcomes and Measures: Time to readmission or death within 12 months adjusted for the number of previous COPD admissions, previous use of long-term oxygen, age, and BMI. Results: A total of 116 patients (mean [SD] age of 67 [10] years, 53% female, mean BMI of 21.6 [IQR, 18.2-26.1], mean [SD] forced expiratory volume in the first second of expiration of 0.6 L [0.2 L], and mean [SD] Paco2 while breathing room air of 59 [7] mm Hg) were randomized. Sixty-four patients (28 in home oxygen alone and 36 in home oxygen plus home NIV) completed the 12-month study period. The median time to readmission or death was 4.3 months (IQR, 1.3-13.8 months) in the home oxygen plus home NIV group vs 1.4 months (IQR, 0.5-3.9 months) in the home oxygen alone group, adjusted hazard ratio of 0.49 (95% CI, 0.31-0.77; P = .002). The 12-month risk of readmission or death was 63.4% in the home oxygen plus home NIV group vs 80.4% in the home oxygen alone group, absolute risk reduction of 17.0% (95% CI, 0.1%-34.0%). At 12 months, 16 patients had died in the home oxygen plus home NIV group vs 19 in the home oxygen alone group. Conclusions and Relevance: Among patients with persistent hypercapnia following an acute exacerbation of COPD, adding home noninvasive ventilation to home oxygen therapy prolonged the time to readmission or death within 12 months. Trial Registration: clinicaltrials.gov Identifier: NCT00990132.

Lettau F, Schwarz EI, Stradling JR, Kohler M. 2017. Blood Pressure Variability in Obstructive Sleep Apnoea: Data from 4 Randomised Controlled CPAP Withdrawal Trials. Respiration, 93 (5), pp. 311-318. | Show Abstract | Read more

BACKGROUND: Increased daytime blood pressure variability (BPV) is associated with cardiovascular risk. Preliminary data suggest that obstructive sleep apnoea (OSA) might contribute to increased daytime BPV. OBJECTIVE: The aim of this study was to evaluate the effect of continuous positive airway pressure (CPAP) therapy withdrawal on daytime BPV. METHODS: A total of 183 patients previously diagnosed with OSA and treated with CPAP were randomised to either continue or withdraw from CPAP within 4 trials. Office morning BP was measured in triplicate at baseline and at follow-up (day 14). In addition, the participants performed BP measurements at home on a daily basis (days 1-13). The main outcome of interest was the treatment effect on within-visit BPV expressed as the standard deviation (SD) of the triplicate measurements. Additional outcomes included morning home BPV and day-to-day home BPV. RESULTS: Within-visit variability in systolic BP significantly increased in response to recurrence of OSA in the CPAP withdrawal group (difference between groups in SD of systolic BPV, +1.14 mm Hg, 95% CI +0.20/+2.09, p = 0.02). There was no statistically significant effect on within-visit variability in diastolic BP (p = 0.38) or heart rate (p = 0.07). Neither morning home BP variability (systolic BPV, p = 0.81; diastolic BPV, p = 0.46) nor day-to-day variability in home BP measurements (systolic BPV, p = 0.61; diastolic BPV, p = 0.58) differed significantly between the groups. CONCLUSION: CPAP withdrawal results in a minor increase in within-visit variability in office systolic BP, but it has no effect on home BPV or day-to-day BPV. Although the treatment effect may be blunted by antihypertensives, it is unlikely that OSA contributes to cardiovascular risk via elevated daytime BPV.

Turnbull CD, Akoumianakis I, Antoniades C, Stradling JR. 2017. Overnight urinary isoprostanes as a marker of oxidative stress in obstructive sleep apnoea. Eur Respir J, 49 (2), pp. 1601787-1601787. | Read more

Turnbull CD, Rossi VA, Santer P, Schwarz EI, Stradling JR, Petousi N, Kohler M. 2017. Effect of OSA on hypoxic and inflammatory markers during CPAP withdrawal: Further evidence from three randomized control trials. Respirology, 22 (4), pp. 793-799. | Show Abstract | Read more

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is associated with cardiovascular disease. Intermittent hypoxia, endothelial dysfunction and adipose tissue-mediated inflammation have all been linked to cardiovascular disease in OSA. We therefore explored the effect of OSA on relevant associated blood markers: adrenomedullin (ADM), endocan, endothelin-1 (ET-1), resistin and vascular endothelial growth factor (VEGF). METHODS: Patients with OSA, established on and compliant with continuous positive airways pressure (CPAP) therapy for >1 year were included from three randomized controlled trials, conducted at two centres. Patients were randomized to either continued therapeutic CPAP or sham CPAP (CPAP withdrawal) for 2 weeks. Blood markers were measured at baseline and at 14 days and the treatment effect between sham CPAP and therapeutic CPAP was analysed. RESULTS: A total of 109 patients were studied (therapeutic CPAP n = 54, sham CPAP n = 55). Sham CPAP was associated with a return of OSA (between-group difference in oxygen desaturation index (ODI) 36.0/h, 95% CI 29.9-42.2, P < 0.001). Sham CPAP was associated with a reduction in ADM levels at 14 days (-26.0 pg/mL, 95% CI -47.8 to -4.3, P = 0.02), compared to therapeutic CPAP. Return of OSA was not associated with changes in endocan, ET-1, resistin or VEGF. CONCLUSION: Whilst CPAP withdrawal was associated with return of OSA, it was associated with an unexpected significant reduction in the vasodilator ADM and not with expected increases in hypoxia-induced markers, markers of endothelial function or resistin. We propose that the vascular effects occurring in OSA may be brought about by other mechanisms, perhaps partly through a reduction in ADM.

Schwarz EI, Schlatzer C, Stehli J, Kaufmann PA, Bloch KE, Stradling JR, Kohler M. 2016. Effect of CPAP Withdrawal on myocardial perfusion in OSA: A randomized controlled trial. Respirology, 21 (6), pp. 1126-1133. | Show Abstract | Read more

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is highly prevalent and associated with an increased incidence of cardiovascular events. Endothelial dysfunction is the proposed causative mechanism. Continuous positive airway pressure (CPAP) is presumed to improve cardiovascular outcome in OSA. CPAP withdrawal was recently shown to lead to peripheral endothelial dysfunction. However, it is not known whether short-term CPAP withdrawal reduces myocardial perfusion in OSA. METHODS: In this double-blind randomized controlled study, 45 patients with moderate to severe OSA previously adherent to CPAP were assigned to either subtherapeutic or continuing therapeutic CPAP for 2 weeks. The primary outcome was adenosine-induced myocardial blood flow (MBF) as a measure of endothelial function, assessed by (13) N-ammonia positron emission tomography. Secondary outcomes were measures of dermal and renal microvascular function, morning blood pressure (BP) and heart rate. RESULTS: Despite return of OSA associated with significant increases in BP (+9.1 mm Hg, 95% CI +4.9 to +13.4 mm Hg, P < 0.001) and heart rate (+9.6 bpm, 95% confidence interval (CI) +4.6 to +14.6 bpm, P < 0.001), CPAP withdrawal had no significant effect on maximal myocardial perfusion capacity (hyperaemic MBF -0.01 ml/min/g, 95% CI -0.33 to +0.24 ml/min/g, P = 0.91), nor renal and dermal microvascular function. CONCLUSION: In patients with OSA, a short-term CPAP withdrawal does not lead to detectable impairment of coronary endothelial function, as has been demonstrated in the brachial artery, despite a clinically relevant increase in BP of nearly 10 mm Hg. There was also no evidence of an impairment of renal or dermal microvascular function.

Schwarz EI, Schlatzer C, Rossi VA, Stradling JR, Kohler M. 2016. Effect of CPAP Withdrawal on BP in OSA: Data from Three Randomized Controlled Trials. Chest, 150 (6), pp. 1202-1210. | Show Abstract | Read more

BACKGROUND: Based on meta-analyses, the BP-lowering effect of CPAP therapy in patients with OSA is reported to be approximately 2 to 3 mm Hg. This figure is derived from heterogeneous trials, which are often limited by poor CPAP adherence, and thus the treatment effect may possibly be underestimated. We analyzed morning BP data from three randomized controlled CPAP withdrawal trials, which included only patients with optimal CPAP compliance. METHODS: Within the three trials, 149 patients with OSA who were receiving CPAP were randomized to continue therapeutic CPAP (n = 65) or to withdraw CPAP (n = 84) for 2 weeks. Morning BP was measured at home before and after sleep studies in the hospital. RESULTS: CPAP withdrawal was associated with a return of OSA (apnea-hypopnea index [AHI] at a baseline of 2.8/h and at follow-up of 33.2/h). Office systolic BP (SBP) increased in the CPAP withdrawal group compared with the CPAP continuation group by +5.4 mm Hg (95% CI, 1.8-8.9 mm Hg; P = .003) and in the home SBP group by +9.0 mm Hg (95% CI, 5.7-12.3 mm Hg; P < .001). Office diastolic BP (DBP) increased by +5.0 mm Hg (95% CI, 2.7-7.3 mm Hg; P < .001), and home DBP increased by +7.8 mm Hg (95% CI, 5.6-10.4 mm Hg; P < .001). AHI, baseline home SBP, use of statin drugs, sex, and the number of antihypertensive drugs prescribed were all independently associated with SBP change in multivariate analysis, controlling for age, BMI, smoking status, diabetes, and sleepiness. CONCLUSIONS: CPAP withdrawal results in a clinically relevant increase in BP, which is considerably higher than in conventional CPAP trials; it is also underestimated when office BP is used. Greater OSA severity is associated with a higher BP rise in response to CPAP withdrawal. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01332175 and NCT01797653) URL: www.clinicaltrials.gov and ISRCTN registry (ISRCTN 93153804) URL: http://www.isrctn.com/.

Dattani RS, Swerner CB, Stradling JR, Manuel AR. 2016. Exploratory study into the effect of abdominal mass loading on airways resistance and ventilatory failure. BMJ Open Respir Res, 3 (1), pp. e000138. | Show Abstract | Read more

OBJECTIVE: We hypothesised that the airway resistance during tidal breathing would correlate with a particular pattern of increasing obesity, particularly when supine, and would differ between participants with and without ventilatory failure. METHODS: In our cross-sectional cohort study, 72 morbidly obese patients (40 males, 32 females, mean body mass index (BMI) 47.2) had measurements of both airways resistance (by impulse oscillometry (IOS)) and adiposity (by dual-energy X-ray absorptiometry (DXA)). RESULTS: All measures of airways resistance increased in the supine position: total airways resistance (R5) +37% (p<0.0005); large airways resistance (R20) +29% (p<0.0005); and small airways resistance (R5-R20) +52% (p<0.0005). BMI was correlated with seated R5, seated R5-R20, supine R5 and supine R5-R20 (r=0.33 p<0.006, r=0.32 p<0.004, r=0.30 p<0.02 and r=0.36 p<0.04, respectively). Visceral adipose tissue mass was correlated with supine R5-20 (r=0.46 p<0.05). Supine measures of total airways resistance (R5) and large airways resistance (R20) differed between those with and without ventilatory failure, as did mean weight and BMI. CONCLUSIONS: Our study identifies a potentially detrimental effect of the supine posture on tidal breathing airways resistance in obese patients. This change is correlated most with visceral adipose tissue mass and the small airways. We were able to demonstrate that supine increases in airways resistance during tidal breathing, within obese patients, are different between those with and without ventilatory failure. TRIAL REGISTRATION NUMBER: NCT01380418; pre-results.

McDermott CJ, Bradburn MJ, Maguire C, Cooper CL, Baird WO, Baxter SK, Cohen J, Cantrill H, Dixon S, Ackroyd R et al. 2016. DiPALS: Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis - a randomised controlled trial. Health Technol Assess, 20 (45), pp. 1-186. | Show Abstract | Read more

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in death, usually from respiratory failure, within 2-3 years of symptom onset. Non-invasive ventilation (NIV) is a treatment that when given to patients in respiratory failure leads to improved survival and quality of life. Diaphragm pacing (DP), using the NeuRx/4(®) diaphragm pacing system (DPS)™ (Synapse Biomedical, Oberlin, OH, USA), is a new technique that may offer additional or alternative benefits to patients with ALS who are in respiratory failure. OBJECTIVE: The Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis (DiPALS) trial evaluated the effect of DP on survival over the study duration in patients with ALS with respiratory failure. DESIGN: The DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy. PARTICIPANTS: Eligible participants had a diagnosis of ALS (ALS laboratory-supported probable, clinically probable or clinically definite according to the World Federation of Neurology revised El Escorial criteria), had been stabilised on riluzole for 30 days, were aged ≥ 18 years and were in respiratory failure. We planned to recruit 108 patients from seven UK-based specialist ALS or respiratory centres. Allocation was performed using 1 : 1 non-deterministic minimisation. INTERVENTIONS: Participants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS. MAIN OUTCOME MEASURES: The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Secondary outcomes were patient quality of life [assessed by European Quality of Life-5 Dimensions, three levels (EQ-5D-3L), Short Form questionnaire-36 items and Sleep Apnoea Quality of Life Index questionnaire]; carer quality of life (EQ-5D-3L and Caregiver Burden Inventory); cost-utility analysis and health-care resource use; tolerability and adverse events. Acceptability and attitudes to DP were assessed in a qualitative substudy. RESULTS: In total, 74 participants were randomised into the trial and analysed, 37 participants to NIV plus pacing and 37 to standard care, before the Data Monitoring and Ethics Committee advised initial suspension of recruitment (December 2013) and subsequent discontinuation of pacing (on safety grounds) in all patients (June 2014). Follow-up assessments continued until the planned end of the study in December 2014. The median survival (interquartile range) was 22.5 months (lower quartile 11.8 months; upper quartile not reached) in the NIV arm and 11.0 months (6.7 to 17.0 months) in the NIV plus pacing arm, with an adjusted hazard ratio of 2.27 (95% confidence interval 1.22 to 4.25; p = 0.01). CONCLUSIONS: Diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure. FUTURE WORK: It may be that certain population subgroups benefit from DP. We are unable to explain the mechanism behind the excess mortality in the pacing arm, something the small trial size cannot help address. Future research should investigate the mechanism by which harm or benefit occurs further. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53817913. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 45. See the HTA programme website for further project information. Additional funding was provided by the Motor Neurone Disease Association of England, Wales and Northern Ireland.

Ayers L, Turnbull C, Petousi N, Ferry B, Kohler M, Stradling J. 2016. Withdrawal of Continuous Positive Airway Pressure Therapy for 2 Weeks in Obstructive Sleep Apnoea Patients Results in Increased Circulating Platelet and Leucocyte-Derived Microvesicles. Respiration, 91 (5), pp. 412-413. | Read more

Turnbull CD, Kohler M, Stradling JR. 2016. Efficacy of EPAP. Sleep Breath, 20 (1), pp. 259-260. | Read more

Antoniades C, Lee R, Kohler M, Stradling J. 2016. Paradoxical decrease in isoprostane and increase in superoxide dismutase following CPAP withdrawal in OSA. Eur Respir J, 47 (3), pp. 1014-1015. | Read more

Schlatzer C, Bratton DJ, Craig SE, Kohler M, Stradling JR. 2016. ECG risk markers for atrial fibrillation and sudden cardiac death in minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised trial. BMJ Open, 6 (3), pp. e010150. | Show Abstract | Read more

OBJECTIVE: Obstructive sleep apnoea (OSA), atrial fibrillation (AF) and sudden cardiac death (SCD) may occur concomitantly, and are of considerable epidemiological interest, potentially leading to morbidity and mortality. Effective treatment of OSA with continuous positive airway pressure (CPAP) could prevent progression and/or recurrence of AF and factors leading to SCD. Recently, a randomised controlled trial showed a statistically and clinically significant prolongation of measures of cardiac repolarisation after CPAP withdrawal in symptomatic patients with moderate to severe OSA. Whether or not CPAP therapy improves ECG risk markers of AF and SCD in patients with minimally symptomatic OSA as well, is unknown. METHODS: 3 centres taking part in the MOSAIC (Multicentre Obstructive Sleep Apnoea Interventional Cardiovascular) trial randomised 303 patients with minimally symptomatic OSA to receive either CPAP or standard care for 6 months. Treatment effects of CPAP on P-wave duration, P-wave dispersion, QT interval, QT dispersion, Tpeak-to-Tend (TpTe) and TpTe/QT ratio were analysed. RESULTS: Participants were primarily men (83%). Mean age was 57.8 (7.2) and mean ODI (Oxygen Desaturation Index) at baseline was 13.1/h (12.3). Full 12-lead ECG data was available in 250 patients. Mean (SD) baseline intervals of P-wave duration, P-wave dispersion, QTc interval, QT dispersion, TpTe and TpTe/QT ratio in ms were 87.4 (8.3), 42.3 (11.9), 397.8 (22.7), 43.1 (16.7), 73.5 (13.7) and 0.19 (0.0), respectively. No treatment effect of CPAP on risk markers for AF and SCD was found. CONCLUSIONS: There seems to be no effect of CPAP on ECG measures of arrhythmia risk in patients with minimally symptomatic OSA. TRIAL REGISTRATION NUMBER: ISRCTN34164388; Post-results.

Kohler M, Stradling JR. 2016. Does continuous positive airway pressure therapy improve non-alcoholic fatty liver disease? Respirology, 21 (2), pp. 209-210. | Read more

Manuel AR, Hart N, Stradling JR. 2016. Correlates of obesity-related chronic ventilatory failure. BMJ Open Respir Res, 3 (1), pp. e000110. | Show Abstract | Read more

INTRODUCTION: Only a third of obese patients develop chronic ventilatory failure. This cross-sectional study assessed multiple factors potentially associated with chronic ventilatory failure. MATERIALS/PATIENTS AND METHODS: Participants had a body mass index (BMI) >30 kg/m(2), with or without chronic ventilatory failure (awake arterial partial pressure of carbon dioxide >6 kPa or base excess (BE) ≥2 mmols/L). Factors investigated were grouped into domains: (1) obesity measures, (2) pulmonary function, (3) respiratory and non-respiratory muscle strength, (4) sleep study derivatives, (5) hypoxic and hypercapnic responses, and (6) some hormonal, nutritional and inflammatory measures. RESULTS: 71 obese participants (52% male) were studied over 27 months, 52 (SD 9) years and BMI 47 (range 32-74) kg/m(2). The best univariate correlates of BE from each domain were: (1) dual-energy X-ray absorptiometry measurement of visceral fat (r=+0.50, p=0.001); (2) supine forced expiratory volume in 1 s (r=-0.40, p=0.001); (3) sniff maximum pressure (r=-0.28, p=0.02); (4) mean overnight arterial oxygen saturation (r=-0.50, p<0.001); (5) ventilatory response to 15% O2 breathing (r=-0.28, p=0.02); and (6) vitamin D (r=-0.30, p=0.01). In multivariate analysis, only visceral fat and ventilatory response to hypoxia remained significant. CONCLUSIONS: We have confirmed that in the obese, BMI is a poor correlate of chronic ventilatory failure, and the best independent correlates are visceral fat and hypoxic ventilatory response. TRIAL REGISTRATION NUMBER: NCT01380418.

Stradling J. 2016. Obstructive sleep apnoea: is it moving into primary care? Br J Gen Pract, 66 (643), pp. e149-e151. | Show Abstract | Read more

OSAS is common and under-recognised and can cause disabling and dangerous sleepiness. It is easily and cheaply diagnosed with home monitors and can be effectively treated with CPAP applied during sleep. OSA is sufficiently common that some aspects of its diagnosis and management (and associated funding) will have to move out of secondary and into primary care. Third-party providers may provide a costeffective solution to the long-term care of patients on CPAP. OSA in commercial drivers is a particular concern and requires special attention.

Turnbull CD, Bratton DJ, Craig SE, Kohler M, Stradling JR. 2016. In patients with minimally symptomatic OSA can baseline characteristics and early patterns of CPAP usage predict those who are likely to be longer-term users of CPAP. J Thorac Dis, 8 (2), pp. 276-281. | Show Abstract | Read more

BACKGROUND: Long-term continuous positive airway pressure (CPAP) usage varies between individuals. It would be of value to be able to identify those who are likely to benefit from CPAP (and use it long term), versus those who would not, and might therefore benefit from additional help early on. First, we explored whether baseline characteristics predicted CPAP usage in minimally symptomatic obstructive sleep apnoea (OSA) patients, a group who would be expected to have low usage. Second, we explored if early CPAP usage was predictive of longer-term usage, as has been shown in more symptomatic OSA patients. METHODS: The MOSAIC trial was a multi-centre randomised controlled trial where minimally symptomatic OSA patients were randomised to CPAP, or standard care, for 6 months. Here we have studied only those patients randomised to CPAP treatment. Baseline characteristics including symptoms, questionnaires [including the Epworth sleepiness score (ESS)] and sleep study parameters were recorded. CPAP usage was recorded at 2-4 weeks after initiation and after 6 months. The correlation and association between baseline characteristics and 6 months CPAP usage was assessed, as was the correlation between 2 and 4 weeks CPAP usage and 6 months CPAP usage. RESULTS: One hundred and ninety-five patients randomised to CPAP therapy had median [interquartile range (IQR)] CPAP usage of 2:49 (0:44, 5:13) h:min/night (h/n) at the 2-4 weeks visit, and 2:17 (0:08, 4:54) h/n at the 6 months follow-up visit. Only male gender was associated with increased long-term CPAP use (male usage 2:56 h/n, female 1:57 h/n; P=0.02). There was a moderate correlation between the usage of CPAP at 2-4 weeks and 6 months, with about 50% of the variability in long-term use being predicted by the short-term use. CONCLUSIONS: In patients with minimally symptomatic OSA, our study has shown that male gender (and not OSA severity or symptom burden) is associated with increased long-term use of CPAP at 6 months. Although, in general, early patterns of CPAP usage predicted longer term use, there are patients in whom this is not the case, and patients with low initial usage may need to extend their CPAP trial before a decision about longer-term use is made.

Schwarz EI, Martinez-Lozano Sinues P, Bregy L, Gaisl T, Garcia Gomez D, Gaugg MT, Suter Y, Stebler N, Nussbaumer-Ochsner Y, Bloch KE et al. 2016. Effects of CPAP therapy withdrawal on exhaled breath pattern in obstructive sleep apnoea. Thorax, 71 (2), pp. 110-117. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea (OSA) is highly prevalent and associated with cardiovascular and metabolic changes. OSA is usually diagnosed by polysomnography which is time-consuming and provides little information on the patient's phenotype thus limiting a personalised treatment approach. Exhaled breath contains information on metabolism which can be analysed by mass spectrometry within minutes. The objective of this study was to identify a breath profile in OSA recurrence by use of secondary-electrospray-ionization-mass spectrometry (SESI-MS). METHODS: Patients with OSA effectively treated with CPAP were randomised to either withdraw treatment (subtherapeutic CPAP) or continue therapeutic CPAP for 2 weeks. Exhaled breath analysis by untargeted SESI-MS was performed at baseline and 2 weeks after randomisation. The primary outcome was the change in exhaled molecular breath pattern. RESULTS: 30 patients with OSA were randomised and 26 completed the trial according to the protocol. CPAP withdrawal led to a recurrence of OSA (mean difference in change of oxygen desaturation index between groups +30.3/h; 95% CI 19.8/h,40.7/h, p<0.001) which was accompanied by a significant change in 62 exhaled features (16 metabolites identified). The panel of discriminating mass-spectral features allowed differentiation between treated and untreated OSA with a sensitivity of 92.9% and a specificity of 84.6%. CONCLUSION: Exhaled breath analysis by SESI-MS allows rapid and accurate detection of OSA recurrence. The technique has the potential to characterise an individual's metabolic response to OSA and thus makes a comprehensible phenotyping of OSA possible. TRIAL REGISTRATION NUMBER: NCT02050425 (registered at ClinicalTrials.gov).

Turnbull C, Manuel A, Stradling J. 2015. Quality of life, diet and exercise measurements in obese individuals with and without ventilatory failure. Obes Res Clin Pract, 9 (6), pp. 639-640. | Read more

Turnbull CD, Manuel AR, Stradling JR. 2016. Does either obesity or OSA severity influence the response of autotitrating CPAP machines in very obese subjects? Sleep Breath, 20 (2), pp. 647-652. | Show Abstract | Read more

PURPOSE: The pressures delivered by autotitrating continuous positive airways pressure (CPAP) devices not only treat obstructive sleep apnoea (OSA) effectively but also give potentially interesting physiological information about the forces impinging on the pharynx. In earlier work from this unit, we used correlations between autoCPAP pressure and both OSA severity and obesity, to construct an algorithm to estimate the fixed CPAP pressure a patient required for subsequent clinical use. We wished to discover if these relationships could be reliably extended to a much more obese group. METHODS: We performed a prospective cohort study in an obese population. Measurements of obesity were made, OSA severity was recorded, and the 95th centile autoCPAP pressure was recorded during 1 week of autoCPAP. Spearman's rank correlation was performed between measurements of obesity and autoCPAP pressure, and between OSA severity and autoCPAP pressure. RESULTS: Fifty-four obese individuals (median body mass index (BMI) 43.0 kg/m(2)), 52 % of whom had OSA (apnoea-hypopnoea index (AHI) ≥ 15), had a median 95th centile autoCPAP pressure of 11.8 cmH2O. We found no significant correlation between autoCPAP pressure and neck circumference, waist circumference or BMI. There was a moderate correlation between autoCPAP pressure and OSA severity (AHI r = 0.34, p = 0.02; oxygen desaturation index (ODI) r = 0.48, p < 0.001). CONCLUSIONS: In this population, neither BMI nor neck circumference nor waist circumference is predictive of autoCPAP pressure. Therefore, the previously derived algorithm does not adequately predict the fixed CPAP pressure for subsequent clinical use in these obese individuals. In addition, some subjects without OSA generated high autoCPAP pressures, and thus, the correlation between OSA severity and autoCPAP pressure was only moderate.

DiPALS Writing Committee, DiPALS Study Group Collaborators. 2015. Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial. Lancet Neurol, 14 (9), pp. 883-892. | Show Abstract | Read more

BACKGROUND: Non-invasive ventilation is part of the standard of care for treatment of respiratory failure in patients with amyotrophic lateral sclerosis (ALS). The NeuRx RA/4 Diaphragm Pacing System has received Humanitarian Device Exemption approval from the US Food and Drug Administration for treatment of respiratory failure in patients with ALS. We aimed to establish the safety and efficacy of diaphragm pacing with this system in patients with respiratory muscle weakness due to ALS. METHODS: We undertook a multicentre, open-label, randomised controlled trial at seven specialist ALS and respiratory centres in the UK. Eligible participants were aged 18 years or older with laboratory supported probable, clinically probable, or clinically definite ALS; stable riluzole treatment for at least 30 days; and respiratory insufficiency. We randomly assigned participants (1:1), via a centralised web-based randomisation system with minimisation that balanced patients for age, sex, forced vital capacity, and bulbar function, to receive either non-invasive ventilation plus pacing with the NeuRx RA/4 Diaphragm Pacing System or non-invasive ventilation alone. Patients, carers, and outcome assessors were not masked to treatment allocation. The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Analysis was by intention to treat. This trial is registered, ISRCTN number 53817913. FINDINGS: Between Dec 5, 2011, and Dec 18, 2013, we randomly assigned 74 participants to receive either non-invasive ventilation alone (n=37) or non-invasive ventilation plus diaphragm pacing (n=37). On Dec 18, 2013, the Data Monitoring and Ethics Committee (DMEC) recommended suspension of recruitment on the basis of overall survival figures. Randomly assigned participants continued as per the study protocol until June 23, 2014, when the DMEC advised discontinuation of pacing in all patients. Follow-up assessments continued until the planned end of the study in December, 2014. Survival was shorter in the non-invasive ventilation plus pacing group than in the non-invasive ventilation alone group (median 11·0 months [95% CI 8·3-13·6] vs 22·5 months [13·6-not reached]; adjusted hazard ratio 2·27, 95% CI 1·22-4·25; p=0·009). 28 (76%) patients died in the pacing group and 19 (51%) patients died in the non-invasive ventilation alone group. We recorded 162 adverse events (5·9 events per person-year) in the pacing group, of which 46 events were serious, compared with 81 events (2·5 events per person-year) in the non-invasive ventilation alone group, of which 31 events were serious. INTERPRETATION: Addition of diaphragm pacing to standard care with non-invasive ventilation was associated with decreased survival in patients with ALS. Our results suggest that diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure. FUNDING: The National Institute for Health Research Health Technology Assessment Programme; the Motor Neurone Disease Association of England, Wales, and Northern Ireland.

Schwarz EI, Puhan MA, Schlatzer C, Stradling JR, Kohler M. 2015. Effect of CPAP therapy on endothelial function in obstructive sleep apnoea: A systematic review and meta-analysis. Respirology, 20 (6), pp. 889-895. | Show Abstract | Read more

Obstructive sleep apnoea (OSA) is a prevalent sleep-related breathing disorder associated with adverse cardiovascular outcome. Endothelial dysfunction is one of the proposed mechanistic links between OSA and the increased cardiovascular risk. Treatment with continuous positive airway pressure (CPAP) may reverse this detrimental pathophysiological consequence of OSA. Most studies on the effect of CPAP on endothelial function in OSA are limited by their low sample size. The objective of this systematic review was to assess the effect CPAP therapy on endothelial function in patients with OSA. We conducted a systematic review and meta-analysis searching literature databases up to August 2013 for randomized controlled trials (RCTs) on the effect of CPAP on endothelial function in OSA, assessed by flow-mediated dilatation (FMD) and other validated techniques. The primary outcome for the meta-analysis (DerSimonian/Laird random-effects method) was the treatment effect on FMD. Eight RCTs comparing the effects of therapeutic CPAP versus subtherapeutic CPAP (or no intervention) on endothelial function involving 245 OSA patients were included in the systematic review. The studies are consistent in effect direction, showing an improvement of endothelial function by CPAP. Four RCTs involving 150 patients could be used for the meta-analysis. Compared to the control group, CPAP therapy (range 2-24 weeks) significantly increased absolute % FMD by 3.87% (95% confidence interval: 1.93-5.80, P < 0.001). In patients with OSA, CPAP therapy improves endothelial function significantly and to a clinically important extent.

McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Davies RJ, Nunn AJ, Stradling JR, Riha RL, Morrell MJ. 2015. A multicentre randomised controlled trial and economic evaluation of continuous positive airway pressure for the treatment of obstructive sleep apnoea syndrome in older people: PREDICT. Health Technol Assess, 19 (40), pp. 1-188. | Show Abstract | Read more

BACKGROUND: The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnoea syndrome (OSAS) have been established in middle-aged people. In older people there is a lack of evidence. OBJECTIVE: To determine the clinical efficacy of CPAP in older people with OSAS and to establish its cost-effectiveness. DESIGN: A randomised, parallel, investigator-blinded multicentre trial with within-trial and model-based cost-effectiveness analysis. METHODS: Two hundred and seventy-eight patients, aged ≥ 65 years with newly diagnosed OSAS [defined as oxygen desaturation index at ≥ 4% desaturation threshold level for > 7.5 events/hour and Epworth Sleepiness Scale (ESS) score of ≥ 9] recruited from 14 hospital-based sleep services across the UK. INTERVENTIONS: CPAP with best supportive care (BSC) or BSC alone. Autotitrating CPAP was initiated using standard clinical practice. BSC was structured advice on minimising sleepiness. COPRIMARY OUTCOMES: Subjective sleepiness at 3 months, as measured by the ESS (ESS mean score: months 3 and 4) and cost-effectiveness over 12 months, as measured in quality-adjusted life-years (QALYs) calculated using the European Quality of Life-5 Dimensions (EQ-5D) and health-care resource use, information on which was collected monthly from patient diaries. SECONDARY OUTCOMES: Subjective sleepiness at 12 months (ESS mean score: months 10, 11 and 12) and objective sleepiness, disease-specific and generic quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, cardiovascular risk factors and events at 3 and 12 months. RESULTS: Two hundred and seventy-eight patients were randomised to CPAP (n = 140) or BSC (n = 138) over 27 months and 231 (83%) patients completed the trial. Baseline ESS score was similar in both groups [mean (standard deviation; SD) CPAP 11.5 (3.3), BSC 11.4 (4.2)]; groups were well balanced for other characteristics. The mean (SD) in ESS score at 3 months was -3.8 (0.4) in the CPAP group and -1.6 (0.3) in the BSC group. The adjusted treatment effect of CPAP compared with BSC was -2.1 points [95% confidence interval (CI) -3.0 to -1.3 points; p < 0.001]. At 12 months the effect was -2.0 points (95% CI -2.8 to -1.2 points; p < 0.001). The effect was greater in patients with increased CPAP use or higher baseline ESS score. The number of QALYs calculated using the EQ-5D was marginally (0.005) higher with CPAP than with BSC (95% CI -0.034 to 0.044). The average cost per patient was £1363 (95% CI £1121 to £1606) for those allocated to CPAP and £1389 (95% CI £1116 to £1662) for those allocated to BSC. On average, costs were lower in the CPAP group (mean -£35; 95% CI -£390 to £321). The probability that CPAP was cost-effective at thresholds conventionally used by the NHS (£20,000 per QALY gained) was 0.61. QALYs calculated using the Short Form questionnaire-6 Dimensions were 0.018 higher in the CPAP group (95% CI 0.003 to 0.034 QALYs) and the probability that CPAP was cost-effective was 0.96. CPAP decreased objective sleepiness (p = 0.02), increased mobility (p = 0.03) and reduced total and low-density lipoprotein cholesterol (p = 0.05, p = 0.04, respectively) at 3 months but not at 12 months. In the BSC group, there was a fall in systolic blood pressure of 3.7 mmHg at 12 months, which was not seen in the CPAP group (p = 0.04). Mood, functionality, nocturia, accidents, cognitive function and cardiovascular events were unchanged. There were no medically significant harms attributable to CPAP. CONCLUSION: In older people with OSAS, CPAP reduces sleepiness and is marginally more cost-effective than BSC over 12 months. Further work is required in the identification of potential biomarkers of sleepiness and those patients at increased risk of cognitive impairment. Early detection of which could be used to inform the clinician when in the disease cycle treatment is needed to avert central nervous system sequelae and to assist patients decision-making regarding treatment and compliance. Treatment adherence is also a challenge in clinical trials generally, and adherence to CPAP therapy in particular is a recognised concern in both research studies and clinical practice. Suggested research priorities would include a focus on optimisation of CPAP delivery or support and embracing the technological advances currently available. Finally, the improvements in quality of life in trials do not appear to reflect the dramatic changes noted in clinical practice. There should be a greater focus on patient centred outcomes which would better capture the symptomatic improvement with CPAP treatment and translate these improvements into outcomes which could be used in health economic analysis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN90464927. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 40. See the NIHR Journals Library website for further project information.

Stradling JR, Schwarz EI, Schlatzer C, Manuel AR, Lee R, Antoniades C, Kohler M. 2015. Biomarkers of oxidative stress following continuous positive airway pressure withdrawal: data from two randomised trials. Eur Respir J, 46 (4), pp. 1065-1071. | Show Abstract | Read more

There is conflicting evidence whether intermittent hypoxia in obstructive sleep apnoea (OSA) influences oxidative stress. We hypothesised that withdrawal of continuous positive airway pressure (CPAP) from patients with OSA would raise markers of oxidative stress.59 patients with CPAP-treated moderate-to-severe OSA (oxygen desaturation index (ODI) >20 events·h(-1)) were randomised 1:1 to either stay on CPAP (n=30) or change to sham CPAP (n=29) for 2 weeks. Using samples from two similar studies at two sites, we measured early morning blood malondialdehyde (MDA, a primary outcome in one study and a secondary outcome in the other), lipid hydroperoxides, total antioxidant capacity, superoxide generation from mononuclear cells and urinary F2-isoprostane. We also measured superoxide dismutase as a marker of hypoxic preconditioning. "Treatment" effects (sham CPAP versus CPAP) were calculated via linear regression.Sham CPAP provoked moderate-to-severe OSA (mean ODI 46 events·h(-1)), but blood markers of oxidative stress did not change significantly (MDA "treatment" effect (95% CI) -0.02 (-0.23 to +0.19) μmol·L(-1)). Urinary F2-isoprostane fell significantly by ~30% (-0.26 (-0.42 to -0.10) ng·mL(-1)) and superoxide dismutase increased similarly (+0.17 (+0.02 to +0.30) ng·mL(-1)).We found no direct evidence of increased oxidative stress in patients experiencing a return of their moderate-to-severe OSA. The fall in urinary F2-isoprostane and rise in superoxide dismutase implies that hypoxic preconditioning may have reduced oxidative stress.

Schlatzer C, Schwarz EI, Sievi NA, Clarenbach CF, Gaisl T, Haegeli LM, Duru F, Stradling JR, Kohler M. 2016. Intrathoracic pressure swings induced by simulated obstructive sleep apnoea promote arrhythmias in paroxysmal atrial fibrillation. Europace, 18 (1), pp. 64-70. | Show Abstract | Read more

AIMS: There is preliminary evidence for a link between obstructive sleep apnoea (OSA) and arrhythmias such as paroxysmal atrial fibrillation (PAF) and sudden cardiac death but underlying mechanisms remain largely unknown. METHODS AND RESULTS: In this interventional crossover study, we evaluated whether intrathoracic pressure changes, induced by simulated OSA, trigger premature cardiac beats, and alter measures of ventricular repolarization [QTc and Tpeak-to-Tend (TpTec) intervals] in patients with PAF. 12-Lead-electrocardiograms were recorded continuously in 44 patients, while simulating obstructive apnoea (Mueller manoeuvre, MM), obstructive hypopnoea (inspiration through a threshold load, ITH), end-expiratory central apnoea (AP), and during normal breathing (NB) in randomized order. The prevalence of OSA in these 44 patients was assessed by a sleep study. Atrial premature beats (APBs) occurred more frequently during MM (55% of patients) and ITH (32%), but not during AP (14%), compared with NB (9%) (P < 0.001, P = 0.006 and P = 0.688, respectively). Mueller manoeuvre led to a significant prolongation of QTc and TpTec intervals (+17.3 ms, P < 0.001 and +4.3 ms, P = 0.005). Inspiration through a threshold load significantly increased QTc (+9.6 ms, P < 0.001) but not TpTec. End-expiratory central apnoea did not alter QTc and TpTec intervals. According to the sleep study, 56% of patients had OSA (apnoea hypopnoea index ≥5). CONCLUSION: Simulated OSA induces APBs which may be important in patients with PAF, because the majority of episodes of PAF has been shown to be triggered by APBs. Simulated OSA leads to a significant prolongation of ventricular repolarization.

Mishra EK, Corcoran JP, Hallifax RJ, Stradling J, Maskell NA, Rahman NM. 2015. Defining the minimal important difference for the visual analogue scale assessing dyspnea in patients with malignant pleural effusions. PLoS One, 10 (4), pp. e0123798. | Show Abstract | Read more

BACKGROUND: The minimal important difference (MID) is essential for interpreting the results of randomised controlled trials (RCTs). Despite a number of RCTs in patients with malignant pleural effusions (MPEs) which use the visual analogue scale for dyspnea (VASD) as an outcome measure, the MID has not been established. METHODS: Patients with suspected MPE undergoing a pleural procedure recorded their baseline VASD and their post-procedure VASD (24 hours after the pleural drainage), and in parallel assessed their breathlessness on a 7 point Likert scale. FINDINGS: The mean decrease in VASD in patients with a MPE reporting a 'small but just worthwhile decrease' in their dyspnea (i.e. equivalent to the MID) was 19mm (95% CI 14-24mm). The mean drainage volume required to produce a change in VASD of 19mm was 760ml. INTERPRETATION: The mean MID for the VASD in patients with a MPE undergoing a pleural procedure is 19mm (95% CI 14-24mm). Thus choosing an improvement of 19mm in the VASD would be justifiable in the design and analysis of future MPE studies.

Craig S, Kylintireas I, Kohler M, Nicoll D, Bratton DJ, Nunn AJ, Leeson P, Neubauer S, Stradling JR. 2015. Effect of CPAP on Cardiac Function in Minimally Symptomatic Patients with OSA: Results from a Subset of the MOSAIC Randomized Trial. J Clin Sleep Med, 11 (9), pp. 967-973. | Show Abstract | Read more

STUDY OBJECTIVES: Minimally symptomatic obstructive sleep apnea (OSA) is highly prevalent, and the effects of continuous positive airway pressure (CPAP) on myocardial function in these patients are unknown. The MOSAIC randomized, controlled trial of CPAP for minimally symptomatic OSA assessed the effect of CPAP on myocardial function in a subset of patients. METHODS: Two centers taking part in the MOSAIC trial randomized 238 patients in parallel to 6 months of CPAP (120) or standard care (118). Of these, 168 patients had echocardiograms, and 68 patients had a cardiac magnetic resonance scan (CMR). A larger group (314) from 4 centers had brain natriuretic peptide (BNP) measured. RESULTS: Mean (SD) baseline oxygen desaturation index (ODI) and Epworth sleepiness score (ESS) were 13.5 (13.2), and 8.4 (4.0), respectively. CPAP significantly reduced ESS and ODI. Baseline LV ejection fraction (LVEF) was well preserved (60.4%). CPAP had no significant effect on echo-derived left atrial (LA) area (-1.0 cm2, 95% CI -2.6 to +0.6, p = 0.23) or early to late left ventricular filling velocity (E/A) ratio (-0.01, 95% CI -0.07 to +0.05, p = 0.79). There was a small change in echo-derived LV end diastolic volume (EDV) with CPAP (-5.9 mL, 95% CI -10.6 to -1.2, p = 0.015). No significant changes were detected by CMR on LV mass index (+1.1 g/m(2), 95% CI -5.9 to +8.0, p = 0.76) or LVEF (+0.8%, 95% CI -1.2 to +2.8, p = 0.41). CPAP did not affect BNP levels (p = 0.16). CONCLUSIONS: Six months of CPAP therapy does not change cardiac functional or structural parameters measured by echocardiogram or CMR in patients with minimally symptomatic mild-to-moderate OSA. CLINICAL TRIAL REGISTRATION: ISRCTN 34164388 (http://isrctn.org).

Stradling JR, Craig SE, Kohler M. 2015. Markers of inflammation: data from the MOSAIC randomised trial of CPAP for minimally symptomatic OSA (vol 70, pg 181, 2015) THORAX, 70 (4), pp. 319-319. | Read more

Rossi VA, Stradling J, Kohler M. 2015. CPAP holiday: are we there yet? Eur Respir J, 45 (2), pp. 575-576. | Read more

Behar J, Roebuck A, Shahid M, Daly J, Hallack A, Palmius N, Stradling J, Clifford GD. 2015. SleepAp: an automated obstructive sleep apnoea screening application for smartphones. IEEE J Biomed Health Inform, 19 (1), pp. 325-331. | Show Abstract | Read more

Obstructive sleep apnoea (OSA) is a sleep disorder with long-term consequences. Long-term effects include sleep-related issues and cardiovascular diseases. OSA is often diagnosed with an overnight sleep test called a polysomnogram. Monitoring can be costly with long wait times for diagnosis. In this paper, a novel OSA screening framework and prototype phone application are introduced. A database of 856 patients that underwent at-home polygraphy was collected. Features were derived from audio, actigraphy, photoplethysmography (PPG), and demographics, and used as the inputs of a support vector machine (SVM) classifier. The SVM was trained on 735 patients and tested on 121 patients. Classification on the test set had an accuracy of up to 92.2% when classifying subjects as having moderate or severe OSA versus being healthy or a snorer based on the clinicians' diagnoses. The signal processing and machine learning algorithms were ported to Java and integrated into the phone application-SleepAp. SleepAp records the body position, audio, actigraphy and PPG signals, and implements the clinically validated STOP-BANG questionnaire. It derives features from the signals and classifies the user as having OSA or not using the SVM trained on the clinical database. The resulting software could provide a new, easy-to-use, low-cost, and widely available modality for OSA screening.

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Schwarz EI, Puhan MA, Schlatzer C, Stradling JR, Kohler M. 2015. Effect of CPAP therapy on endothelial function in obstructive sleep apnoea: A systematic review and meta-analysis Respirology, 20 (6), pp. 889-895. | Show Abstract | Read more

© 2015 Asian Pacific Society of Respirology. Obstructive sleep apnoea (OSA) is a prevalent sleep-related breathing disorder associated with adverse cardiovascular outcome. Endothelial dysfunction is one of the proposed mechanistic links between OSA and the increased cardiovascular risk. Treatment with continuous positive airway pressure (CPAP) may reverse this detrimental pathophysiological consequence of OSA. Most studies on the effect of CPAP on endothelial function in OSA are limited by their low sample size. The objective of this systematic review was to assess the effect CPAP therapy on endothelial function in patients with OSA. We conducted a systematic review and meta-analysis searching literature databases up to August 2013 for randomized controlled trials (RCTs) on the effect of CPAP on endothelial function in OSA, assessed by flow-mediated dilatation (FMD) and other validated techniques. The primary outcome for the meta-analysis (DerSimonian/Laird random-effects method) was the treatment effect on FMD. Eight RCTs comparing the effects of therapeutic CPAP versus subtherapeutic CPAP (or no intervention) on endothelial function involving 245 OSA patients were included in the systematic review. The studies are consistent in effect direction, showing an improvement of endothelial function by CPAP. Four RCTs involving 150 patients could be used for the meta-analysis. Compared to the control group, CPAP therapy (range 2-24 weeks) significantly increased absolute % FMD by 3.87% (95% confidence interval: 1.93-5.80, P < 0.001). In patients with OSA, CPAP therapy improves endothelial function significantly and to a clinically important extent.

McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Nunn AJ, Stradling JR, Riha RL, Morrell MJ. 2014. Sleep apnoea in the elderly - authors' reply. Lancet Respir Med, 2 (11), pp. e21-e22. | Read more

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McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Davies RJ, Nunn AJ, Stradling JR, Riha RL, Morrell MJ. 2014. Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): A 12-month, multicentre, randomised trial The Lancet Respiratory Medicine, 2 (10), pp. 804-812. | Show Abstract | Read more

© 2014 McMillan et al. Background: The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap. Methods: This 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927. Findings: Between Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2·1 points (95% CI -3·0 to -1·3; p<0·0001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2·0 points (-2·8 to -1·2; p<0·0001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0·01 (95% CI -0·03 to 0·04; p=0·787) and health-care costs were marginally reduced with CPAP (-£35, -390 to 321; p=0·847). CPAP improved objective sleepiness (p=0·024), mobility (p=0·029), total cholesterol (p=0·048), and LDL cholesterol (p=0·042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use. Interpretation: In older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome. Funding: National Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

Stradling JR, Craig SE, Kohler M, Nicoll D, Ayers L, Nunn AJ, Bratton DJ. 2015. Markers of inflammation: data from the MOSAIC randomised trial of CPAP for minimally symptomatic OSA. Thorax, 70 (2), pp. 181-182. | Show Abstract | Read more

UNLABELLED: The Multi-centre Obstructive Sleep Apnoea Interventional Cardiovascular (MOSAIC) trial compared 6 months of CPAP therapy, versus no CPAP, in 391 patients with minimally symptomatic obstructive sleep apnoea (OSA). We now report some exploratory outcomes, markers of systemic inflammation (interleukin 6 (IL-6), IL-10, C reactive protein, tumour necrosis factor). We found no consistent changes (all p values >0.13). TRIAL REGISTRATION NUMBER: ISRCTN 34164388.

Taheri S, Guest JF, Stradling JR. 2014. Response to comment on Guest et al. Clinical outcomes and cost-effectiveness of continuous positive airway pressure to manage obstructive sleep apnea in patients with type 2 diabetes in the U.K. Diabetes Care 2014;37:1263-1271. Diabetes Care, 37 (9), pp. e202-e203. | Read more

McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Davies RJ, Nunn AJ, Stradling JR, Riha RL, Morrell MJ, PREDICT Investigators. 2014. Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial. Lancet Respir Med, 2 (10), pp. 804-812. | Show Abstract | Read more

BACKGROUND: The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap. METHODS: This 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927. FINDINGS: Between Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2·1 points (95% CI -3·0 to -1·3; p<0·0001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2·0 points (-2·8 to -1·2; p<0·0001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0·01 (95% CI -0·03 to 0·04; p=0·787) and health-care costs were marginally reduced with CPAP (-£35, -390 to 321; p=0·847). CPAP improved objective sleepiness (p=0·024), mobility (p=0·029), total cholesterol (p=0·048), and LDL cholesterol (p=0·042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use. INTERPRETATION: In older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome. FUNDING: National Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

Manuel ARG, Hart N, Stradling JR. 2015. Is a raised bicarbonate, without hypercapnia, part of the physiologic spectrum of obesity-related hypoventilation? Chest, 147 (2), pp. 362-368. | Show Abstract | Read more

BACKGROUND: Obesity hypoventilation syndrome (OHS) conventionally includes awake hypercapnia, but an isolated raised bicarbonate, even in the absence of awake hypercapnia, may represent evidence of "early" OHS. We investigated whether such individuals exhibit certain features characteristic of established OHS. METHODS: Obese subjects (BMI > 30 kg/m(2)) were identified from a variety of sources and divided into those with (1) normal blood gas measurements and normal acid-base balance, (2) an isolated raised base excess (BE) (≥ 2 mmol/L), and (3) awake hypercapnia (> 6 kPa; ie, established OHS). Two-point ventilatory responses to hypoxia and hypercapnia were performed. Polygraphic sleep studies were done to identify intermittent and prolonged hypoxia. RESULTS: Seventy-one subjects (BMI, 47.2; SD, 9.8; age, 52.1 years; SD, 8.8 years) were recruited into three groups (33, 22, and 16 respectively). The Paco2 and BE values were 5.15, 5.42, 6.62 kPa, and +0.12, +3.01, +4.78 mmol/L, respectively. For nearly all the ventilatory response and sleep study measures, group 2 (with only an isolated raised BE) represented an intermediate group, and for some of the measures they were more similar to the third group with established OHS. CONCLUSIONS: These data suggest that obese individuals with a raised BE, despite normocapnia while awake, should probably be regarded as having early obesity-related hypoventilation. This has important implications for clinical management as well as randomized controlled treatment trials, as they may represent a group with a more reversible disease process. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01380418; URL: www.clinicaltrials.gov.

Bratton DJ, Stradling JR, Barbé F, Kohler M. 2014. Effect of CPAP on blood pressure in patients with minimally symptomatic obstructive sleep apnoea: a meta-analysis using individual patient data from four randomised controlled trials. Thorax, 69 (12), pp. 1128-1135. | Show Abstract | Read more

BACKGROUND: CPAP reduces blood pressure (BP) in patients with symptomatic obstructive sleep apnoea (OSA). Whether the same benefit is present in patients with minimally symptomatic OSA is unclear, thus a meta-analysis of existing trial data is required. METHODS: The electronic databases Medline, Embase and trial registries were searched. Trials were eligible if they included patients with minimally symptomatic OSA, had randomised them to receive CPAP or either sham-CPAP or no CPAP, and recorded BP at baseline and follow-up. Individual participant data were obtained. Primary outcomes were absolute change in systolic and diastolic BP. FINDINGS: Five eligible trials were found (1219 patients) from which data from four studies (1206 patients) were obtained. Mean (SD) baseline systolic and diastolic BP across all four studies was 131.2 (15.8) mm Hg and 80.9 (10.4) mm Hg, respectively. There was a slight increase in systolic BP of 1.1 mm Hg (95% CI -0.2 to 2.3, p=0.086) and a slight reduction in diastolic BP of 0.8 mm Hg (95% CI -1.6 to 0.1, p=0.083), although the results were not statistically significant. There was some evidence of an increase in systolic BP in patients using CPAP <4 h/night (1.5 mm Hg, 95% CI -0.0 to 3.1, p=0.052) and reduction in diastolic BP in patients using CPAP >4 h/night (-1.4 mm Hg, 95% CI -2.5 to -0.4, p=0.008). CPAP treatment reduced both subjective sleepiness (p<0.001) and OSA severity (p<0.001). INTERPRETATION: Although CPAP treatment reduces OSA severity and sleepiness, it seems not to have a beneficial effect on BP in patients with minimally symptomatic OSA, except in patients who used CPAP for >4 h/night.

Hart N, Mandal S, Manuel A, Mokhlesi B, Pepin J-L, Piper A, Stradling J. 2014. Rebuttal: 'Obesity hypoventilation syndrome (OHS): does the current definition need revisiting?'. Thorax, 69 (10), pp. 955. | Read more

Guest JF, Panca M, Sladkevicius E, Taheri S, Stradling J. 2014. Clinical outcomes and cost-effectiveness of continuous positive airway pressure to manage obstructive sleep apnea in patients with type 2 diabetes in the U.K. Diabetes Care, 37 (5), pp. 1263-1271. | Show Abstract | Read more

OBJECTIVE: To assess clinical outcomes and cost-effectiveness of using continuous positive airway pressure (CPAP) to manage obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) from the perspective of the U.K.'s National Health Service (NHS). RESEARCH DESIGN AND METHODS: Using a case-control design, 150 CPAP-treated patients with OSA and T2D were randomly selected from The Health Improvement Network (THIN) database (a nationally representative database of patients registered with general practitioners in the U.K.) and matched with 150 OSA and T2D patients from the same database who were not treated with CPAP. The total NHS cost and outcomes of patient management in both groups over 5 years and the cost-effectiveness of CPAP compared with no CPAP treatment were estimated. RESULTS: Using CPAP was associated with significantly lower blood pressure at 5 years and increasingly lower HbA1c levels over 5 consecutive years compared with untreated OSA patients. At 5 years, the HbA1c level in the CPAP-treated group was 8.2% (66.0 mmol/mol) vs. 12.1% (108.4 mmol/mol) in the control group (P < 0.03). Use of CPAP significantly increased patients' health status by 0.27 quality-adjusted life years (QALYs) per patient over 5 years (P < 0.001) and NHS management costs by £4,141 per patient over 5 years; the cost per QALY gained with CPAP was £15,337. CONCLUSIONS: Initiating treatment with CPAP in OSA patients with T2D leads to significantly lower blood pressure and better controlled diabetes and affords a cost-effective use of NHS resources. These observations have the potential for treatment modification if confirmed in a prospective study.

Stradling J, Kohler M. 2014. SKUP3 trial: Comment Thorax, 69 (4), pp. 386. | Read more

Turnbull CD, Craig SE, Kohler M, Nicoll D, Stradling J. 2014. Cardiovascular event rates in the MOSAIC trial: 2-year follow-up data. Thorax, 69 (10), pp. 950. | Show Abstract | Read more

The Multicentre Obstructive Sleep Apnoea Intervention Cardiovascular (MOSAIC) trial investigated the effect of continuous positive airway pressure (CPAP) on both sleepiness and predicted cardiovascular risk over 6 months in minimally symptomatic patients with obstructive sleep apnoea. Although there was clear benefit in terms of Epworth Sleepiness Score, there was no improvement in blood pressure and predicted vascular risk score. In order to calculate the required size of future trials, with real vascular events as the endpoint, the rate of such events in this population is needed. 188 patients from the original trial were followed for 2 years. The overall number of new vascular events over the 2 years was 25, and all-cause mortality was 4. There was a weak statistically significant reduction in vascular events in the CPAP group (p=0.049). Large-scale randomised trials are needed to determine if CPAP causes a real reduction in vascular events in minimally symptomatic patients. Based on our figures, future trials of CPAP versus no treatment would need to randomise approximately 2540 patients to not miss a real reduction in vascular events and over 6000 for mortality.

Rossi VA, Schwarz EI, Bloch KE, Stradling JR, Kohler M. 2014. Is continuous positive airway pressure necessarily an everyday therapy in patients with obstructive sleep apnoea? Eur Respir J, 43 (5), pp. 1387-1393. | Show Abstract | Read more

There are limited data on the evolution of obstructive sleep apnoea (OSA) during continuous positive airway pressure (CPAP) therapy and whether this treatment is required every night. 125 OSA patients with an original oxygen desaturation index (ODI) >10 events per hour, established on CPAP, were asked to withdraw CPAP for four nights and performed ambulatory nocturnal pulse oximetry on the fourth night of CPAP withdrawal. An ODI >10 events per hour during pulse oximetry was considered to indicate persistent OSA. Patients not experiencing recurrence of OSA underwent repeat ambulatory pulse oximetry after a further 2-week period off CPAP. In 71% of the patients, OSA recurred after four nights of CPAP withdrawal (group 1); thus, OSA did not recur in 29% (group 2). 55% of group 2 had an ODI >10 events per hour after 2 weeks off CPAP; thus, 45% remained without a recurrence. In multivariate analysis, higher original ODI, longer duration of CPAP therapy, current smoking status and larger neck circumference were independently associated with a higher ODI after four nights of CPAP withdrawal (all p<0.05). Following CPAP withdrawal, a third of CPAP-treated patients do not experience significant recurrence of oxygen desaturations after 4 days and ∼10% do not after 2 weeks. Thus, a significant proportion of patients may be able to stop CPAP for short periods.

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Hart N, Mandal S, Manuel A, Mokhlesi B, Pépin JL, Piper A, Stradling JR. 2014. Obesity hypoventilation syndrome: Does the current definition need revisiting? Thorax, 69 (1), pp. 83-84. | Read more

Turnbull CD, Craig SE, Kohler M, Nicoll D, Stradling J. 2014. Cardiovascular event rates in the MOSAIC trial: 2-year follow-up data. Thorax, 69 (10), pp. 950. | Show Abstract

The Multicentre Obstructive Sleep Apnoea Intervention Cardiovascular (MOSAIC) trial investigated the effect of continuous positive airway pressure (CPAP) on both sleepiness and predicted cardiovascular risk over 6 months in minimally symptomatic patients with obstructive sleep apnoea. Although there was clear benefit in terms of Epworth Sleepiness Score, there was no improvement in blood pressure and predicted vascular risk score. In order to calculate the required size of future trials, with real vascular events as the endpoint, the rate of such events in this population is needed. 188 patients from the original trial were followed for 2 years. The overall number of new vascular events over the 2 years was 25, and all-cause mortality was 4. There was a weak statistically significant reduction in vascular events in the CPAP group (p=0.049). Large-scale randomised trials are needed to determine if CPAP causes a real reduction in vascular events in minimally symptomatic patients. Based on our figures, future trials of CPAP versus no treatment would need to randomise approximately 2540 patients to not miss a real reduction in vascular events and over 6000 for mortality. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Hart N, Mandal S, Manuel A, Mokhlesi B, Pepin JL, Piper A, Stradling J. 2014. Rebuttal: 'Obesity hypoventilation syndrome (OHS): does the current definition need revisiting?'. Thorax, 69 (10), pp. 955.

McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Davies RJ, Nunn AJ, Stradling JR, Riha RL, Morrell MJ, Investigators PREDICT. 2014. A 12 Month Multicenter, Parallel, Randomized Trial Of Continuous Positive Airway Pressure In Older People With Obstructive Sleep Apnea Syndrome AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 189

Prudon B, Roddy E, Stradling JR, West SD. 2013. Serum urate levels are unchanged with continuous positive airway pressure therapy for obstructive sleep apnea: a randomized controlled trial. Sleep Med, 14 (12), pp. 1419-1421. | Show Abstract | Read more

OBJECTIVE: Hyperuricemia is associated with the presence and severity of obstructive sleep apnea (OSA). Previous work has shown that treatment of OSA with continuous positive airway pressure (CPAP) therapy reduces urinary uric acid excretion and serum urate, but there has been no previous randomized controlled investigation on the effects of CPAP therapy on serum urate; we aimed to assess this association. METHODS: Serum urate was measured in samples from participants of a previously published randomized controlled trial. Samples were taken at baseline and after 3months from men with known type 2 diabetes mellitus (T2DM) and newly diagnosed OSA, randomized to receive either therapeutic (n=19) or placebo (n=19) CPAP for 3months. RESULTS: Both groups were well matched at baseline, with no significant difference in age, body mass index (BMI), glycosylated hemoglobin (HbA1c), or oxygen desaturation index (ODI). There was no significant difference in therapeutic or placebo CPAP usage. There was no significant difference in urate levels between groups at baseline (362μmol/L [standard deviation {SD}, 96] vs 413μmol/L [SD, 91] [reference range, 110-428μmol/L]) or at 3months. Baseline urate did not correlate with ODI, BMI, or HbA1c. The mean change in urate at 3months did not significantly differ between treatment groups (-7.6μmol/L [SD, 35.9] vs -6.2μmol/L [SD, 46.2]) (P=.9; [95% confidence interval, -28.7 to +25.9]). CONCLUSION: Our randomized controlled trial has shown no significant reduction in serum urate following 3months treatment with therapeutic or placebo CPAP.

Bratton DJ, Stradling JR, Barbe F, Kohler M. 2013. EFFECT OF CONTINUOUS POSITIVE AIRWAY PRESSURE ON BLOOD PRESSURE IN PATIENTS WITH MINIMALLY SYMPTOMATIC OBSTRUCTIVE SLEEP APNOEA: A META-ANALYSIS USING INDIVIDUAL PATIENT DATA FROM FOUR RANDOMISED CONTROLLED TRIALS THORAX, 68 (Suppl 3), pp. A4-A5. | Read more

Mishra EK, Corcoran J, Hallifax R, Stradling J, Maskell N, Rahman N. 2013. DEFINING THE MINIMAL IMPORTANT DIFFERENCE FOR THE VISUAL ANALOGUE SCALE FOR DYSPNOEA IN PATIENTS WITH MALIGNANT PLEURAL EFFUSIONS THORAX, 68 (Suppl 3), pp. A171-A171. | Read more

Manuel A, Hart N, Stradling JR. 2013. FACTORS DRIVING THE DEVELOPMENT OF CHRONIC RESPIRATORY FAILURE IN OBESE PATIENTS THORAX, 68 (Suppl 3), pp. A61-A62. | Read more

Proudlove K, Manuel A, Hall R, Rieu R, Villarroel M, Stradling J. 2014. Effect of continuous positive airway pressure treatment for obstructive sleep apnoea on visual processing of degraded words. Respiration, 87 (2), pp. 144-148. | Show Abstract | Read more

BACKGROUND: In a previous uncontrolled study, continuous positive airway pressure (CPAP) therapy for obstructive sleep apnoea (OSA) improved vision in patients with diabetic macular oedema. OBJECTIVES: We investigated whether the above improvement in vision (or visual processing) might have been due to reduced sleepiness, rather than a true improvement in retinal function. METHODS: Twelve normal control subjects and 20 patients with OSA were tested for their ability to recognise degraded words, by means of a computer programme displaying 5-letter words every 4 s for 10 min, with variable amounts of the bottom half of the word missing; the percentage of the word necessary to achieve correct identification on average half the time was 'hunted' (the test score). All subjects were tested twice, 2-3 weeks apart; the OSA group after the commencement of CPAP. The Epworth Sleepiness Score (ESS) in patients was measured at the same visit. RESULTS: The test score at visit 1 was 26.7% for normal subjects and 31.6% for patients with OSA. At visit 2, the test score was 25.0% for normal subjects and 29.9% for patients with OSA. The groups showed a small and identical improvement over the trial period in the test score, of 1.7% (p = 0.01 and p = 0.03 for the normal and OSA groups, respectively). The group with OSA experienced a drop in ESS of 7.5 (SD 5.5) points following treatment. CONCLUSION: The small and identical improvement in both groups suggests only a similar learning effect rather than any improvement due to reduced sleepiness.

Kohler M, Stradling JR. 2013. OSA and hypertension: do we know all the answers? Chest, 144 (5), pp. 1433-1435. | Read more

Stradling J, Kohler M. 2014. SKUP3 trial: comment. Thorax, 69 (4), pp. 386. | Read more

Manuel A, Stradling J, McIntrye A, Karpe F, Hart N, Rich S, Christopher K, Sarika S. 2013. Relationship between upper airway structures and pathogenesis in obesity hypoventilation syndrome (OHS) EUROPEAN RESPIRATORY JOURNAL, 42

Clarenbach CF, Camen G, Sievi NA, Wyss C, Stradling JR, Kohler M. 2013. The effect of simulated obstructive hypopnea and apnea on thoracic aortic wall transmural pressures EUROPEAN RESPIRATORY JOURNAL, 42

Hart N, Mandal S, Manuel A, Mokhlesi B, Pépin J-L, Piper A, Stradling JR. 2014. Obesity hypoventilation syndrome: does the current definition need revisiting? Thorax, 69 (1), pp. 83-84. | Read more

Clarenbach CF, Camen G, Sievi NA, Wyss C, Stradling JR, Kohler M. 2013. Effect of simulated obstructive hypopnea and apnea on thoracic aortic wall transmural pressures. J Appl Physiol (1985), 115 (5), pp. 613-617. | Show Abstract | Read more

Preliminary evidence supports an association between obstructive sleep apnea (OSA) and thoracic aortic dilatation, although potential causative mechanisms are incompletely understood; these may include an increase in aortic wall transmural pressures, induced by obstructive apneas and hypopneas. In patients undergoing cardiac catheterization, mean blood pressure (MBP) in the thoracic aorta and esophageal pressure was simultaneously recorded by an indwelling aortic pigtail catheter and a balloon-tipped esophageal catheter in randomized order during: normal breathing, simulated obstructive hypopnea (inspiration through a threshold load), simulated obstructive apnea (Mueller maneuver), and end-expiratory central apnea. Aortic transmural pressure (aortic MBP minus esophageal pressure) was calculated. Ten patients with a median age (range) of 64 (46-75) yr were studied. Inspiration through a threshold load, Mueller maneuver, and end-expiratory central apnea was successfully performed and recorded in 10, 7, and 9 patients, respectively. The difference between aortic MBP and esophageal pressure (and thus the extra aortic dilatory force) was median (quartiles) +9.3 (5.4, 18.6) mmHg, P = 0.02 during inspiration through a threshold load, +16.3 (12.8, 19.4) mmHg, P = 0.02 during the Mueller maneuver, and +0.4 (-4.5, 4.8) mmHg, P = 0.80 during end-expiratory central apnea. Simulated obstructive apnea and hypopnea increase aortic wall dilatory transmural pressures because intra-aortic pressures fall less than esophageal pressures. Thus OSA may mechanically promote thoracic aortic dilatation and should be further investigated as a risk factor for the development or accelerated progression of thoracic aortic aneurysms.

Rossi VA, Winter B, Rahman NM, Yu L-M, Fallon J, Clarenbach CF, Bloch KE, Stradling JR, Kohler M. 2013. The effects of Provent on moderate to severe obstructive sleep apnoea during continuous positive airway pressure therapy withdrawal: a randomised controlled trial. Thorax, 68 (9), pp. 854-859. | Show Abstract | Read more

OBJECTIVES: The aim of this study was to test the effectiveness of Provent, an expiratory nasal resistance valve, to prevent the recurrence of OSA following CPAP withdrawal. DESIGN: Randomised, partially blinded, parallel, placebo-controlled trial. SETTING: Outpatient sleep clinics in the UK (Oxford) and Switzerland (Zurich). PARTICIPANTS: 67 patients with OSA receiving CPAP were randomised to one of three groups for 2 weeks: continuing CPAP, Provent or placebo Provent. MAIN OUTCOME MEASURES: Primary outcomes included for Provent versus placebo Provent, OSA severity (oxygen desaturation index (ODI), apnoea-hypopnoea index (AHI)) and Epworth Sleepiness Scale (ESS) score. Secondary outcomes for Provent versus placebo Provent included ODI from ambulatory pulse oximetry and blood pressure (BP). For CPAP versus Provent, or CPAP versus placebo Provent, secondary outcomes included ODI/AHI, ESS and BP. RESULTS: 63 patients were included in the per protocol analysis. OSA recurred in the Provent (ODI 35.8, SD 17.4) and placebo Provent (ODI 28.2, SD 18.3) groups, and there was no significant difference in ODI, AHI and ESS between Provent and placebo Provent at 2 weeks (mean difference ODI -1.0, 95% CI -10.0 to +12.0, p=0.85; AHI +3.2, 95% CI -7.7 to +14.1, p=0.52; and ESS -1.4, 95% CI -4.1 to +1.4, p=0.33). ODI from ambulatory pulse-oximetry and BP at 2 weeks were not different in the Provent versus placebo Provent groups. ODI, AHI and BP, but not ESS, were significantly higher in the Provent and placebo Provent groups compared with CPAP. CONCLUSIONS: Provent cannot be recommended as an alternative short-term therapy for patients with moderate to severe OSA already on CPAP. TRIALREGNO: NCT01332175.

Kohler M, Craig S, Pepperell JCT, Nicoll D, Bratton DJ, Nunn AJ, Leeson P, Stradling JR. 2013. CPAP improves endothelial function in patients with minimally symptomatic OSA: results from a subset study of the MOSAIC trial. Chest, 144 (3), pp. 896-902. | Show Abstract | Read more

BACKGROUND: Minimally symptomatic OSA is a highly prevalent disorder, and the effects of CPAP on vascular function in these patients are unknown. This trial aimed to investigate whether CPAP improves vascular function in minimally symptomatic OSA. METHODS: In two centers taking part in the MOSAIC (Multicentre Obstructive Sleep Apnoea Interventional Cardiovascular) trial, 253 patients with minimally symptomatic OSA were randomized to 6 months of CPAP or standard care. Two hundred eight patients attended their follow-up visit within the predefined time window and had complete measurements of arterial stiffness (augmentation index [AIx]), and 64 patients had endothelial function measurements by brachial artery flow-mediated dilatation (FMD). Multivariable analyses adjusting for baseline measurements and minimization factors were performed to assess the effect of CPAP treatment on FMD (% dilatation) and AIx (% augmentation) compared with standard care. RESULTS: The mean ± SD baseline oxygen desaturation index and Epworth Sleepiness Score (ESS) of the 208 patients (age 58 ± 7.3 years, 31 women) were 13.7 ± 12.8 events/h and 8.3 ± 4.2, respectively. There was no CPAP treatment effect on arterial stiffness (AIx, -1.4%; 95% CI, -3.6 to +0.9%; P = .23), but CPAP improved endothelial function (FMD, +2.1%; 95% CI, +1.0 to +3.2%; P &lt; .0001). CPAP reduced daytime sleepiness (ESS, -2.2; 95% CI, -3.0 to -1.5; P &lt; .0001) compared with standard care. There was a larger improvement in FMD in patients using CPAP for &gt; 4 h/night than those who used it less (P = .013). CONCLUSIONS: CPAP improves endothelial function, but not arterial stiffness, in minimally symptomatic OSA. Thus, minimally symptomatic OSA may be a cardiovascular risk factor. TRIAL REGISTRY: ISRCTN Register; No.: ISRCTN 34164388; URL: http://isrctn.org.

Schulz UG, Mason RH, Craig SE, Howard S, Nicoll DJ, Kohler M, Rothwell PM, Stradling JR. 2013. Leukoaraiosis on MRI in patients with minimally symptomatic obstructive sleep apnoea. Cerebrovasc Dis, 35 (4), pp. 363-369. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with hypertension, nocturnal blood pressure (BP) surges, and increased risk of stroke. It may therefore also be associated with a higher risk of developing leukoaraiosis. Only few data about the prevalence of leukoaraiosis in patients with OSA, and any association between degrees of severity of either condition, exist. METHODS: We studied patients who were part of a clinical trial (MOSAIC) in minimally symptomatic OSA. All patients had brain MRI (T2, FLAIR) at baseline. A single observer assessed the images for the presence and severity of leukoaraiosis (ARWMC-score). We related the extent of leukoaraiosis to the severity of OSA (measured by oxygen desaturation index [ODI]) and the presence of other vascular risk factors. RESULTS: 183 patients (156 men, 85.2%; mean age ± SD = 57.7 ± 7.4 years; median oxygen desaturation index = 9.6, interquartile range = 4.6-16.0) took part in the study. Although 135 (74%) patients had some leukoaraiosis, this was generally mild. We confirmed the well-known risk factor associations between leukoaraiosis, increasing age (p < 0.0001) and hypertension (p = 0.003), but we did not find any association between OSA and leukoaraiosis (p = 0.33), despite both conditions being associated with increasing current BP and a history of hypertension. CONCLUSION: Our data confirm the well-known association between leukoaraiosis, age and increasing BP. However, we found no association between OSA and leukoaraiosis despite some shared risk factor associations. Our findings suggest that OSA is not a strong independent risk factor for leukoaraiosis. Confounding by hypertension may explain any apparent association in previously reported studies of patients with severer OSA.

Hopkinson NS, Moxham J, Montgomery H, West R, Scally G, McKee M, Spiro S, Bush A, Stradling J, Wells A et al. 2013. Tobacco industry lobbyists and their health-care clients. Lancet, 381 (9865), pp. 445. | Read more

Manuel A, Kim C, Cheeseman J, McIntyre A, Madgill R, Shinde S, Karpe F, Hart N, Schwab RJ, Stradling JR, Grp OHS. 2013. Does Variation In Fat Distribution Influence The Development Of Ventilatory Failure In Obesity? AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 187

Manuel A, Cheeseman J, Karpe F, Hart N, Stradling JR, OHS. 2013. Do Simple Tests Of Ventilatory Drive (hypoxic Challenge Testing, And Hypercapnic Response) Help Identify Obese Patients With Early Obesity Hypoventilation Syndrome (ohs)? AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 187

Rossi V, Winter B, Rahman NM, Yu L-M, Fallon J, Clarenbach C, Bloch KE, Stradling JR, Kohler M. 2013. The Effects Of Provent (TM) On Moderate-To-Severe Obstructive Sleep Apnea During Continuous Positive Airway Pressure Therapy Withdrawal: Primary Outcomes From A Randomized Controlled Trial AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 187

Rossi VA, Stradling JR, Kohler M. 2013. Effects of obstructive sleep apnoea on heart rhythm. Eur Respir J, 41 (6), pp. 1439-1451. | Show Abstract | Read more

Symptomatic obstructive sleep apnoea (OSA) has been proven to be a risk factor for hypertension and vascular dysfunction, and has been proposed to be causally related with cardiac arrhythmias and sudden cardiac death. Searches of bibliographical databases revealed that several mechanisms seem to underpin the association between OSA and cardiac arrhythmias: intermittent hypoxia associated with autonomic nervous system activation and increased oxidative stress, which may lead to cardiac cellular damage and alteration in myocardial excitability; recurrent arousals, resulting in sympathetic activation and coronary vasoconstriction; and increased negative intrathoracic pressure which may mechanically stretch the myocardial walls and, thus, promote acute changes in myocardial excitability as well as structural remodelling of the myocardium. Findings from cross-sectional studies suggest a high prevalence of cardiac arrhythmias in patients with OSA and a high prevalence of OSA in those with cardiac arrhythmias. Preliminary evidence from uncontrolled interventional studies suggests that treatment of OSA may prevent cardiac arrhythmias. In conclusion, there is preliminary evidence that OSA is associated with the development of cardiac arrhythmias. Data from randomised controlled studies are needed to definitively clarify the role of OSA in arrhythmogenesis.

Craig SE, Kohler M, Nicoll D, Bratton DJ, Nunn A, Davies R, Stradling J. 2012. Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial. Thorax, 67 (12), pp. 1090-1096. | Show Abstract | Read more

BACKGROUND: Continuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious. METHODS: This multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status. RESULTS: Of 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2 : 39 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components. CONCLUSIONS: In patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.

Ayers L, Stoewhas A-C, Ferry B, Stradling J, Kohler M. 2013. Elevated levels of endothelial cell-derived microparticles following short-term withdrawal of continuous positive airway pressure in patients with obstructive sleep apnea: data from a randomized controlled trial. Respiration, 85 (6), pp. 478-485. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnea has been associated with impaired endothelial function; however, the mechanisms underlying this association are not completely understood. Cell-derived microparticles may provide a link between obstructive sleep apnea and endothelial dysfunction. OBJECTIVES: This randomized controlled trial aimed to examine the effect of a 2-week withdrawal of continuous positive airway pressure (CPAP) therapy on levels of circulating microparticles. METHODS: Forty-one obstructive sleep apnea patients established on CPAP treatment were randomized to either CPAP withdrawal (subtherapeutic CPAP) or continuing therapeutic CPAP, for 2 weeks. Polysomnography was performed and circulating levels of microparticles were analyzed by flow cytometry at baseline and 2 weeks. RESULTS: CPAP withdrawal led to a recurrence of obstructive sleep apnea. Levels of CD62E+ endothelium-derived microparticles increased significantly in the CPAP withdrawal group compared to the continuing therapeutic CPAP group (median difference in change +32.4 per µl; 95% CI +7.3 to +64.1 per µl, p = 0.010). CPAP withdrawal was not associated with a statistically significant increase in granulocyte, leukocyte, and platelet-derived microparticles when compared with therapeutic CPAP. CONCLUSIONS: Short-term withdrawal of CPAP therapy leads to a significant increase in endothelium-derived microparticles, suggesting that microparticle formation may be causally linked to obstructive sleep apnea and may promote endothelial activation.

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Mason RH, West SD, Kiire CA, Groves DC, Lipinski HJ, Jaycock A, Chong VN, Stradling JR. 2012. High prevalence of sleep disordered breathing in patients with diabetic macular edema Retina, 32 (9), pp. 1791-1798. | Show Abstract | Read more

BACKGROUND: Diabetic retinopathy is more common and severe in patients with sleep disordered breathing (SDB). This study aimed to establish whether this is also true for patients with diabetic clinically significant macular edema (CSME). It is hypothesized that SDB, through intermittent hypoxia and blood pressure oscillations, might provoke worsening of CSME. METHODS: Patients with CSME had a home sleep study (ApneaLink; ResMed) to identify SDB. These results were compared with relevant control populations. Macular thickness was measured using optical coherence tomography, and retinal photographs were graded to assess the severity of retinopathy. RESULTS: Eighty of 195 patients (40 men) consented, with average age of 64.7 (11.7) years, neck circumference of 40.4 (5.4) cm, body mass index of 30.2 (6.2) kg/m, glycosylated hemoglobin (HbA1c) 7.8% (1.4%) [62 (8.0) mmol/mol], and Epworth sleepiness scale of 7.4 (4.8). Overall, 54% had an oxygen desaturation index ≥10, and 31% had an apnea-hypopnea index ≥15. This SDB prevalence is probably higher than would be expected from the available matched control data. Those with SDB were not sleepier, but they were older and more obese. No significant relationship was identified between the degree of macular thickness and the severity of SDB. CONCLUSION: Individuals with CSME have a high prevalence of SDB. Sleep disordered breathing may contribute to the pathophysiology of CSME, but the mechanism remains unclear. Given the high prevalence, retinal specialists should perhaps consider a diagnosis of SDB in patients with CSME. © Lippincott Williams & Wilkins.

Kohler M, Pitcher A, Blair E, Risby P, Senn O, Forfar C, Wordsworth P, Stradling JR. 2013. The impact of obstructive sleep apnea on aortic disease in Marfan's syndrome. Respiration, 86 (1), pp. 39-44. | Show Abstract | Read more

BACKGROUND: Aortic dissection is a life-threatening manifestation of Marfan's syndrome. Preliminary evidence suggests that obstructive sleep apnea (OSA) is associated with aortic disease in Marfan's syndrome. OBJECTIVES: To study the effect of OSA on aortic events in Marfan's syndrome. METHODS: In patients with Marfan's syndrome, a sleep study was performed at baseline and OSA was defined as >5 events of apnea/hypopnea (A+H) per hour in bed. Operation because of progressive aortic dilatation and death because of aortic rupture were defined as 'aortic events'. Kaplan-Meier survival analyses were used to compare event-free survival in patients with and without OSA. Cox regression models were used to explore the effects of covariates on event-free survival. RESULTS: Data from 44 patients (mean age 37.4 years, 30 females) were available for analysis; 15 patients (34.1%) had OSA. The median follow-up time was 29 (interquartile range 24-36) months. Five patients had an aortic event within the follow-up time. Median event-free survival was 51.6 months. Event-free survival was significantly shorter in patients with OSA compared to patients without OSA (p = 0.012). In univariate analysis, A+H was associated with aortic events [hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.01-1.18, p = 0.023]. Taking the interaction between BMI and A+H into account increased the HR for A+H (HR 1.75, 95% CI 1.003-3.048, p = 0.049). This association was no longer significant when other covariates were forced into the multivariate analysis. CONCLUSIONS: These data suggest that aortic event-free survival may be shorter in patients with Marfan's syndrome and OSA compared to patients without OSA, but more data from well-designed studies are needed to prove this association.

McDermott CJ, Maguire C, Cooper CL, Ackroyd R, Baird WO, Baudouin S, Bentley A, Bianchi S, Bourke S, Bradburn MJ et al. 2012. Protocol for diaphragm pacing in patients with respiratory muscle weakness due to motor neurone disease (DiPALS): a randomised controlled trial. BMC Neurol, 12 (1), pp. 74. | Show Abstract | Read more

BACKGROUND: Motor neurone disease (MND) is a devastating illness which leads to muscle weakness and death, usually within 2-3 years of symptom onset. Respiratory insufficiency is a common cause of morbidity, particularly in later stages of MND and respiratory complications are the leading cause of mortality in MND patients. Non Invasive Ventilation (NIV) is the current standard therapy to manage respiratory insufficiency. Some MND patients however do not tolerate NIV due to a number of issues including mask interface problems and claustrophobia. In those that do tolerate NIV, eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. The NeuRx RA/4 Diaphragm Pacing System was originally developed for patients with respiratory insufficiency and diaphragm paralysis secondary to stable high spinal cord injuries. The DiPALS study will assess the effect of diaphragm pacing (DP) when used to treat patients with MND and respiratory insufficiency. METHOD/DESIGN: 108 patients will be recruited to the study at 5 sites in the UK. Patients will be randomised to either receive NIV (current standard care) or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 follow up time points (2, 3, 6, 9 and 12 months) plus an additional surgery and 1 week post operative visit for those in the DP group. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews. DISCUSSION: The primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND with respiratory muscle weakness. The project is funded by the National Institute for Health Research, Health Technology Assessment (HTA) Programme (project number 09/55/33) and the Motor Neurone Disease Association and the Henry Smith Charity. TRIAL REGISTRATION: Current controlled trials ISRCTN53817913. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

Mason RH, Mehta Z, Fonseca AC, Stradling JR, Rothwell PM. 2012. Snoring and severity of symptomatic and asymptomatic carotid stenosis: a population-based study. Sleep, 35 (8), pp. 1147-1151. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnea has increasingly been linked to cardiovascular damage. More recently, the snoring component itself has been independently linked to the presence of carotid atheroma, via local arterial trauma. We aimed to identify whether a snoring history is a risk factor for carotid stenosis in individuals presenting with a TIA or ischemic stroke. METHODS: Participants in the Oxford Vascular Study (OXVASC) were asked about their snoring history as part of an entry questionnaire. In 561 individuals with a recent TIA or stroke, who had both a complete snoring questionnaire and carotid imaging, the relationship between presence and severity of snoring and the degree of carotid artery stenosis in both the symptomatic (culprit) and asymptomatic (non-culprit) sides. RESULTS: Of 561 participants (287 male, mean/SD age = 73.3/11.0 years), 90 (16.0%) had ≥ 50% carotid stenosis, and 154 (27.5%) snored frequently (≥ 1-2 times/week). No significant associations were identified between frequency of self-reported snoring, and the degree of culprit and non-culprit carotid vessel stenosis, or plaque morphology. CONCLUSIONS: No significant association could be identified between a history of frequent snoring and the presence of carotid atheroma, degree of stenosis, or plaque type.

Camen G, Clarenbach CF, Stöwhas A-C, Rossi VA, Sievi NA, Stradling JR, Kohler M. 2013. The effects of simulated obstructive apnea and hypopnea on arrhythmic potential in healthy subjects. Eur J Appl Physiol, 113 (2), pp. 489-496. | Show Abstract | Read more

Preliminary evidence supports an association between OSA and cardiac dysrhythmias. Negative intrathoracic pressure, as occurring during OSA, may provoke cardiac dysrhythmias. Thus, we aimed to study the acute effects of simulated apnea and hypopnea on arrhythmic potential and measures of cardiac repolarization [QT(C) and T (peak) to T (end) intervals [TpTec]) in humans. In 41 healthy volunteers, ECG was continuously recorded prior, during and after simulated obstructive hypopnea (inspiration through a threshold load), simulated apnea (Mueller maneuver), end-expiratory central apnea and normal breathing in randomized order. The number of subjects with premature beats was significantly higher during inspiration through a threshold load (n = 7), and the Mueller maneuver (n = 7) compared to normal breathing (n = 0) (p = 0.008 for all comparisons), but not during end-expiratory central apnea (n = 3, p = 0.125). Inspiration through a threshold load was associated with a non-significant mean (SD) increase of the QT(C) interval [+5.4 (22.4) ms, 95 %CI -1.7 to +12.4 ms, p = 0.168] and a significant increase of the TpTcc interval [+3.7 (8.9) ms, 95 %CI +0.9 to +6.6 ms, p = 0.010]. The Mueller maneuver induced a significant increase of the QT(C) interval [+8.3 (23.4) ms, 95 %CI 0.9 to +15.6 ms, p = 0.035] and the TpTec interval (+4.2 (8.2) ms, 95 %CI +1.6 to +6.8 ms, p = 0.002). There were no significant changes of the QT(C) and TpTec intervals during central end-expiratory apnea. These data indicate that simulated obstructive apnea and hypopnea are associated with an increase of premature beats and prolongation of QT(C) and TpTec intervals. Therefore, negative intrathoracic pressure changes may be a contributory mechanism for the association between OSA and cardiac dysrhythmias.

Mason RH, West SD, Kiire CA, Groves DC, Lipinski HJ, Jaycock A, Chong VN, Stradling JR. 2012. High prevalence of sleep disordered breathing in patients with diabetic macular edema. Retina, 32 (9), pp. 1791-1798. | Show Abstract | Read more

BACKGROUND: Diabetic retinopathy is more common and severe in patients with sleep disordered breathing (SDB). This study aimed to establish whether this is also true for patients with diabetic clinically significant macular edema (CSME). It is hypothesized that SDB, through intermittent hypoxia and blood pressure oscillations, might provoke worsening of CSME. METHODS: Patients with CSME had a home sleep study (ApneaLink; ResMed) to identify SDB. These results were compared with relevant control populations. Macular thickness was measured using optical coherence tomography, and retinal photographs were graded to assess the severity of retinopathy. RESULTS: Eighty of 195 patients (40 men) consented, with average age of 64.7 (11.7) years, neck circumference of 40.4 (5.4) cm, body mass index of 30.2 (6.2) kg/m2, glycosylated hemoglobin (HbA1c) 7.8% (1.4%) [62 (8.0) mmol/mol], and Epworth sleepiness scale of 7.4 (4.8). Overall, 54% had an oxygen desaturation index ≥ 10, and 31% had an apnea-hypopnea index ≥ 15. This SDB prevalence is probably higher than would be expected from the available matched control data. Those with SDB were not sleepier, but they were older and more obese. No significant relationship was identified between the degree of macular thickness and the severity of SDB. CONCLUSION: Individuals with CSME have a high prevalence of SDB. Sleep disordered breathing may contribute to the pathophysiology of CSME, but the mechanism remains unclear. Given the high prevalence, retinal specialists should perhaps consider a diagnosis of SDB in patients with CSME.

Kohler M, Stradling JR. 2012. CrossTalk proposal: Most of the cardiovascular consequences of OSA are due to increased sympathetic activity. J Physiol, 590 (12), pp. 2813-2815. | Read more

Kohler M, Stradling JR. 2012. Rebuttal from malcolm kohler and john R. Stradling. J Physiol, 590 (Pt 12), pp. 2821. | Read more

Kohler M, Stradling JR. 2012. Rebuttal from Malcolm Kohler and John R. Stradling Journal of Physiology, 590 (12), pp. 2821-2821. | Read more

Kohler M, Stradling JR. 2012. CrossTalk proposal: Most of the cardiovascular consequences of OSA are due to increased sympathetic activity Journal of Physiology, 590 (12), pp. 2813-2815. | Read more

Kylintireas I, Craig S, Nethononda R, Kohler M, Francis J, Choudhury R, Stradling J, Neubauer S. 2012. Atherosclerosis and arterial stiffness in obstructive sleep apnea--a cardiovascular magnetic resonance study. Atherosclerosis, 222 (2), pp. 483-489. | Show Abstract | Read more

OBJECTIVE: Obstructive sleep apnoea (OSA) has been linked to cardiovascular risk factors, such as hypertension, and clinical cardiovascular endpoints. Our aim was to assess whether OSA is independently associated with atherosclerosis and vascular dysfunction as assessed by cardiovascular magnetic resonance (CMR). METHODS: 58 patients with OSA and 39 matched control subjects without OSA underwent CMR of the aorta and carotid arteries. Carotid and aortic wall thickness and aortic distensibility were measured. Multi-weighted, high resolution CMR imaging was used for carotid atheroma characterization according to the American Heart Association (AHA) atheroma classification, modified for CMR. RESULTS: Carotid [1.47±0.03 mm vs. 1.26±0.05 mm, (P<0.01)] and aortic wall thickness [2.95±0.09 mm vs. 2.05±0.07 mm, (P<0.001)] were increased in patients with OSA compared to controls. Aortic distensibility was decreased in patients with OSA [3.62±0.3 vs. 4.75±0.2 mmHg(-1)×10(-3), (P<0.05)]. Prevalence of carotid plaque, average carotid atheroma class, and prevalence of high risk features of carotid atheroma were increased in patients with OSA (P<0.005 for all). On multivariate analysis, Oxygen desaturation index (ODI) emerged as an independent predictor of carotid and aortic wall thickness, but not of aortic stiffness. CONCLUSIONS: OSA is associated with increased carotid and aortic atheroma burden and with advanced, high risk carotid atherosclerotic plaques, but not with aortic stiffening.

Rossi VA, Stoewhas A-C, Camen G, Steffel J, Bloch KE, Stradling JR, Kohler M. 2012. The effects of continuous positive airway pressure therapy withdrawal on cardiac repolarization: data from a randomized controlled trial. Eur Heart J, 33 (17), pp. 2206-2212. | Show Abstract | Read more

AIMS: The preliminary evidence supports an association between obstructive sleep apnoea (OSA), disturbed cardiac repolarization, and consequent cardiac dysrhythmias. The aim of the current trial was to assess the effects of continuous positive airway pressure (CPAP) therapy withdrawal on the measures of cardiac repolarization in patients with OSA. METHODS AND RESULTS: Forty-one OSA patients established on CPAP treatment were randomized to either CPAP withdrawal (subtherapeutic CPAP) or continue therapeutic CPAP for 2 weeks. Polysomnography was performed, and indices of cardiac repolarization (QT(c), TpTe(c) intervals) and dispersion of repolarization (TpTe/QT ratio) were derived from 12-lead electrocardiography (ECG) at baseline and 2 weeks. Continuous positive airway pressure withdrawal led to a recurrence of OSA. Compared with therapeutic CPAP, subtherapeutic CPAP for 2 weeks was associated with a significant increase in the length of the QT(c) and TpTe(c) intervals (mean difference between groups 21.4 ms, 95% CI 11.3-1.6 ms, P < 0.001 and 14.4 ms, 95% CI 7.2-21.5 ms, P < 0.001, respectively) and in the TpTe/QT ratio (mean difference between groups 0.02, 95% CI 0.00-0.03, P = 0.020). There was a statistically significant correlation between the change in apnoea/hypopnoea index (AHI) from baseline, and both the change in the QT(c) interval and the TpTe(c) interval (r = 0.60, 95% CI 0.36-0.77, P < 0.001 and r = 0.45, 95% CI 0.17-0.67, P = 0.003, n = 41, respectively). CONCLUSION: Continuous positive airway pressure withdrawal is associated with the prolongation of the QT(c) and TpTe(c) intervals and TpTe/QT ratio, which may provide a possible mechanistic link between OSA, cardiac dysrhythmias, and thus sudden cardiac death.

Mason RH, Kiire CA, Groves DC, Lipinski HJ, Jaycock A, Winter BC, Smith L, Bolton A, Rahman NM, Swaminathan R et al. 2012. Visual improvement following continuous positive airway pressure therapy in diabetic subjects with clinically significant macular oedema and obstructive sleep apnoea: proof of principle study. Respiration, 84 (4), pp. 275-282. | Show Abstract | Read more

BACKGROUND: Diabetic retinopathy and diabetic macular oedema are more prevalent in patients with coexistent obstructive sleep apnoea (OSA). OBJECTIVES: We assessed if treatment of OSA with continuous positive airway pressure (CPAP) might improve visual acuity (VA). METHODS: A total of 35 patients with clinically significant macular oedema (CSMO) and OSA [oxygen desaturation index (ODI) ≥10 or apnoea-hypopnoea index (AHI) ≥15] were identified and agreed to be studied. VA (expressed as the logarithm of the minimum angle of resolution, logMAR), macular thickness, fundal photographs, glycosylated haemoglobin (HbA1c) and rhodopsin mRNA were measured twice at baseline and at 3 and 6 months post-CPAP. Fluorescein angiography and the Epworth Sleepiness Scale (ESS) were obtained once at baseline and at 6 months. RESULTS: Three patients withdrew before the first trial visit. Thus, a total of 32 patients (17 males) entered the study, and 4 subsequently withdrew; thus 28 completed 6 months of follow-up. Baseline characteristics of the subjects were as follows [mean (SD or inter-quartile range)]: age 66.2 (7.1) years, body mass index 31.7 (6.3), HbA1c 7.4% (1.44) [57.1 (15.7) mmol/mol], AHI 16.5 (11-25), ODI 16.0 (12-25), ESS 6.5 (4.0-12.0) and duration of diabetes 9.5 years (5.0-16.5). Participants were divided into 13 high and 15 low CPAP compliers (≥ and <2.5 h/night over the 6 months, respectively). At 6 months, the adjusted treatment effect on VA of high compliance versus low compliance was 0.11 (95% confidence interval 0.21 to -0.002; p = 0.047), equivalent to a one-line improvement on the logMAR chart. There was no significant improvement in macular oedema or fundal photographs. CONCLUSIONS: This hypothesis-generating, uncontrolled study suggests that ≥2.5 h/night CPAP usage over 6 months in individuals with CSMO and OSA may be associated with improvement in VA. This provides justification for a randomised controlled trial of CPAP therapy in such patients.

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Kohler M, Stoewhas AC, Ayers L, Senn O, Bloch KE, Russi EW, Stradling JR. 2011. Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea A randomized controlled trial American Journal of Respiratory and Critical Care Medicine, 184 (10), pp. 1192-1199. | Show Abstract | Read more

Rationale: To establish a new approach to investigate the physiological effects of obstructive sleep apnea (OSA), and to evaluate novel treatments, during a period of continuous positive airway pressure (CPAP) withdrawal. Objectives: To determine the effects of CPAP withdrawal. Methods: Forty-one patients with OSA and receiving CPAP were randomized to either CPAP withdrawal (subtherapeutic CPAP), or continued CPAP, for 2 weeks. Polysomnography, sleepiness, psychomotorperformance, endothelial function, blood pressure (BP), heart rate (HR), urinary catecholamines, blood markers of systemic inflammation, and metabolism were assessed. Measurements and Main Results: CPAP withdrawal led to arecurrence of OSA within a few days and a return of subjective sleepiness, but was not associated with significant deterioration of psychomotor performance within 2 weeks. Endothelial function, assessed by flow-mediated dilatation, decreased significantly in the CPAP withdrawal group compared with therapeutic CPAP (mean difference in change, -3.2%; 95% confidence interval [CI], -4.5, -1.9%; P < 0.001). Compared with continuing CPAP, 2 weeks of CPAP withdrawal was associated with a significant increase in morning systolic BP (mean difference in change, 18.5 mm Hg; 95% CI, +1.7, +15.3 mm Hg; P=0.016), morning diastolic BP (mean difference in change, +6.9 mm Hg; 95% CI, +1.9, +11.9 mm Hg; P =0.008), and morning HR (mean difference in change, +6.3 bpm, 95% CI, +0.4, +12.2 bpm; P = 0.035). CPAP withdrawal was associated with an increase in urinary catecholamines but did not lead to an increase in markers of systemic inflammation, insulin resistance, or blood lipids. Conclusions: CPAP withdrawal usually leads to a rapid recurrence of OSA, a return of subjective sleepiness, andis associated with impaired endothelial function, increased urinary catecholamines, blood pressure, and heart rate. Thus the proposed study model appears to be suitable to evaluate physiological and therapeutic effects in OSA. Clinical trial registered with www.controlled-trials.com (ISRCTN 93153804). Copyright ©2011 by the American Thoracic Society.

Kohler M, Stoewhas A-C, Ayers L, Senn O, Bloch KE, Russi EW, Stradling JR. 2011. Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med, 184 (10), pp. 1192-1199. | Show Abstract | Read more

RATIONALE: To establish a new approach to investigate the physiological effects of obstructive sleep apnea (OSA), and to evaluate novel treatments, during a period of continuous positive airway pressure (CPAP) withdrawal. OBJECTIVES: To determine the effects of CPAP withdrawal. METHODS: Forty-one patients with OSA and receiving CPAP were randomized to either CPAP withdrawal (subtherapeutic CPAP), or continued CPAP, for 2 weeks. Polysomnography, sleepiness, psychomotor performance, endothelial function, blood pressure (BP), heart rate (HR), urinary catecholamines, blood markers of systemic inflammation, and metabolism were assessed. MEASUREMENTS AND MAIN RESULTS: CPAP withdrawal led to a recurrence of OSA within a few days and a return of subjective sleepiness, but was not associated with significant deterioration of psychomotor performance within 2 weeks. Endothelial function, assessed by flow-mediated dilatation, decreased significantly in the CPAP withdrawal group compared with therapeutic CPAP (mean difference in change, -3.2%; 95% confidence interval [CI], -4.5, -1.9%; P < 0.001). Compared with continuing CPAP, 2 weeks of CPAP withdrawal was associated with a significant increase in morning systolic BP (mean difference in change, +8.5 mm Hg; 95% CI, +1.7, +15.3 mm Hg; P = 0.016), morning diastolic BP (mean difference in change, +6.9 mm Hg; 95% CI, +1.9, +11.9 mm Hg; P = 0.008), and morning HR (mean difference in change, +6.3 bpm, 95% CI, +0.4, +12.2 bpm; P = 0.035). CPAP withdrawal was associated with an increase in urinary catecholamines but did not lead to an increase in markers of systemic inflammation, insulin resistance, or blood lipids. CONCLUSIONS: CPAP withdrawal usually leads to a rapid recurrence of OSA, a return of subjective sleepiness, and is associated with impaired endothelial function, increased urinary catecholamines, blood pressure, and heart rate. Thus the proposed study model appears to be suitable to evaluate physiological and therapeutic effects in OSA. Clinical trial registered with www.controlled-trials.com (ISRCTN93153804).

Weatherly HLA, Griffin SC, Mc Daid C, Duree KH, Davies RJO, Stradling JR, Westwood ME, Sculpher MJ. 2011. An economic analysis of continuous positive airway pressure for the treatment of obstructive sleep apnea-hypopnea syndrome (vol 25, pg 26, 2009) INTERNATIONAL JOURNAL OF TECHNOLOGY ASSESSMENT IN HEALTH CARE, 27 (3), pp. 271-271. | Read more

Weatherly HLA, Griffin SC, Mc Daid C, Durée KH, Davies RJO, Stradling JR, Westwood ME, Sculpher MJ. 2011. Erratum: An economic analysis of continuous positive airway pressure for the treatment of obstructive sleep apnea-hypopnea syndrome (International Journal of Technology Assessment in Health Care (2009) 25 (26-43) DOI: 10.1017/S0266462309090047) International Journal of Technology Assessment in Health Care, 27 (3), pp. 271. | Read more

Kohler M, Stradling JR. 2011. Pitfalls of clinical trials on pharmacological treatment for obstructive sleep apnoea: future directions. Expert Opin Investig Drugs, 20 (8), pp. 1033-1037. | Show Abstract | Read more

The standard treatment for obstructive sleep apnoea (OSA) is continuous positive airway pressure (CPAP). Depending on selection criteria and quality of care, up to 50% of patients with OSA do not tolerate CPAP. For patients who cannot tolerate CPAP despite good quality care, pharmacological treatment would be a desirable alternative. The mechanisms by which pharmacological treatment is supposed to improve OSA include, amongst others, an augmentation in pharyngeal dilator muscle tone, an increase in ventilatory drive, a reduction in airway resistance and alterations in pharyngeal surface tension forces. In humans, most recent pharmacological approaches to the treatment of OSA in clinical trials have focused on modulating serotoninergic and cholinergic activities, as both have been shown to augment pharyngeal dilator muscle tone. However, currently there is not enough evidence to recommend any particular drug treatment for OSA. Methodological issues of published clinical trials on pharmacological OSA treatment make it difficult to draw definitive conclusions and inform further drug developments in this area. In this article, the pitfalls of clinical trials on pharmacological OSA therapy are summarised and potential solutions and directions for future studies are given.

Stöwhas A-C, Namdar M, Biaggi P, Russi EW, Bloch KE, Stradling JR, Kohler M. 2011. The effect of simulated obstructive apnea and hypopnea on aortic diameter and BP. Chest, 140 (3), pp. 675-680. | Show Abstract | Read more

BACKGROUND: Preliminary evidence supports an association between obstructive sleep apnea (OSA) and thoracic aortic dilatation. The mechanisms through which OSA may promote thoracic aortic dilatation are incompletely understood. Therefore, we studied the acute effects of simulated apnea and hypopnea on aortic diameter and BP in humans. METHODS: The diameter of the aortic root was measured in 20 healthy volunteers by echocardiography, and peripheral BP was continuously recorded prior, during, and immediately after simulated obstructive hypopnea (inspiration through threshold load), simulated obstructive apnea (Müller maneuver), end-expiratory central apnea, and normal breathing in randomized order. RESULTS: Proximal aortic diameter increased significantly during inspiration through a threshold load (+6.48%; SE, 3.03; P = .007), but not during Müller maneuver (+3.86%; SE, 2.71; P = .336) or end-expiratory central apnea (+0.62%; SE, 2.94; P = .445). Maneuver-induced changes in mean BP were observed during inspiration through a threshold load (-10.5 mm Hg; SE, 2.2; P < .001), the Müller maneuver (-8.8 mm Hg; SE, 2.4; P < .001), and end-expiratory central apnea (-4.2 mm Hg; SE, 1.4; P = .052). There was a significant increase in mean BP on release of threshold load inspiration (+8.1 mm Hg; SE, 2.9 mm Hg; P = .002), Müller maneuver (+10.7 mm Hg; SE, 2.9; P < .001), and end-expiratory central apnea (+10.6 mm Hg; SE, 2.5; P < .001). CONCLUSIONS: Simulated obstructive hypopnea/apnea and central apnea induced considerable changes in BP, and obstructive hypopnea was associated with an increase in proximal aortic diameter. Further studies are needed to investigate effects of apnea and hypopnea on transmural aortic pressure and aortic diameter to define the role of OSA in the pathogenesis of aortic dilatation.

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Mason RH, Ruegg G, Perkins J, Hardinge M, Amann-Vesti B, Senn O, Stradling JR, Kohler M. 2011. Obstructive Sleep Apnea in Patients with Abdominal Aortic Aneurysms Highly Prevalent and Associated with Aneurysm Expansion AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 183 (5), pp. 668-674. | Read more

Stradling J, Dookun R. 2011. The role of the dentist in sleep disorders. Dent Update, 38 (2), pp. 136.

Stradling J, Mumford C. 2011. Robert John Oriel Davies Obituary BRITISH MEDICAL JOURNAL, 342 (feb14 2), pp. d1026-d1026. | Read more

Kohler M, Stradling JR. 2010. Mechanisms of vascular damage in obstructive sleep apnea. Nat Rev Cardiol, 7 (12), pp. 677-685. | Show Abstract | Read more

Obstructive sleep apnea (OSA) is characterized by repetitive apnea-hypopnea cycles during sleep, which are associated with oxygen desaturation and sleep disruption. Up to 30% of the adult population in Western countries are thought to be affected by asymptomatic OSA and approximately 2-4% by symptomatic OSA (also known as obstructive sleep apnea syndrome, or OSAS). Controlled trials have demonstrated that OSAS causes hypertension and prospective epidemiological studies have indicated that OSAS might be an independent risk factor for stroke and myocardial ischemia. Three biological mechanisms are thought to underpin the association of OSA with endothelial dysfunction and arterial disease: intermittent hypoxia leading to increased oxidative stress, systemic inflammation, and sympathetic activity; intrathoracic pressure changes leading to excessive mechanical stress on the heart and large artery walls; and arousal-induced reflex sympathetic activation with resultant repetitive blood-pressure rises. More clinical interventional trials are needed to determine the magnitude of the effect OSA has on cardiovascular damage and to enable a comparison with conventional vascular risk factors.

Stradling J. 2010. Peter Stradling Obituary BRITISH MEDICAL JOURNAL, 341 (sep20 2), pp. c5080-c5080. | Read more

Kohler M, Smith D, Tippett V, Stradling JR. 2010. Predictors of long-term compliance with continuous positive airway pressure. Thorax, 65 (9), pp. 829-832. | Show Abstract | Read more

BACKGROUND: There are very few data on objectively assessed long-term compliance with continuous positive airway pressure (CPAP). No single factor has been consistently identified as predictive of continued CPAP use. METHODS: Adherence to and associations with objective CPAP use were examined in 639 of 3900 patients in whom CPAP treatment was started between 1994 and 2005. Kaplan-Meier survival analyses were used to estimate the proportion of patients still on CPAP. Cox regression models were used to explore the effects of covariates on continued use of CPAP. RESULTS: The median (IQR) follow-up time after initiating CPAP therapy was 3.9 (1.5-6.9) years and the average use of CPAP was 6.2 (4.5-7.3) h/night. The percentage of patients adherent to CPAP after 5 and 10 years was 81% and 70%, respectively. Multivariate analysis, including gender, age, neck circumference, Epworth Sleepiness Score, oxygen desaturation index (ODI) and research study participation, indicated that ODI was the only clinical variable independently associated with long-term adherence to CPAP (HR per 1 event=0.97, p<0.001, 95% CI 0.96 to 0.98). ODI categories were significantly associated with the risk for stopping CPAP in multivariate analysis (using ODI group 0-15/h as reference, HR for ODI group >15-30/h=0.68, p=0.100, 95% CI 0.43 to 1.08; for ODI group >30-60/h=0.37, p<0.001, 95% CI 0.22 to 0.60; and for ODI group >60/h=0.17, p=0.001, 95% CI 0.06 to 0.48). CONCLUSIONS: The majority of patients with sleep-disordered breathing are using CPAP in the long term and the severity of sleep-disordered breathing rather than sleepiness determines long-term adherence to CPAP therapy.

Ruegg G, Mason RH, Hardinge M, Perkins J, Husmann M, Russi EW, Bloch KE, Stradling JR, Kohler M. 2010. Augmentation index and central aortic blood pressure in patients with abdominal aortic aneurysms. J Hypertens, 28 (11), pp. 2252-2257. | Show Abstract | Read more

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a life-threatening disease as rupture of the aneurysm is associated with high mortality. The likelihood that an AAA will rupture is particularly influenced by the diameter of the aneurysm and the rate of expansion; the reasons for fast expansion are largely unknown. Applanation tonometry (APT) can predict outcome in certain cardiovascular diseases by measuring arterial stiffness (augmentation index, AIx) and central aortic blood pressure (CABP). We tested the hypothesis that AIx and CABP would be higher in patients with fast-progressing AAA. METHODS: We performed APT and peripheral blood pressure measurements in 114 patients with AAA (11 women) with a mean ± SD age of 67.4±6.1 years. Annual AAA progression rate was determined by ultrasound. Patients were grouped into fast progressors (progression ≥2 mm/year) and slow progressors (progression <2 mm/year). RESULTS: Mean follow-up time after inclusion into the AAA surveillance programme was 22.1 ± 16.3 months. AIx was similar in fast progressors (27.3 ± 13.0%) and slow progressors (26.5 ± 12.6%) (P = 0.73). Fast progressors had a significantly higher CABP during systole (116.0 ± 16.0 mmHg) and diastole (95.7 ± 12.6 mmHg) than slow progressors (109.5 ± 16.3 and 90.0 ± 13.2 mmHg) (P = 0.04 and P = 0.02, respectively). Mean peripheral blood pressure was significantly higher in fast progressors (102.7 ± 12.8 mmHg) than in slow progressors (97.7 ± 12.9 mmHg) (P = 0.04). CONCLUSION: Augmentation index did not differ in patients with fast and slow-progressing AAA. However, fast progressors had higher central aortic blood pressures suggesting that elevated aortic blood pressure is a risk factor for faster AAA progression, but this needs to be proven in controlled interventional studies.

Kohler M, West S, Stradling J. 2010. Diabetes in obstructive sleep apnea. Am J Respir Crit Care Med, 182 (2), pp. 286-287. | Read more

Mason RH, Ruegg G, Perkins J, Hardinge M, Amann-Vesti B, Senn O, Stradling JR, Kohler M. 2011. Obstructive sleep apnea in patients with abdominal aortic aneurysms: highly prevalent and associated with aneurysm expansion. Am J Respir Crit Care Med, 183 (5), pp. 668-674. | Show Abstract | Read more

RATIONALE: Abdominal aortic aneurysms (AAA) are associated with life-threatening complications. The likelihood that an AAA will rupture is influenced by the aneurysm diameter and its expansion rate; reasons for rapid expansion are largely unknown. OBJECTIVES: To determine the prevalence of obstructive sleep apnea (OSA) in patients with AAA, and investigate a possible association between OSA and rate of AAA expansion. METHODS: A total of 127 patients (11 females), included in an AAA surveillance program, agreed to participate and underwent a sleep study. Annual AAA expansion was determined retrospectively from available ultrasound measurements. OSA was characterized using both oxygen desaturation index (ODI) and apnea-hypopnea index (AHI). Univariate and multivariate analysis was performed to assess the effect of OSA severity on AAA expansion. MEASUREMENTS AND MAIN RESULTS: Mean age was 67.9 (SD, 6) years. Median interval between the first and last AAA measurements was 18 (range, 2-113) months. An ODI or AHI of greater than 10 was found in 40.5% and 41.5% of the patients, respectively. Patients with an ODI greater than 30 (n = 12) had a significantly faster median yearly AAA expansion rate (2.9; quartiles 2/5.7 mm/y) than patients with an ODI 0-5 (n = 47; 1.2; quartiles 0/3.1 mm/y) or 6-15 (n = 43; 1.3; quartiles 0/2.7 mm/y) (P < 0.05). In multivariate regression analysis, controlling for cardiovascular risk factors and medications, ODI greater than 30 remained an independent risk factor for AAA expansion. CONCLUSIONS: In patients with AAA, OSA is highly prevalent. Severe OSA may be a causal factor for faster AAA expansion, but this needs to be proved in a randomized controlled intervention trial.

West SD, Groves DC, Lipinski HJ, Nicoll DJ, Mason RH, Scanlon PH, Stradling JR. 2010. The prevalence of retinopathy in men with Type 2 diabetes and obstructive sleep apnoea. Diabet Med, 27 (4), pp. 423-430. | Show Abstract | Read more

AIMS: To clarify the relationship between obstructive sleep apnoea (OSA) and diabetic retinopathy. RESEARCH DESIGN AND METHODS: A cohort of 240 men from primary and secondary care previously participated in a study on the prevalence of OSA in Type 2 diabetes and provided anthropometric information, details of their diabetes, had glycated haemoglobin (HbA1c) measured and overnight oximetry performed. They were re-contacted for permission to review their routine screening clinical retinal photographs, which were then scored by a trained grader, providing detailed retinopathy, maculopathy and photocoagulation scores. RESULTS: One hundred and eighteen men both consented and had retinal photographs available to review. Of these, 24% had OSA, with mean+/-sd 4% oxygen saturation (SaO2) dips/h of 20.9+/-16.6 vs. 2.8+/-2.1 in the non-OSA group. As expected, the OSA group had a significantly higher mean body mass index of 31.9+/-5.2 vs. 28.5+/-5.1 kg/m2 and neck size 44.5+/-3.6 vs. 41.9+/-2.5 cm, but the two groups did not differ significantly in age, diabetes duration, diabetes treatment, HbA1c, smoking history or proportion with known hypertension. Retinopathy and maculopathy scores were significantly worse in the OSA group (P<0.0001). Multiple regression analysis showed only OSA (R2=0.19, P<0.0001) and HbA1c (R2=0.04, P=0.03) to be significant independent predictors of retinopathy. OSA was the only independent significant predictor of the total microaneurysm score (R2=0.21, P=0.004), a detailed retinopathy subclassification. OSA was the only independent significant predictor of maculopathy (R2=0.3, P<0.001). CONCLUSION: In men with Type 2 diabetes, there is a strong association between retinopathy and OSA, independent of conventional retinopathy risk factors.

Cited:

235

Scopus

Kohler M, Stradling JR. 2010. Mechanisms of vascular damage in obstructive sleep apnea Nature Reviews Cardiology, 7 (12), pp. 677-685. | Show Abstract | Read more

Obstructive sleep apnea (OSA) is characterized by repetitive apnea-hypopnea cycles during sleep, which are associated with oxygen desaturation and sleep disruption. Up to 30% of the adult population in Western countries are thought to be affected by asymptomatic OSA and approximately 2-4% by symptomatic OSA (also known as obstructive sleep apnea syndrome, or OSAS). Controlled trials have demonstrated that OSAS causes hypertension and prospective epidemiological studies have indicated that OSAS might be an independent risk factor for stroke and myocardial ischemia. Three biological mechanisms are thought to underpin the association of OSA with endothelial dysfunction and arterial disease: intermittent hypoxia leading to increased oxidative stress, systemic inflammation, and sympathetic activity; intrathoracic pressure changes leading to excessive mechanical stress on the heart and large artery walls; and arousal-induced reflex sympathetic activation with resultant repetitive blood-pressure rises. More clinical interventional trials are needed to determine the magnitude of the effect OSA has on cardiovascular damage and to enable a comparison with conventional vascular risk factors. © 2010 Macmillan Publishers Limited. All rights reserved.

Craig SE, Kylintireas I, Kohler M, Gosling O, Davies RJO, Neubauer S, Stradling JR. 2010. Mild To Moderate, Minimally Symptomatic, Obstructive Sleep Apnoea (OSA) Is Associated With 'Vulnerable' Carotid Atherosclerotic Plaques AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 181

McDaid C, Durée KH, Griffin SC, Weatherly HLA, Stradling JR, Davies RJO, Sculpher MJ, Westwood ME. 2009. A systematic review of continuous positive airway pressure for obstructive sleep apnoea-hypopnoea syndrome. Sleep Med Rev, 13 (6), pp. 427-436. | Show Abstract | Read more

We conducted a systematic review of current evidence on the effectiveness of continuous positive airway pressure (CPAP) for treatment of obstructive sleep apnoea-hypopnoea syndrome (OSAHS). The primary outcomes were subjective sleepiness, using Epworth Sleepiness Scale (ESS) and objective sleepiness using Maintenance of Wakefulness Test (MWT) and Multiple Sleep Latency Test (MSLT). Mean difference (MD) in endpoints was used to compare CPAP to usual care, placebo and dental devices. The analysis was stratified by symptom and disease severity at baseline. CPAP significantly reduced ESS score compared to control (MD -2.7, 95% CI -3.45, -1.96). The benefit was greatest in patients whose symptoms were severe at baseline: severely symptomatic population (MD -5.0, -6.5, -3.5); moderate (MD -2.3, -3.0, -1.6); mild (MD -1.1, -1.8, -0.3). CPAP significantly improved MWT score compared to control (MD 3.3, 1.3, 5.3) but not on the MSLT. There was no statistically significant difference between CPAP and dental devices on the ESS, MWT or MSLT, in a population with moderate symptoms. There was some evidence of benefit for blood pressure with CPAP compared to control. CPAP is an effective treatment for OSAHS in moderate to severe symptomatic patients and there may be benefits for mild symptoms. Dental devices may be a treatment option for moderate symptoms.

Stradling J, Kohler M. 2009. Indices of hypoxic stress in sleep apnea. Am J Respir Crit Care Med, 180 (9), pp. 910. | Read more

Stradling JR. 2009. Residual sleepiness in patients with OSA on CPAP. Eur Respir J, 34 (5), pp. 1209. | Read more

West SD, Kohler M, Nicoll DJ, Stradling JR. 2009. The effect of continuous positive airway pressure treatment on physical activity in patients with obstructive sleep apnoea: A randomised controlled trial. Sleep Med, 10 (9), pp. 1056-1058. | Show Abstract | Read more

BACKGROUND: Continuous positive airway pressure (CPAP) improves daytime sleepiness in patients with obstructive sleep apnoea (OSA). The effect of CPAP on physical activity is unclear. We hypothesized that activity would increase after CPAP treatment. METHODS: A double blind, parallel, randomised, controlled trial using therapeutic and placebo CPAP was performed in men with newly diagnosed OSA (more than 10>4% SaO(2) dips/hour and Epworth Sleepiness Score [ESS] 9). Activity was measured by wrist actigraphy before and after three months of CPAP therapy. RESULTS: Thirty-six men completed 1 week of continuous actigraphy before and after therapeutic CPAP (n=16) or placebo CPAP (n=20). The two groups were well-matched at baseline, with no significant differences in mean age, body mass index, ESS and SaO(2) dips/hour. Mean (SD) ESS and modified maintenance of wakefulness test (OSLER) improved significantly after CPAP. ESS change in the therapeutic group was -6.1 (4.4), compared to placebo, -2.8 (5.0); difference between groups p=0.04; OSLER (minutes), therapeutic +10.4 (14.4), placebo -5.0 (12.0), p=0.003. There was no significant difference between groups in mean hourly activity levels for the seven days at baseline; activity levels did not significantly change in either group after CPAP [daytime activity (arbitrary units): therapeutic -13.9 (93.1) vs. placebo +8.3 (62.9), p=0.4]. There was no correlation between change in activity and CPAP use. CONCLUSION: Activity does not increase after CPAP in men with OSA, despite improvements in daytime sleepiness. The reasons for this are not clear, but may be due to longstanding, habitual patterns of activity.

Craig S, Pepperell JCT, Kohler M, Crosthwaite N, Davies RJO, Stradling JR. 2009. Continuous positive airway pressure treatment for obstructive sleep apnoea reduces resting heart rate but does not affect dysrhythmias: a randomised controlled trial. J Sleep Res, 18 (3), pp. 329-336. | Show Abstract | Read more

Obstructive sleep apnoea (OSA) is associated with cardiovascular morbidity and may precipitate cardiac dysrhythmias. Uncontrolled reports suggest that continuous positive airway pressure (CPAP) may reduce dysrhythmia frequency and resting heart rate. We undertook a randomised controlled trial of therapeutic CPAP and compared with a subtherapeutic control which included an exploration of changes in dysrhythmia frequency and heart rate. Values are expressed as mean (SD). Eighty-three men [49.5 (9.6) years] with moderate-severe OSA [Oxygen Desaturation Index, 41.2 (24.3) dips per hour] underwent 3-channel 24-h electrocardiograms during normal daily activities, before and after 1 month of therapeutic (n = 43) or subtherapeutic (n = 40) CPAP. Recordings were manually analysed for mean heart rate, pauses, bradycardias, supraventricular and ventricular dysrhythmias. The two groups were well matched for age, body mass index, OSA severity, cardiovascular risk factors and history. Supraventricular ectopics and ventricular ectopics were frequently found in 95.2% and 85.5% of patients, respectively. Less common were sinus pauses (42.2%), episodes of bradycardia (12%) and ventricular tachycardias (4.8%). Compared with subtherapeutic control, CPAP reduced mean 24-h heart rate from 83.0 (11.5) to 79.7 (9.8) (P < 0.002) in the CPAP group compared with a non-significant rise (P = 0.18) from 79.0 (10.4) to 79.9 (10.4) in the subtherapeutic group; this was also the case for the day period analysed separately. There was no significant change in the frequencies of dysrhythmias after CPAP. Four weeks of CPAP therapy reduces mean 24-h heart rate possibly due to reduced sympathetic activation but did not result in a significant decrease in dysrhythmia frequency.

Kylintireas I, Craig S, Nethononda MR, Kohler M, Francis JM, Choudhury RP, Stradling J, Neubauer S. 2009. Increased obstructive sleep apnoea severity is associated with aortic distensibility reduction and atheroma burden increase EUROPEAN HEART JOURNAL, 30 pp. 744-744.

Sadatsafavi M, Marra CA, Ayas NT, Stradling J, Fleetham J. 2009. Cost-effectiveness of oral appliances in the treatment of obstructive sleep apnoea-hypopnoea. Sleep Breath, 13 (3), pp. 241-252. | Show Abstract | Read more

PURPOSE: Oral appliances (OA) are commonly prescribed for the treatment of obstructive sleep apnoea-hypopnoea (OSAH), but there is limited evidence on their cost-effectiveness. MATERIALS AND METHODS: A model was designed to simulate the costs and benefits of treatment of OSAH with OA or continuous positive airway pressure (CPAP) based on their effects on quality of life, motor vehicle crashes, and cardiovascular effects. The primary outcome was the incremental cost-effectiveness ratio (ICER) in terms of costs per one quality-adjusted life year (QALY) gained 5 years after treatment. RESULTS: Compared with no treatment, OA results in $268 higher costs and an incremental QALY of 0.0899 per patient (ICER = $2,984/QALY). Compared with OA, CPAP resulted in $1,917 more costs and 0.0696 additional QALYs (ICER = $27,540/QALY). For the most part in the sensitivity analyses, CPAP remained cost-effective compared to OA, and OA remained cost-effective with respect to no treatment in almost all scenarios. CONCLUSIONS: OAs are less economically attractive than CPAP but remain a cost-effective treatment for patients who are unwilling or unable to adhere to CPAP therapy.

Heffner JE, Holgate ST, Chung KF, Niederman MS, Daley CL, Jett JR, Stradling JR, Wells AU, Light RW, Tapson VF et al. 2009. Road ahead to respiratory health: experts chart future research directions. Respirology, 14 (5), pp. 625-636. | Show Abstract | Read more

Respiratory illnesses are a huge and rising burden to health-care systems and societies worldwide. Research is crucial to tackle the enormous problem of chest diseases. However the vast number of research questions and available research approaches often creates confusion and risks dilution of resources by spreading them too diffusely. Clear research directions will help to use research funds efficiently to provide treatment advances that benefit patient care. This paper presents the visions of leading experts on future research directions, focusing on what should rather than what is going to be done. These opinions provide a guide for new investigators and a platform for intellectual debates through which coordinated research efforts can help progress towards respiratory health.

Kohler M, Stradling JR. 2009. Cardiovascular Risk in Asymptomatic OSA AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179 (10), pp. 969-970. | Read more

Kohler M, Bloch KE, Stradling JR. 2009. Pharmacological approaches to the treatment of obstructive sleep apnoea. Expert Opin Investig Drugs, 18 (5), pp. 647-656. | Show Abstract | Read more

BACKGROUND: Currently the treatment of choice for symptomatic obstructive sleep apnoea (OSA) is continuous positive airway pressure (CPAP). Some patients with OSA do not tolerate CPAP or have insufficiently severe symptoms to justify its use; for these patients, drug therapy would be a desirable potential therapeutic alternative. OBJECTIVE: To summarize the current evidence on the effectiveness of drug therapy in patients with OSA. METHODS: A systematic review of randomized controlled trials was performed to investigate the effects of drug therapy on OSA. RESULTS/CONCLUSIONS: Searches of bibliographical databases revealed 33 trials investigating the effects of 27 different drugs on OSA severity and/or symptoms. The mechanisms by which these drugs are supposed to improve OSA include, amongst others, an increase in tone of the upper airways, an increase in ventilatory drive, a reduction in airway resistance, and alterations in surface tension forces in the upper airway. In most of these studies there was no significant effect on OSA observed. However, there is evidence from a few small trials that some drugs, especially those thought to increase upper airway muscle tone, have the potential to reduce OSA severity; but further data from larger studies of adequate duration are needed.

Kohler M, Stradling JR. 2009. Ethnic Effect and the Study of Obstructive Sleep Apnea AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179 (8), pp. 736-736. | Read more

West SD, McBeath HA, Stradling JR. 2009. Easily Missed? Obstructive sleep apnoea in adults BRITISH MEDICAL JOURNAL, 338 (apr07 1), pp. b1165-b1165. | Read more

Stradling J, Dookun R. 2009. Snoring and the role of the GDP: British Society of Dental Sleep Medicine (BSDSM) pre-treatment screening protocol. Br Dent J, 206 (6), pp. 307-312. | Show Abstract | Read more

Snoring is not necessarily a benign condition; it can be linked to the serious condition obstructive sleep apnoea (OSA). In some cases mandibular repositioning devices can be an effective treatment for simple snoring and mild to moderate sleep apnoea, and these devices can be provided by dentists (with appropriate training and in line with Dental Protection Ltd guidelines). Until now, the dental profession has not been given any guidance on how to differentiate between patients who may be treated without further reference to medical colleagues (ie simple snorers), and those who should be referred for specialist assessment. The aim of this paper is to facilitate safe treatment of snoring and OSA and to protect dentists by explaining an accepted method for screening patients for obstructive sleep apnoea.

Ayers L, Ferry B, Craig S, Nicoll D, Stradling JR, Kohler M. 2009. Circulating cell-derived microparticles in patients with minimally symptomatic obstructive sleep apnoea. Eur Respir J, 33 (3), pp. 574-580. | Show Abstract | Read more

Moderate-severe obstructive sleep apnoea (OSA) has been associated with several pro-atherogenic mechanisms and increased cardiovascular risk, but it is not known if minimally symptomatic OSA has similar effects. Circulating cell-derived microparticles have been shown to have pro-inflammatory, pro-coagulant and endothelial function-impairing effects, as well as to predict subclinical atherosclerosis and cardiovascular risk. In 57 patients with minimally symptomatic OSA, and 15 closely matched control subjects without OSA, AnnexinV-positive, platelet-, leukocyte- and endothelial cell-derived microparticles were measured by flow cytometry. In patients with OSA, median (interquartile range) levels of AnnexinV-positive microparticles were significantly elevated compared with control subjects: 2,586 (1,566-3,964) microL(-1) versus 1,206 (474-2,501) microL(-1), respectively. Levels of platelet-derived and leukocyte-derived microparticles were also significantly higher in patients with OSA (2,267 (1,102-3,592) microL(-1) and 20 (14-31) microL(-1), respectively) compared with control subjects (925 (328-2,068) microL(-1) and 15 (5-23) microL(-1), respectively). Endothelial cell-derived microparticle levels were similar in patients with OSA compared with control subjects (13 (8-25) microL(-1) versus 11 (6-17) microL(-1)). In patients with minimally symptomatic obstructive sleep apnoea, levels of AnnexinV-positive, platelet- and leukocyte-derived microparticles are elevated when compared with closely matched control subjects without obstructive sleep apnoea. These findings suggest that these patients may be at increased cardiovascular risk, despite being minimally symptomatic.

Kohler M, Blair E, Risby P, Nickol AH, Wordsworth P, Forfar C, Stradling JR. 2009. The prevalence of obstructive sleep apnoea and its association with aortic dilatation in Marfan's syndrome. Thorax, 64 (2), pp. 162-166. | Show Abstract | Read more

BACKGROUND: Craniofacial abnormalities and increased pharyngeal collapsibility due to abnormal connective tissue suggest the possibility of an increased prevalence of obstructive sleep apnoea (OSA) in patients with Marfan's syndrome but the actual prevalence is uncertain. Aortic dilatation and dissection are life threatening manifestations of Marfan's syndrome and case reports have suggested a possible association with OSA but data from cohort studies are not available. METHODS: A sleep study was performed in 61 patients with Ghent criteria positive Marfan's syndrome (mean age 38.3 (SD 12.9) years; 37 females) and in 26 control subjects matched for age, gender, height and weight. OSA was defined using two conventional levels of apnoea-hypopnoea index (AHI), >5 and >15/h. In patients with Marfan's syndrome, aortic root diameter was measured by echocardiography. RESULTS: More patients with Marfan's syndrome than controls had OSA (AHI >5, 32.8% compared with 11.5%, mean difference +21.3%, 95% CI 4.2% to 38.3%, p = 0.04; AHI >15, 18.0% compared with 0%, mean difference +18.0%, 95% CI 8.4% to 27.7%, p = 0.02). AHI was correlated with aortic root diameter (r = 0.50, 95% CI 0.26 to 0.69, p = 0.0003), and mean aortic root diameter was significantly greater in patients with OSA (4.5 (SD 0.6) cm) compared with those without OSA (3.7 (0.6) cm) (mean difference 0.8 cm, 95% CI 0.4 to 1.2 cm, p<0.0001). CONCLUSIONS: In patients with Marfan's syndrome, the prevalence of OSA is considerably higher than in matched control subjects. OSA may be a risk factor for aortic root dilatation in Marfan's syndrome.

Stradling JR. 2009. Sleep study predictors of prevalent cardiovascular disease. Am J Respir Crit Care Med, 179 (3), pp. 254. | Read more

Kohler M, Bloch KE, Stradling JR. 2009. The role of the nose in the pathogenesis of obstructive sleep apnea. Curr Opin Otolaryngol Head Neck Surg, 17 (1), pp. 33-37. | Show Abstract | Read more

PURPOSE OF REVIEW: To define the relationship between obstructive sleep apnea (OSA) and nasal obstruction, we have reviewed the literature on epidemiological, physiological, and randomized controlled studies in which the relationship between nasal obstruction and OSA was investigated. RECENT FINDINGS: Data from observational studies suggest that nasal obstruction contributes to the pathogenesis of OSA. Recently, studies have mainly focused on the effects of therapeutic interventions on the nose and OSA. Eleven trials with randomized controlled designs were found; external nasal dilators were used in five studies, topically applied steroids in one, nasal decongestants in three, and surgical treatment in two studies. Data from these studies showed only minor improvement in the symptoms and severity of OSA. SUMMARY: The current evidence suggests that the nose may not play a significant role in the pathogenesis of OSA. The impact of treating nasal obstruction in patients with OSA on long-term outcome remains to be defined more accurately through randomized controlled trials of medical and surgical therapies with large numbers of patients.

Kohler M, Stradling JR. 2009. From the authors American Journal of Respiratory and Critical Care Medicine, 179 (10), pp. 969-970.

Kohler M, Ayers L, Pepperell JCT, Packwood KL, Ferry B, Crosthwaite N, Craig S, Siccoli MM, Davies RJO, Stradling JR. 2009. Effects of continuous positive airway pressure on systemic inflammation in patients with moderate to severe obstructive sleep apnoea: a randomised controlled trial. Thorax, 64 (1), pp. 67-73. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) has been associated with cardiovascular disease in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on systemic inflammation involved in the atherosclerotic process remains unclear. METHODS: 100 men with moderate-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 49) CPAP treatment for 4 weeks to investigate the effects of active treatment on inflammatory markers such as highly sensitive C reactive protein (hsCRP), interleukin (IL)6, interferon gamma (IFNgamma) and anti-inflammatory adiponectin. RESULTS: 4 weeks of therapeutic CPAP did not significantly change blood levels of hsCRP compared with the subtherapeutic control group (difference between median changes -0.24 mg/l (95% CI -0.88 to +0.24); p = 0.30). Plasma levels of IL6 and IFNgamma did not change significantly following therapeutic compared with subtherapeutic CPAP (difference between median changes +0.52 and -0.07 pg/ml (95% CI -0.72 to +1.94 and -0.81 to +0.44); p = 0.45 and p = 0.82, respectively). Furthermore, 4 weeks of therapeutic CPAP did not significantly change levels of adiponectin in plasma compared with the subtherapeutic control group (difference between median changes +0.05 pg/ml (95% CI -0.36 to +0.47); p = 0.84). If patients with hsCRP values above 8 mg/l at baseline were excluded, differences between the changes in hsCRP, IL6, IFNgamma and adiponectin after 4 weeks of CPAP were smaller, and again not statistically different between groups. CONCLUSIONS: 4 weeks of CPAP treatment has no beneficial effect on blood markers of inflammation and adiponectin in patients with moderate-severe obstructive sleep apnoea.

Kohler M, Pepperell JCT, Davies RJO, Stradling JR. 2009. Continuous positive airway pressure and liver enzymes in obstructive sleep apnoea: data from a randomized controlled trial. Respiration, 78 (2), pp. 141-146. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) has been suggested to be an independent risk factor for non-alcoholic fatty liver disease (NAFLD), possibly via intermittent hypoxia that influences blood pressure, lipid levels and insulin resistance, factors themselves known to cause NAFLD. In observational studies, OSAS has been associated with elevated levels of liver enzymes. Continuous positive airway pressure (CPAP) is the treatment for OSAS, but the effects of CPAP on liver enzymes have not been studied in a randomized controlled trial. OBJECTIVE: To determine if 4 weeks of CPAP influence alanine-aminotransferase (ALT) and aspartate-aminotranferase (AST) levels. METHODS: 94 patients with moderate-to-severe OSAS were randomized to therapeutic or sub-therapeutic CPAP treatment. Plasma ALT and AST were measured before and after 4 weeks of CPAP. RESULTS: Results are means +/- SD. ALT levels decreased from 39.1 +/- 26.3 to 30.3 +/- 16.4 IU/l in patients treated with therapeutic CPAP, but also decreased from 36.9 +/- 20.7 to 31.5 +/- 16.5 IU/l in patients treated with sub-therapeutic CPAP (difference between mean changes -3.4, 95% CI -7.8 to 1.0 IU/l, p = 0.13 between groups). AST levels did not change significantly with therapeutic CPAP (from 29.1 +/- 14.7 to 30.2 +/- 13.6 IU/l), nor with sub-therapeutic CPAP (from 28.2 +/- 16.2 to 29.5 +/- 12.6 IU/l; difference between mean changes -0.2, 95% CI -3.0 to 2.6 IU/l, p = 0.87 between groups). CONCLUSIONS: Four weeks of active CPAP has no beneficial effect on aminotransferase levels when compared to sub-therapeutic CPAP in patients with OSAS. Therefore, CPAP does not seem to improve biochemical markers of potential NAFLD in OSAS patients.

Craig SE, Kylintireas I, Kohler M, Nethononda R, Neubauer S, Stradling JR. 2009. In Patients with Obstructive Sleep Apnoea Oxygen Desaturation Index (ODI) Is Associated with Aortic Distensibility and Atheroma Burden. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179

Kohler M, Ayers L, Ferry B, Craig S, Nicoll D, Stradling JR. 2009. Circulating Cell-Derived Microparticles in Patients with Minimally Symptomatic Obstructive Sleep Apnea AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179

Craig SE, Kohler M, Nicoll D, Siccoli M, Davies RJ, Stradling JR. 2009. Metabolic Sydrome Prediction in Mild/Moderate OSA Patients - Anthropometric Measures and Abdominal Fat Estimations by MRI AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179

Weatherly HLA, Griffin SC, Mc Daid C, Durée KH, Davies RJO, Stradling JR, Westwood ME, Sculpher MJ. 2009. An economic analysis of continuous positive airway pressure for the treatment of obstructive sleep apnea-hypopnea syndrome. Int J Technol Assess Health Care, 25 (1), pp. 26-34. | Show Abstract | Read more

OBJECTIVES: An important option for the medical treatment of obstructive sleep apnea-hypopnea syndrome (OSAHS) is continuous positive airway pressure (CPAP) during sleep. This study reports on the cost-effectiveness of CPAP compared with dental devices and lifestyle advice. The work was commissioned by the NHS HTA Programme to inform the National Institute of Health and Clinical Excellence's (NICE) appraisal of CPAP. METHODS: A Markov model compared the interventions over the expected patient lifetime. The primary measure of cost-effectiveness was the incremental cost per quality-adjusted life-year (QALY) gained. The QALY incorporated the impact of treatments on daytime sleepiness, blood pressure and health-related quality of life (HRQoL). RESULTS: On average, CPAP was associated with higher costs and QALYs compared with dental devices or lifestyle advice. In the base-case analysis, the incremental cost-effectiveness ratio (ICER) for CPAP compared with dental devices was around 4,000 pounds per QALY (2005--06 prices). The probability that CPAP is more cost-effective than dental devices or lifestyle advice at a threshold value of 20,000 pounds per QALY was 0.78 for men and 0.80 for women. Several sensitivity analyses were undertaken and it was found that the ICER for CPAP consistently fell below 20,000 pounds per QALY gained, apart from in a subgroup with mild disease. CONCLUSIONS: The model suggests that CPAP is cost-effective compared with dental devices and lifestyle advice for adults with moderate or severe symptomatic OSAHS at the cost-effectiveness thresholds used by NICE. This finding is reflected in the NICE guidance.

West SD, McBeath HA, Stradling JR. 2009. Obstructive sleep apnoea in adults. BMJ, 338 pp. b1165. | Read more

Cited:

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Weatherly HLA, Griffin SC, Mc Daid C, Durée KH, Davies RJO, Stradling JR, Westwood ME, Sculpher MJ. 2009. An economic analysis of continuous positive airway pressure for the treatment of obstructive sleep apnea-hypopnea syndrome International Journal of Technology Assessment in Health Care, 25 (1), pp. 26-34. | Show Abstract | Read more

Objectives: An important option for the medical treatment of obstructive sleep apnea-hypopnea syndrome (OSAHS) is continuous positive airway pressure (CPAP) during sleep. This study reports on the cost-effectiveness of CPAP compared with dental devices and lifestyle advice. The work was commissioned by the NHS HTA Programme to inform the National Institute of Health and Clinical Excellence's (NICE) appraisal of CPAP. Methods: A Markov model compared the interventions over the expected patient lifetime. The primary measure of cost-effectiveness was the incremental cost per quality-adjusted life-year (QALY) gained. The QALY incorporated the impact of treatments on daytime sleepiness, blood pressure and health-related quality of life (HRQoL). Results: On average, CPAP was associated with higher costs and QALYs compared with dental devices or lifestyle advice. In the base-case analysis, the incremental cost-effectiveness ratio (ICER) for CPAP compared with dental devices was around £4,000 per QALY (2005-06 prices). The probability that CPAP is more cost-effective than dental devices or lifestyle advice at a threshold value of £20,000 per QALY was 0.78 for men and 0.80 for women. Several sensitivity analyses were undertaken and it was found that the ICER for CPAP consistently fell below £20,000 per QALY gained, apart from in a subgroup with mild disease. Conclusions: The model suggests that CPAP is cost-effective compared with dental devices and lifestyle advice for adults with moderate or severe symptomatic OSAHS at the cost-effectiveness thresholds used by NICE. This finding is reflected in the NICE guidance. Copyright © 2009 Cambridge University Press.

Cited:

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McDaid C, Durée KH, Griffin SC, Weatherly HLA, Stradling JR, Davies RJO, Sculpher MJ, Westwood ME. 2009. A systematic review of continuous positive airway pressure for obstructive sleep apnoea-hypopnoea syndrome Sleep Medicine Reviews, 13 (6), pp. 427-436. | Show Abstract | Read more

We conducted a systematic review of current evidence on the effectiveness of continuous positive airway pressure (CPAP) for treatment of obstructive sleep apnoea-hypopnoea syndrome (OSAHS). The primary outcomes were subjective sleepiness, using Epworth Sleepiness Scale (ESS) and objective sleepiness using Maintenance of Wakefulness Test (MWT) and Multiple Sleep Latency Test (MSLT). Mean difference (MD) in endpoints was used to compare CPAP to usual care, placebo and dental devices. The analysis was stratified by symptom and disease severity at baseline. CPAP significantly reduced ESS score compared to control (MD -2.7, 95% CI -3.45, -1.96). The benefit was greatest in patients whose symptoms were severe at baseline: severely symptomatic population (MD -5.0, -6.5, -3.5); moderate (MD -2.3, -3.0, -1.6); mild (MD -1.1, -1.8, -0.3). CPAP significantly improved MWT score compared to control (MD 3.3, 1.3, 5.3) but not on the MSLT. There was no statistically significant difference between CPAP and dental devices on the ESS, MWT or MSLT, in a population with moderate symptoms. There was some evidence of benefit for blood pressure with CPAP compared to control. CPAP is an effective treatment for OSAHS in moderate to severe symptomatic patients and there may be benefits for mild symptoms. Dental devices may be a treatment option for moderate symptoms. Crown Copyright © 2009.

Kohler M, Pepperell JCT, Casadei B, Craig S, Crosthwaite N, Stradling JR, Davies RJO. 2008. CPAP and measures of cardiovascular risk in males with OSAS. Eur Respir J, 32 (6), pp. 1488-1496. | Show Abstract | Read more

Obstructive sleep apnoea syndrome (OSAS) has been associated with hypertension, stroke and myocardial ischaemia in epidemiological and observational studies. Continuous positive airway pressure (CPAP) is the treatment of choice for OSAS, but the impact of this intervention on established risk factors for cardiovascular disease remains incompletely understood. A total of 102 males with moderate-to-severe OSAS were randomised to therapeutic (n = 51) or subtherapeutic (n = 51) CPAP treatment for 4 weeks to investigate the effects of active treatment on 24-h urinary catecholamine excretion, baroreflex sensitivity (BRS), arterial stiffness (augmentation index) and 24-h ambulatory blood pressure (ABP). After 4 weeks of therapeutic CPAP, significant reductions were seen in urine normetanephrine excretion (from mean+/-sd 179.7+/-80.1 to 132.7+/-46.5 micromol x mol(-1) creatinine) and augmentation index (from 14.5+/-11.3 to 9.1+/-13.8%) compared with the subtherapeutic control group. Furthermore, therapeutic CPAP significantly improved BRS (from 7.1+/-3.3 to 8.8+/-4.2 ms x mmHg(-1)) and reduced mean arterial ABP by 2.6+/-5.4 mmHg. In conclusion, treatment of obstructive sleep apnoea with continuous positive airway pressure may lower cardiovascular risk by reducing sympathetic nerve activity, ambulatory blood pressure and arterial stiffness and by increasing sensitivity of the arterial baroreflex.

Kohler M, Craig S, Nicoll D, Leeson P, Davies RJO, Stradling JR. 2008. Endothelial function and arterial stiffness in minimally symptomatic obstructive sleep apnea. Am J Respir Crit Care Med, 178 (9), pp. 984-988. | Show Abstract | Read more

RATIONALE: Moderate-severe obstructive sleep apnea (OSA) is associated with endothelial dysfunction, increased arterial stiffness, and hypertension. It is not known whether minimally symptomatic OSA is also associated with impaired vascular function. OBJECTIVES: To determine whether minimally symptomatic OSA is associated with impaired vascular function. METHODS: In 64 patients (7 females) with minimally symptomatic OSA (oxygen desaturation index, 23.1 [SD, 15.6]; Epworth Sleepiness Scale score, 8 [SD, 3.8]), and 15 matched control subjects without OSA, endothelial function was assessed by ultrasonographic measurement of flow-mediated dilatation, and by applanation tonometry-derived pulse wave analysis (forearm ischemia and salbutamol-induced changes in augmentation index, AI(x)). Arterial stiffness was assessed by AI(x) and ambulatory blood pressure (ABP) was measured over 1 week. MEASUREMENTS AND MAIN RESULTS: In patients with OSA, flow-mediated dilatation was significantly lower than in control subjects (5.0% [SD, 2.7%] and 7.5% [SD, 3.3%], respectively; P = 0.003). AI(x) was significantly higher in the OSA group compared with the control group (26.0% [interquartile range (IQR), 19.0-29.5%] and 21.0% [IQR, 8.0-27.0%], respectively; P = 0.04). Change in AI(x) after both forearm ischemia and salbutamol was significantly smaller in patients with OSA (-2.0% [IQR, -5.0 to +4.0%] and -3.0% [IQR, -7.0 to 0.0%], respectively), than in control subjects (-6.0% [IQR, -8.0 to -5.0%] and -7.0% [IQR, -10.0 to -3.0%]; P = 0.005 and P = 0.04, respectively). ABP was similar (97.6 mm Hg [SD, 7.9 mm Hg] and 94.8 mm Hg [SD, 7.4 mm Hg], OSA and control groups, respectively; P = 0.21). CONCLUSIONS: In patients with minimally symptomatic OSA, diverse properties of endothelial function are impaired and arterial stiffness is increased. Although this was not associated with a significantly increased ABP, the findings suggest that patients with minimally symptomatic OSA are at increased cardiovascular risk.

Siccoli MM, Pepperell JCT, Kohler M, Craig SE, Davies RJO, Stradling JR. 2008. Effects of continuous positive airway pressure on quality of life in patients with moderate to severe obstructive sleep apnea: data from a randomized controlled trial. Sleep, 31 (11), pp. 1551-1558. | Show Abstract | Read more

STUDY OBJECTIVES: Previous studies have shown that CPAP has a substantial impact on daytime symptoms and quality of life (QOL). It remains unclear which outcome measures best identify real CPAP effects and carry independent information. METHODS: One hundred-two men with moderate-severe obstructive sleep apnea were randomized to either "real" or "sham" CPAP for one month. Outcome measures were subjective sleepiness (Epworth Sleepiness Scale [ESS]) and QOL measures includiig SF-36/SF-12 and Calgary Sleep Apnea Quality of Life Index (SAQLI). The bed partner's QOL and rating of patient's response to CPAP were assessed with the Dublin questionnaire. All data were standardized using effect sizes and expressed as real minus sham to remove the nonspecific effects of placebo. RESULTS: Real CPAP was superior to sham CPAP in almost all outcome measures. ESS, patient's component from Dublin, and social interactions from SAQLI showed the largest differences in effect sizes between real and sham (1.33, 0.98, and 0.92 respectively). ESS carried the highest predictive power of real CPAP response (P < 0.0001, r2 = 0.21). Question number 5 from Dublin (partner assessed patient's sleep quality) and question 6 from ESS (dozing while talking) were the best single item predictors of real CPAP response. CONCLUSIONS: Real CPAP reduces subjective sleepiness and improves QOL of both patients and bed partners. ESS is the best score; question number 5 from Dublin and question number 6 from ESS are the best single item predictors of real CPAP response. This information should allow the selection of appropriate questions in clinical practice and research protocols.

Robinson GV, Langford BA, Smith DM, Stradling JR. 2008. Predictors of blood pressure fall with continuous positive airway pressure (CPAP) treatment of obstructive sleep apnoea (OSA). Thorax, 63 (10), pp. 855-859. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality. Randomised controlled trials have shown that, on average, treatment of OSA with continuous positive airway pressure (CPAP) reduces blood pressure (BP) by 3-5 mm Hg, although with considerable variation between individuals. No predictors of the change in BP with CPAP have been convincingly identified. This prospective study aimed to determine predictors of BP change, which might provide an insight into the aetiology of the raised BP seen in untreated OSA. METHODS: Eighty-six patients with daytime hypersomnolence warranting treatment with CPAP were recruited. 24 h mean BP (24 hMBP), subjective sleepiness, fasting venous blood samples and anthropometric measurements were assessed at baseline and after 6 months of CPAP treatment. RESULTS: The mean (SD) 24 hMBP fell at 6 months from 101.0 (10.3) mm Hg to 96.1 (9.1) mm Hg (change -4.92 mm Hg (95% CI -2.8 to -7.1)). The Epworth Sleepiness Score (ESS) fell from a median of 16 (IQR 12-18) to 4 (2-7) with a mean fall of 9.7 (95% CI 8.6 to 10.8). Several factors correlated with the fall in 24 hMBP but, after allowing for the baseline 24 hMBP, only the fall in ESS and the body mass index (BMI) remained significant independent predictors (p = 0.006 and 0.007, respectively). There was also a correlation between the fall in 24 hMBP and the fall in pulse rate (r = 0.44, p<0.001). Baseline severity of OSA, overnight hypoxia, caffeine intake or being on antihypertensive drugs were not independent predictors of a fall in 24 hMBP. CONCLUSION: Improvement in hypersomnolence and the BMI are independent correlates of the fall in 24 hMBP following CPAP therapy. Markers of initial OSA severity did not predict the fall in 24 hMBP. This suggests that sleep fragmentation and its effects may be more important than hypoxia in the pathogenesis of the hypertension associated with human sleep apnoea.

Guest JF, Helter MT, Morga A, Stradling JR. 2008. Cost-effectiveness of using continuous positive airway pressure in the treatment of severe obstructive sleep apnoea/hypopnoea syndrome in the UK. Thorax, 63 (10), pp. 860-865. | Show Abstract | Read more

OBJECTIVE: A study was undertaken to estimate the cost-effectiveness of using continuous positive airway pressure (CPAP) in the management of patients with severe obstructive sleep apnoea/hypopnoea syndrome (OSAHS) compared with no treatment from the perspective of the UK's National Health Service (NHS). METHODS: A Markov model was constructed to assess the cost-effectiveness of CPAP compared with no treatment. The model depicted the management of a 55-year-old patient with severe OSAHS as defined by an apnoea-hypopnoea index (AHI) >30 and daytime sleepiness (Epworth Sleepiness Scale score >or=12). The model spans a period of 14 years. RESULTS: According to the model, 57% of untreated patients are expected to be alive at the end of 14 years compared with 72% of patients treated with CPAP. Untreated patients are expected to cost the NHS pound10 645 (95% CI pound7988 to pound14,098) per patient over 14 years compared with pound9672 (95% CI pound8057 to pound12,860) per CPAP-treated patient. Treatment with CPAP for a period of 1 year was found not to be a cost-effective option since the cost per quality-adjusted life year (QALY) gained is expected to be > pound20,000, but after 2 years of treatment the cost per QALY gained is expected to be pound10,000 or less and, after 13 years of treatment, CPAP becomes a dominant treatment (ie, more effective than no treatment for less cost). CONCLUSION: Within the limitations of the model, CPAP was found to be clinically more effective than no treatment and, from the perspective of the UK's NHS, a cost-effective strategy after a minimum of 2 years of treatment.

Stradling J. 2008. Driving and obstructive sleep apnoea. Thorax, 63 (6), pp. 481-483. | Read more

West S, Stradling J. 2008. Effect of CPAP on insulin resistance in patients with obstructive sleep apnoea and type 2 diabetes - Authors' reply THORAX, 63 (4), pp. 385-385.

Fabbri L. 1994. AUTHORS' REPLY Thorax, 49 (4), pp. 385-385. | Read more

Kohler M, Bloch KE, Stradling JR. 2007. The role of the nose in the pathogenesis of obstructive sleep apnoea and snoring. Eur Respir J, 30 (6), pp. 1208-1215. | Show Abstract | Read more

Data from observational studies suggest that nasal obstruction contributes to the pathogenesis of snoring and obstructive sleep apnoea (OSA). To define more accurately the relationship between snoring, OSA and nasal obstruction, the current authors have summarised the literature on epidemiological and physiological studies, and performed a systematic review of randomised controlled trials in which the effects of treating nasal obstruction on snoring and OSA were investigated. Searches of bibliographical databases revealed nine trials with randomised controlled design. External nasal dilators were used in five studies, topically applied steroids in one, nasal decongestants in two, and surgical treatment in one study. Data from studies using nasal dilators, intranasal steroids and decongestants to relieve nasal congestion showed beneficial effects on sleep architecture, but only minor improvement of OSA symptoms or severity. Snoring seemed to be reduced by nasal dilators. Nasal surgery also had minimal impact on OSA symptoms. In conclusion, chronic nasal obstruction seems to play a minor role in the pathogenesis of obstructive sleep apnoea, and seems to be of some relevance in the origin of snoring. The impact of treating nasal obstruction in patients with snoring and obstructive sleep apnoea on long-term outcome remains to be defined through randomised controlled trials of medical and surgical therapies.

Stradling JR, Smith D, Crosby J. 2007. Post-CPAP sleepiness--a specific syndrome? J Sleep Res, 16 (4), pp. 436-438. | Show Abstract | Read more

Following treatment with continuous positive airway pressure (CPAP), some patients with obstructive sleep apnoea (OSA) remain sleepy despite effective CPAP and attention to other diagnoses that can provoke sleepiness. It is unclear if this residual sleepiness is an irreversible result of their previous OSA and merits consideration for pharmacological treatment or simply because of the many and varied causes of sleepiness normally found in the community. We have measured levels of sleepiness, using the Epworth Sleepiness Score (ESS), in 572 patients on CPAP and compared them with a control group of 525 subjects from a community survey, which would have included the usual lifestyle reasons for sleepiness as well as any undiagnosed sleep disorders. There was no difference in the percentage of patients with an ESS >10 in the CPAP group compared with the controls (16.1 versus 14.3, P = 0.54). Thus, although there clearly are sleepy patients within the CPAP group, the prevalence is no higher than in the community. We question whether so-called 'post-CPAP sleepiness' should be regarded as any more abnormal and worthy of treatment than a 'normal' population. Post-CPAP sleepiness as a specific disorder may not exist.

West SD, Nicoll DJ, Wallace TM, Matthews DR, Stradling JR. 2007. Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax, 62 (11), pp. 969-974. | Show Abstract | Read more

BACKGROUND: The effects of continuous positive airway pressure (CPAP) for obstructive sleep apnoea (OSA) on insulin resistance are not clear. Trials have found conflicting results and no appropriate control groups have been used. METHODS: Forty-two men with known type 2 diabetes and newly diagnosed OSA (>10 dips/h in oxygen saturation of >4%) were randomised to receive therapeutic (n = 20) or placebo CPAP (n = 22) for 3 months. Baseline tests were performed and repeated after 3 months. The study was double blind. RESULTS: Results are expressed as mean (SD). CPAP improved the Epworth sleepiness score significantly more in the therapeutic group than in the placebo group (-6.6 (4.5) vs -2.6 (4.9), p = 0.01). The maintenance of wakefulness test improved significantly in the therapeutic group but not in the placebo group (+10.6 (13.9) vs -4.7 (11.8) min, p = 0.001). Glycaemic control and insulin resistance did not significantly change in either the therapeutic or placebo groups: HbA1c (-0.02 (1.5) vs +0.1 (0.7), p = 0.7, 95% CI -0.6% to +0.9%), euglycaemic clamp (M/I: +1.7 (14.1) vs -5.7 (14.8), p = 0.2, 95% CI -1.8 to +0.3 l/kg/min(1000)), HOMA-%S (-1.5 (2.3) vs -1.1 (1.8), p = 0.2, 95% CI -0.3% to +0.08%) and adiponectin (-1.1 (1.2) vs -1.1 (1.3), p = 0.2, 95% CI -0.7 to +0.6 microg/ml). Body mass index, bioimpedance and anthropometric measurements were unchanged. Hours of CPAP use per night were 3.6 (2.8) in the treatment group and 3.3 (3.0) in the placebo group (p = 0.8). There was no correlation between CPAP use and the measures of glycaemic control or insulin resistance. CONCLUSION: Therapeutic CPAP does not significantly improve measures of glycaemic control or insulin resistance in men with type 2 diabetes and OSA.

Stradling J. 2007. Obstructive sleep apnoea. BMJ, 335 (7615), pp. 313-314. | Read more

Stradling J. 2007. European guidelines for accreditation of sleep medicine Centres. J Sleep Res, 16 (2), pp. 239-240. | Read more

Stradling J. 2007. Untitled JOURNAL OF SLEEP RESEARCH, 16 (2), pp. 239-240. | Read more

Stradling J. 2007. Letter to the Editor Journal of Sleep Research, 16 (2), pp. 239-240. | Read more

Pepperell J, Stradling J, Davies R. 2006. Brain natriuretic peptide is unchanged after 4 weeks of continuous positive airway pressure therapy. J Sleep Res, 15 (4), pp. 463-464. | Read more

Nickol AH, Leverment J, Richards P, Seal P, Harris GA, Cleland J, Dubowitz G, Collier DJ, Milledge J, Stradling JR, Morrell MJ. 2006. Temazepam at high altitude reduces periodic breathing without impairing next-day performance: a randomized cross-over double-blind study. J Sleep Res, 15 (4), pp. 445-454. | Show Abstract | Read more

The aim of the study was to examine the efficacy and safety of temazepam on nocturnal oxygenation and next-day performance at altitude. A double-blind, randomized, cross-over trial was performed in Thirty-three healthy volunteers. Volunteers took 10 mg of temazepam and placebo in random order on two successive nights soon after arrival at 5000 m, following a 17-day trek from 410 m. Overnight SaO(2) and body movements, and next-day reaction time, maintenance of wakefulness and cognition were assessed. Compared with placebo, temazepam resulted in a reduction in periodic breathing from a median (range) of 16 (0-81.3)% of the night to 9.4 (0-79.6)% (P = 0.016, Wilcoxon's signed-rank test), associated with a small but significant decrease in mean nocturnal SaO(2) from 78 (65-84)% to 76 (64-83)% (P = 0.013). There was no change in sleep latency (P = 0.40) or restlessness (P = 0.30). Temazepam had no adverse effect on next-day reaction time [241 (201-380) ms postplacebo and 242 (204-386) ms post-temazepam], maintenance of wakefulness (seven trekkers failed to maintain 40 min of wakefulness postplacebo, and four post-temazepam), cognition or acute mountain sickness. At high altitude temazepam reduces periodic breathing during sleep without an adverse effect on next-day reaction time, maintenance of wakefulness or cognition. The 2% reduction in mean SaO(2) post-temazepam is likely to be predominantly because of acclimatization, as by chance more trekkers took temazepam on the first night (19 versus 14). We conclude that at high altitude temazepam is effective in reducing periodic breathing, and is safe to use, without any adverse effect upon next-day performance.

West SD, Nicoll DJ, Stradling JR. 2006. Prevalence of obstructive sleep apnoea in men with type 2 diabetes. Thorax, 61 (11), pp. 945-950. | Show Abstract | Read more

BACKGROUND: A study was undertaken to establish the prevalence of obstructive sleep apnoea (OSA) in men with type 2 diabetes. METHODS: Men with type 2 diabetes from local hospital and selected primary care practitioner databases received questionnaires about snoring, apnoeas, and daytime sleepiness based on the Berlin questionnaire. Selected respondents had overnight oximetry to establish whether they had OSA. Comparisons of oximetry were made with those from a previous general population study. HbA1c results were collected. RESULTS: 1682 men were sent questionnaires, 56% of whom replied. 57% scored as "high" and 39% as "low" risk for OSA; 4% were already known to have OSA. Oximetry was performed in 240 respondents from both risk groups: 31% of the "high" and 13% of the "low" risk group had significant OSA (more than 10 >4% Sao(2) dips/hour or Sao(2) tracing consistent with OSA). These results were verified by detailed sleep studies. Extrapolation of the oximetry data to the questionnaire respondent population suggests that 23% had OSA. Comparison of the oximetry results with men from a previous general population study (using only more than 10 >4% Sao(2) dips/hour to define OSA) showed the prevalence of OSA is significantly higher in this diabetes population (17% v 6%, p<0.001). Multiple linear regression revealed BMI and diabetes as significant independent predictors of OSA. Following correction for BMI (which explained 13% of the variance in OSA), diabetes explained a further 8% of the variance (p<0.001). There was a low correlation between OSA severity and HbA1c in the subgroup recruited from the hospital database (r = 0.2, p = 0.006) which remained significant after allowing for obesity (p = 0.03). CONCLUSIONS: OSA is highly prevalent in men with type 2 diabetes; most are undiagnosed. Diabetes itself may be a significant independent contributor to the risk of OSA.

Robinson GV, Smith DM, Langford BA, Davies RJO, Stradling JR. 2006. Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur Respir J, 27 (6), pp. 1229-1235. | Show Abstract | Read more

Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality. Several randomised controlled trials have shown that continuous positive airway pressure (CPAP) treatment of OSA reduces blood pressure (BP). This randomised, sham-placebo controlled crossover trial assesses whether CPAP produces a similar clinically significant fall in BP in hypertensive OSA patients, but without hypersomnolence. Thirty-five, nonsleepy, hypertensive patients with OSA were treated with CPAP for 1 month, randomised first to either therapeutic or sham-placebo (subtherapeutic CPAP, about 1 cmH(2)O pressure). The second months' alternative treatment followed a 2-week washout period. BP was measured over 24 h, before and at the end of the two treatment periods: mean 24-h BP was the primary outcome variable. There was no overall significant difference in mean 24-h BP: the change in mean 24-h BP on therapeutic CPAP was -2.1 mmHg (sd 8.1), and -1.1 mmHg (sd 8.1) on subtherapeutic CPAP, with a difference of 0.7 mmHg (95% confidence interval (CI) +2.9- -4.4). There was a small significant fall in Epworth Sleepiness Score, therapeutic (-1.4) versus sham (-0.3), and difference -1.2 (95% CI -2.0- -0.4), but no change in objective sleepiness. In nonhypersomnolent hypertensive patients with obstructive sleep apnoea, there is no significant fall in mean 24-h blood pressure with continuous positive airway pressure, in contrast to the fall seen in hypersomnolent patients with obstructive sleep apnoea.

West SD, Jones DR, Stradling JR. 2006. Comparison of three ways to determine and deliver pressure during nasal CPAP therapy for obstructive sleep apnoea. Thorax, 61 (3), pp. 226-231. | Show Abstract | Read more

BACKGROUND: The simplest method of initiating and maintaining therapeutic continuous positive airways pressure (CPAP) therapy for obstructive sleep apnoea (OSA) has not been established. METHODS: Ninety eight subjects with OSA requiring CPAP treatment (more than 10 dips in oxygen desaturation of >4% per hour of sleep study and Epworth Sleepiness Score (ESS) >9) were randomised prospectively to three different methods of CPAP delivery for 6 months: (1) autotitration pressure throughout; (2) autotitration pressure for 1 week followed by fixed pressure (95th centile) thereafter; and (3) fixed pressure determined by algorithm (based on neck size and dip rate). Patients and investigators were blind to group allocation. One week after initiation the patients were routinely reviewed by sleep nurses. Study assessments took place before starting CPAP treatment and 1 and 6 months after to assess ESS, maintenance of wakefulness test, 24 hour blood pressure, general health (SF-36), and sleep apnoea related quality of life. CPAP internal monitoring data were also collected. RESULTS: There were no significant differences in any of the outcome measures or CPAP monitoring data between the three groups. The 95th centile CPAP pressures delivered in the 6 month and 1 week autotitration groups were higher than in the algorithm group, but the median pressures were lowest in the 6 month autotitration group. CONCLUSIONS: The method of determining CPAP pressure for treatment of moderate to severe OSA makes no significant difference to clinical outcome measures. The autotitration CPAP machine used has no advantage in this setting over simpler methods of pressure determination.

Prasad A, Langford B, Stradling JR, Ho L-P. 2006. Exhaled nitric oxide as a screening tool for asthma in school children. Respir Med, 100 (1), pp. 167-173. | Show Abstract | Read more

It is now widely accepted that augmented levels of fractional exhaled nitric oxide (FeNO) reflect airway inflammation and the methodology has been optimised for potential clinical use. We were interested in investigating whether this measurement can be used as a tool to screen and identify school children with asthma. To do this, FeNO was measured using an on-line single exhalation analyser in 368 children aged 8-10 years in six Oxfordshire primary schools, by two investigators blinded to the disease status of the children. The children were then categorised into 'normal', 'atopic asthma', 'non-atopic asthma' and 'atopy only' groups, according to their responses to the ISAAC questionnaire and perusal of the children's medical records kept by their family practitioners. Increased levels of FeNO were found in 'atopic asthmatic', 'non-atopic asthmatics' and 'atopic only' groups (median values of 24.4, 7.8 and 15.3 ppb, respectively, compared to normal controls' of 6.9 ppb). Levels were increased in atopic children regardless of whether they had asthma and were significantly higher than non-atopic asthmatics. We conclude that FeNO measurement is not a useful tool for identifying children with asthma in the community, as increased levels did not discriminate between those with asthmatic and atopic symptoms.

DAHL RONALD, GREEFHORST LOUISAPM, NOWAK DARIUSZ, NONIKOV VLADIMIR, BYRNE AIDANM, THOMSON MOIRAH, TILL DENISE, DELLA CIOPPA GIOVANNI. 2001. Inhaled Formoterol Dry Powder Versus Ipratropium Bromide in Chronic Obstructive Pulmonary Disease American Journal of Respiratory and Critical Care Medicine, 164 (5), pp. 778-784. | Show Abstract | Read more

© 2006, American Thoracic Society. All rights reserved. We compared the effectiveness of inhaled formoterol with that of ipratropium in the treatment of chronic obstructive pulmonary disease (COPD). After a 2-wk run-in period, 780 patients with COPD were randomized to receive for 12 wk formoterol dry powder 12 or 24 μg twice daily, ipratropium bromide 40 μg four times daily, or placebo in a multicenter, double-blind, parallel-group study. The primary efficacy variable was the area under the curve for forced expiratory volume in 1 s (FEV 1 ) measured over 12 h after 12 wk of treatment. Secondary variables included diary symptoms and quality of life. Both doses of formoterol and ipratropium significantly increased the area under the curve for FEV 1 in comparison with placebo (all p < 0.001). Both doses of formoterol were also significantly superior to ipratropium (all p < 0.025). Compared with placebo, both doses of formoterol significantly improved symptoms (all p ≤ 0.007) and quality of life (p < 0.01 for total scores) whereas ipratropium did not show significant effects (all p ≥ 0.3). All study treatments exhibited a similar safety profile. We conclude that formoterol is more effective than ipratropium bromide in the treatment of COPD, as the efficacy of ipratropium on airflow obstruction does not translate into a clinical benefit that patients can perceive.

West S, Segal H, Harrison P, Stradling J. 2005. Platelet function (measured by Platelet Function Analyser--100) and obstructive sleep apnoea. J Sleep Res, 14 (3), pp. 325-327. | Read more

Robinson GV, Stradling JR, Davies RJO. 2004. Sleep . 6: obstructive sleep apnoea/hypopnoea syndrome and hypertension. Thorax, 59 (12), pp. 1089-1094. | Show Abstract | Read more

The use of CPAP to control excessive daytime sleepiness in OSAHS probably also produces a substantial reduction in vascular risk. This is reviewed with particular reference to hypertension.

Stradling JR. 2004. Reducing the cost of treating obstructive sleep apnea: good news for patients. Am J Respir Crit Care Med, 170 (11), pp. 1143-1144. | Read more

Robinson GV, Stradling JR, Davies RJO, Roberts ISD. 2004. Post mortem diagnosis of fatal obstructive sleep apnoea. Histopathology, 45 (5), pp. 542-544. | Read more

Robinson GV, Pepperell JCT, Segal HC, Davies RJO, Stradling JR. 2004. Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials. Thorax, 59 (9), pp. 777-782. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with high cardiovascular morbidity and mortality and is an independent risk factor for hypertension. Novel circulating cardiovascular risk markers enabling a more accurate prediction of cardiovascular risk have been identified. Examination of these markers may clarify the increased risk in OSA and contribute to an analysis of the benefits of treatment. METHODS: Plasma levels of total cholesterol and triglyceride and activated coagulation factors XIIa and VIIa, factors VII, VIII, XII, fibrinogen, thrombin-antithrombin (TAT), von Willebrand factor antigen (vWFAg), soluble P-selectin (sP-sel), and homocysteine were measured before and after treatment for 1 month with therapeutic or subtherapeutic (control) continuous positive airways pressure (CPAP) in 220 patients with OSA. RESULTS: Levels of activated coagulation factors XIIa, VIIa, TAT and sP-sel were higher in OSA patients at baseline than in unmatched controls, but did not fall with 1 month of therapeutic CPAP treatment. The raised sP-sel levels correlated only with body mass index (p = 0.002). There was a trend towards a significant fall in total cholesterol with therapeutic CPAP (p = 0.06) compared with the control group. In the therapeutic group there was a clinically significant mean fall in total cholesterol of 0.28 mmol/l (95% confidence interval 0.11 to 0.45, p = 0.001) which may reduce cardiovascular risk by about 15%. CONCLUSION: A number of activated coagulation factors are increased in untreated OSA patients, potentially contributing to vascular risk, but they do not fall with 1 month of CPAP treatment. Nasal CPAP may produce a clinically relevant fall in total cholesterol level, potentially reducing cardiovascular risk, but this needs to be verified in a larger prospective study.

McCann FJ, Slade MG, Stradling J. 2004. Atrial septostomy in the treatment of severe pulmonary arterial hypertension. Thorax, 59 (5), pp. 450.

Stradling JR, Hardinge M, Smith DM. 2004. A novel, simplified approach to starting nasal CPAP therapy in OSA. Respir Med, 98 (2), pp. 155-158. | Show Abstract | Read more

BACKGROUND: Due to ever increasing referral rates, we have had to move the nasal CPAP induction program for patients with obstructive sleep apnoea (OSA) out of the sleep laboratories and into an outpatient setting. We report the effects this has had on patient outcomes. METHODS: The last 75 patients with OSA who had an overnight CPAP titration in the sleep laboratory (group 1) were compared with the first 75 coming to an afternoon clinic and set up on CPAP in groups, and who had their CPAP pressure determined from an algorithm (group 2). They were assessed at 1 and 11 months using the Epworth Sleepiness Score, compliance with CPAP (h/night), whether still using CPAP, and the number of clinic appointments required in the first 11 months. RESULTS: The two groups were similar at baseline. There were no differences in any of the outcome measures. ESS values fell from 14.6 to 5.0 and from 14.0 to 5.1 at 11 months in groups 1 and 2, respectively: compliance, 5.2 versus 5.1 h/night; clinic appointments, 1.75 versus 1.96; discontinuation rates at 1 month, 8% and 7%, and at 11 months, 25% and 21%. CONCLUSIONS: Using these simple outcome measures, we have shown that using an outpatient-based approach, and CPAP pressure based on an algorithm, have not reduced the efficacy of our CPAP induction program for patients with OSA.

Stradling JR, Hardinge M, Paxton J, Smith DM. 2004. Relative accuracy of algorithm-based prescription of nasal CPAP in OSA. Respir Med, 98 (2), pp. 152-154. | Show Abstract | Read more

BACKGROUND: Patients with OSA on nasal continuous positive airway pressure (CPAP) have considerable night-to-night variation in their pressure requirements, suggesting that a one-night titration might not be very precise. This study investigates the likely error incurred using a one-night titration, and explores whether an algorithm-based approach to determine the pressure is as accurate. METHODS: Thirty patients with OSA used an autotitrating CPAP device for 28 nights and the average was regarded as the 'reference' pressure for that patient. Using estimates of precision and bias, this 'reference' pressure was compared with (1) an algorithm-derived pressure (based on neck circumference and OSA severity), (2) a one-night titration (using four alternative nights), and (3) a fixed pressure of 10 cmH2O. RESULTS: The mean 'reference' pressure for the group was 9.83 (SD 2.12) cmH2O. There was little bias from any of the alternatives. However, the precision varied between 1.65 and 2.45 cmH2O for the four one-night titrations, was 2.00 for the algorithm, and was 2.12 using a fixed pressure of 10 cmH2O. CONCLUSIONS: Considerable night-to-night variation means that a one-night titration is not very precise and is subject to random variation. A one-night titration has a similar inaccuracy to that resulting from using an algorithm, based on OSA severity and neck circumference. Setting all patients with OSA at 10 cmH2O is little worse.

Stradling J. 2004. Con: Sleep apnea does not cause cardiovascular disease. Am J Respir Crit Care Med, 169 (2), pp. 148-149. | Read more

McNicholas WT, Calverley PMA, Lee A, Edwards JC, Tiotropium Sleep Study in COPD Investigators. 2004. Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in COPD. Eur Respir J, 23 (6), pp. 825-831. | Show Abstract | Read more

Oxygen desaturation occurs during sleep in severe chronic obstructive pulmonary disease (COPD), especially during rapid eye movement (REM) sleep, due to hypoventilation and ventilation-perfusion mismatching, but the possible contribution of airflow limitation is unclear. In a randomised, placebo-controlled, double-blind study of severe, stable COPD patients, the authors compared 4 weeks treatment with a long-acting inhaled anticholinergic agent (tiotropium), taken in the morning (tiotropium-AM), or in the evening (tiotropium-PM), on sleeping arterial oxygen saturation (Sa,O2) and sleep quality. Overnight polysomnography was performed at baseline and after 4 weeks treatment. A total of 95 patients with awake resting arterial oxygen tension < or = 9.98 kPa (75 mmHg) were randomised, with a mean age of 66.4 yrs and mean forced expiratory volume in one second (FEV1) of 32% predicted. A total of 80 patients completed the study, of which 56 fulfilled the polysomnographic criterion of at least 2 h sleep in both sleep study nights and represent the group analysed. Tiotropium significantly improved spirometry compared with placebo. Both tiotropium-AM and tiotropium-PM groups had higher Sa,O2 during REM than placebo (+2.41% and +2.42%, respectively, and both pooled and tiotropium-PM groups had higher Sa,O2 during total sleep time (+2.49% and +3.06%, respectively). End-of-treatment FEV1 correlated with Sa,O2 during REM sleep, however, tiotropium did not change sleep quality. Sustained anticholinergic blockade improves sleeping arterial oxygen saturation without affecting sleep quality.

McCann FJ, Slade MG, Stradling J, Pepke-Zaba J. 2004. Atrial septostomy in the treatment of severe pulmonary arterial hypertension [3] (multiple letters) Thorax, 59 (5), pp. 450.

Stradling JR, Davies RJO. 2004. Sleep. 1: Obstructive sleep apnoea/hypopnoea syndrome: definitions, epidemiology, and natural history. Thorax, 59 (1), pp. 73-78. | Show Abstract | Read more

Arguments over the definition of obstructive sleep apnoea/hypopnoea syndrome (OSAHS) have still not been satisfactorily resolved. As a result, robust estimates of the prevalence of OSAHS are not possible. New approaches are needed to identify those who have "CPAP responsive" disease, enabling more accurate estimates to be made of the prevalence of the sleep apnoea syndrome in the community.

Robinson GV, Stradling JR, Davies RJO, Roberts ISD. 2004. Post mortem diagnosis of fatal obstructive sleep apnoea [3] Histopathology, 45 (5), pp. 542-544. | Read more

Pepperell JCT, Maskell NA, Jones DR, Langford-Wiley BA, Crosthwaite N, Stradling JR, Davies RJO. 2003. A randomized controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure. Am J Respir Crit Care Med, 168 (9), pp. 1109-1114. | Show Abstract | Read more

Heart failure is associated with Cheyne-Stokes breathing, which fragments patients' sleep. Correction of respiratory disturbance may reduce sleep fragmentation and excessive daytime sleepiness. This randomized prospective parallel trial assesses whether nocturnal-assist servoventilation improves daytime sleepiness compared with the control. A total of 30 subjects (29 male) with Cheyne-Stokes breathing (mean apnea-hypopnea index 19.8 [SD 2.6] and stable symptomatic chronic heart failure (New York Heart Association Class II-IV) were treated with 1 month's therapeutic (n = 15) or subtherapeutic adaptive servoventilation. Daytime sleepiness (Osler test) was measured before and after the trial with change in measured sleepiness the primary endpoint. Secondary endpoints included brain natriuretic peptide levels and catecholamine excretion. Active treatment reduced excessive daytime sleepiness; the mean Osler change was +7.9 minutes (SEM 2.9), when compared with the control, the change was -1.0 minutes (SEM, 1.7), and the difference was 8.9 minutes (95% confidence interval, 1.9-15.9 minutes; p = 0.014, unpaired t test). Significant falls occurred in plasma brain natriuretic peptide and urinary metadrenaline excretion. We conclude that adaptive servoventilation produces an improvement in excessive daytime sleepiness in patients with Cheyne-Stokes breathing and chronic heart failure. This study suggests improvements in neurohormonal activation with this treatment.

Meston N, Davies RJO, Mullins R, Jenkinson C, Wass JAH, Stradling JR. 2003. Endocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea. J Intern Med, 254 (5), pp. 447-454. | Show Abstract | Read more

OBJECTIVE: Obstructive sleep apnoea (OSA) is a relatively common condition producing disabling somnolence and profound physiological responses to hypoxaemic episodes during sleep, including significant oscillations in blood pressure. This study aimed to provide controlled data on the interaction between OSA and endocrine axes to establish whether overrepresentation of pathology such as hypertension and hypogonadism in OSA subjects might have an endocrine basis. DESIGN, SETTING AND SUBJECTS: Parallel randomized sham placebo controlled 1-month trial of nasal continuous positive airway pressure (nCPAP) in 101 male subjects with OSA presenting to a respiratory sleep clinic. METHODS: Analysis of gonadotrophins, testosterone, sex hormone binding protein (SHBG), prolactin, cortisol, thyroid stimulating hormone (TSH), free thyroxine (free T4), insulin-like growth factor-1 (IGF-1), renin and aldosterone were performed at baseline and after 1 month's active or placebo nCPAP intervention. Quality of life questionnaire scoring was also recorded over the same time period. RESULTS: Testosterone and SHBG showed significant negative correlations with baseline OSA severity. Active treatment of OSA produced SHBG elevation and TSH reduction (P< or =0.03). Both groups showed an increase in aldosterone (P<0.001) and IGF-1 (P< or =0.03), associated with a large improvement in subjective quality of life scoring. CONCLUSIONS: These findings demonstrate significant changes in endocrine axes not previously reported in a placebo-controlled trial. OSA is a recognized reversible cause of testosterone reduction; SHBG suppression correlating to baseline OSA severity supports a diagnosis of secondary hypogonadism. Significant rises in aldosterone and IGF-1 on treatment coincide with increased physical activity and an improved quality of life score.

Robinson GV, Pepperell JC, Davies RJO, Stradling JR. 2003. Caffeine levels following treatment of obstructive sleep apnoea. Thorax, 58 (9), pp. 801-802. | Show Abstract | Read more

BACKGROUND: Randomised trials show that treatment of obstructive sleep apnoea (OSA) with nasal continuous positive airway pressure (CPAP) greatly improves sleepiness and also lowers diurnal systemic blood pressures (BP). Such patients consume more coffee than controls (presumably to combat their sleepiness) and might reduce their consumption following effective treatment, thus lowering BP by this mechanism rather than via a direct effect of alleviating OSA. METHODS: Plasma caffeine levels before and after treatment with either therapeutic (n=52) or subtherapeutic (control, n=49) CPAP were measured in stored blood samples from a previous randomised controlled trial of CPAP for 4 weeks in patients with OSA. RESULTS: There was a small significant rise in caffeine levels when the two groups were analysed as a whole (p=0.02), but not individually. Despite the fall in sleepiness measured objectively in the therapeutic CPAP group, there was no difference in absolute (or change in) caffeine levels between the two groups (mean (SE) micro mol/l; therapeutic CPAP 9.2 (1.2), 10.2 (1.0), subtherapeutic 6.7 (0.9), 8.6 (0.9) before and after treatment, respectively). CONCLUSION: Reduced coffee consumption is unlikely to be the explanation for the falls in BP following treatment of OSA.

Stradling J, Smith D, Radulovacki M, Carley D. 2003. Effect of ondansetron on moderate obstructive sleep apnoea, a single night, placebo-controlled trial. J Sleep Res, 12 (2), pp. 169-170. | Read more

Talbot K, Stradling J, Crosby J, Hilton-Jones D. 2003. Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy. Neuromuscul Disord, 13 (5), pp. 357-364. | Show Abstract | Read more

Patients with myotonic dystrophy frequently suffer from excess daytime sleepiness, which can be a significant cause of disability. Previous studies have indicated that this excess daytime sleepiness is only occasionally due to obstructive sleep apnoea and may be principally of central nervous system origin. Modafinil has been successfully used to treat narcolepsy, a central disorder causing excess daytime sleepiness. We have investigated the use of this drug in myotonic dystrophy patients with excess daytime sleepiness. Patients were recruited from a clinic population on the basis of screening with the Epworth Sleepiness Scale. Patients scoring 10 and above were invited to participate in a randomized double-blind crossover trial of modafinil versus placebo, with four weeks in each arm of the study separated by a 2-week washout period. Patients were assessed by polysomnography at baseline. The primary outcome measures were change in both the Epworth Sleepiness Scale and a modified Maintenance of Wakefulness Test, which were measured at the start of each arm of the trial and in week 3 of each intervention period. In agreement with previous smaller studies, sleepiness is not correlated with CTG expansion size. Treatment with modafinil showed a non-significant reduction in median Epworth Sleepiness Scale. However, the median Maintenance of Wakefulness Test score was prolonged by treatment (31.7-40 min, P=0.006). There were no significant adverse cardiac effects of the drug in this group of patients (resting 12 lead and 24 h ECG monitoring). Selected patients with myotonic dystrophy and excess daytime sleepiness may benefit from modafinil. In this patient group the Epworth Sleepiness Scale may not be the most reliable measure of sleepiness. Despite the potential for cardiac disease in these patients, the drug was well tolerated with no adverse effects.

Pepperell J, Stradling J, Davies R. 2002. Ambulatory blood pressure after sleep apnoea treatment - Reply LANCET, 360 (9329), pp. 341-342. | Read more

Pepperell JCT, Davies RJO, Stradling JR. 2002. Systemic hypertension and obstructive sleep apnoea. Sleep Med Rev, 6 (3), pp. 157-173. | Show Abstract | Read more

This article is a review of the current evidence that links systemic hypertension with obstructive sleep apnoea. Whilst a causal association has been suspected for some time, the day to day variability of both blood pressure and sleep apnoea severity, and clustering of confounding cardiovascular risk factors in sleep apnoea patients has made this association difficult to prove. There is unassailable evidence that obstructive apnoeas raise blood pressure acutely in both animal models and humans, through a combination of autonomic and state dependent arousal with some mechanical influences, and these rises can be controlled by nasal continuous positive airway pressure. Thus, although repetitive apnoeas alter the blood pressure variability and raise sleeping blood pressure in patients with OSA and sophisticated animal models have demonstrated increases in daytime blood pressure after the onset of OSA in the short term, such effects on diurnal BP have yet to be proven in humans. Recent rigorously designed large epidemiological studies have proven an independent association between OSA and systemic hypertension in both general and sleep clinic populations, with closely matched case control series also reporting raised blood pressure in OSA patients. A direct temporal causal association between the onset of obstructive sleep apnoea and raised blood pressure is expected to be confirmed by longitudinal data from the continuing epidemiological population studies. Finally, several studies on the beneficial effects of nasal continuous positive airway pressure in reducing blood pressure in OSA patients have preliminary results in abstract form, with one published in full.

Pepperell JCT, Davies RJO, Stradling JR. 2002. Sleep studies for sleep apnoea. Physiol Meas, 23 (2), pp. R39-R74. | Show Abstract | Read more

Sleep studies have grown to encompass a broad range of technologies employed to study and diagnose a variety of sleep disorders. From their inception in neurophysiology laboratories interested in investigating primary disorders of sleep architecture from psychiatric illness, their remit has widened such that their most common role is currently to diagnose secondary sleep disruption from respiratory, cardiovascular or other systemic causes. This review outlines the pathophysiology of obstructive sleep apnoea in particular and how sleep studies have improved our understanding of the complex dynamic changes in blood gas tensions, cardiovascular control and cerebral arousal that occur with these repetitive events. We review the historical development of standard laboratory-based sleep studies and discuss their limitations in staging sleep, reflecting the episodes of increased upper airway resistance that underlie these disorders and their ability to predict individuals' symptoms or response to medical or surgical therapies. We then describe some alternative signals that have been employed to monitor the physiological changes in upper airway resistance and arousal with a discussion of some of the evidence that these 'limited' studies may provide diagnostic information that can guide clinical decision making and may predict the outcome without the need, in some cases, for more complex and costly laboratory-based studies.

Smith DM, Stradling JR. 2002. Can mandibular advancement devices be a satisfactory substitute for short term use in patients on nasal continuous positive airway pressure? Thorax, 57 (4), pp. 305-308. | Show Abstract | Read more

BACKGROUND: Mandibular advancement devices (MADs) can successfully control both snoring and obstructive sleep apnoea (OSA). Many patients on nasal continuous positive airway pressure (NCPAP) for OSA would like a more portable alternative, even if only temporarily. This study assesses what proportion of patients with OSA already on NCPAP can successfully use a MAD for short periods (up to 1 month) as a temporary alternative to NCPAP. METHODS: Fifty patients with OSA, already on NCPAP for at least 3 months, were recruited by invitation. They were provided with a simple fixed MAD estimated to provide 75% of maximum mandibular protrusion. Sleep studies using a portable home recorder were performed on and after three nights without NCPAP to provide control data. Following acclimatisation to the MAD, sleep studies were also planned after 3, 7, and 28 days while using the MAD. If their overnight >4% SaO(2) dips per hour deteriorated to >20 or the Epworth sleepiness score (ESS) rose to >9 (or increased by >4 over baseline) on nights 3 or 7, they were then deemed to have failed the trial and were withdrawn. RESULTS: Of the 50 patients entered, one had inadequate teeth for a MAD and 31 gave up trying to use the device during the acclimatisation period because of side effects. Of the 18 prepared to use the device, two patients failed at night 3, five at night 7, and two at night 28. Thus, nine patients remained controlled by our criteria at night 28. On average, sleep study indices while using the MAD were poor compared with the night on NCPAP. CONCLUSIONS: Simple MADs are poorly tolerated by patients with OSA already on NCPAP. OSA was adequately controlled by our criteria in 32% of those recruited for the equivalent of a weekend, in 22% for 1 week, and in 18% for up to 1 month. Better tolerated devices would be likely to improve on these figures.

Pepperell JCT, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson C, Stradling JR, Davies RJO. 2002. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet, 359 (9302), pp. 204-210. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea is associated with raised blood pressure. If blood pressure can be reduced by nasal continuous positive airway pressure (nCPAP), such treatment could reduce risk of cardiovascular disease in patients with obstructive sleep apnoea. Our aim was to see whether nCPAP for sleep apnoea reduces blood pressure compared with the most robust control intervention subtherapeutic nCPAP. METHODS: We did a randomised parallel trial to compare change in blood pressure in 118 men with obstructive sleep apnoea (Epworth score > 9, and a > 4% oxygen desaturation index of > 10 per h) who were assigned to either therapeutic (n=59) or subtherapeutic (59) nCPAP (about 1 cm H(2)O pressure) for 1 month. The primary outcome was the change in 24-h mean blood pressure. Secondary outcomes were changes in systolic, diastolic, sleep, and wake blood pressure, and relations between blood pressure changes, baseline blood pressure, and severity of sleep apnoea. FINDINGS: Therapeutic nCPAP reduced mean arterial ambulatory blood pressure by 2.5 mm Hg (SE 0.8), whereas subtherapeutic nCPAP increased blood pressure by 0.8 mm Hg (0.7) (difference -3.3 [95% CI -5.3 to -1.3]; p=0.0013, unpaired t test). This benefit was seen in both systolic and diastolic blood pressure, and during both sleep and wake. The benefit was larger in patients with more severe sleep apnoea than those who had less severe apnoea, but was independent of the baseline blood pressure. The benefit was especially large in patients taking drug treatment for blood pressure. INTERPRETATION: In patients with most severe sleep apnoea, nCPAP reduces blood pressure, providing significant vascular risk benefits, and substantially improving excessive daytime sleepiness and quality of life.

Teramoto S, Kume H, Matsuse T. 2002. Ambulatory blood pressure after sleep apnoea treatment. Lancet, 360 (9329), pp. 341. | Read more

Tasker C, Crosby JH, Stradling JR. 2002. Evidence for persistence of upper airway narrowing during sleep, 12 years after adenotonsillectomy. Arch Dis Child, 86 (1), pp. 34-37. | Show Abstract | Read more

AIMS: To establish whether subjects with previous evidence of sleep apnoea prior to adenotonsillectomy continue to have evidence of narrower upper airways during sleep, 12 years later. METHODS: Twenty subjects (median age 16 years) underwent repeat sleep studies at home, 12 years after such studies had shown significant sleep apnoea in many of them prior to an adenotonsillectomy. Twenty control subjects, also studied 12 years ago, underwent repeat home sleep studies as well. The sleep studies provided information on snoring, hypoxia, and inspiratory effort (from measures of pulse transit time). A questionnaire was also administered, the subjects were weighed, and their heights measured. RESULTS: There was more reported snoring in the previous adenotonsillectomy group (50% versus 20%) and also during the sleep study (80 versus 31 snores per hour). The measure of inspiratory effort overnight was higher in the previous adenotonsillectomy group (15.6 versus 12.3 ms). Allowance for potentially confounding variables (obesity and nasal congestion) partially reduced the statistical significance of the difference in snoring, but not that of the measure of inspiratory effort. CONCLUSION: Results suggest that a narrower upper airway during sleep, to the point of snoring, persists 12 years after adenotonsillectomy, and may partly account for the occurrence earlier of preoperative sleep apnoea while adenotonsillar hypertrophy was present. It is not known if this narrowing is one of the risk factors for later development of adult sleep apnoea.

Pepperell JCT, Maskell NA, Crosthwaite NJ, Stradling JR, Davies RJO. 2001. Baroreflex sensitivity increases after 4 weeks of nasal continuous positive airway presure therapy in patients with obstructive sleep apnoea THORAX, 56 pp. 28-28.

Davies CW, Crosby JH, Mullins RL, Traill ZC, Anslow P, Davies RJ, Stradling JR. 2001. Case control study of cerebrovascular damage defined by magnetic resonance imaging in patients with OSA and normal matched control subjects. Sleep, 24 (6), pp. 715-720. | Show Abstract | Read more

STUDY OBJECTIVES: To assess whether MRI detectable evidence of silent cerebrovascular disease is more prevalent in patients with obstructive sleep apnea (OSA) when compared to carefully matched control subjects. DESIGN AND SETTING: Case-control study of patients with OSA attending a specialist sleep clinic and matched control subjects drawn from the normal community. PARTICIPANTS: Forty-five sleep clinic patients with moderate to severe OSA and excessive daytime sleepiness, matched to 45 control subjects without excessive sleepiness or evidence of OSA on a sleep study. Matched variables included age, body mass index (BMI), alcohol and cigarette consumption, treated hypertension, and ischaemic heart disease. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: All subjects underwent 24-hour ambulatory blood pressure recordings (before treatment in OSA patients) and sagittal T1, axial T2, and coronal dual echo cerebral MRI imaging to detect clinically silent abnormalities related to hypertensive cerebrovascular disease; areas of high signal foci in deep white matter (DWM), lacunae, and periventricular hyperintensity. Lacunae/high signal foci in DWM and/or periventricular hyperintensity were present in 15 (33%) OSA subjects and 16 (35%) controls, despite significant increases in mean daytime diastolic blood pressure (4.6mmHg, p<0.05), and both nighttime diastolic (7.2mmHg, p<0.001) and systolic blood pressures (9.2mmHg, p<0.05) in OSA subjects. These data exclude more than a 17% excess prevalence of MRI detected minor cerebrovascular disease in the OSA patients, with 95% confidence. CONCLUSIONS: Sub-clinical cerebrovascular disease is prevalent in both clinic patients with OSA and their matched control subjects. Despite the increased arterial blood pressures, there is, however, no apparent excess of MRI-evident subclinical cerebrovascular disease in patients with OSA compared to appropriately matched control subjects.

Choi S, Mullins R, Crosby JH, Davies RJ, Stradling JR. 2001. Is (re)titration of nasal continuous positive airway pressure for obstructive sleep apnoea necessary? Sleep Med, 2 (5), pp. 431-435. | Show Abstract | Read more

OBJECTIVE: To assess changes in nasal continuous positive airway pressure (nCPAP) pressure requirements across time in obstructive sleep apnoea (OSA), and whether routine retitrations are indicated. BACKGROUND: Most sleep laboratories perform one nCPAP titration, although some authors have found changes in pressures with time. A cohort of patients with OSA in a randomised controlled trial of nCPAP provided us with data on changes in titration pressures with time. METHODS: One hundred and one patients with symptomatic OSA (Epworth Sleepiness Scale > or =10, and >10 episodes/h of >4% dips in SaO(2) overnight) were recruited to a 1 month trial comparing real (autotitrated) and placebo nCPAP. At 1 month all patients were titrated and received real nCPAP thereafter. Eighty five were retitrated at about 6 months. RESULTS: Average pressures did not change between the initial value and 1 month (95th centile, 8.47 (SD 3.00), 8.94 (2.85) cm H(2)O), although there were large individual changes (mean difference, +0.47, SD 2.30, range -5 to +6 cm H(2)O). There was a small fall at 6 months (mean difference -0.68, SD 2.60, range -6 to +6 cm H(2)O, P<0.03) with no suggestion that the changes from 1-6 months were clinically important. CONCLUSIONS: This study suggests that routine nCPAP retitrations are not necessary. In conjunction with other published data, the night to night variation we found implies that a nCPAP calibration using an algorithm (based on obesity and OSA severity) might be as clinically successful as conventional one night titrations. However, further studies will be needed to specifically confirm this hypothesis.

Stradling JR, Pepperell JCT, Davies RJ. 2001. Sleep apnoea and hypertension: Proof at last? THORAX, 56 pp. 45-49.

Stradling JR, Pepperell JC, Davies RJ. 2001. Sleep apnoea and hypertension: proof at last? Thorax, 56 Suppl 2 (SUPPL. 2), pp. ii45-ii49.

Hack MA, Choi SJ, Vijayapalan P, Davies RJ, Stradling JR. 2001. Comparison of the effects of sleep deprivation, alcohol and obstructive sleep apnoea (OSA) on simulated steering performance. Respir Med, 95 (7), pp. 594-601. | Show Abstract | Read more

Patients with obstructive sleep apnoea (OSA) are reported to have an increased risk of road traffic accidents. This study examines the nature of the impairment during simulated steering in patients with OSA, compared to normal subjects following either sleep deprivation or alcohol ingestion. Twenty-six patients with OSA and 12 normal subjects, either deprived of one night's sleep or following alcohol ingestion [mean (SD) alcohol blood level 71.6 mg dl(-1) (19.6)], performed a simulated steering task for a total of 90 min. Performance was measured using the tendency to wander (SD), deterioration across the task, number of 'off-road' events and the reaction time to peripheral events. Control data for OSA, sleep deprivation and alcohol were obtained following treatment with nasal continuous positive airway pressure (nCPAP), after a normal night of sleep, and following no alcohol, respectively. Patients with untreated OSA, and sleep-deprived or alcohol-intoxicated normal subjects performed significantly less well, compared to their respective controls (P<0.01 for all tests), with untreated OSA lying between that of alcohol intoxication and sleep deprivation. Alcohol impaired steering error equally throughout the whole drive, whilst sleep deprivation caused progressive deterioration through the drive, but not initially. Untreated OSA was more like sleep deprivation than alcohol, although there was a wide spread of data. This suggests that the driving impairment in patients with OSA is more compatible with sleep deprivation or fragmentation as the cause, rather than abnormal cognitive or motor skills.

Jenkinson C, Davies RJ, Mullins R, Stradling JR. 2001. Long-term benefits in self-reported health status of nasal continuous positive airway pressure therapy for obstructive sleep apnoea. QJM, 94 (2), pp. 95-99. | Show Abstract | Read more

Doubt has been expressed about the efficacy of nasal continuous positive airways pressure (NCPAP) therapy for sleep apnoea. Recent evidence from a randomized controlled trial of 1 month duration, suggested that NCPAP therapy can have a substantial impact on subjective and clinical outcomes in the short term, but data was not available to determine whether these effects were sustained over the long term. This study, an extension of the original trial, examined whether the beneficial impacts of NCPAP continued over the longer term. Patients were followed-up 1 month after being placed on active or sub-therapeutic NCPAP. They completed health status measures and a clinical test of sleepiness. After this period, all patients were placed on NCPAP and followed up 5 months later. The beneficial impact of NCPAP on sleep apnoea was sustained on all measures at follow-up. Furthermore, those who had initially been in the sub-therapeutic arm gained scores after 5 months of NCPAP similar to those of the active group. The impact of NCPAP appears sustained in the longer term. Subjective health status instruments have been advocated as important outcome points in randomized trials. This study would support such a use, and shows the important role of patient report in the evaluation of health care.

Allen M, Anderson P, Barnes N, Campbell J, Laszlo G, Millar A, Morice A, Peake M, Rogers T, Stern M et al. 2001. Assessing the acceptability of a novel dry powder inhaler A multicentre study in adult asthmatic patients using routine bronchodilator therapy Primary Care Respiratory Journal, 10 (1), pp. 8-11. | Show Abstract | Read more

Objective: To assess patient acceptability of a novel dry powder inhaler (DPI), Clickhaler® (Innovata Biomed Ltd., the Respiratory Division of ML Laboratories PLC) in routine clinical use as a first-line bronchodilator treatment. Design: In a multicentre open label study, asthma patients taking bronchodilators via a metered dose inhaler (MDI) or DPI (Turbohaler®) were given salbutamol via the Clickhaler®. Questionnaires before and after four weeks of treatment were used to assess the clinicians' and patients' opinions of the device. Subjects: 184 asthma patients aged ≥18 years, showing a good DPI technique. Results: Of the 175 patients completing the study, 121 found the Clickhaler® as easy (30%) or easier (39%) to use than their pre-study inhaler and 87 patients (50%) liked the Clickhaler® as much as (15%) or more than (35%) their pre-study inhaler. Investigators considered it more suitable (26%)/as suitable (39%) as the pre-study device for 65% of patients. Correct technique was easy to teach and was maintained by 98% of the patients after four weeks. Conclusion: The Clickhaler® is easy to operate and well accepted by adult asthma patients.

Ho LP, Bray M, Stradling JR. 2000. Exhaled nitric oxide as a screening test for asthma in children. THORAX, 55 (SUPPL. 3), pp. A19-A19. | Show Abstract

Exhaled NO is known to be elevated in patients with asthma and may reflect airway inflammation. We wish to examine if increased levels of exhaled NO could be used as an initial screening test for asthma in children. Methods: We measured exhaled NO in 155 children aged 8-9 years and then classified them as normal (non - asthmatic, non- atopic), asthmatic, atopic asthmatic or atopic on the basis of the ISAAC questionnaire (Asher MI et al. ERJ 1995). Parents who answered 'yes' to the question 'has your child ever had asthma', 'wheeze or dry cough at night apart from cough associated with cold or chest infection in last 12 months' were classified as asthmatic. Those who were defined to have seasonal allergic rhinitis or eczema from the questionnaire were classified as atopic. All children came from the Oxfordshire town of Abingdon, were born in 1991 and 1992 and registered with a specific GP practice. Exhaled NO measurements were made over a 2 weeks period in July, and parents completed the ISAAC questionnaire within 1 week of the measurements. Exhaled NO was measured using a single exhalation method (Model LR2000, Logan Research, UK). All children exhaled at a rate of 75 ml/sec with mouth pressure maintained at 10 cm H2O. Results: All but 13 parents returned the questionnaire. Four children were not able to perform the exhaled NO measurements adequately. From the ISAAC questionnaire, 26 of 138 children were classified as asthmatics, 36 were atopic and the rest non-atopic and non asthmatics. The atopic subjects (with or without asthma) had significantly greater levels of exhaled NO levels compared to normal subjects (Mann Whitney Rank Sum Test). There was no significant difference in exhaled NO levels between asthmatic and atopic subjects. Non - atopic Atopic Asthma No asthma Asthma No asthma normal) N 6 55 20 36 NO 5.5 5.2 14.5* 6.4* I.Q 4.9-6.4 4.0-6.7 5.8-24.1 4.7-10.9 Range *significantly higher levels compared to normal ; p<0.05 Conclusion: We found no significant difference in exhaled NO levels between non asthmatic, atopic children and those with asthma. High exhaled NO levels do not appear to discriminate between atopy and asthma, and therefore is unlikely to be useful as an initial screening test for asthma.

Stradling JR, Barbour C, Glennon J, Langford BA, Crosby JH. 2000. Prevalence of sleepiness and its relation to autonomic evidence of arousals and increased inspiratory effort in a community based population of men and women. J Sleep Res, 9 (4), pp. 381-388. | Show Abstract | Read more

Degrees of sleep apnoea and daytime sleepiness are quite common in community populations. However the relationship between the two is poor, although sleepiness does correlate better with a history of snoring. It has been suggested that sleep can be fragmented by upper airways obstructive events, short of full apnoeas or hypopnoeas, and that these events may not provoke full cortical arousal, but be detectable through activation of the autonomic system. Failure to detect both these could mask a relationship between 'sleep apnoea' and daytime sleepiness. We have therefore measured sleepiness (Epworth Sleepiness Scale) in addition to both autonomic 'arousals' and inspiratory effort (using pulse transit time) in 473 men and women at home. Although sleepiness was related to a history of snoring, it was not significantly predicted by the measures of autonomic 'arousal', or inspiratory effort. Reported snoring and objectively measured snoring correlated poorly. As in other studies, nocturnal hypoxic dips were correlated with obesity, age, alcohol consumption, drug usage and a history of snoring. These data make it unlikely that sleep fragmentation from subtle variants of sleep apnoea and 'autonomic' (or 'subcortical') arousals are an important source of daytime sleepiness in the community.

Pepperell JCT, Mullins B, Dow SR, Crosthwaite N, Stradling JR, Davies RJO. 2000. Blood pressure change after treatment for obstructive sleep apnoea (OSA) with continuous positive airway pressure (CPAP) THORAX, 55 (SUPPL. 3), pp. A24-A24. | Show Abstract

It is unclear whether OSA is an independent risk factor for hypertension and whether CPAP treatment reduces blood pressure (BP). We conducted a randomised parallel controlled trial of 4 weeks therapeutic versus sub-therapeutic CPAP treatment (as a control) in men with OSA (Epworth Score (ESS) >10, >4% SaO2 dips >10 per hour). We measured 24-hour BP at home using the TM-2420 ambulatory BP monitoring system before and after treatment. Diary cards were used to report sleep and wake periods. BP changes with treatment were compared between groups using independent samples T-Tests. 85 patients completed the trial. Median (range), age 50 (33-73) years; Body Mass Index 33.7 (24.9-53.9); ESS 16 (10-24); SaO2 dip rate 32.1 (10.6-101.3) and similar between groups. Machine use hours CPAP per night was equivalent between therapeutic 5.4 (2.3-9) and control groups 5.5 (0.4-10). The groups had similar baseline 24 hour BP, mean (SD) therapeutic 132.7 (14.5) / 85.3 (9.5), controls 132.5 (16.6)/84.5 (9.1). Change in BP with Treatment Systolic(mmHg) Diastolic(mmHg) Overall Wake Sleep Overall Wake Sleep Therapeutic -2.4 -1.4 -5.8 -1.6 -1.9 -2.0 n=41 (1.4) (1.4) (1.8) (1.3) (1.4) (1.4) Control +1.4 +2.8 -0.4 +0.6 +1.5 -0.8 n=44 (1.3) (1.4) (1.7) (0.8) (.86) (1.3) p value <0.05 <0.05 <0.04 ns <0.05 ns Mean change (SEM) in Systolic and Diastolic BP by treatment group. Post treatment, sleep period systolic BP was also significantly different on a between groups comparison of means, therapeutic mean (SD) 118.1 (13.3) mmHg versus control 125.6 (18.4), p<0.05. These results support OSA as an independent risk factor for the elevation of blood pressure in men, and shows a blood pressure fall with CPAP treatment.

Smith DM, Stradling JR. 2000. In patients on nasal CPAP, can mandibular advancement devices (MADs) be a satisfactory substitute in the short term? THORAX, 55 (SUPPL. 3), pp. A53-A53. | Show Abstract

Use of nasal CPAP for OSA can be very restricting on lifestyle. We were interested to see if MADs could satisfactorily treat OSA for the equivalent of a weekend, a week, or a month, whilst off nasal CPAP. Patients were eligible for this trial if they used nasal CPAP on average for >4hrs/night, their original Epworth Sleepiness score (ESS) was >12, their original >4%SaO2 dip rate was >15/hr, and they had sound teeth. Fixed MADs were made with estimated 75% maximum protrusion of the mandible. Patients were studied at home with a portable monitor (RM50) whilst using, and after 3 days off, nasal CPAP. In addition they were studied on the 3rd night of wearing their MAD, and potentially on their 7th and 28th nights if their OSA remained controlled. The return of the >4%SaO2 dip rate to >20/hr, or an ESS rise to >10, or an absolute rise of >4 points above their baseline ESS, defined arbitrarily the failure of the MAD to control their OSA. So far 41 patients, out of an intended 50, have completed the protocol. 25 patients did not wish to continue using their MAD for a variety of reasons, usually jaw/gum discomfort, excessive salivation, or due to concerns that the MAD was not working. Of the remaining 16, OSA was controlled satisfactorily in 14 of them at night 3, in 9 at night 7, and in 8 at night 28. Thus 20% of patients on nasal CPAP may be able to use a MAD as a substitute for up to 1 month, 22% up to a week, and 34% for a week end, without return of their OSA by our criteria.

Hack MA, Davies RJO, Stradling JR. 2000. Predictors of steering simulation performance in patients undergoing investigation for obstuctive sleep apnoea (OSA). THORAX, 55 pp. A53-A53.

Choi S, Bennett LS, Mullins R, Davies RJ, Stradling JR. 2000. Which derivative from overnight oximetry best predicts symptomatic response to nasal continuous positive airway pressure in patients with obstructive sleep apnoea? Respir Med, 94 (9), pp. 895-899. | Show Abstract | Read more

The cost and inconvenience of polysomnography for the investigation of obstructive sleep apnoea (OSA) has led to the search for simpler and cheaper alternatives. These are usually compared to an apnoea/hypopnoea index (AHI) derived from oro-nasal airflow and ribcage/abdominal effort sensors. However, AHI is not a proven gold standard for the identification of clinically important OSA. Recent work has shown that correctly analysed oximetry indices not only mimic AHI with considerable accuracy, but also predict the symptomatic response to nasal continuous positive airway pressure (nCPAP) at least as well as conventional polysomnographic indices. This current study looks at 10 different derivatives of all-night oximeter tracings in 81 patients with OSA, and compares their ability to predict the improvement in subjective sleepiness after 6 months of nCPAP therapy. Sleep apnoea in this study was defined as a > 4% SaO2 dip rate of > 10 h(-1), and an Epworth sleepiness score (ESS) of > 10 on presentation. Subjects took part in a placebo-controlled trial of nCPAP for 1 month and thereafter were all supplied with nCPAP set at an effective pressure. All night SaO2 was sampled every 2 sec and later analysed for mean, median, mean nadir of SaO2 dip, time below 90%, 2 and 12 sec delta index (an average measure of SaO2 change across these two time periods), rapid resaturation index (rises in SaO2 > 3% within 10 sec per hour), and > 4, > 3, and > 2% dips per hour. These indices were then correlated with the change in ESS seen after 6 months on nCPAP. Median compliance for the group was 5.8 (5/95% range, 1.5-8.0) h night(-1). The two best correlates of improvement in ESS were the > 4% SaO2 dips h(-1) (Spearman's r = -0.33 P=0.002) and the delta 12 sec index (r = -0.33, P = 0.003). Cumulative time below 90% SaO2 was almost as good (r = -0.29, P = 0.009). The worst correlate was the > 2% SaO2 dips h(-1) (r = 0.01, not significant). This study has identified which of several analyses of overnight oximeter recordings best identify nCPAP responsive OSA. Both > 4% SaO2 dips and 12 sec delta index are equally predictive and presumably the most appropriate derivatives to calculate from overnight records of SaO2.

Davies CW, Crosby JH, Mullins RL, Barbour C, Davies RJ, Stradling JR. 2000. Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects. Thorax, 55 (9), pp. 736-740. | Show Abstract | Read more

BACKGROUND: There is considerable debate regarding the relationship between obstructive sleep apnoea (OSA) and hypertension. It is unclear whether OSA is an independent vascular risk factor as studies attempting to assess this association have produced conflicting results because of confounding variables such as upper body obesity, alcohol, and smoking. A case-control study of 24 hour ambulatory blood pressure was undertaken in patients with OSA and matched controls to assess whether OSA is an independent correlate of diurnal hypertension. METHODS: Forty five patients with moderate to severe OSA and excessive daytime sleepiness were matched with 45 controls without OSA in a sleep study. Matched variables included age, body mass index (BMI), alcohol, cigarette usage, treated hypertension, and ischaemic heart disease. Upper body obesity was compared by waist:hip and waist:height ratios; 24 hour ambulatory blood pressure recordings were performed (before treatment for OSA) in all subjects. RESULTS: Patients with OSA had significantly increased mean (SD) diastolic blood pressure (mm Hg) during both daytime (87.4 (10.2) versus 82.8 (9.1); p=0.03, mean difference 4.6 (95% CI 0.7 to 8.6) and night time (78.6 (9.3) versus 71.4 (8.0); p<0.001, mean difference 7.2 (95% CI 3.7 to 10.6)), and higher systolic blood pressure at night (119.4 (20.7) versus 110.2 (13.9); p=0.01, mean difference 9.2 (95% CI 2.3 to 16.1)). The nocturnal reduction in blood pressure ("dipping") was smaller in patients with OSA than in control subjects. CONCLUSIONS: Compared with closely matched control subjects, patients with OSA have increased ambulatory diastolic blood pressure during both day and night, and increased systolic blood pressure at night. The magnitude of these differences is sufficient to carry an increased risk of cardiovascular morbidity. The slight excess of upper body fat deposition in the controls may make these results conservative.

Stradling JR, Davies RJ. 2000. Is more NCPAP better? Sleep, 23 Suppl 4 (SUPPL. 4), pp. S150-S153. | Show Abstract

STUDY OBJECTIVES: To assess the benefit of NCPAP in OSA and its relation to the degree of use of NCPAP. DESIGN: Randomised parallel controlled one month study comparing NCPAP set at therapeutic levels of pressure, with NCPAP set at sub-therapeutic pressure levels. SETTING: Teaching hospital sleep clinic and laboratory SUBJECTS: 101 men referred for investigation of possible OSA who were sleepy (Epworth Sleepiness Score > or = 10) and had > or = 10/hr of >4% dips in SaO2 due to OSA. OUTCOME MEASURES: Baseline and one month measures of Epworth Sleepiness Score (ESS), Maintenance of Wakefulness Test (MWT), and the Energy/Vitality dimension of the SF-36 (health status questionnaire). Correlation of these outcome measures with NCPAP usage. RESULTS: All outcome measures improved significantly more in the therapeutic, compared to the sub-therapeutic, group (e.g. ESS 15.0 to 13.0 on sub-therapeutic, and 15.5 to 7.0 on therapeutic, p<1x10(-6)). The degree of improvement correlated significantly with NCPAP usage in the therapeutic group (ESS, r=-0.60; MWT, r=0.55) but insignificantly in the sub-therapeutic group (ESS, r=-0.15; MWT, r=-0.06). Sub-therapeutic NCPAP did not improve OSA severity and acted as a control. CONCLUSIONS: NCPAP is clearly effective in relieving the sleepiness of OSA compared to a control group identical in every way, except for receiving a nasal pressure inadequate to control the OSA.

Stradling JR, Barbour C, Glennon J, Langford BA, Crosby JH. 2000. Which aspects of breathing during sleep influence the overnight fall of blood pressure in a community population? Thorax, 55 (5), pp. 393-398. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea (OSA) causes recurrent rises in blood pressure during sleep, and recent community surveys have suggested a link between mild OSA and diurnal hypertension. The fact that OSA and hypertension share some risk factors, as well as problems accurately quantifying OSA severity, have diluted the power of such studies. This study tries to circumvent some of these problems by measuring the overnight change in blood pressure and relating it to relevant measures of the severity of upper airway obstruction on the same night. METHODS: Men born between 1930 and 1960 and their wives living in a market town north of Oxford were identified from a GP practice register. Enough couples were recruited to provide approximately 10 (20 individuals) per year of birth. Subjects were visited at home where a questionnaire was administered, anthropometric measurements made, blood pressures taken (including by the subject), and sensors applied for a subsequent overnight sleep study. The sleep study measured indices of hypoxia, snoring, autonomic arousal, degree of respiratory effort; the last two of these derived from measurements of pulse transit time (indirect beat to beat blood pressure). After waking the following morning, the subjects took their own blood pressures again. RESULTS: Data were available from 224 couples (448 subjects). On average, systolic BP fell 8 mm Hg from evening to morning. Only hypoxic dips (>4% SaO(2) dips/h) and the measure of degree of respiratory effort were significant independent predictors of this overnight change in systolic BP, together accounting for 7-10% of the variation (p<0.0001). Dividing the subjects into quartiles according to the respiratory effort overnight showed a progressive reduction in the fall of systolic BP overnight: 13.6, 10.8, 7.3, and 5.6 mm Hg, lowest to highest quartiles. CONCLUSIONS: This study suggests that increased respiratory effort during sleep (seen in OSA and related syndromes of increased upper airway resistance during sleep) offsets the normal fall in BP that occurs overnight, even within this community population. This may be one of the mechanisms by which hypertension is carried over into the waking hours in patients with OSA.

Stradling JR, Pearson MG, Morice AH, Peake MD, Barnes NC. 2000. Efficacy and safety of a novel beclomethasone dipropionate dry powder inhaler (Clickhaler) for the treatment of adult asthma. Amsterdam Clinical Study Group. J Asthma, 37 (2), pp. 183-190. | Show Abstract | Read more

A randomized, double-blind, double-dummy protocol was used to compare the safety and efficacy of beclomethasone dipropionate (BDP) delivered by a novel dry powder inhaler (DPI, Clickhaler) or by a pressurized metered-dose inhaler (MDI) plus spacer. There was a four-week run-in period, completed by 240 adult patients, who received BDP via an MDI. Patients with stable asthma were then randomized into a 12-week treatment period and received BDP (< or =2 mg/day via DPI or MDI). There were no significant differences in morning peak expiratory flow (PEF) (primary endpoint), evening PEF, overall daytime or nighttime symptom scores, or lung function parameters (forced expiratory volume in 1 sec, forced vital capacity) between DPI and MDI. The safety profiles were similar and patient acceptability for Clickhaler was high. In conclusion, BDP administered via Clickhaler was found to be clinically equivalent to an optimally used MDI. Patients with stable asthma currently receiving BDP via MDI may be effectively switched to treatment via Clickhaler DPI.

Juniper M, Hack MA, George CF, Davies RJ, Stradling JR. 2000. Steering simulation performance in patients with obstructive sleep apnoea and matched control subjects. Eur Respir J, 15 (3), pp. 590-595. | Show Abstract | Read more

Patients with obstructive pulmonary disease (OSA) have an increased rate of driving accidents, perhaps due to poor vigilance or impaired cognitive skills that influence their driving ability. The authors have assessed whether patients with OSA perform differently to control subjects on a steering simulator which allows the separate assessment of the two visual tasks required for steering a car, immediate positioning on road with reference to the road edges, and assessment of the curve of the oncoming road which allows faster driving. Twelve patients with OSA and 12 control subjects, matched for age, sex and driving experience, performed three 30-min drives with either all the oncoming road visible, only the near part of the road visible, or only the distant part of the road visible. Steering was assessed by measuring the SD around the theoretical perfect path (steering error) and the number of times the driver went "off road". Subjects identified the appearance of target numbers at the four corners of the screen as quickly as possible, thus making the test a divided attention task. Patients with OSA performed significantly less well on the three different road fields as measured by steering error (p<0.001), time to detect the target number (p<0.03), and off road events (p<0.03). The patients appeared to be particularly impaired on the two drives when only part of the road ahead was available to guide steering. This steering simulator, with its more realistic view of the road ahead, identifies impaired performance in patients with obstructive sleep apnoea. In addition it suggests that patients with obstructive sleep apnoea may be more disadvantaged compared to normal subjects when the view of the road ahead is limited (such as in fog).

Hack M, Davies RJ, Mullins R, Choi SJ, Ramdassingh-Dow S, Jenkinson C, Stradling JR. 2000. Randomised prospective parallel trial of therapeutic versus subtherapeutic nasal continuous positive airway pressure on simulated steering performance in patients with obstructive sleep apnoea. Thorax, 55 (3), pp. 224-231. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea (OSA) impairs vigilance and may lead to an increased rate of driving accidents. In uncontrolled studies accident rates and simulated steering performance improve following treatment with nasal continuous positive airway pressure (NCPAP). This study seeks to confirm the improvement in steering performance in a randomised controlled trial using subtherapeutic NCPAP as a control treatment. METHODS: Fifty nine men with OSA (Epworth Sleepiness Score (ESS) of > or =10, and > or =10/h dips in SaO(2) of >4% due to OSA) received therapeutic or subtherapeutic NCPAP ( approximately 1 cm H(2)O) for one month. Simulated steering performance over three 30-minute "drives" was quantified as: standard deviation (SD) of road position, deterioration in SD across the drive, length of drive before "crashing", and number of off-road events. The reaction times to peripheral target stimuli during the drive were also measured. RESULTS: Subtherapeutic NCPAP did not improve overnight >4% SaO(2) dips/h compared with baseline values, thus acting as a control. The SD of the steering position improved from 0.36 to 0.21 on therapeutic NCPAP, and from 0.35 to 0.30 on subtherapeutic NCPAP (p = 0.03). Deterioration in SD of the steering position improved from 0.18 to 0.06 SD/h with therapeutic NCPAP and worsened from 0.18 to 0.24 with subtherapeutic NCPAP (p = 0.04). The reaction time to target stimuli was quicker after therapeutic than after subtherapeutic NCPAP (2.3 versus 2.7 seconds, p = 0.04). CONCLUSIONS: Therapeutic NCPAP improves steering performance and reaction time to target stimuli in patients with OSA, lending further support to the hypothesis that OSA impairs driving, increases driving accident rates, and that these improve following treatment with NCPAP.

Morice AH, Stradling JR, Barnes NC, Grp COMPACT1CS. 2000. Assessment of the acceptability of a new salbutamol multidose dry powder inhaler (DPI) in patients with asthma CLINICAL DRUG INVESTIGATION, 19 (3), pp. 195-199. | Show Abstract | Read more

Introduction: Because of environmental concerns, the use of chlorofluorocarbons in pressurised metered dose inhalers (pMDI) is being phased out. Innovata Biomed Ltd has developed an alternative device, the Clickhaler®, which is a multiple-dose dry powder inhaler (DPI). The present study compared patient acceptability of the salbutamol Clickhaler® with a prestudy device. Patients and Methods: Adult patients with asthma who were receiving bronchodilator therapy (either salbutamol pMDI or terbutaline Turbuhaler® DPI) were entered into this open-label study, which was designed to assess the acceptability of the salbutamol Clickhaler® before and after a 4-week period of routine clinical use. Results: Overall acceptability questions showed that 99% of patients found the new DPI very easy/easy to use at visit 1 and 94% at visit 2. At the same two visits, the salbutamol Clickhaler® was rated very good/good overall by 98 and 80% of the patients, respectively. The number of patients finding the salbutamol Clickhaler® easier to use (44%) was statistically significantly higher (p < 0.05) than the number who found their prestudy inhaler easier to use (27%). Conclusion: This study demonstrated that the salbutamol Clickhaler® showed a high degree of acceptability and ease of use when used routinely by adult patients with asthma.

Stradling JR, Pearson MG, Morice AH, Peake MD, Barnes NC, Grp ACS. 2000. Efficacy and safety of a novel beclomethasone dipropionate dry powder inhaler (Clickhaler (R)) for the treatment of adult asthma JOURNAL OF ASTHMA, 37 (2), pp. 183-190. | Show Abstract | Read more

A randomized, double-blind, double-dummy protocol was used to compare the safety and efficacy of beclomethasone dipropionate (BDP) delivered by a novel dry powder inhaler (DPI, Clickhaler®) or by a pressurized metered-dose inhaler (MDI) plus spacer. There was a four-week run-in period, completed by 240 adult patients, who received BDP via an MDI. Patients with stable asthma were then randomized into a 12-week treatment period and received BDP (≤2 mg/day via DPI or MDI). There were no significant differences in morning peak expiratory flow (PEF) (primary endpoint), evening PEF, overall daytime or nighttime symptom scores, or lung function parameters (forced expiratory volume in 1 sec, forced vital capacity) between DPI and MDI. The safety profiles were similar and patient acceptability for Clickhaler was high. In conclusion, BDP administered via Clickhaler was found to be clinically equivalent to an optimally used MDI. Patients with stable asthma currently receiving BDP via MDI may be effectively switched to treatment via Clickhaler DPI.

Cited:

184

Scopus

Davies CWH, Crosby JH, Mullins RL, Barbour C, Davies RJO, Stradling JR. 2000. Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects Thorax, 55 (9), pp. 736-740. | Show Abstract | Read more

Background - There is considerable debate regarding the relationship between obstructive sleep apnoea (OSA) and hypertension. It is unclear whether OSA is an independent vascular risk factor as studies attempting to assess this association have produced conflicting results because of confounding variables such as upper body obesity, alcohol, and smoking. A case-control study of 24 hour ambulatory blood pressure was undertaken in patients with OSA and matched controls to assess whether OSA is an independent correlate of diurnal hypertension. Methods - Forty five patients with moderate to severe OSA and excessive daytime sleepiness were matched with 45 controls without OSA in a sleep study. Matched variables included age, body mass index (BMI), alcohol, cigarette usage, treated hypertension, and ischaemic heart disease. Upper body obesity was compared by waist:hip and waist:height ratios; 24 hour ambulatory blood pressure recordings were performed (before treatment for OSA) in all subjects. Results - Patients with OSA had significantly increased mean (SD) diastolic blood pressure (mm Hg) during both daytime (87.4 (10.2) versus 82.8 (9.1); p=0.03, mean difference 4.6 (95% CI 0.7 to 8.6) and night time (78.6 (9.3) versus 71.4 (8.0); p<0.001, mean difference 7.2 (95% CI 3.7 to 10.6)), and higher systolic blood pressure at night (119.4 (26.7) versus 116.2 (13.9); p=0.01, mean difference 9.2 (95% CI 2.3 to 16.1)). The nocturnal reduction in blood pressure ('dipping') was smaller in patients with OSA than in control subjects. Conclusions - Compared with closely matched control subjects, patients with OSA trove increased ambulatory diastolic blood pressure during both day and nigher, and increased systolic blood pressure at night. The magnitude of these differences is sufficient to carry an increased risk of cardiovascular morbidity. The slight excess of upper body fat deposition in the controls may make these results conservative.

Davies RJ, Stradling JR. 2000. The efficacy of nasal continuous positive airway pressure in the treatment of obstructive sleep apnea syndrome is proven. Am J Respir Crit Care Med, 161 (6), pp. 1775-1776. | Read more

Hack MA, Davies RJO, Stradling JR. 2000. Predictors of steering simulation performance in patients undergoing investigation for Obstuctive Sleep Apnoea (OSA) Thorax, 55 (SUPPL. 3), | Show Abstract

The raised rate of road accidents in OSA has stimulated a search for predictors of driving performance. 34 patients investigated for possible OSA (age 47.8 SD10.1, BMI 29.6 SD 6.3, ESS 11.9 SD4.0, >4%SaO2 dips/hr 10.4 SD 13.1) performed a steering simulation, including responses to peripheral events. Subjects performed a modified maintenance of wakefulness test (MWT 28.5 SD9.9 mins). The eventual diagnosis ranged from normal to severe OSA. Two steering simulation parameters (SD of steering error from the theoretical perfect path, and reaction time) were correlated against age, measures of sleepiness (ESS, MWT) and measures of OSA severity (autonomic arousals/hr, >4%SaO2 dips/hr, and body movements/hr). R age ESS MWT autonomic >4% body values arousals SaO2 movements /h dips/h /h steering 0.39* 0.28 -0.36* 0.23 0.22 0.40* error reaction 0.11 0.33 -0.04 0.35* 0.32 0.27 time * p <0.05. There were no correlations between the number of self-reported accidents or driving experience, and the steering error or reaction time. Steering error and reaction time did not have the same pattern of correlation with potential predictors, perhaps suggesting different impairment factors. Although correlations exist, they are not close and the prediction of individual driving performance remains imprecise.

Hack M, Choi S, Mullins R, Dow S, Davies RJO, Stradling JR. 1999. Performance of patients with obstructive sleep apnoea (OSA) on a steering simulation after six months treatment with nasal continuous positive airway pressure (NCPAP) THORAX, 54 pp. A9-A9.

Davies CWH, Crosby JH, Mullins RL, Traill ZC, Anslow P, Davies RJO, Stradling JR. 1999. Case control study of magnetic resonance image defined subclinical cerebrovascular damage in patients with obstructive sleep apnoea and normal control subjects THORAX, 54 pp. A10-A10.

Davies CWH, Crosby JH, Mullins RL, Barbour C, Davies R, Stradling JR. 1999. Case control study of 24-hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects THORAX, 54 pp. A47-A47.

Stradling JR, Davies RJO, Mullins R, Jenkinson C. 1999. Obstructive sleep apnoea - Reply LANCET, 354 (9185), pp. 1213-1213. | Read more

Davies RJ, Bennet LS, Barbour C, Tarassenko L, Stradling JR. 1999. Second by second patterns in cortical electroencephalograph and systolic blood pressure during Cheyne-Stokes. Eur Respir J, 14 (4), pp. 940-945. | Show Abstract | Read more

Little is known about how arousal develops during the ventilatory phase of Cheyne-Stokes breathing. This study employs neural network analysis of electroencephalograms (EEGs) to describe these changes and relate them to changes in systolic blood pressure, which is probably a subcortical marker of arousal. Six patients with Cheyne-Stokes respiration (apnoea/hypopnoea index 32-69 h(-1)) caused by stable chronic heart failure underwent polysomnography including arterial beat-to-beat systolic blood pressure determination. Periods of 15 sequential apnoeas during nonrapid eye movement sleep were identified for each subject. For each apnoea, the EEG was examined second-by-second using neural net analysis from 28 s before to 28 s after apnoea termination (first return of oronasal airflow), and this was compared with the systolic blood pressure pattern. During the apnoeic phase, sleep deepened progressively. Arousal started to develop at or just before apnoea termination and progresses through the breathing phase. The rise and fall in the systolic blood pressure closely followed the rise and fall in electroencephalographic sleep depth. In conclusion, during Cheyne-Stokes breathing, cortical electroencephalographic arousal begins at or just before the resumption of breathing. Cortical electroencephalographic sleep depth changes are closely mirrored by changes in arterial systolic blood pressure, suggesting that the state changes in the cortical and basal brain structures may be synchronous.

Gibson GJ, Douglas NJ, Stradling JR, Semple SJG. 1999. Sleep apnoea - In response JOURNAL OF THE ROYAL COLLEGE OF PHYSICIANS OF LONDON, 33 (5), pp. 484-484.

Jenkinson C, Davies RJ, Mullins R, Stradling JR. 1999. Comparison of therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised prospective parallel trial. Lancet, 353 (9170), pp. 2100-2105. | Show Abstract | Read more

BACKGROUND: Nasal continuous positive airway pressure (NCPAP) is widely used as a treatment for obstructive sleep apnoea. However, to date there are no randomised controlled trials of this therapy against a well-matched control. We undertook a randomised prospective parallel trial of therapeutic NCPAP for obstructive sleep apnoea compared with a control group on subtherapeutic NCPAP. METHODS: Men with obstructive sleep apnoea, defined as an Epworth sleepiness score of 10 or more and ten or more dips per h of more than 4% SaO2 caused by obstructive sleep apnoea on overnight sleep study, were randomly assigned therapeutic NCPAP or subtherapeutic NCPAP (about 1 cm H2O) for 1 month. Primary outcomes were subjective sleepiness (Epworth sleepiness score), objective sleepiness (maintenance of wakefulness test), and SF-36 questionnaire measurements of self-reported functioning and well-being. FINDINGS: 107 men entered the study: 53 received subtherapeutic NCPAP and 54 therapeutic NCPAP. Use of NCPAP by the two treatment groups was similar: 5.4 h (therapeutic) and 4.6 h (subtherapeutic) per night. Subtherapeutic NCPAP did not alter the overnight number of SaO2 dips per h compared with baseline, and thus acted as a control. Therapeutic NCPAP was superior to subtherapeutic NCPAP in all primary outcome measures. The Epworth score was decreased from a median of 15.5 to 7.0 on therapeutic NCPAP, and from 15.0 to 13.0 on subtherapeutic NCPAP (between treatments, p<0.0001). Mean maintenance-of-wakefulness time increased from 22.5 to 32.9 min on therapeutic NCPAP and, not significantly, from 20.0 to 23.5 min on subtherapeutic NCPAP (between treatments p<0.005). Effect sizes for SF-36 measures of energy and vitality were 1.68 (therapeutic) and 0.97 (subtherapeutic) NCPAP (between treatments p<0.0001). For mental summary score, the corresponding values were 1.02 and 0.4 (between treatments p=0.002). INTERPRETATION: Therapeutic NCPAP reduces excessive daytime sleepiness and improves self-reported health status compared with a subtherapeutic control. Compared with controls, the effects of therapeutic NCPAP are large and confirm previous uncontrolled clinical observations and the results of controlled trials that used an oral placebo.

Bennett LS, Barbour C, Langford B, Stradling JR, Davies RJ. 1999. Health status in obstructive sleep apnea: relationship with sleep fragmentation and daytine sleepiness, and effects of continuous positive airway pressure treatment. Am J Respir Crit Care Med, 159 (6), pp. 1884-1890. | Show Abstract | Read more

Patients with obstructive sleep apnea (OSA) have impaired health status that improves with nasal continuous positive airway pressure (nCPAP). The study reported here explored the relationships between health status, its improvement with nCPAP, sleep fragmentation, and daytime sleepiness. In the study, 51 patients (46 male, five female) ranging from nonsnorers to individuals with severe OSA (median apnea/hypopnea index [AHI] 25, 90% central range: 1 to 98) had polysomnography with microarousal scoring, respiratory arousal scoring, and measurement of pulse transit time. The Short Form-36 Health Survey (SF-36) questionnaire was administered before and after 4 wk of nCPAP treatment; daytime sleepiness was also measured before starting nCPAP. Relationships between pretreatment health status and sleep fragmentation were weak, but significant associations were found between all sleep fragmentation indices and health status improvement with nCPAP (e.g., arousals according to the criteria of the American Sleep Disorders Association versus change in the physical component summary, r = 0.44, p < 0.001). Compared with general population data, the dimensions of energy and vitality and physical role limitation were abnormal before nCPAP (p < 0.05) and normalized with treatment. Sleepiness and pretreatment SF-36 values correlated significantly (Epworth Sleepiness Scale versus energy and vitality, r = -0.47, p < 0.001; modified Maintenance of Wakefulness Test versus energy and vitality, r = 0.32, p < 0.05). We conclude that the health status of patients with OSA improves with nCPAP and this improvement correlates with sleep fragmentation severity. However, the correlation is not very close, which may reflect the improvement with nCPAP of other symptoms not directly related to disease severity.

Hack MA, Davies RJO, Mullins R, Stradling JR. 1999. Randomised, sham placebo controlled study of nasal continuous positive airway pressure (NCPAP) on simulated steering in obstructive sleep apnoea (OSA). AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 159 (3), pp. A429-A429.

Stradling JR, Jenkinson C, Davies RJO, Mullins B. 1999. Randomised, sham placebo controlled, parallel study of nCPAP on quality of life (SF36) in obstructive sleep apnoea. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 159 (3), pp. A770-A770.

Choi SJ, Mullins B, Nicoll D, Smith D, Davies RJO, Stradling JR. 1999. Is there a significant change in nasal continuous positive airway pressure (NCPAP) requirements after one month? AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 159 (3), pp. A427-A427.

Bennett LS, Davies RJO, Stradling JR. 1999. Oximetry derivatives in the assessment of OSA AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 159 (3), pp. A795-A795.

Benatar SR. 1999. Obstructive sleep apnoea. Lancet, 354 (9185), pp. 1212. | Read more

Stradling JR, Pitson DJ, Bennett L, Barbour C, Davies RJ. 1999. Variation in the arousal pattern after obstructive events in obstructive sleep apnea. Am J Respir Crit Care Med, 159 (1), pp. 130-136. | Show Abstract | Read more

The relationship between the severity of obstructive sleep apnea (OSA) (measured by sleep study) and daytime sleepiness is poor. Variation in the degree of arousal accompanying obstructive respiratory events might help explain this poor correlation. Polysomnographic records from patients with OSA were reviewed in order to extract representative examples of apneas and hypopneas (in 10 patients), as well as events both supine and decubitus (in 12 patients). The EEG accompanying each obstructive event was processed with a neural network technique to describe sleep depth on a second-by-second basis. The lengths of any visually evident microarousals were also measured manually. There was considerable interindividual variation in the degree of sleep disturbance using the neural network technique (p < 0.005), but not using the lengths of the visually scored microarousals (p = 0.6). The arousals accompanying apneic events caused greater variability in sleep depth quantified using the neural network technique (p = 0.03), and also lasted longer based on the visual scoring (mean, 12.6; SD, 1.7 s) than the hypopneic events (mean, 9.9; SD, 2.4 s; p = 0.02). There were no significant differences between events occurring supine versus decubitus with either technique (p = 0.7). These differences in arousal magnitude may explain some of the poor correlations between conventional measures of sleep apnea severity and daytime sleepiness.

Davies CWH, Crosby JH, Mullins RL, Barbour C, Davies RJO, Stradling JR. 1999. Case control study of 24-hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects Thorax, 54 (SUPPL. 3), | Show Abstract

There is considerable debate regarding the relationship between obstructive sleep apnoea (OSA) and hypertension. Many studies attempting to assess the association, have produced conflicting results, which may be due to variable allowance for confounding variables such as upper body obesity, alcohol and smoking. We performed a case control study of 24-hour ambulatory blood pressure (ABP) monitoring in patients with OSA, compared to closely matched controls from the general population, to assess whether OSA is an independent contributor to diurnal hypertension. 45 sleep clinic patients with moderate to severe OSA and excessive daytime sleepiness were matched to 45 controls without evidence of OSA on a sleep study. Matched variables included age, body mass index (BMI), alcohol and cigarette consumption, treated hypertension and history of ischaemic heart disease. Upper body obesity was measured using waist:hip and waist:height ratios. 24-hour ABP recordings were performed in all subjects, and before treatment in the patients with OSA. Compared to controls, OSA patients had significantly increased mean (SD) diastolic blood pressure (DBP) during both the daytime (87.4 (10.2) versus 82.8 (9.1) mmHg, p<0.05) and night-time (78.6 (9.3) versus 71.4 (8.0), p<0.001), and higher systolic blood pressure (SBP) at night (119.4 (20.7) versus 110.2 (13.9), p<0.05). There was less nocturnal reduction in SBP ("dipping") in patients with OSA (day to night fall SBP, 13.5 v 21.0mmHg, p<0.005). The relatively increased nocturnal SBP in patients with OSA persisted briefly into the morning. Compared to closely matched control subjects, patients with OSA have increased DBP during both day and night, and increased SBP at night. The magnitude, of these differences is such that by extrapolation it should carry increased relative risk of cardiovascular morbidity. Further studies are required to establish whether cardiovascular morbidity is in fact raised and whether treatment of OSA reduces blood pressure and its complications.

Davies CWH, Crosby JH, Mullins RL, Traill ZC, Anslow P, Davies RJO, Stradling JR. 1999. Case control study of magnetic resonance image defined subclinical cerebrovascular damage in patients with obstructive sleep apnoea and normal control subjects Thorax, 54 (SUPPL. 3), | Show Abstract

A number of studies have demonstrated a relationship between the clinical syndrome of obstructive sleep apnoea (OSA) and hypertension. There is also an excess of cardiovascular morbidity and mortality in subjects with OSA, but studies examining important clinical endpoints of cardiovascular disease, e.g. left ventricular hypertrophy (LVH) in OSA subjects have produced conflicting results. Cerebral magnetic resonance imaging (MRI) detects clinically silent abnormalities relating to hypertensive cerebrovascular disease, which are seen as small areas of high signal foci in deep white matter (DWM) and lacunae. These lesions are permanent and known to be associated with stroke, age, hypertension, LVH and carotid atherosclerosis. We performed a case control study of cerebral MRI in patients with OSA and closely matched controls. 37 sleep clinic patients with moderate to severe OSA and excessive daytime sleepiness were matched to 37 controls without evidence of OSA on a sleep study. Matched variables included age, body mass index (BMI), alcohol and cigarette consumption, treated hypertension and history of ischaemic heart disease. 24-hour ABP recordings were performed in all subjects, and before treatment in the patients with OSA. All subjects underwent standard sagittal T1 and axial T2 MRI imaging, which were analysed for high signal abnormalities. Lacunae/high signal foci in DWM were present in 15 (40%) OSA subjects and 19 (51%) controls, despite significant increases in mean daytime diastolic blood pressure (5.0mmHg,p<0.05) and nighttime diastolic (7.8mmHg,p<0.001) and systolic blood pressures (11.7mmHg,p<0.05). Subclinical cerebrovascular disease is common in the populations studied - both OSA and matched controls. Despite increased ABP, there is no increase in MRI evident subclinical cerebrovascular disease in OSA.

Hack M, Choi S, Mullins R, Dow S, Davies RJO, Stradling JR. 1999. Performance of patients with Obstructive Sleep Apnoea (OSA) on a steering simulation after six months treatment with Nasal Continuous Positive Airway Pressure (NCPAP) Thorax, 54 (SUPPL. 3), | Show Abstract

The long-term effect of nCPAP on steering performance in OSA has not been assessed. 42 OSA patients (Epworth Sleepiness Score (ESS) ≥ 10, and ≥ 10/hr >4% SaO 2 dips) performed three simulator drives each lasting for 30 minutes, and maintenance of wakefulness tests (MWT) at baseline, 1 month and 6 months. Patients were randomised to receive either sub-therapeutic or real nCPAP (Lancet 1999, 352:2100). Patients were retitrated at 1 month to therapeutic nCPAP. Performance was quantified by the standard deviation of steering error across the drive (sd), and reaction time (reactn) to identification of a target digit. Results are median, significance by Wilcoxon test. Median Sub-therapeutic (n = 23) Therapeutic (n = 19) 5/95 MONTH P P MONTH P P centile 0 1 6 0/1 1/6 0 1 6 0/1 1/6 Steer 0.36 0.42 0.23 NS 0.003 0.44 0.20 0.19 0.004 NS Error 0.15 0.14 0.14 0.15 0.13 0.08 (sd) /1.4 /1.2 /0.8 /1.2 /0.7 /0.5 Reactn 2.8 3.2 2.5 NS 0.04 2.7 2.1 2.2 0.001 NS /sec 1.4 1.7 1.3 1.7 1.5 1.2 /5.3 /3.9 /3.6 /5.3 /3.4 /3.2 MWT 20.1 25.7 37.6 NS 0.002 19.5 38.3 40.0 0.001 0.02 /min 7.7 7.1/ 9.5 6.8 15 29 /40 40 /40 /35 /40 /40. Therapeutic NCPAP significantly improves simulated steering performance in OSA. Despite improvement at 6 months the steering performance did not return to that of a group of controls (sd 0.16(0.13/0.31), although reaction time and sleepiness measurements were normal. This differential outcome suggests factors other than sleepiness may contribute to the impaired steering simulation performance in OSA, which persists after treatment.

Gibson GJ, Douglas NJ, Stradling JR, London DR, Semple SJ. 1998. Sleep apnoea: clinical importance and facilities for investigation and treatment in the UK. Addendum to the 1993 Royal College of Physicians Sleep Apnoea report. J R Coll Physicians Lond, 32 (6), pp. 540-544. | Show Abstract

The potential importance of the obstructive sleep apnoea syndrome (OSA) has been recognized only in the last few years. Epidemiological studies suggest that symptomatic OSA occurs in 1-2% of middle-aged men and in approximately half that number of women. The relation of OSA to vascular disease is uncertain and the main indication for treatment is the relief of disabling sleepiness. Two recent evidence based analyses have produced diametrically opposed conclusions on the efficacy of treatment with nasal continuous positive airway pressure (CPAP). However, recent controlled studies confirm the overwhelming clinical experience of benefit. Facilities for the investigation and treatment of patients with OSA in the UK are subject to severe financial constraints and the availability of CPAP treatment lags markedly behind that in other countries for which data are available.

Bennett LS, Langford BA, Stradling JR, Davies RJ. 1998. Sleep fragmentation indices as predictors of daytime sleepiness and nCPAP response in obstructive sleep apnea. Am J Respir Crit Care Med, 158 (3), pp. 778-786. | Show Abstract | Read more

Sleep fragmentation and respiratory disturbance measures are used in the assessment of obstructive sleep apnea (OSA) but have proved to be disappointingly poor correlates of daytime sleepiness. This study investigates the ability of electroencephalograph (EEG) and non-EEG sleep fragmentation indices to predict both presenting sleepiness and the improvement in sleepiness with subsequent nasal continuous positive airway pressure (nCPAP) therapy (nCPAP responsive sleepiness). Forty-one patients (36 men, 5 women), ranging from nonsnorers to severe OSA (> 4% O2 dip rate, median 11.1, range 0.4 to 76.5), had polysomnography with microarousal scoring, computerized EEG analysis, autonomic arousal detection, and body movement analysis. All patients received a trial of nCPAP regardless of sleep study outcome. Spearman's correlation analysis showed significant and similar associations between all sleep fragmentation indices with both pretreatment and nCPAP responsive sleepiness. There was no deterioration in sleepiness on nCPAP in the nonsnorers. Using stepwise multiple regression analysis, the best predictor of nCPAP responsive subjective and objective sleepiness was body movement index, explaining 38% and 43% of the variance, respectively. Variability in EEG sleep depth, quantified from computerized EEG analysis, was the only other index to contribute to these models. Together these indices explained 44% and 51% of the subjective and objective response to nCPAP, respectively. These results suggest that sleep fragmentation indices are useful for identifying OSA patients with sleepiness likely to respond to nCPAP.

Pitson DJ, Stradling JR. 1998. Value of beat-to-beat blood pressure changes, detected by pulse transit time, in the management of the obstructive sleep apnoea/hypopnoea syndrome. Eur Respir J, 12 (3), pp. 685-692. | Show Abstract | Read more

Two important aspects of a respiratory sleep study are a measure of inspiratory effort and an estimate of the number of arousals. These can be derived from an indirect estimate of beat-to-beat blood pressure (BP), pulse transit time (PTT). This study investigated the reproducibility of inspiratory BP falls (reflecting inspiratory effort), and BP arousals derived from PTT, and the contribution they could make to the management of the obstructive sleep apnoea/hypopnoea syndrome (OSAHS). Overnight PTT was recorded at home in 40 patients being investigated for OSAHS, and a second PTT recording was made in the sleep laboratory with full polysomnography. Patients were divided into three groups according to the severity of their sleep disorder, and a third PTT recording was made at home in 13 patients subsequently established on nasal continuous positive airway pressure (CPAP). The reproducibility between the home and laboratory studies was reasonable (r=0.87 for inspiratory BP falls, r=0.81 for BP arousals). Both derivatives showed a clear progression through the three patient groups, which returned to normal on treatment. The differences between the groups were significant (p<0.001 for inspiratory BP falls, p=0.0014 for BP arousals). Receiver operator characteristic curves, used to compare polysomnography variables and PTT variables, confirmed that the PTT variables were as good as apnoea-hypopnoea index (AHI), >4% arterial oxygen saturation dip rate and electroencephalography micro-arousals at dividing patients into two groups, either requiring nasal CPAP or not requiring CPAP. Pulse transit time can provide a noninvasive estimate of inspiratory effort and a measure of arousals that together document disease severity and response to treatment and may be useful in managing obstructive sleep apnoea/hypopnoea syndrome.

Bennett LS, Davies RJ, Stradling JR. 1998. Oral appliances for the management of snoring and obstructive sleep apnoea. Thorax, 53 Suppl 2 (Supplement 2), pp. S58-S64. | Show Abstract | Read more

BACKGROUND: Although oral appliances are effective in some patients with obstructive sleep apnoea (OSA), they are not universally effective. A novel anterior mandibular positioner (AMP) has been developed with an adjustable hinge that allows progressive advancement of the mandible. The objective of this prospective crossover study was to compare efficacy, side effects, patient compliance, and preference between AMP and nasal continuous positive airway pressure (nCPAP) in patients with symptomatic mild to moderate OSA. METHODS: Twenty four patients of mean (SD) age 44.0 (10.6) years were recruited with a mean (SD) body mass index of 32.0 (8.2) kg/m2, Epworth sleepiness score 10.7 (3.4), and apnoea/hypopnoea index 26.8 (11.9)/hour. There was a two week wash-in and a two week wash-out period and two treatment periods (AMP and nCPAP) each of four months. Efficacy, side effects, compliance, and preference were evaluated by a questionnaire and home sleep monitoring. RESULTS: One patient dropped out early in the study and three refused to cross over so treatment results are presented on the remaining 20 patients. The apnoea/hypopnoea index (AHI) was lower with nasal CPAP 4.2 (2.2)/hour than with the AMP 13.6 (14.5)/hour (p < 0.01). Eleven of the 20 patients (55%) who used the AMP were treatment successes (reduction of AHI to < 10/hour and relief of symptoms), one (5%) was a compliance failure (unable or unwilling to use the treatment), and eight (40%) were treatment failures (failure to reduce AHI to < 10/hour and/or failure to relieve symptoms). Fourteen of the 20 patients (70%) who used nCPAP were treatment successes, six (30%) were compliance failures, and there were no treatment failures. There was greater patient satisfaction with the AMP (p < 0.01) than with nCPAP but no difference in reported side effects or compliance. CONCLUSIONS: AMP is an effective treatment in some patients with mild to moderate OSA and is associated with greater patient satisfaction than nCPAP.

Stradling J, Roberts D, Wilson A, Lovelock F. 1998. Controlled trial of hypnotherapy for weight loss in patients with obstructive sleep apnoea. Int J Obes Relat Metab Disord, 22 (3), pp. 278-281. | Show Abstract | Read more

OBJECTIVE: To assess if hypnotherapy assists attempts at weight loss. DESIGN: Randomised, controlled, parallel study of two forms of hypnotherapy (directed at stress reduction or energy intake reduction), vs dietary advice alone in 60 obese patients with obstructive sleep apnoea on nasal continuous positive airway pressure treatment. SETTING: National Health Service hospital in the UK. MEASURES: Weight lost at 1, 3, 6, 9, 12, 15 and 18 months after dietary advice and hypnotherapy, as a percentage of original body weight. RESULTS: All three groups lost 2-3% of their body weight at three months. At 18 months only the hypnotherapy group (with stress reduction) still showed a significant (P < 0.02), but small (3.8 kg), mean weight loss compared to baseline. Analysed over the whole time period the hypnotherapy group with stress reduction achieved significantly more weight loss than the other two treatment arms (P < 0.003), which were not significantly different from each other. CONCLUSIONS: This controlled trial on the use of hypnotherapy, as an adjunct to dietary advice in producing weight loss, has produced a statistically significant result in favour of hypnotherapy. However, the benefits were small and clinically insignificant. More intensive hypnotherapy might of course have been more successful, and perhaps the results of the trial are sufficiently encouraging to pursue this approach further.

Pitson DJ, Stradling JR. 1998. Autonomic markers of arousal during sleep in patients undergoing investigation for obstructive sleep apnoea, their relationship to EEG arousals, respiratory events and subjective sleepiness. J Sleep Res, 7 (1), pp. 53-59. | Show Abstract | Read more

Estimating the degree of sleep fragmentation is an important part of a respiratory sleep study and is conventionally measured using EEG micro arousals or is inferred indirectly from respiratory abnormalities such as apnoeas and desaturations. There is a need for less labour-intensive measures of sleep fragmentation, and transient rises in blood pressure and heart rate may fulfil this role. Forty unselected sleep clinic referrals undergoing investigation for possible obstructive sleep apnoea (OSA) were studied with one night of polysomnography. Three conventional indices of sleep fragmentation (EEG micro arousals, apnoea/hypopnoea index (AHI) and oxygen saturation dip rate (SaO2 dips)) and two autonomic indices (heart rate and blood pressure rises) have been compared. Correlations between these five indices ranged from r=0.38 to r=0.73. Of the two autonomic indices, the correlations for blood pressure rises with SaO2 dips and EEG micro arousals were stronger (r=0.71 and r=0.65, respectively) than those for heart rate rises (0.55 and 0.51). All indices of sleep fragmentation, apart from heart rate rises, were similar in their correlation with subjective sleepiness (r-values 0.21-0.36). Arousals implied from blood pressure rises (using pulse transit time) can be measured easily, are objective, and appear no worse at predicting subjective sleepiness than either EEG micro arousals or AHI. They may therefore provide a useful alternative to manual scoring of micro arousals from the EEG as an index of sleep fragmentation in sleep clinic patients undergoing investigation for possible OSA.

Jenkinson C, Stradling J, Petersen S. 1998. How should we evaluate health status? A comparison of three methods in patients presenting with obstructive sleep apnoea. Qual Life Res, 7 (2), pp. 95-100. | Show Abstract | Read more

The purpose of this paper is to compare three approaches to the measurement of patient-reported health status which produce summary scales of health status: the Patient-generated Index (PGI) is a measure of individual quality of life (QoL), the EuroQol is a measure of QoL the results of which are weighted by utility values gained from community surveys and the SF-36 which produces two summary scales of health status (the physical component summary (PCS) and the mental component summary (MCS) scores). A follow-up interview survey of patients with obstructive sleep apnoea (OSA) was conducted. The patients received continuous positive airways pressure therapy (CPAP) between the two administrations of the questionnaires. One hundred patients presenting with OSA and who were suitable for CPAP therapy were asked if they would take part in the study. The results on the PGI, EuroQol EQ-5D utility weighted scores and 'thermometer' scores and SF-36 physical and mental summary scores were measured. Eighty-nine respondents provided sufficient data to calculate PGI and EuroQol scores and 86 patients provided sufficient data to calculate SF-36 summary scores. The PGI indicated substantial improvement after CPAP treatment whereas the EuroQol indicated little or no improvement on either utility weighted or thermometer scores. The SF-36 PCS and MCS scores were lower than those of the general population at baseline, but had improved to the normative levels after treatment. The EuroQol provided a substantially different picture of change to either of the ones gained from the SF-36 or PGI. It is suggested that the EuroQol does not contain questions which relate to important aspects of health and well-being and may not accurately reflect the health state of individuals. Consequently, caution must be exercised to assure that an appropriate instrument has been employed when using health outcomes data to assess or prioritize available health care treatments.

Stradling JR, Negus TW, Smith D, Langford B. 1998. Mandibular advancement devices for the control of snoring. Eur Respir J, 11 (2), pp. 447-450. | Show Abstract | Read more

Patients presenting with the complaint of antisocial snoring have very few options available to them of proven efficiency. Mandibular advancement devices worn intra-orally at night, have recently been shown in controlled trials to help mild to moderate obstructive sleep apnoea. However, there are no properly controlled studies with objective measurements on the use of such appliances for the management of antisocial snoring. Fifteen patients, already established on mandibular advancement devices for the control of snoring, were asked to participate in this study. They were studied over two nights, using a portable sleep monitoring device at home, both with and without their mandibular advancement devices in place (in randomized order). Snoring was measured using a surface throat microphone. In addition oxygen saturation and indirect beat to beat blood pressure were measured. The latter (using pulse transit time) provided an index of autonomic "arousals" and a measure of inspiratory effort. In nearly all of these highly selected patients the mandibular advancement devices reduced significantly the amount of snoring from a median of 193 to 20 snores x h(-1) (p<0.0001). In addition there was a reduction in respiratory effort, implying enlargement of the upper airway whilst wearing the appliance. These patients only represent those who were able to tolerate the appliance. With such clear evidence of their potential efficacy, and no suggestion from other studies of any harm, it would seem reasonable to introduce this approach into the management of antisocial snoring.

Stradling JR, Negus TW, Smith D, Langford B. 1998. Mandibular advancement devices for the control of snoring Pneumologie, 52 (11), pp. 653.

Gibson GJ, Douglas NJ, Stradling JR, London DR, Semple SJG. 1998. Sleep apnoea: Clinical importance and facilities for investigation and treatment in the UK Journal of the Royal College of Physicians of London, 32 (6), pp. 540-544. | Show Abstract

The potential importance of the obstructive sleep apnoea syndrome (OSA) has been recognised only in the last few years. Epidemiological studies suggest that symptomatic OSA occurs in 1-2% of middle-aged men and in approximately half that number of women. The relation of OSA to vascular disease is uncertain and the main indication for treatment is the relief of disabling sleepiness. Two recent evidence based analyses have produced diametrically opposed conclusions on the efficacy of treatment with nasal continuous positive airway pressure (CPAP). However, recent controlled studies confirm the overwhelming clinical experience of benefit. Facilities for the investigation and treatment of patients with OSA in the UK are subject to severe financial constraints and the availability of CPAP treatment lags markedly behind that in other countries for which data are available.

Hack MA, Davies RJO, Stradling JR. 1998. Randomised, sham placebo, parallel study of the effect of Nasal Continuous Positive Airway Pressure (NCPAP) on steering performance in patients with Obstructive Sleep Apnoea (OSA) - interim analysis Thorax, 53 (SUPPL. 4), | Show Abstract

Steering a car involves the two visual functions of predicting road curvature and maintaining road position (Nature 1995;377:339-340). OSA patients show substantial impairment in these visual tasks of steering on a simulator, compared to normals (AJRCCM 1998; 157: A50). 38 untreated OSA patients (Epworth sleepiness score > 9, and >10/hr > 4% SaO2 dips) have so far been randomised to receive placebo or real NCPAP. Placebo NCPAP is provided by using a mask pressure <2 cmsH2O (achieved by adjusting the pressure setting to 3 cmsH2O and providing extra air leaks at the mask). All patients performed three simulator drives at entry to the study and at one month following treatment. Each drive involves steering along a road display that bends pseudo-randomly for thirty minutes. Performance is quantified as the standard deviation (SD) of the steering error from the theoretical perfect path (AJRCCM 1996;154:175-81). Results are the mean (SEM) of the standard deviation of steering error for 16 patients on real NCPAP, and 22 on placebo; significance by unpaired T test. Pre Post Pre Post Significance of Real Real Placebo Placebo changes produced by real v placebo mean SD of 0.47 0.28 0.44 0.44 p = 0.038 steering (SEM) 0.07 0.04 0.07 0.07 Compliance over the 4 weeks was 5.6 and 4.7 hrs/night, real and placebo respectively (NS). Compared to the placebo treated group, OSA patients treated with real NCPAP show a significant improvement in the visual tasks of steering.

Stradling JR, Jenkinson C, Davies RJO, Mullins B. 1998. Randomised, sham-placebo, parallel study of Nasal Continuous Positive Airway Pressure (NCPAP) for the treatment of Obstructive Sleep Apnoea (OSA) Thorax, 53 (SUPPL. 4), | Show Abstract

Doubt has been expressed as to the true symtomatic benefit derived from NCPAP in patients with OSA. We are carrying out a randomised, sham placebo-controlled trial. Patients are recruited who have more than 10/hr >4%SaO2 dips, and Epworth sleepiness scores (ESS) of more than 9. Initial assessment includes the ESS (range 0-24) and a behavioural maintenance of wakefulness test (OSLER test, J.Sleep Res. 1997;6:142, range 0-40mins). Patients are told we are comparing two pressures for treating OSA, either of which may work. Following randomisation, patients are either auto-titrated with a DeVilbiss Horizon or receive a low fixed pressure. Thereafter they spend 4 weeks set at either their required titration pressure, or at <2cms H2O (achieved by adjusting the pressure setting to 3cmsH2O and providing extra air leaks at the mask). At 4 weeks the assessments are repeated blind and patients retitrated to their required levels. 100 patients have so far been randomised and 91 have completed the protocol. Results are medians and 25/75th centiles, significance by Wilcoxon rank sum tests. Pre Post Pre Post Significance of Real Real Placebo Placebo changes produced by real v placebo ESS 16 7 16 14 <0.001 13-19 4-9 13-18 7-16 OSLER 22 36 20 24 <0.003 mins 13-32 22-40 12-32 15-35. Compliance over the 4 weeks was 5.4 and 4.2 hrs/night, real and placebo respectively (P=0.02). Despite a small placebo effect there is clear significance in favour of active treatment.

Davies RJ, Bennett LS, Stradling JR. 1997. What is an arousal and how should it be quantified? Sleep Med Rev, 1 (2), pp. 87-95. | Show Abstract | Read more

Pathologically severe daytime sleepiness is one of the main symptoms seen in a respiratory sleep clinic and is due to repeated arousal from sleep. Which types of arousal are most important in causing this is uncertain and most studies have only found loose relationships between indices of arousal frequency and the severity of the ensuing daytime sleepiness. Recent attempts to improve these disappointing correlations have concentrated on detecting more minor arousal events through the use of novel EEG signal analysis techniques and non-EEG based signals such as blood pressure and heart rate. To date there are no good data sets which allow the relative merits of these various techniques to be compared and it is unclear whether these efforts to increase the sensitivity of arousal detection will lead to improvements in the clinical usefulness of sleep fragmentation scoring. Studies which relate both the traditional indices of sleep fragmentation and the newer methodologies to clinically relevant reference standards (such as measured excessive daytime sleepiness) are needed to clarify these issues.

Stradling J, Davies RJ. 1997. Sleep apnea and hypertension--what a mess! Sleep, 20 (9), pp. 789-793. | Show Abstract | Read more

It is unarguable that obstructive sleep apnea (OSA) causes pulsatile hypertension during sleep, but whether there is significant carryover of hypertension into waking hours is far from clear. It is perhaps more useful to consider whether OSA is related to the consequences of hypertension (e.g. stroke), since both nocturnal and daytime hypertension could be responsible for these. Furthermore, the effects of nasal continuous positive airway pressure (CPAP) on hypertension (or its consequences) must be assessed by randomized controlled studies, in exactly the same way as trials on hypotensive drugs would be carried out, before treatment is prescribed for OSA in the absence of any daytime symptoms.

Jenkinson C, Stradling J, Petersen S. 1997. Comparison of three measures of quality of life outcome in the evaluation of continuous positive airways pressure therapy for sleep apnoea. J Sleep Res, 6 (3), pp. 199-204. | Show Abstract | Read more

Treatment of obstructive sleep apnoea (OSA) with nasal continuous positive airway pressure (NCPAP) has become a standard treatment since its introduction in 1981. Following such treatment the apnoeas disappear, sleep quality improves as apparently do daytime symptoms of sleepiness. Sleepiness is an unusual symptom and its impact on conventional indices of quality of life has rarely been measured. To allow comparison of NCPAP therapy with treatments for other conditions, measurements of quality of life before and after treatment using standard techniques are required. It is not clear which of the standard measures is most suited to measuring the health gain from nasal NCPAP, and indeed whether the disability of excessive sleepiness is included in all such measures. This study looks at three well recognized quality of life measures in OSA, before and after NCPAP therapy; the Short Form 36 (SF-36), Functional Limitations Profile (FLP), and the EuroQol (EQ-5D). The results were compared with data from normal populations. One hundred and eight patients with OSA undergoing a therapeutic assessment of NCPAP completed the three quality of life questionnaires before and 5 weeks after commencing treatment. Over 90 subjects completed all sections of the three measures on both occasions. The SF-36 revealed substantial adverse effects on subjective health of OSA and that NCPAP treatment produced dramatic positive effects. For example, the effect sizes (difference in score, divided by SD of baseline score) in the Energy/Vitality dimension was 0.98 and for the overall Mental and Physical Component Scores, 0.76 and 0.57, respectively: an effect size over 0.5 is considered moderate and over 0.8 as large. The FLP data showed similar pre treatment decrements in quality of life and substantial improvements following NCPAP. The changes with treatment in the majority of the dimensions from both the SF-36 and FLP were statistically significant (P < 0.01). In contrast the EQ-5D did not show significant improvements with therapy, presumably because of its failure to measure the aspects of quality of life related to severe sleep fragmentation and daytime sleepiness. In conclusion, this study has clearly shown considerable decrements in quality of life in patients with OSA, similar to other chronic disabling conditions. Furthermore, NCPAP therapy returns patients to a quality of life similar to the normal population.

Stradling JR, Davies RJ. 1997. Obstructive sleep apnoea. Evidence for efficacy of continuous positive airways pressure is compelling. BMJ, 315 (7104), pp. 368.

Shneerson J, Smith I. 1997. Obstructive sleep apnoea. False impression of objectivity may deny patients affordable treatment. BMJ, 315 (7104), pp. 367. | Read more

Bennett LS, Stradling JR, Davies RJ. 1997. A behavioural test to assess daytime sleepiness in obstructive sleep apnoea. J Sleep Res, 6 (2), pp. 142-145. | Show Abstract | Read more

Daytime sleepiness is an important symptom of obstructive sleep apnoea syndrome (OSAS). The standard tests for its objective quantification use EEG recordings, and are time consuming and expensive, which makes them difficult to use for large studies. This study assesses the ability of a simple test of sustained 'wakefulness' to discriminate the excessive somnolence of severe symptomatic obstructive sleep apnoea from normality, and compares its results to the traditional EEG based Maintenance of Wakefulness Test (MWT). Ten subjects (7M 3F) with severe sleep apnoea (> 4% SaO2 dip rate median 32.7 (90% central range 9.7-65.6)) and symptoms of daytime sleepiness, (Epworth Sleepiness Score (ESS)17(10-24)) and 10 normal subjects (4M 6F, ESS 3.5(1-8)) were studied. The MWT and the behavioural test (Oxford SLEep Resistance test - OSLER test) were performed on each subject in random order on 2 separate days. The protocol for both tests was the same with 4 X 40 min sleep resistance challenges throughout the day while sound isolated in a darkened room. During the OSLER test subjects were asked to press a switch in response to a light emitting diode (LED), which was lit for 1 s in every three. Both the switch and the light were connected to a computer that stored both the number of times the light was illuminated and whether a correct response was made. The OSLER test discriminated the normal subjects from the sleep apnoea group (mean sleep latency (min) normal group 39.8, OSA group 10.5) as well as the traditional MWT (normal group 38.1 OSA group 7.3) and was much simpler to administer. This test has the advantage that sleep onset is defined objectively and automatically as a failure to respond to the light, rather than from EEG interpretation, which is inevitable partly subjective. This technique may provide a simple and robust method of objectively quantifying daytime sleepiness for large studies.

Jenkinson C, Layte R, Jenkinson D, Lawrence K, Petersen S, Paice C, Stradling J. 1997. A shorter form health survey: can the SF-12 replicate results from the SF-36 in longitudinal studies? J Public Health Med, 19 (2), pp. 179-186. | Show Abstract | Read more

BACKGROUND: The SF-36 is a generic health status measure which has gained popularity as a measure of outcome in a wide variety of patient groups and social surveys. However, there is a need for even shorter measures, which reduce respondent burden. The developers of the SF-36 have consequently suggested that a 12-item sub-set of the items may accurately reproduce the two summary component scores which can be derived from the SF-36 [the Physical Component Summary Score (PCS) and Mental Health Component Summary Score (MCS)]. In this paper, we adopt scoring algorithms for the UK SF-36 and SF-12 summary scores to evaluate the picture of change gained in various treatment groups. METHODS: The SF-36 was administered in three treatment groups (ACE inhibitors for congestive heart failure, continuous positive airways therapy for sleep apnoea, and open vs laparoscopic surgery for inguinal hernia). RESULTS: PCS and MCS scores calculated from the SF-36 or a sub-set of 12 items (the 'SF-12') were virtually identical, and indicated the same magnitude of ill-health and degree of change over time. CONCLUSION: The results suggest that where two summary scores of health status are adequate than the SF-12 may be the instrument of choice.

Stradling JR, Davies RJ. 1997. The unacceptable face of evidence-based medicine. J Eval Clin Pract, 3 (2), pp. 99-103. | Read more

Bennett LS, Stradling JR. 1997. Who should receive treatment for sleep apnoea? Thorax, 52 (2), pp. 103-104. | Read more

Stradling J. 1997. Sleep apnoea and the misuse of evidence-based medicine. Lancet, 349 (9046), pp. 201-202. | Read more

Bennett LS, Langford BA, Stradling JR, Davies RJO. 1997. Can autonomic arousals and neural net EEG analysis predict daytime sleepiness and its response to nCPAP in OSA? Thorax, 52 (SUPPL. 6), | Show Abstract

The main symptom of OSA is daytime sleepiness due to sleep fragmentation. An automated marker which detects which OSA patients have sleep fragmentation likely to respond to nCPAP would be clinically useful. This study examines how well autonomic ('sub-cortical') arousals, neural network EEG analysis and ASDA arousal scoring predict objective and subjective sleepiness before nCPAP and the improvement in objective and subjective daytime sleepiness with nCPAP in patients with OSA. 41 (36M, SF) patients with the full spectrum of upper airway narrowing during sleep from normal to severe OSA, (AHI med 18, range 0-123), had polysomnography with ASDA arousal scoring, neural net EEG analysis and autonomic arousal detection (arterial pulse transit time, PTT). Neural net EEG analysis was post-processed using our 'sleep depth descent index'(AJRCCM 155(4pt2): 132) and the average of the SD of the neural net sleep depth index gathered for each one minute of EEG analysis. The autonomic arousal index was the number of PTT falls per hour of sleep. Objective sleepiness (Oxford Sleep Resistance (OSLER) test (JSR 6; 142-145)) and subjective sleepiness (Epworth Score) were performed before and after one month on nCPAP. All subjects, including the normals, received nCPAP. Pearson's correlation was used to examine the relationships with sleepiness and its response to nCPAP. ASDA PTT Neural Net indices descent SD sleep depth ESS (pre-nCPAP) 0.51 0.49 0.45 0.46 OSLER (pre-nCPAP) -0.49 -0.49 -0.47 -0.50 ESS change with nCPAP -0.46 -0.48 -0.56 -0.57 OSLER change with nCPAP 0.51 0.56 0.62 0.64 (r values-all p<0.05) These automated sleep fragmentation indices predict pre-treatment sleepiness and nCPAP related improvement in sleepiness at least as well as ASDA arousal scoring. These techniques provide objective and cost effective methods of quantifying OSA related sleep fragmentation.

Stradling J, Crosby J, Partlett J, Barbour C. 1997. Predictors of overnight Blood Pressure (BP) changes in normal subjects Thorax, 52 (SUPPL. 6), | Show Abstract

Recent evidence has suggested that obstructive sleep apnoea (OSA) may affect the normal overnight fall in blood pressure more so than the average diurnal figure. The aspect of OSA responsible for higher BP is far from clear, possibilities being hypoxia, sleep disturbance or increased inspiratory effort. This abstract reports an interim analysis from a community survey of 326 randomly selected men and women aged 35-65 addressing this issue. Following random selection from a GP practice's patient records, subjects were visited at home by a specially trained nurse. Husbands and wives were usually studied on the same occasion. Questionnaires were administered and anthropometric measurements made. BPs were measured with an automatic device three times by the nurse, three times by the subject themselves (after instruction), and again three times the following morning by the subject immediately on arousal. Overnight recordings were made using the RM50 recorder (SaO2, snoring (throat microphone), posture, heart rate, thoracic movement, and indirect beat to beat blood pressure (pulse transit time)). These data were processed to give >4%SaO2dip rate, snores/hr, mean inspiratory effort across the night (pulsus paradoxus), and autonomic (blood pressure) 'arousals'/hr. The difference between the morning and evening BP measured by the subjects was calculated. The relationship between morning to evening BP change and potential predictors was explored using linear modelling (SAS), any non-normally distributed data was logged first. Evening to morning systolic BP change averaged -9.5mmHg (95th centiles, - 32 to +11). Independent predictors of this evening to morning change in SBP were average overnight inspiratory effort (P<0.0001) and >4%SaO2 dip rate (P=0.03); autonomic arousals, snoring, mean blood pressure and anthropometric variables were not independent correlates. Inspiratory effort, arousals and snoring were inter-correlated, as would be predicted. This suggests that inspiratory effort may be one of the characteristics of OSA and its variants that influence BP beyond the sleeping period.

Stradling J, Roberts D, Wilson A, Lovelock F. 1997. Controlled trial of hypnotherapy for weight loss in patients with Obstructive Sleep Apnoea (OSA) Thorax, 52 (SUPPL. 6), | Show Abstract

The main cause of OSA is upper body obesity. Despite this, most patients do not lose sufficient weight to get off nasal continuous positive airway pressure (CPAP). In a controlled trial we have explored the use of hypnotherapy, in conjunction with modern dietary advice, in helping OSA patients already on CPAP to lose weight. Hypnotherapy was given in two sessions, a month apart, by an experienced medical hypnotherapist. This was accompanied either by stress reduction strategies, or by suggestions designed to promote reduced calorie intake. An audiotape was provided for continued use at home. Dietary advice was given on two occasions, a month apart, by an experienced dietician, supplemented by appropriate literature. Sixty CPAP patients were randomly assigned to three experimental groups:- dietary advice alone, dietary advice plus hypnotherapy aimed at stress reduction, and dietary advice plus hypnotherapy aimed at calorie reduction. Weights were measured at 1, 3, 6, 9, 12, 15 and 18 months. Analysis of Variance (ANOVA) was used to compare the %weight lost in the three groups. 14 out of 60 patients (25%) railed to complete (5,5 and 4 in the three groups). Initial Body Mass Index was 39.2 (SD6.8) kg/m2. When analysed separately, only the hypnotherapy/stress reduction group maintained a significant, but small, weight loss at 18 months (P<0.02, 3.8 (SD5.8) kg). ANOVA of the three groups showed no significant difference at any one time point, but using the 'area under the curve' (which considers the whole time period) indicated that hypnotherapy with stress reduction produced significantly more weight loss that the other two treatment arms (P<0.003), which were not significantly different from each other. This weight loss trial, conducted in an NHS setting on patients with OSA using CPAP, has shown a small, statistically significant, benefit from adding hypnotherapy (aimed at stress reduction) to conventional dietary advice.

Bennett LS, Langford BA, Stradling JR, Davies RJO. 1997. The relationship between sleep fragmentation, daytime sleepiness and quality of life in OSA and predictors of improvement in quality of life on NCPAP Thorax, 52 (SUPPL. 6), | Show Abstract

Obstructive sleep apnoea (OSA) causes disabling daytime sleepiness and impairs quality of life. Quality of life measures and their improvement on nCPAP treatment may be related to daytime sleepiness and sleep fragmentation. This study investigates tiw relationship between quality of life (using the SF-36), daytime sleepiness and sleep fragmentation and improvement in quality of life on nCPAP treatment. The SF-36 provides several dimensions (eg energy/vitality), totalled as the Physical and Mental Component Summaries (PCS and MCS). 51 patients (46M, 5F) with the full spectrum of upper airway narrowing during sleep from normal to severe OSA (AHI med 24.9 range 0-151 ) had polysomnography with ASDA arousal scoring and autonomic arousal detection (arterial pulse transit time, PTT). The autonomic arousal index was the number of PTT falls per hour of sleep. All subjects completed SF-36 questionnaires and baseline measures of objective daytime sleepiness (Oxford Sleep Resistance (OSLER) test (JSR 6;142-145) and these measures were repeated following 4 weeks on nCPAP. All subjects, including the normals, received nCPAP. Pearson's correlation was used to examine the relationships with quality of life and the response to nCPAP. SF-36(*=p<0.05) OSLER test AHI ASDA PTT PCS 0.3* -0.27 -0.44* -0.38* MCS 0.32* -0.30* -0.36* 0.30* PCS change on nCPAP -0.30* 0.35« 0.54* 0.48* MCS change on nCPAP -0.27 0.31* 0.49* 0.48* Impairment of quality of life in OSA is associated with pre-treatment objective daytime sleepiness and with severity of sleep fragmentation (using both cortical and autonomic indices) and to a lesser extent with respiratory disturbance (AHI). These indices of sleep fragmentation also best predict improvement in quality of life on nCPAP.

Stradling JR, Barbour C, Pitson DJ, Davies RJ. 1997. Automatic nasal continuous positive airway pressure titration in the laboratory: patient outcomes. Thorax, 52 (1), pp. 72-75. | Show Abstract | Read more

BACKGROUND: Manual titration of nasal continuous positive airway pressure (NCPAP) treatment for obstructive sleep apnoea (OSA) is time consuming and expensive. There are now "intelligent" NCPAP machines that try to find the ideal pressure for a patient by monitoring a combination of apnoeas, hypopnoeas, inspiratory flow limitation, and snoring. Although these machines usually find similar pressures to skilled technicians, it is not clear if their use in the sleep laboratory influences subsequent acceptance by patients. This study addresses this question. METHODS: One hundred and twenty two patients undergoing a trial of NCPAP were randomly allocated to either manual or automatic (Horizon, DeVilbiss) titration of pressure during their first night on NCPAP in a hospital sleep laboratory. The primary outcome (available on 112 patients) was the acceptance of NCPAP or otherwise six weeks following the initial titration night. Baseline indicators of severity were compared between the groups, as were the pressures selected and the subsequent improvement in the sleepiness of the patients. RESULTS: The initial severity of OSA was not significantly different in the two groups and the mean (SD) NCPAP pressures were similar (manual 8.7 (2.5) cm H2O, automatic 8.2 (2.1) cm H2O). The percentage of patients successfully established on CPAP at six weeks was 64% and 73% for the manual and automatic groups, respectively; 13% and 2%, respectively, in the manual and automatic groups had given up completely (p < 0.05), and there were about equal numbers (23% versus 25%) in the two groups who were still undecided. CONCLUSIONS: The substitution of automatic NCPAP titration for manual titration during the first night of NCPAP in patients with OSA does not reduce the number accepting the treatment at six weeks and may slightly improve it. This has important cost saving potential.

Stradling JR. 1997. Medical approaches to snoring and sleep apnoea. Trans Med Soc Lond, 114 pp. 17-19.

Shneerson J, Smith I, Pack AI, Young T, Stradling JR, Davies RJO, Gibson GJ, Prowse K, Semple SJG, London DR et al. 1997. Obstructive sleep apnoea (multiple letters) [1] British Medical Journal, 315 (7104), pp. 367-369.

Stradling JR, Davies RJ. 1996. Is it necessary to record sleep? Sleep, 19 (10 Suppl), pp. S251-S254. | Show Abstract | Read more

The severe limitations of conventional sleep staging during sleep apnea are now understood. Microarousals are likely to be the dominant cause of symptoms in sleep apnea, but it has been extremely difficult to quantify them in a way that will predict daytime sleepiness or poor vigilance any better than respiratory indices. It is clear that not all apneas are equal on sleep, differences in the degree of arousal required to end an apnea and open the pharynx may help to explain why some individuals with apnea-plus-hypopnea indices (AHIs) of 15 may be symptomless, whereas others are severely disabled. Use of newer techniques to measure arousals, both cortical and autonomic, may produce a better understanding of how to measure sleep.

Pardey J, Roberts S, Tarassenko L, Stradling J. 1996. A new approach to the analysis of the human sleep/wakefulness continuum. J Sleep Res, 5 (4), pp. 201-210. | Show Abstract | Read more

The conventional approach to the analysis of human sleep uses a set of pre-defined rules to allocate each 20 or 30-s epoch to one of six main sleep stages. The application of these rules is performed either manually, by visual inspection of the electroencephalogram and related signals, or, more recently, by a software implementation of these rules on a computer. This article evaluates the limitations of rule-based sleep staging and then presents a new method of sleep analysis that makes no such use of pre-defined rules and stages, tracking instead the dynamic development of sleep on a continuous scale. The extraction of meaningful features from the electroencephalogram is first considered, and for this purpose a technique called autoregressive modelling was preferred to the more commonly-used methods of band-pass filtering or the fast Fourier transform. This is followed by a qualitative investigation into the dynamics of the electroencephalogram during sleep using a technique for data visualization known as a self-organizing feature map. The insights gained using this map led to the subsequent development of a new, quantitative method of sleep analysis that utilizes the pattern recognition capabilities of an artificial neural network. The outputs from this network provide a second-by-second quantification of the sleep/wakefulness continuum with a resolution that far exceeds that of rule-based sleep staging. This is demonstrated by the neural network's ability to pinpoint micro-arousals and highlight periods of severely disturbed sleep caused by certain sleep disorders. Both these phenomena are of considerable clinical value, but neither are scored satisfactorily using rule-based sleep staging.

Stradling JR, Davies RJ, Pitson DJ. 1996. New approaches to monitoring sleep-related breathing disorders. Sleep, 19 (9 Suppl), pp. S77-S84. | Show Abstract

Conventional approaches to the analysis of sleep and sleep apnea do not describe all of the critical events that result from upper airway narrowing during sleep. The hypersomnolence that drives treatment is mainly due to microarousals, but these are poorly documented with conventional epoch-based sleep staging. The counting of apneas and hypopneas also fails to document other equally important events, such as the arousals due to increased respiratory effort in response to partial upper airway narrowing that may not cause significant hypopnea, hypoxemia, or even snoring. Modifications of conventional polysomnography, such as microarousal detection and analysis of the ribcage/abdominal paradox, may be an improvement. However, no system has been shown to be better than any other at identifying the critical events that produce symptoms of sleep-related breathing disorders, and thus be likely to respond to effective treatment. The time is right to explore innovative ways to characterize sleep-related breathing disorders, such as those derived from the cardiovascular change related to upper airway obstruction and arousal, without the shackles of conventional polysomnography. New monitoring techniques need to identify patients with events that will respond to treatment, not mimic the flawed gold standard of polysomnography.

Davies RJ, Stradling JR. 1996. The epidemiology of sleep apnoea. Thorax, 51 Suppl 2 (Suppl 2), pp. S65-S70. | Read more

Stradling JR, Partlett J, Davies RJ, Siegwart D, Tarassenko L. 1996. Effect of short term graded withdrawal of nasal continuous positive airway pressure on systemic blood pressure in patients with obstructive sleep apnoea. Blood Press, 5 (4), pp. 234-240. | Show Abstract | Read more

It is debated whether obstructive sleep apnoea (OSA) is a significant independent risk factor for sustained hypertension or cardiovascular morbidity and mortality. In an attempt to avoid the problem of confounding variables we have investigated whether withdrawing nasal continuous positive airway pressure (NCPAP) from patients with OSA for different proportions of the night leads to a subsequent rise in their morning blood pressures. Six patients with treated OSA had their NCPAP automatically varied between 3 cms H2O and a therapeutic pressure over 5 successive nights. The proportion of therapeutic NCPAP given was kept constant over the 5 nights and blood pressure measured the morning after the 5th night. Each patient had 5 different levels of sleep disruption, from no therapeutic NCPAP at all, through to 100% NCPAP. The nocturnal consequences of these different proportions of NCPAP were quantified both by oximetry and by a new EEG analysis that provides an objective estimate of the periodicity (fluctuations in the EEG depth) of the time course seen in patients with OSA. Increasing degrees of nocturnal hypoxic dipping and EEG periodicity were positively correlated with the subsequent morning systolic and diastolic blood pressures (p < 0.02). About 20% of the variance in systolic and diastolic blood pressure could be accounted for by the amount of either hypoxic dipping or EEG periodicity. The results of this study suggest that acute changes in awake blood pressure can be caused by sleep apnoea. It agrees with other data suggesting that OSA can have an independent influence on morning BP, but that this effect may have worn off by the afternoon and evening. Some of the discrepancies between the numerous studies in this area may be due to the timing of blood pressure measurements.

Bennett LS, Stradling JR, Barbour CJ, Davies RJO. 1996. Detection of cortical EEG arousals from a Neural Network (NN) analysis Thorax, 51 (SUPPL. 3), | Show Abstract

Traditionally EEG sleep fragmentation is scored according to simple arbitrary thresholds which ignore large amounts of EEG information Computer based analyses may improve this situation. To begin assessing this approach we used a neural network system that provides a second by second output of sleep 'depth' (Questar, Oxford Medical, UK) to attempt to identify ASDA EEG arousals. 8 men with severe obstructive sleep apnoea were studied. EEG from 20 minutes of continuous OSA with obvious EEG arousal was analysed with the neural network system and then computer processed for arousal detection. By trial and error, we devised an algorithm looking for changes above a baseline. The baseline was defined as the second highest value of a 10 second moving rank filter against which we compared the next 5 one-second data points of EEG. Events were scored 5 times depending on whether 1, 2, 3, 4, or 5 of these points exceeded the baseline (X axis). We compared neural network events with ASDA arousals identifying events as true positive, false positive or false negative. ASDA EEG arousals were consensus scored by 2 scorers. (Graph Presented) When 1 prospective observation exceeded the baseline our algorithm detected 229 of 237 (97%) ASDA arousals with 68 false positives. When 3 prospective points exceeded the filter threshold it detected 198 of 237(84%) ASDA arousals with 19 false positives. Neural network EEG analysis can be post processed to detect some ASDA arousals. It also detects other events which may represent arousal from sleep not detected using the ASDA criteria.

Stradling JR, Negus T, Langford B, Smith DM. 1996. Mandibular positioning devices for the control of snoring Thorax, 51 (SUPPL. 3), | Show Abstract

Patients complaining of antisocial snoring have few options available to them of proven efficacy. There are a plethora of 'gadgets', most having no evidence to justify their appearance on the market. Surgery, such as uvulopalatopharyngoplasty, is an option but many patients do not feel that the pain, risks, and unpredictability of this operation are justified. Oral devices worn at night, to hold the lower jaw forward, have recently been shown to help mild to moderate obstructive sleep apnoea (OSA). There are no controlled studies on the use of such devices for the management of antisocial snoring. 14 snorers with no evidence of significant OSA on their diagnostic study, already established on oral appliances for the control of snoring, participated in this study. They were studied overnight at home on two occasions, using a portable device (RM50, Parametric Recorders) on the third consecutive night sleeping either with, or without, their oral devices (in randomised order). Snoring (using a throat microphone), oxygen saturation, posture, and indirect beat to beat blood pressure were measured. The latter (using pulse transit time) provided an index of 'autonomic arousals' as well as a measure of respiratory effort. In all but one of these highly selected patients, the oral devices clearly reduced the amount of snoring (P<0.006) from an average of 205(SD147) to 68(SD80) snores/hour (maximum number about 900/hr with a respiratory rate of 15/min). There were no significant overall changes in respiratory effort, arousals or >4%SaO2 diprates. These patients represent only those who were able to tolerate the appliance, and we do not know how many snorers referred for the provision of such devices use them long term. However, with such clear evidence of their potential efficacy, and no suggestion from other studies of any harm, it would seem reasonable to introduce this approach into the management of antisocial snoring.

Bennett LS, Stradling JR, Davies RJO. 1996. Comparison of a behavioural test to assess daytime sleepiness with the traditional MWT Thorax, 51 (SUPPL. 3), | Show Abstract

Standard objective tests of daytime sleepiness include the MSLT and maintenance of wakefulness test (MWT). These require continual EEG monitoring and are cumbersome and expensive. We have devised a simple test of 'wakefulness' based on a behavioural response to an intermittently illuminating light emitting diode (LED). This study reports this tests ability to discriminate subjects with severe symptomatic OSA from normals and compares this result with the traditional EEG based MWT. 10 subjects (7M 3F) with severe OSA (>4% SaO2 dip rate 33.5 (SD 19.7)) and symptoms of daytime sleepiness (Epworth Sleepiness Score (ESS) 17 (5.1)) and 10 normal subjects (4M 6F, ESS 4.4(2.5)) were studied. The EEG MWT and the behavioural LED test were performed on each subject in random order on 2 separate days. Both tests included 4x40 minute sleep resistance challenges at 2 hourly intervals. Tests were performed under the same conditions while sound isolated in a darkened room. During the behavioural test, instead of EEG monitoring, subjects were asked to press a switch in response to a LED regularly illuminating for 1 second in 3. When there was no response for 21 seconds the test was terminated. Both tests effectively discriminated the normals from the sleepy OSA subjects. The mean sleep latency during the behavioural test was longer than for the EEG MWT and this difference was significant in the OSA group but not in the normal group (see below). Retrospective analysis showed there was no difference in these results if sleep onset was defined as no response for 15 seconds instead of 21. Mean Sleep latency in minutes (SD) Difference between EEG MWT and behavioural test EEG MWT LED test Mean(SD) Paired t test Normal subjects 38.1 (2.8) 39.8 (0.6) 1.7 (3.0) p > 0.1 OSA patients 7.3 (3.7) 10.5 (3.9) 3.2 (4.2) p < 0.05 The behavioural test discriminated normal subjects from sleepy patients as well as the MWT and was simpler to administer. It has the advantage that sleep onset is defined objectively as a failure to respond rather than from subjective EEG interpretation. This technique may provide a simple method of objectively quantifying daytime sleepiness.

Pitson DJ, Stradling JR. 1996. Relationship between autonomic arousals, EEG arousals, respiratory events and subjective sleepiness in patients undergoing investigation for obstructive sleep apnoea Thorax, 51 (SUPPL. 3), | Show Abstract

Daytime hypersomnolence is an important symptom of the sleep apnoea/hypopnoea syndrome and the most compelling reason for treatment. Measuring sleep fragmentation is thus critical in a respiratory sleep study. Sleep fragmentation can be estimated from respiratory events (apnoeas, hypopnoeas, dips in oxygen saturation), EEG arousals, and autonomic changes (heart rate and blood pressure rises). We have compared these different approaches in 40 patients having polysomnography for possible sleep apnoea, as well as their correlation with subjective sleepiness (Epworth Sleepiness Score, ESS). Respiratory signals were scored for apnoeas / hypopnoeas (AHI) and dips in arterial oxygen saturation of >4% (Dip rate); EEG was scored by the American Sleep Disorders Association criteria for 3 second arousals (ASDA); autonomic measures were heart rate rises of > 10 bpm (HR) and indirect blood pressure rises (pulse transit time, PTT, Clin Sci 1994;87:269). The number of events/hour was used to calculate the correlation between each of these and their correlation with ESS (P < 0.05 for all correlations displayed). Data analysis is not yet complete, n > 21 for all correlations. HR ASDA AHI Dip rate ESS PTT r = 0.87 r = 0.91 r = 0.72 r = 0.87 r = 0.38 HR r = 0.73 r = 0.53 r = 0.80 ASDA r = 0.92 r = 0.92 r = 0.39 AHI r = 0.88 Dip rate r = 0.49 Respiratory events, EEG arousals and autonomic arousals are closely correlated. Dip rate is the best predictor of ESS. PTT measured blood pressure rises may provide a useful automated alternative to manual scoring of EEG arousals as an index of sleep fragmentation.

Stradling JR, Barbour C, Pitson DJ. 1996. Automatic nasal continuous positive airway pressure titration in the laboratory, patient outcomes Thorax, 51 (SUPPL. 3), | Show Abstract

Manual titration of nasal continuous positive airway pressure (NCPAP) treatment for obstructive sleep apnoea (OSA) is time consuming and expensive. There are now 'intelligent' NCPAP machines that try to find the ideal pressure for a patient by monitoring some combination of apnoeas, hypopnoeas, inspiratory flow limitation and snoring. Although these machines usually find similar pressures to skilled technicians, it is not clear if their use in the sleep laboratory influences subsequent acceptance by patients. 122 patients with OSA undergoing a trial of NCPAP were randomly allocated to either manual or automatic (Horizon, DeVilbiss) titration of pressure during their first night on NCPAP in a hospital sleep laboratory. The primary outcome (available on 112 patients) was the acceptance of NCPAP or otherwise, six weeks following the initial titration night. Baseline indicators of severity were compared in the groups, as were the pressures selected and the patients' subsequent improvement in sleepiness. Initial OSA severity was not significantly different in the two groups. The mean NCPAP pressures (cmH2O) in the two groups were similar (manual 8.7 SD2.5, automatic 8.2 SD2.1). The % of patients successfully established on CPAP at six weeks was 64% and 73% for the manual and automatic groups respectively: 13% versus 2% had given up completely (manual and automatic respectively, P<0.05) and there were about equal numbers (23% versus 25%) in each group who were still undecided. The improvement in the Epworth sleepiness score was similar in the two groups. The substitution of automatic NCPAP titration instead of a manual titration during the first night of NCPAP in patients with OSA does not reduce the numbers accepting the treatment at six weeks, and may slightly improve it. This has important cost saving potential.

Stradling JR, Barbour C, Langford B, Smith DM, Pitson DJ. 1996. Effect of snoring on respiratory effort measured indirectly by beat to beat blood pressure Thorax, 51 (SUPPL. 3), | Show Abstract

The size of the respiratory swings in blood pressure (pulsus paradoxus) correlate well with the degree of inspiratory effort measured with an oesophageal balloon. To take advantage of this phenomenon to estimate changes in inspiratory effort requires a measure of beat to beat blood pressure. In a respiratory sleep study to identify obstructive sleep apnoea (OSA) and its variants, such measurements are useful to indicate increased inspiratory effort following upper airway narrowing. Our unit has shown that two non-invasive devices, the photoplethysmographic volume clamp (Finapres, Ohmeda) and pulse transit time (RM50, Parametric Recorders) can provide this information. Pulse transit time (PTT) measures BP indirectly because the pulse wave propagation time (eg from heart to finger) is inversely related to arterial wall tension, which in turn depends on blood pressure. This report on snorers, taking part in another study on oral appliances, was done to verify that indirect measurements of PTT could detect the increases in inspiratory effort that usually accompany snoring. In 14 snorers (with no evidence of significant OSA on their diagnostic study) snoring (using a throat microphone), posture, oxygen saturation, thoracic excursions, and indirect blood pressure (PTT) were measured during overnight studies at home. Where available, paired ten minute periods each of continuous regular snoring, and of no snoring, were selected when there was no evidence of accompanying apnoeas, desaturations or hypopnoeas. These periods were during assumed sleep (no body movements on the thoracic excursion tracings) and selected blind of the PTT measurements. The mean size of the respiratory swings in PTT were then calculated for each of the 18 paired data sets available from 13 patients. All but three of the paired data sets showed a rise in respiratory swings during snoring periods, with the means swings being 13.5ms (SD10.5) and 18.6 (SD8.7) silence and snoring respectively. This study shows that swings in PTT can detect the increased inspiratory effort during snoring, even in the absence of any associated apnoeas and hypopnoeas.

Stradling JR, Jenkinson C, Petersen S. 1996. Quality of life before and after Nasal Continuous Positive Airway Pressure (NCPAP) treatment for Obstructive Sleep Apnoea (OSA) Thorax, 51 (SUPPL. 3), | Show Abstract

Although the benefits of treating OSA are obvious to patient and physician, purchasers of health care are not impressed by this subjective and anecdotal evidence. Controlled data are available, but not always using outcome measures that allow the estimation of health gain to be compared with other treatments in other conditions. This study compares the quality of life of OSA patients with a normal population, and measures the health gain from NCPAP treatment using two well accepted assessment techniques, the SF-36 and Functional Limitations Profile (FLP). The SF-36 provides a set of indices (eg energy/vitality), conveniently totalled as the Physical and Mental Component Summaries (PCS and MCS) standardised against a normal population. The FLP also provides a set of indices (eg alertness) summarised as the Total Score. 64 patients completed the SF-36 and FLP questionnaires prior to, and 6 weeks after, starting NCPAP for OSA. The response to treatment is quoted as 'effect size' (mean change in variable divided by SD of variable, where 0.2 is regarded as small, 0.5 moderate, and 0.8 large). Measure Before After Effect size SF-36 Energy/vitality* 38 (21) 60 (22) 1.0 Physical Component *x 39 (12) 47 (12) 0.6 Mental Component*x 40 (12) 49 (10) 0.8 FLP Sleep and Rest† 30 (24) 9 (18) 0.9 Alertness† 29 (28) 12 (24) 0.6 Social Interaction† 19 (20) 8 (16) 0.6 Total Score† 11 (9) 4 (7) 0.7 *100=best,0=worst. x50=normal population mean. †0=best, 100=worst. These results (all P<0.001) indicate a pre-treatment reduction in quality of life similar to many other severe disorders (e.g. Parkinson's, chronic heart failure) and a large response to treatment compared to other therapies in other disorders.

Gibson GJ, Douglas NJ, Stradling JR. 1996. Facilities for investigation and treatment of Sleep Apnoea in the UK Thorax, 51 (SUPPL. 3), | Show Abstract

We have surveyed the current facilities for investigation and treatment of obstructive sleep apnoea (OSA) in the UK by sending a questionnaire to all physicians known to be offering this service in the financial year 1995-6. Replies were received from 42 of the 45 physicians approached. The number of diagnostic sleep studies performed over 12 months was 11, 486. The total number of patients receiving treatment with nasal continuous positive airway pressure (CPAP) was 7006. Of these, CPAP treatment had been initiated in 2288 (32.7%) during the year surveyed. Based on the conservative estimates of prevalence of OSA used in the Royal College of Physicians Report on Sleep Apnoea (1993), the approximate number of patients with symptomatic OSA who might benefit from CPAP treatment in the UK is at least 51, 480. Of the 42 physicians who responded, the numbers reporting problems with NHS funding for sleep apnoea services in relation to diagnostic studies, CPAP systems and support staff were respectively 23, 25 and 24. Only 9 physicians experienced no financial problems related to the service in 1995-6. We conclude that less than 1 in 7 of potentially suitable patients with OSA in the UK are currently being treated with CPAP and that major problems of funding are being faced by the majority of physicians attempting to provide an appropriate level of service.

Ali NJ, Pitson D, Stradling JR. 1996. Sleep disordered breathing: effects of adenotonsillectomy on behaviour and psychological functioning. Eur J Pediatr, 155 (1), pp. 56-62. | Show Abstract | Read more

UNLABELLED: Children on the adenotonsillectomy waiting list aged 6 years or more were screened by questionnaire and overnight sleep monitoring to identify 12 with a moderate sleep and breathing disorder (SBD) group. They were matched by age and sex with 11 children who had a similar history of snoring and sleep disturbance but without an obvious sleep and breathing problem when monitored (snorer group) and also with a group of ten children most of whom were refered for an unrelated surgical procedure (control group). All children were studied before and 3-6 months after surgery. Pre-operatively the SBD and snorer groups both had significantly more restless sleep than the control group. The SBD group also had significantly more (> 4%) dips in oxygen saturation than the other two groups. After surgery there were no longer any significant differences between the three groups. After adenotonsillectomy the SBD group showed a significant reduction in aggression, inattention and hyperactivity on the parent Conners scale, and an improvement in vigilance on the Continuous Performance Test. The snorer group also improved showing less hyperactive behaviour than pre-operatively and better vigilance. The control groups's behaviour and performance did not change significantly. There were no significant changes in the performance of the Matching Familiar Figures Test in any of the groups. CONCLUSION: Relief of mild to moderate sleep and breathing disorders in children is associated with improved behaviour and functioning. We confirm previous work which suggests that the relation between sleep disordered breathing and daytime problems in children is a causal one.

Davies RJO, Kendrick A, Wiltshire N, Catterall J, Crosby J, Stradling JR. 1996. The effect of regression dilution bias on the nocturnal hypoxaemia V blood pressure relationship Thorax, 51 (SUPPL. 3), | Show Abstract

Nocturnal hypoxaemia is inaccurately assessed by one night's sleep study which will artifactually reduce its relationship with blood pressure through regression dilution bias. This study aims to quantify this effect. Two data sets were analysed. 893 normal men aged 35-60, studied during a survey of OSA and mean blood pressure (MBP) (BMJ: 1990:300:75) and 204 subjects (162M, 42F, Age 49SD10.8, >4%SaO2 diprate 14SD20.3) referred with possible sleep apnoea to centre 2. The normal subjects received one night of arterial pulse oximetry (Biox 3700) at home, and the sleep clinic group two nights (Pulsox 5). The severity of nocturnal hypoxaemia was quantified as the number of >4% falls in SaO2 per recording hour (>4% diprate). To describe how regression to the mean affects nocturnal hypoxaemia, the log10>4% diprate on the first night's oximetry in the 204 sleep clinic patients was sorted into ascending order and divided into 12, 0.25 range cells with the first two cells collapsed. For the resulting 11 cells, the difference between the average log10>4% diprates on the first and second nights was calculated. Above log10>4% diprate of 1.2 (=16hr-1) regression to the mean is minor as nocturnal hypoxaemia is reproducible. Below this threshold regression to the mean changes in an approximately linear way: diff log10diprate = -0.29 x mean first night log10diprate +0.12(r2=0.81) Since only 4 of the 893 (<0.5%) normal subjects had a >4% diprate >16 hr-1 this equation was used to correct the normal data for regression dilution bias. These 893 subjects were sorted into ascending log10>4% diprate and grouped into 9, 0.20 range cells with the first two cells collapsed. The cell average MBP was plotted against the cell average log10>4% diprate and the corrected cell average log10>4% diprate and their linear relationships described: MBP = 5.4 x log10>4%diprate+103.6 (r2=0.75) MBP = 7.0 x corrected log10>4%diprate+102.8 (r2=0.83) Correction for regression dilution bias strengthens the relationship between MBP and nocturnal hypoxaemia severity. This previously unconsidered effect may have distorted apparent relationships between OSA, MBP and obesity in community studies.

Hardinge FM, Pitson DJ, Stradling JR. 1995. Use of the Epworth Sleepiness Scale to demonstrate response to treatment with nasal continuous positive airways pressure in patients with obstructive sleep apnoea. Respir Med, 89 (9), pp. 617-620. | Show Abstract | Read more

The Epworth Sleepiness Scale (ESS) was used to measure the degree of daytime sleepiness in two groups of patients with obstructive sleep apnoea (OSA), before and after treatment with nasal continuous positive airways pressure (CPAP). One group (50 patients) were assessed after 2 months CPAP treatment after which the mean ESS fell from 16.4 [standard error of mean (SEM) 0.52] to 7.0 (SEM 0.56). A second group (25 patients) were assessed after 1 yr of treatment: a similar fall in mean ESS was seen from 15.2 (SEM 1.13) before treatment to 6.0 (SEM 0.72). These results imply that the ESS can be used clinically to demonstrate the response of daytime sleepiness in OSA to treatment with CPAP, and that the fall in ESS seen after 2 months is sustained after 1 yr of treatment. It is also possible that this approach could be used to monitor the progress of treatment with CPAP.

Pitson DJ, Sandell A, van den Hout R, Stradling JR. 1995. Use of pulse transit time as a measure of inspiratory effort in patients with obstructive sleep apnoea. Eur Respir J, 8 (10), pp. 1669-1674. | Show Abstract | Read more

Pulse transit time (PTT) is the time taken for the arterial pulse pressure wave to travel from the aortic valve to a peripheral site. For convenience, it is usually measured from the R wave on the electrocardiogram to the pulse wave arrival at the finger. Pulse transit time is inversely proportional to blood pressure, and the falls in blood pressure which occur with inspiration (pulsus paradoxus) correspond to rises (lengthening) in pulse transit time. In awake normal subjects, the size of these inspiratory rises in pulse transit time correlate well with the degree of inspiratory effort. The aim of this study was to investigate whether inspiratory rises in pulse transit time could provide a quantitative measure of inspiratory effort in patients with obstructive sleep apnoea. Eight patients with obstructive sleep apnoea, attending the laboratory for institution of nasal continuous positive airway pressure, took part in the study. Once asleep, airway pressure was varied between optimal treatment level and minimum pressure, to produce a range of inspiratory efforts whilst continuous recordings of oesophageal pressure and pulse transit time were made. There was an excellent correlation between the size of the swings in oesophageal pressure and the size of the swings in pulse transit time (mean r = 0.94). Pulse transit time may, therefore, provide a clinically useful noninvasive and quantitative measure of inspiratory effort in patients with sleep-related breathing disorders.

Stradling JR. 1995. Sleep-related breathing disorders. 1. Obstructive sleep apnoea: definitions, epidemiology, and natural history. Thorax, 50 (6), pp. 683-689. | Read more

STRADLING JR. 1995. COMMENTARY - UPPER AIRWAYS DYSFUNCTION THORAX, 50 (6), pp. 696-697. | Read more

Stradling JR. 1995. Epidemiology of snoring and its consequences. Monaldi Arch Chest Dis, 50 (2), pp. 123-128. | Show Abstract

Much has been written about snoring and its affects on health, in particular its possible influence on cardiovascular disease. However, there are many assumptions made when linking the report of snoring to any consequences such as hypertension, heart disease or stroke. In particular it is not clear how snoring might influence the cardiovascular system, whether subjective reports of snoring are accurate, and snoring might only be acting as a marker for some common risk factor such as upper body obesity; a particular risk factor for cardiovascular disease, and through neck circumference, snoring. There is much better evidence that snoring is an important cause of sleepiness, even in the absence of conventional sleep apnoea.

Koay CB, Freeland AP, Stradling JR. 1995. Short- and long-term outcomes of uvulopalatopharyngoplasty for snoring. Clin Otolaryngol Allied Sci, 20 (1), pp. 45-48. | Show Abstract | Read more

Uvulopalatopharyngoplasty is a well established and highly successful operation in the treatment of snoring. However, most published data are based on relatively short-term follow-up results. Anecdotal cases of late recurrence of snoring after an initially successful surgical result have been reported but few formal studies have been performed to determine the true magnitude of this problem. We compared the short-term and long-term results on our patients and found the late recurrence rate after a minimum follow-up period of 12 months (range: 12-84 months, mean 31.3 months) to be in the region of 13%. The risk of recurrence was directly related to the body mass index.

Hardinge FM, Davies RJ, Stradling JR. 1995. Effects of short term high frequency negative pressure ventilation on gas exchange using the Hayek oscillator in normal subjects. Thorax, 50 (1), pp. 44-49. | Show Abstract | Read more

BACKGROUND: The Hayek oscillator is a negative pressure cuirass that can operate at a range of frequencies to provide ventilation, and is a technique which could potentially be used on a general ward. This study examined the effect of different frequencies and different ranges of inspiratory and expiratory pressures on gas exchange, respiratory rate, and blood pressure in normal subjects. METHODS: Eight normal subjects received five minute periods of ventilation using the Hayek oscillator at five different frequencies, and a combination of two spans of inspiratory and expiratory pressures and two mean chamber pressures. A "sham" or control period was also performed at each frequency. Measurements were made of changes in gas exchange, spontaneous respiratory rate, and blood pressure before and after ventilation. RESULTS: There was significant intersubject variation in all results, independent of their height and weight. "Sham" settings acted as true controls in terms of gas exchange, but produced a fall in respiratory rate at 30 oscillations/min. The lower oscillatory frequencies of 30 and 60 oscillations/min produced the greatest increase in oxygenation, decrease in end tidal carbon dioxide pressure, and decrease in spontaneous respiratory rate. These effects were most significant at higher spans of pressure and were different from "sham" settings. No adverse effects were observed on blood pressure. CONCLUSIONS: The Hayek oscillator can provide assisted ventilation for short periods in normal conscious subjects with no adverse side effects on blood pressure. Maximal changes in gas exchange and a significant reduction in the spontaneous respiratory rate are seen when a combination of lower frequencies (30 and 60 oscillations/min) and higher spans of pressure are used.

Siegwart DK, Tarassenko L, Roberts SJ, Stradling JR, Partlett J. 1995. Sleep apnoea analysis from neural network post-processing IEE Conference Publication, (409), pp. 427-432. | Show Abstract

Methods of analysis of electroencephalogram (EEG) signals using artificial neural networks are presented, as well as subsequent methods of detection of obstructive sleep apnoea (OSA). The methods of detection described are based on post-processing sleep state probabilities obtained with a 10-6-4 multi-layer perceptron. Results show periodic changes in sleep states highly correlated with changes in blood oxygen saturation.

Davies RJ, Turner R, Crosby J, Stradling JR. 1994. Plasma insulin and lipid levels in untreated obstructive sleep apnoea and snoring; their comparison with matched controls and response to treatment. J Sleep Res, 3 (3), pp. 180-185. | Show Abstract | Read more

Obstructive sleep apnoea (OSA), and snoring are associated with coronary heart disease. To assess whether OSA or snoring may contribute to this by raising fasting lipid or insulin levels, venous fasting total cholesterol, triglyceride, very-low-density lipoprotein, low-density lipoprotein, high-density lipoprotein, and insulin were measured in 15 untreated OSA patients and 18 snorers. Each of these subjects was individually matched to a control of the same sex, age +/- 10%, body index +/- 15%, smoking and drinking habits. This produced study groups which did not differ significantly by any of these criteria. Fasting venous blood samples were collected at 06.30 hours following polysomnography, and analysed blind of the subjects respiratory status. The OSA patients were then treated with nasal continuous positive airway pressure. In 10 of these subjects lipid and insulin levels were repeated after more than three months treatment. Lipid and insulin levels were also remeasured in the controls matched to these 10 subjects. The end points were compared with paired t-tests. There was no difference in any of the end points when the untreated OSA patients and the snorers were compared to their matched controls (P > 0.25 for all comparisons), and none of the indices changed when OSA was corrected with nasal continuous positive airway pressure (P > 0.25 for all comparisons). Patients with obstructive sleep apnoea or snoring do not have significant fasting hyperlipidaemia or hyperinsulinaemia when compared to carefully matched controls. These factors are therefore unlikely to be the cause of the excess cardiovascular mortality experienced by this patient group.

Davies RJ, Stradling JR. 1994. Nocturnal ambulatory blood pressure measurement. BMJ, 309 (6953), pp. 543. | Read more

Pitson D, Chhina N, Knijn S, van Herwaaden M, Stradling J. 1994. Changes in pulse transit time and pulse rate as markers of arousal from sleep in normal subjects. Clin Sci (Lond), 87 (2), pp. 269-273. | Show Abstract | Read more

1. Obstructive sleep apnoea and its variants often provoke hundreds of short arousals that lead to the most important symptom, disabling hypersomnolence. The measurement of sleep in these conditions requires the documentation of these short arousals and this is conventionally done by manual inspection of the sleeping EEG, a laborious procedure. 2. Other markers of 'arousal', that are easier to measure and document, include several cardiovascular signals that change as part of the orienting reflex: pulse rate rise, blood pressure rise, skin vasoconstriction, for example. 3. Pulse transit time (measured as the interval from the ECG R-wave until the arrival of the pulse pressure wave at the periphery, about 250 ms) varies inversely with blood pressure and provides a beat-to-beat estimation of blood pressure changes. 4. In eight normal subjects we have assessed the relationship between transient EEG arousals of different length (provoked by external stimuli) and changes in both pulse transit time and heart rate. 5. Significant falls in pulse transit time occurred in response to external stimuli [15.1 (SEM 1.4) ms], indicating a rise in blood pressure, and were significant even when there was no discernible change in the EEG [9.9 (SEM 2.6) ms]. Significant changes in heart rate also occurred [10.3 (SEM 1.2) beats/min], but were slightly less sensitive than changes in pulse transit time. 6. Changes in pulse transit time (and to a lesser extent pulse rate) are sensitive markers of EEG arousal. As such they should be useful to include when monitoring sleep and its disorders, particularly since pulse transit time recorders can easily be made portable for home use.

Ali NJ, Pitson D, Stradling JR. 1994. Natural history of snoring and related behaviour problems between the ages of 4 and 7 years. Arch Dis Child, 71 (1), pp. 74-76. | Show Abstract | Read more

In 1989-90 a survey was carried out of the prevalence of snoring and related symptoms in 782 4 to 5 year old children. Two years later, in 1992, the same group of children was studied to gather information on the natural history of snoring and the related behaviour problems. A total of 507/782 (64.8%) completed questionnaires were received. Comparison of the responses with the 1989-90 survey showed that those who did not reply to the questionnaire were no different from the respondents in terms of the prevalence of snoring, daytime sleepiness, hyperactivity, and restless sleep. The overall prevalence of habitual snoring did not change between the two surveys (12.1% in 1989-90 v 11.4% in 1992), though more than half of the children who snored habitually in the original survey no longer did so. There was little change in the prevalence of hyperactivity (24.2% in 1989-90 v 20.7% in 1992) or restless sleep (both 39%) among the 507 who responded to the present survey. The prevalence of daytime sleepiness, however, did decrease substantially (20.7% in 1989-90 v 10.2% in 1992). There was moderate agreement between the individual questionnaire responses for the 1989-90 and 1992 surveys for snoring (weighted kappa 0.52), but poor agreement for the other symptoms (daytime sleepiness 0.37, hyperactivity 0.35, and restless sleep 0.38). Trend analysis showed that the increasing prevalence of sleepiness, hyperactivity, and restless sleep across the snoring categories was highly significant. Daytime sleepiness, hyperactivity, and restless sleep were all significantly more common in the habitual snorers than in those who never snored. Relative risks (95% confidence interval) were as follows: daytime sleepiness 6.13 (2.5 to 14.9), hyperactivity 2.78 (1.6 to 4.7), and restless sleep 2.3 (1.6 to 3.2). Though habitual snoring and the associated behaviour problems resolved spontaneously over two years in about half of the children with these symptoms, there is still the same overall percentage with these problems due to the emergence of new cases.

Davies RJ, Crosby J, Vardi-Visy K, Clarke M, Stradling JR. 1994. Non-invasive beat to beat arterial blood pressure during non-REM sleep in obstructive sleep apnoea and snoring. Thorax, 49 (4), pp. 335-339. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea, and possibly snoring, are associated with a poorly understood increase in cardiovascular mortality which may be explained by their effects on systemic blood pressure during sleep. This study compares changes in mean blood pressure during obstructive sleep apnoea and snoring without apnoeas with those in matched control subjects during non-REM sleep. METHODS: Eighteen men with obstructive sleep apnoea, 16 men who snored without apnoeas, and 34 control subjects matched for age, sex, obesity, smoking, and alcohol intake were studied. During polysomnography non-invasive mean blood pressure (Finapres) was recorded from each cardiac cycle during non-REM sleep and averaged over a 10 minute period. This was compared with the blood pressure during 10 minutes before sleep onset. The changes in the patients' sleeping blood pressure were compared with those in their individually matched control subjects. RESULTS: Compared with the control subjects the change in mean (SD) arterial blood pressure between being awake and asleep was higher during obstructive sleep apnoea (+6.5 (9) mm Hg v-2 (6.5), difference 8.5 (11)), and the rise from wakefulness to sleep in the obstructive sleep apnoea group was itself significant. The average mean arterial pressure was not raised in those who snored without apnoeas compared with either the control subjects or during wakefulness. CONCLUSIONS: Average mean arterial pressure is higher during obstructive sleep apnoea than it is during wakefulness, while normal subjects show a fall in blood pressure at sleep onset. This sleep related rise in blood pressure may contribute to the excess cardiovascular morbidity and mortality experienced by patients with this condition.

Davies RJ, Crosby J, Prothero A, Stradling JR. 1994. Ambulatory blood pressure and left ventricular hypertrophy in subjects with untreated obstructive sleep apnoea and snoring, compared with matched control subjects, and their response to treatment. Clin Sci (Lond), 86 (4), pp. 417-424. | Show Abstract | Read more

1. Obstructive sleep apnoea and snoring are associated with daytime hypertension. It is uncertain whether this association is directly due to the disturbed sleeping respiration or the result of confounding variables, particularly obesity, smoking and alcohol intake. 2. Ambulatory blood pressure and echocardiographic left ventricular muscle mass were measured in 19 patients with obstructive sleep apnoea, 19 men who snore without apnoea and 38 control subjects matched for age, sex, body mass index, smoking and alcohol intake. Ambulatory blood pressure was also measured before and after treatment in 11 patients with obstructive sleep apnoea and their matched control subjects. 3. Compared with matched control subjects, untreated obstructive sleep apnoea and snoring were not associated with an increase in daytime blood pressure. A daytime elevation of either systolic or diastolic blood pressure of > 3.8 mmHg due to obstructive sleep apnoea or snoring was excluded with 95% confidence in each of the study groups. Daytime blood pressure was also unchanged when obstructive sleep apnoea was treated with nasal continuous positive airway pressure. Night-time blood pressure was not significantly different in the patients with obstructive sleep apnoea or the snorers when compared with their matched control subjects. However, a fall in night-time systolic blood pressure was seen in the patients with obstructive sleep apnoea after treatment [fall in systolic blood pressure -6.3 (SD 8.2) mmHg, P < 0.02]. 4. Left ventricular diameter, wall thickness and calculated mass were similar in each of the study groups and their matched control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Davies RJ, Jenkins NE, Stradling JR. 1994. Effect of measuring ambulatory blood pressure on sleep and on blood pressure during sleep. BMJ, 308 (6932), pp. 820-823. | Show Abstract | Read more

OBJECTIVE: To assess whether recording of ambulatory blood pressure at night causes arousal from sleep and a change in the continuous blood pressure recorded simultaneously. DESIGN: Repeated measurement of blood pressure with two ambulatory blood pressure machines (Oxford Medical ABP and A&D TM2420) during continuous measurement of beat to beat blood pressure and continuous electroencephalography. SETTING: Sleep research laboratory. SUBJECTS: Six normal subjects. MAIN OUTCOME MEASURES: The duration of electroencephalographic arousal and the beat to beat changes in blood pressure produced by the measurement of ambulatory blood pressure; the size of any changes that this arousal and change in blood pressure produced in the blood pressure recorded by the ambulatory machine. RESULTS: Both ambulatory blood pressure machines caused arousal from sleep: the mean duration of arousal was 16 seconds (95% range 0-202) with the ABP and 8 seconds (0-73) with the TM2420. Both also caused a rise in beat to beat blood pressure. During non-rapid eye movement sleep, this rise led to the ABP machine overestimating the true systolic blood pressure during sleep by a mean of 10 (SD 14.8) mm Hg and the TM2420 by a mean of 6.3 (8.2) mm Hg. On average, diastolic pressure was not changed, but measurements in individual subjects changed by up to 23 mm Hg. These changes varied in size among subjects and stages of sleep and were seen after measurements that did not cause any electroencephalographic arousal. CONCLUSIONS: Ambulatory blood pressure machines cause appreciable arousal from sleep and therefore alter the blood pressure that they are trying to record. This effect should be taken into account when recordings of blood pressure at night are interpreted in clinical work and epidemiological research.

Davies RJ, Vardi-Visy K, Clarke M, Stradling JR. 1993. Identification of sleep disruption and sleep disordered breathing from the systolic blood pressure profile. Thorax, 48 (12), pp. 1242-1247. | Show Abstract | Read more

BACKGROUND: Respiratory sleep studies are frequently performed to identify sleep disruption resulting from upper airway obstruction. Traditional polysomnographic studies may not detect brief recurrent sleep disruption and thus fail to recognise a significant problem when apnoea, hypopnoea, or arterial desaturation are not present. Arousal from sleep causes a transient blood pressure rise, and each inspiration causes a transient blood pressure fall. This study assesses whether these blood pressure changes are a useful indirect marker of disturbed sleep, obstructed sleep apnoea, and snoring related sleep disturbance. METHODS: Computer algorithms were developed to identify blood pressure falls caused by inspiration and rises related to arousal from 286 sleeping blood pressure samples of a consistent respiratory state drawn from 51 polysomnographic studies. From these samples, normal ranges for the number of arousal related systolic rises and the average size of the inspiratory falls were established. These were then applied prospectively to all night unedited blood pressure recordings from a further 20 subjects. RESULTS: The size of the inspiratory falls in blood pressure progressively increased from normal sleep, through snoring, to frank obstructive sleep apnoea. The 95th centile of normal was 12.5 mm Hg. The number of arousal related blood pressure rises also increased during obstructive sleep apnoea and periods of snoring with associated arousals, compared with normal undisturbed sleep, and all these periods of disturbed sleep included more than 30 such rises per hour. When these blood pressure features were examined in the 20 subjects studied prospectively, the six with a sleep related breathing disorder could all have been identified from their systolic blood pressure profile alone. CONCLUSIONS: The systolic blood pressure profile may be helpful in identifying patients with obstructive sleep apnoea, snoring with arousals, or other sleep disruption syndromes.

Davies RJ, Stradling JR. 1993. Acute effects of obstructive sleep apnoea. Br J Anaesth, 71 (5), pp. 725-729. | Read more

SEMPLE SJG, GIBSON GJ, BURNEY PGJ, DOUGLAS NJ, DYMOND JP, KOPELMAN PG, MILLER DE, PARKES JD, PROWSE K, SHNEERSON JM et al. 1993. SLEEP-APNEA AND RELATED CONDITIONS - SUMMARY OF A REPORT OF A WORKING PARTY OF THE ROYAL-COLLEGE-OF-PHYSICIANS JOURNAL OF THE ROYAL COLLEGE OF PHYSICIANS OF LONDON, 27 (4), pp. 363-364.

Saunders KB, Stradling J. 1993. Chemoreceptor drives and short sleep-wake cycles during hypoxia: a simulation study. Ann Biomed Eng, 21 (5), pp. 465-474. | Show Abstract | Read more

We used a Grodins-type mathematical model of the cardio-pulmonary system to investigate the cycling behaviour of the respiratory system during hypoxia in response to changes of state between waking and sleeping, namely a diminution of respiratory chemosensitivity during sleep. Shifts between waking and sleeping were triggered by various combinations of threshold values for PAO2. Mild or moderate hypoxia was simulated by values of inspired O2 concentration between 13% and 16% (normal 21%). In mild or moderate hypoxia, reductions of overall respiratory gain from about 2 to 0.8 l.min-1 mmHg-1 at sleep onset will produce falls in PAO2 likely to cause sleep-wake cycles with oscillations in PAO2. The higher the arousal threshold (in relation to steady-state PAO2 during sleep), the shorter and more stable the sleep-wake cycles. As the arousal threshold is raised, and as hypoxia is exacerbated from mild (FIO2 = 16%) to moderate (FIO2 = 13%), the sleep-wake cycle length tends to converge to a value around one minute. The level and determinants of the "back-to-sleep" threshold are hard to define from presently available experimental data, but the level is not important in determining the length of the sleep-wake cycle compared to the arousal threshold. Alinearities in chemoreceptor feedback were introduced first by incorporating "drive" thresholds, to simulate central or obstructive apnoea. This produced larger oscillations in respiratory variables, but no change in cycle length. Chemoreceptor thresholds for PCO2 at the level of 38-39 mmHg did produce shorter ventilation cycles, down to about 20 s in length, but these were not related in any simple way to the resulting sleep-wake cycles. The combination of sleep state changes and chemoreceptor feedback alinearities can produce short sleep-wake cycles despite the diminution in chemoreceptor gain occurring in sleep.

Davies RJ, Harrington KJ, Ormerod OJ, Stradling JR. 1993. Nasal continuous positive airway pressure in chronic heart failure with sleep-disordered breathing. Am Rev Respir Dis, 147 (3), pp. 630-634. | Show Abstract | Read more

Nasal continuous positive airway pressure (NCPAP) has been reported to improve daytime symptoms in patients with sleep disordered breathing due to heart failure. To examine this in a controlled manner, eight men with stable chronic heart failure (mean left ventricular ejection fraction 18% and mean frusemide dose 160 mg) were entered into a controlled trial of domiciliary nocturnal NCPAP. At polysomnography (with sleep apnea quantified as the number of > 4% dips in arterial saturation per hour), seven had nocturnal Cheyne-Stokes respiration (SaO2 dip rate 3 to 27/hr), and one both central and obstructive apneas (SaO2 dip rate 8/hr). After 2 wk nocturnal domiciliary NCPAP at < 1.5 cm H2O (placebo) and 7.5 cm H2O (active) in random order, bicycle exercise tolerance and heart failure symptoms (modified Likert questionnaire) were assessed by an observer unaware of the patients' NCPAP status. Pulse oximetry (all subjects) and radionuclide estimated left ventricular ejection fraction (three subjects) were also measured at the end of each period. Two subjects withdrew from the study because of worsening heart failure during active NCPAP (7.5 cm H2O), and one of these subjects died. In the remaining six subjects exercise tolerance, symptom scores, and the severity of sleep apnea were similar on active NCPAP compared with placebo. When it was measured, resting left ventricular ejection fraction was lower on active therapy than on placebo. These data exclude a 25% improvement in exercise tolerance with 95% confidence and suggest that a study of 160 subjects would be needed to exclude a 10% change in symptom score.(ABSTRACT TRUNCATED AT 250 WORDS)

Davies RJ, Belt PJ, Roberts SJ, Ali NJ, Stradling JR. 1993. Arterial blood pressure responses to graded transient arousal from sleep in normal humans. J Appl Physiol (1985), 74 (3), pp. 1123-1130. | Show Abstract | Read more

During obstructive sleep apnea, transient arousal at the resumption of breathing is coincident with a substantial rise in blood pressure. To assess the hemodynamic effect of arousal alone, 149 transient stimuli were administered to five normal subjects. Two electroencephalograms (EEG), an electrooculogram, a submental electromyogram (EMG), and beat-to-beat blood pressure (Finapres, Ohmeda) were recorded in all subjects. Stimulus length was varied to produce a range of cortical EEG arousals that were graded as follows: 0, no increase in high-frequency EEG or EMG; 1, increased high-frequency EEG and/or EMG for < 10 s; 2, increased high-frequency EEG and/or EMG for > 10 s. Overall, compared with control values, average systolic pressure rose [nonrapid-eye-movement (NREM) sleep 10.0 +/- 7.69 (SD) mmHg; rapid-eye-movement (REM) sleep 6.0 +/- 6.73 mmHg] and average diastolic pressure rose (NREM sleep 6.1 +/- 4.43 mmHg; REM sleep 3.7 +/- 3.02 mmHg) over the 10 s following the stimulus (NREM sleep, P < 0.0001; REM sleep, P < 0.002). During NREM sleep, there was a trend toward larger blood pressure rises at larger grades of arousal (systolic: r = 0.22, 95% confidence interval 0.02-0.40; diastolic: r = 0.48, 95% confidence interval 0.31-0.62). The average blood pressure rise in response to the grade 2 arousals was approximately 75% of that during obstructive sleep apnea. Arousal stimuli that did not cause EEG arousal still produced a blood pressure rise (mean systolic rise 8.6 +/- 7.0 mmHg, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Ali NJ, Pitson DJ, Stradling JR. 1993. Snoring, sleep disturbance, and behaviour in 4-5 year olds. Arch Dis Child, 68 (3), pp. 360-366. | Show Abstract | Read more

Parents of 996 children aged 4-5 years identified consecutively from the Oxford health visitor register were asked to complete a questionnaire about breathing disorders during sleep. A total of 782 (78.5%) was returned. Ninety five (12.1%) children were reported to snore on most nights. Habitual snoring was significantly associated with daytime sleepiness, restless sleep, and hyperactivity. The questionnaire responses were used to select two subgroups, one at high risk of a sleep and breathing disorder and a control group. These children (132 in total) were monitored at home with overnight video recording and oximetry, and had formal behavioural assessment using the Conners scale. Seven (7/66) children from the high risk group and none from the control group had obvious sleep disturbance consequent on snoring and upper airway obstruction. Thus our estimate of the prevalence of sleep and breathing disorders in this age group is 7/996 or 0.7%. The high risk group had significantly higher nocturnal movement, oxygen saturation dip rates, and overnight pulse rates than the controls. Maternal but not paternal smoking was associated with the high risk group. Parents and teachers thought those in the high risk group were more hyperactive and inattentive than the controls, but only their parents thought them more aggressive. Significant sleep and breathing disorders occur in about 0.7% of 4-5 year olds. Children whose parents report snoring and sleep disturbance have objective evidence of sleep disruption and show more behaviour problems than controls.

Jan C, Robert D, Klaus E, Ron G, Jan H, Thomas P, Lawrence S, John S, Tiina T, Clifford Z. 1993. Obstructive sleep apnea and blood pressure elevation: what is the relationship? Working Group on OSA and Hypertension. Blood Press, 2 (3), pp. 166-182. | Show Abstract | Read more

Sleep disordered breathing has increasingly been recognised as a frequent cause of ill-health in the community. Moderate or severe forms of the most common condition, obstructive sleep apnea (OSA), occur in up to 12% of the adult male population. A substantial body of literature has been published on the potential relationship between OSA and cardiovascular disease. In particular, OSA has been associated with cardiac failure, stroke, myocardial infarction and hypertension. Part of this association may be explained by other confounders, mainly obesity, which is common in OSA patients. The present review was prepared following a workshop aimed to critically review available scientific evidence suggesting that hypertension is a direct consequence of OSA. In addition, pathophysiologic mechanisms that may be involved in the relationship between OSA and cardiovascular disease, particularly brief intermittent elevation of blood pressure and sustained systemic hypertension, are discussed.

Stradling JR. 1993. ABC of sleep disorders. Recreational drugs and sleep. BMJ, 306 (6877), pp. 573-575. | Read more

Stradling JR. 1992. Sleep studies for sleep-related breathing disorders. J Sleep Res, 1 (4), pp. 265-273. | Show Abstract | Read more

Our understanding of sleep-related breathing disorders is still in a period of rapid change. Considerable uncertainty exists in several major areas of patient assessment. Although early definitions of sleep apnoea enshrined the concept of rigid guidelines, such an approach is no longer helpful, and may constrain potential advances. The recognition of the basic pathophysiological events in obstructive sleep apnoea (OSA) has evolved from purely apnoeas, to include hypopnoeas, and now to increased upper airway resistance alone. Our view as to the significant consequences of such respiratory events has also evolved from alterations to the classic sleep architecture, to hypoxic events, and now to micro-arousals and cardio-vascular events. The exact nature of a significant arousal is also far from clear, with the suggestion that perhaps even EEG based approaches to their measurement may not be telling us the whole story. Finally, the frequency of such respiratory events and their consequences, that lead to significant symptoms and long-term damage, is not known either. Thus, given this situation, the best we can achieve is broad guidelines that stress the main important physiological events and their consequences that need to be assessed, and then interpreted in conjunction with the patient's symptoms. This will not necessarily be the same for all patients and this report offers some general guidance, based on the experience of several centres throughout Europe.

Short DJ, Stradling JR, Williams SJ. 1992. Prevalence of sleep apnoea in patients over 40 years of age with spinal cord lesions. J Neurol Neurosurg Psychiatry, 55 (11), pp. 1032-1036. | Show Abstract | Read more

Twenty two patients over the age of 40 with stable spinal cord damage underwent overnight sleep studies to investigate the prevalence of sleep apnoea. Ten patients had some evidence of obstructive sleep apnoea (OSA). Hypoxic events were scored as number of dips of SaO2 more than 4% below the preceding 10 minute average (> 4% SaO2 dip rate). All the patients had more than five such dips per hour and six had clearly abnormal dip rates of more than 15 per hour. Two other patients had dip rates above 10 per hour without apnoeas but periods of central hypoventilation mainly during rapid eye movement (REM) sleep. OSA appears to be more common in older patients with spinal cord injury than in the general population. Possible relevant factors include patient selection, reduced ventilatory function secondary to spinal cord damage, sleep posture and medication.

Cripps T, Rocker G, Stradling J. 1992. Nocturnal hypoxia and arrhythmias in patients with impaired left ventricular function. Br Heart J, 68 (4), pp. 382-386. | Show Abstract | Read more

OBJECTIVES: To document the incidence of hypoxic episodes in a series of patients with impaired left ventricular function, and to correlate the occurrence of hypoxia with severity of arrhythmia. PATIENTS: 34 patients with breathlessness and clinical evidence of left ventricular dysfunction. MAIN OUTCOME MEASURES: Simultaneous overnight finger oximetry and electrocardiographic monitoring. RESULTS: High grade arrhythmias (Lown grade > III) occurred in 20/34 (59%) of patients, and frequent dips in oxygen saturation were noticed (mean dip frequency 4.8/h, range 0.1-20.0). 20/34 (59%) of patients had episodic hypoxaemia, including 13/34 (38%) with a classical Cheyne Stokes pattern. There was a correlation between dip frequency and the presence of high grade arrhythmias (those with high grade arrhythmia had mean (SD) 6.7 (5.5) dips/h v 2.2 (3.4) in those without, p < 0.01); there was also a correlation between the presence of arrhythmias and episodic hypoxaemia (episodic hypoxaemia in those with high grade arrhythmias occurred in 17/20 (85%) v 3/14 (21%) of those without arrhythmias, p < 0.002). There was no correlation between the presence of high grade arrhythmias or dip frequency and the extent of left ventricular impairment, which was present in all patients (mean (SD) ejection fraction 26% (13%)). CONCLUSION: Noticeable abnormalities of nocturnal oxygen saturation occur in patients with impaired left ventricular function, and these are associated with high grade arrhythmias. Interventions that limit desaturation may have valuable anti-arrhythmic effects.

Ali NJ, Davies RJ, Fleetham JA, Stradling JR. 1992. The acute effects of continuous positive airway pressure and oxygen administration on blood pressure during obstructive sleep apnea. Chest, 101 (6), pp. 1526-1532. | Show Abstract | Read more

We have measured blood pressure continuously with a digital artery blood pressure monitor in eight patients with severe obstructive sleep apnea (OSA) during 30 min each of wakefulness, OSA, OSA with added oxygen to keep saturation above 96 percent at all times (OSA+O2), and nasal continuous positive airway pressure (CPAP) therapy. Mean blood pressures were not different between wakefulness, OSA, OSA+O2, and CPAP, although the variability in blood pressure was significantly greater during OSA and OSA+O2 than during wakefulness and CPAP. The addition of oxygen did not attenuate the variability in blood pressure. Using multiple linear regression modeling to further dissect out the principal variables determining the postapneic blood pressure rise, we found that only apnea length (r2 = 0.28, p less than 0.0001) and pulse rate changes (r2 = 0.15, p less than 0.0001) remained significantly related to SBPmax, while hypoxemia did not. We found the same trends in the other variables SBPten, DBPmax, and DBPten. Hypoxemia made a small contribution to the size of DBPmax, although this was small by comparison with apnea length. We conclude that CPAP treatment of OSA does not lower mean blood pressure acutely, although it significantly reduces the large oscillations in blood pressure seen in patients with untreated OSA. The rise in blood pressure following each apnea is not primarily due to arterial desaturation but is related to apnea length and may be caused by increased sympathetic activity secondary to arousal.

DAVIES RJO, VARDIVISY K, CLARKE M, STRADLING JR. 1992. NIGHT TIME BLOOD-PRESSURE IN OBSTRUCTIVE SLEEP-APNEA, SNORING, AND NORMAL SLEEP THORAX, 47 (3), pp. P216-P217.

DAVIES RJO, HARRINGTON K, ORMEROD O, STRADLING JR. 1992. CONTROLLED TRIAL OF NASAL CPAP IN HEART-FAILURE WITH SLEEP DISORDERED BREATHING THORAX, 47 (3), pp. P216-P216.

ALI NJ, PITSON D, STRADLING JR. 1992. DAYTIME BEHAVIOR IN 4-5 YEAR OLD CHILDREN WITH MILD TO MODERATE SLEEP DISORDERED BREATHING THORAX, 47 (3), pp. P220-P220.

Davies RJ, Ali NJ, Stradling JR. 1992. Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome. Thorax, 47 (2), pp. 101-105. | Show Abstract | Read more

BACKGROUND: Neck circumference has been suggested to be more predictive of obstructive sleep apnoea than general obesity, but the statistical validity of this conclusion has been questioned. Combining neck circumference with other signs and symptoms may allow the clinical diagnosis or exclusion of sleep apnoea to be made with reasonable confidence. This study examines these issues. METHODS: One hundred and fifty patients referred to a sleep clinic for investigation of sleep related breathing disorders completed a questionnaire covering daytime sleepiness, snoring, driving, and nasal disease. Body mass index and neck circumference corrected for height were measured and obstructive sleep apnoea severity was quantified as number of dips in arterial oxygen saturation (SaO2) of more than 4% per hour of polysomnography. Multiple linear regression was used retrospectively to identify independent predictors of SaO2 dip rate, and the model derived was then prospectively tested in a further 85 subjects. RESULTS: The retrospective analysis showed that the question "Do you fall asleep during the day, particularly when not busy?" was the best questionnaire predictor of variance in the SaO2 dip rate (r2 = 0.13); no other question improved this correlation. This analysis also showed that neither body mass index nor any of the questionnaire variables improved the amount of variance explained by height corrected neck circumference alone (r2 = 0.35). A statistically similar prospective analysis confirmed this relationship (r2 = 0.38). CONCLUSIONS: Prospective study of these patients referred to a sleep clinic with symptoms suggesting sleep apnoea shows that neck circumference corrected for height is more useful as a predictor of obstructive sleep apnoea than general obesity. None of the questionnaire variables examined add to its predictive power, but alone it is inadequate to avoid the need for sleep studies to diagnose this disease.

Goldstein RS, Stradling JR. 1992. An artifact induced by negative pressure ventilation. Chest, 101 (2), pp. 563-565. | Show Abstract | Read more

This report draws attention to an artifact that influences the qualitative information gained from respiratory inductance plethysmography during negative pressure ventilation with a cuirass. This artifact may prevent identification of upper airway obstruction, a manageable complication of this mode of ventilation.

Davies RJ, Stradling JR. 1991. Cephalometric measurements in snorers, non-snorers, and patients with sleep apnoea. Thorax, 46 (12), pp. 938. | Read more

Stradling JR, Crosby JH, Payne CD. 1991. Self reported snoring and daytime sleepiness in men aged 35-65 years. Thorax, 46 (11), pp. 807-810. | Show Abstract | Read more

BACKGROUND: It has been suggested that snoring alone, without conventional sleep apnoea or hypopnoea, may disrupt sleep and produce substantial daytime hypersomnolence. This study addresses this potential relationship. METHOD: Eight hundred and fifty men, aged 35-65 years, drawn from one general practice were visited at home and asked a range of questions potentially related to sleepiness, snoring, and sleep apnoea; these included inquiries about alcohol and cigarette consumption, nasal stuffiness, shift work, hypnotic or other drug use, and medical diagnoses. In addition, measurements of height, weight, and overnight arterial oxygen saturation were made. The relation between snoring and sleepiness, with allowance made for potentially confounding variables, including sleep apnoea, was assessed by multiple logistic regression. RESULTS: Positive answers to all questions about sleepiness were correlated significantly with self reported snoring. After potentially confounding variables and any sleep apnoea had been controlled for, positive answers to four questions about inappropriate drowsiness or sleepiness were independently related to snoring. For example, the odds ratio of admitting to "having almost had two or more car accidents while driving due to sleepiness" was 5.8 (95% confidence intervals: 2.7-12.5) in an "often" snorer. CONCLUSIONS: Although epidemiological associations such as this do not prove a causal relation, the study suggests that snoring (without classical sleep apnoea) may sometimes reduce sleep quality sufficiently to produce substantial daytime drowsiness.

Ali NJ, Davies RJ, Fleetham JA, Stradling JR. 1991. Periodic movements of the legs during sleep associated with rises in systemic blood pressure. Sleep, 14 (2), pp. 163-165. | Show Abstract

We report the relationship between periodic leg movements during sleep and recurrent rises in systemic blood pressure in a patient with narcolepsy. The mean increase in systolic blood pressure following leg movements was 23%, which is of the same order as the rises seen in patients with obstructive sleep apnea. Following treatment with temazepam, the swings in blood pressure were unchanged despite considerably less electroencephalographic evidence of cortical arousal.

Stradling JR, Crosby JH. 1991. Predictors and prevalence of obstructive sleep apnoea and snoring in 1001 middle aged men. Thorax, 46 (2), pp. 85-90. | Show Abstract | Read more

One thousand and one men, aged 35-65 years, were identified from the age-sex register of one group general practice. Over four years 900 men were visited at home and asked questions about symptoms potentially related to sleep apnoea and snoring. Height, weight, neck circumference, resting arterial oxygen saturation (SaO2), and spirometric values were also determined. All night oximetry was then performed at home and the tracing analysed for the number of dips in SaO2 of more than 4%. Subjects with more than five dips of 4% SaO2 or more per hour were invited for sleep laboratory polysomnography. Seventeen per cent of the men admitted to snoring "often." Multiple linear regression techniques identified and ranked neck circumference (r2 = 7.2%), cigarette consumption (r2 = 3.4%), and nasal stuffiness (r2 = 2%) as the only significant independent predictors of snoring. Together these account for at least a sixfold variation in the likelihood of being an "often" snorer. Forty six subjects (5%) had greater than 4% SaO2 dip rates of over five an hour and 31 of these had full sleep studies. Three subjects had clinically obvious and severe symptomatic obstructive sleep apnoea, giving a prevalence of three per 1001 men (0.3%; 95% confidence interval 0.07-0.9%). Eighteen men had obstructive sleep apnoea only when supine and in 10 the cause of the SaO2 dipping on the original home tracing was not elucidated. The greater than 4% SaO2 dip rates correlated with the history of snoring. Multiple linear regression techniques identified and ranked neck circumference (r2 = 7.9%), alcohol consumption (r2 = 3.7%), age (r2 = 1%) and obesity (r2 = 1%) as the only significant independent predictors of the rate of overnight hypoxic dipping. This study shows that snoring in this randomly selected population correlates best with neck size, smoking, and nasal stuffiness. Obstructive sleep apnoea, defined by nocturnal hypoxaemia, correlates best with neck size and alcohol, and less so with age and general obesity.

Davies RJO, Stradling JR. 1991. Cephalometric measurements in snorers, non-snorers, and patients with sleep apnoea Thorax, 46 (12), pp. 938. | Read more

Armitage JM, Lane DJ, Stradling JR, Burton M. 1990. Ear involvement in the yellow nail syndrome. Chest, 98 (6), pp. 1534-1535. | Show Abstract | Read more

Recognized features of the yellow nail syndrome include yellow nails, lymphedema, and pleural effusions. We report a patient with the additional feature of keratosis obturans, which may be a manifestation of this syndrome in the external ear.

Stradling JR, Douglas NJ. 1990. Heart attacks and sleep apnoea. Lancet, 336 (8727), pp. 1378-1379. | Read more

Summers CL, Stradling JR, Baddeley RM. 1990. Treatment of sleep apnoea by vertical gastroplasty. Br J Surg, 77 (11), pp. 1271-1272. | Read more

Stradling J. 1990. Clinical presentation of sleep apnoea. Eur Respir J Suppl, 11 (SUPPL. 11), pp. 548s-549s.

Davies RJ, Stradling JR. 1990. The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. Eur Respir J, 3 (5), pp. 509-514. | Show Abstract

We have studied the predictive importance of neck circumference, obesity, and several radiographic pharyngeal dimensions for obstructive sleep apnoea (OSA), in 66 patients. OSA was quantified as the mean hourly number of greater than 4% dips in arterial oxygen saturation during sleep. Neck circumference (correlation coefficient (r) = 0.63, 95% confidence interval (C.I.) 0.46-0.76), obesity index (r = 0.54, 95% C.I. 0.39-0.69), hyoid position (r = 0.40, 95% C.I. 0.17-0.59), soft palate length (r = 0.31, 95% C.I. 0.08-0.51), and hard palate-to-spine angle (r = 0.29, 95% C.I. 0.04-0.49), correlated significantly with saturation dips in single regression analysis. In stepwise multiple linear regression analysis (saturation dip rate as the dependent variable), only neck size and retroglossal space were significant independent correlates (total r2 = 0.42, 95% C.I. 0.22-0.61, p less than 0.0001). We conclude that the relationships between general obesity, hyoid position, soft palate length, and OSA are probably secondary to variation in neck circumference.

Katz I, Stradling J, Slutsky AS, Zamel N, Hoffstein V. 1990. Do patients with obstructive sleep apnea have thick necks? Am Rev Respir Dis, 141 (5 Pt 1), pp. 1228-1231. | Show Abstract | Read more

During physical examination of patients with suspected obstructive sleep apnea (OSA), a comment is frequently made that they appear to have a short and fat neck. To confirm this subjective impression by objective measurements, we studied a group of 123 patients referred to us because of snoring and suspected OSA, all of whom had nocturnal polysomnography and measurements of external and internal neck circumference. The external neck circumference was measured at the level of the superior border of the cricothyroid cartilage. Internal neck circumferences were calculated from the measurements of pharyngeal, glottic, and tracheal areas obtained by the acoustic reflection technique. Internal pharyngeal circumference was further subdivided into the proximal, middle, and distal thirds. The acoustic technique also permitted us to measure the distance between the teeth and the glottic minimum, which reflects the length of the upper airway. Stepwise multiple linear regression analysis revealed that the apnea/hypopnea index (AHI) correlated only with the external neck circumference, the body mass index, and the internal circumference of the distal pharynx; these three variables accounted for 39% of the variability in AHI. We conclude that the external and internal neck circumferences and the degree of obesity are important predictors of sleep apnea; it is possible that obesity produces its effect via fat in the neck. We speculate that the static pharyngeal size modulated by the dynamic loading of the airway due to the weight of fatty tissue of the neck may contribute to the pathogenesis of OSA.

Warley AR, Fontes F, Wilson M, Raine AE, Stradling JR. 1990. Lack of effect of an inspiratory threshold load on plasma atrial natriuretic peptide levels. Clin Sci (Lond), 78 (3), pp. 311-313. | Show Abstract | Read more

1. After a run-in period, six healthy, recumbent, water-loaded male subjects breathed through an inspiratory threshold load for 90 min. To correct for prolonged recumbency, a similar protocol was followed on a separate control day, but without an inspiratory load. 2. A negative intrathoracic pressure of at least 30 cmH2O was required to overcome the threshold load. 3. Urine was collected every 30 min and analysed for sodium concentration. 4. Plasma samples were collected every 30 min and analysed for atrial natriuretic peptide concentration. 5. The inspiratory load had no effect on urine volume, urinary sodium excretion or plasma atrial natriuretic peptide levels.

Stradling JR, Thomas G, Warley AR, Williams P, Freeland A. 1990. Effect of adenotonsillectomy on nocturnal hypoxaemia, sleep disturbance, and symptoms in snoring children. Lancet, 335 (8684), pp. 249-253. | Show Abstract | Read more

61 snoring children selected for adenotonsillectomy, mainly for recurrent tonsillitis, were compared with a matched group of 31 healthy children for symptoms of sleep apnoea, extent of sleep hypoxaemia, and amount of sleep disturbance. The studies were repeated six months postoperatively, and after six months in the healthy children. Preoperatively, 61% of the children had degrees of sleep hypoxaemia above normal and 65% had abnormally disturbed sleep. A questionnaire administered to the parents about their children showed abnormal patterns of answers about sleep problems daytime sleepiness, hyperactivity, aggression, learning difficulties, restless sleep, and odd sleeping positions. After adenotonsillectomy, the abnormal hypoxaemia, excessive sleep disturbance, and multiple symptoms almost resolved; a growth spurt also occurred.

Stradling JR, Crosby JH. 1990. Relation between systemic hypertension and sleep hypoxaemia or snoring: analysis in 748 men drawn from general practice. BMJ, 300 (6717), pp. 75-78. | Show Abstract | Read more

OBJECTIVE: To establish whether a history of snoring or the degree of overnight hypoxaemia is an important independent predictor of systemic blood pressure. DESIGN: Prospective community based study of blood pressure in relation to overnight oxygen saturation, height, weight, and a questionnaire assessment of snoring, smoking, and alcohol consumption. Analysis was by multiple linear regression techniques and analysis of variance. SETTING: Small town outside Oxford, served by one group general practice of four partners. All measurements were made at home. SUBJECTS: The names of 836 men aged 35-65 were drawn at random from the general practitioners' age and sex register and the men then asked to participate; 752 (90%) agreed. MAIN OUTCOME MEASURES: Systolic, mean, and diastolic blood pressures and their association with age, obesity, alcohol consumption, cigarette consumption, snoring, and overnight hypoxaemia. RESULTS: Though systemic blood pressure correlated significantly with overnight hypoxaemia, this was due to the cross correlation with age, obesity, and alcohol consumption. No independent predictive effect of overnight hypoxaemia was found. Snoring was correlated with systemic blood pressure but not significantly so and also was not an independent predictor once age, obesity, and alcohol consumption had been allowed for. CONCLUSIONS: It is unlikely that snoring and sleep hypoxaemia from occult sleep apnoea are important causes of diurnal systemic hypertension when compared with age, obesity, and alcohol consumption. The increased prevalence of cardiovascular complications reported in snorers may be due to the confounding variable of obesity or to nocturnal rises in blood pressure that are not reflected in the daytime figures.

Bashir Y, Kann M, Stradling JR. 1990. The effect of acetazolamide on hypercapnic and eucapnic/poikilocapnic hypoxic ventilatory responses in normal subjects. Pulm Pharmacol, 3 (3), pp. 151-154. | Show Abstract | Read more

We have studied the effect of acetazolamide 500 mg bd for three days on ventilatory response to CO2 (HCVR) and hypoxia under both isocapnic and poikilocapnic conditions (isocapnic and poikilocapnic HVR) in five normal subjects. Although acetazolamide reduced calculated arterial pH (7.41 [SEM] 0.01 to 7.37 [SEM] 0.01: p less than 0.01) there was no significant change in either isocapnic HVR (with PetCO2 held at the post-drug resting level) or poikilocapnic HVR in terms of slope and ventilation at SaO2 = 80%. HCVR slope rose slightly (+1.82 [SEM] 0.43 to +2.2 [SEM] 0.29 l/min/mmHg: NS) and there was a significant increase in ventilation at Pet-CO2 = 50 mmHg (9.42 [SEM] 3.3 to 31.4 [SEM] 6.31/min: p less than 0.01). These findings are consistent with the claim that acetazolamide stimulates central chemoreceptors and inhibits peripheral chemoreceptors. Increased sensitivity to CO2 would reverse the suppressive effect of respiratory alkalosis on hypoxic ventilatory drive following rapid ascent to high altitude, and this probably accounts for the efficacy of acetazolamide in the prophylaxis of acute mountain sickness. However, inhibition of peripheral chemoreceptors may also result in symptomatic benefit by reducing sleep disturbance due to periodic breathing.

Stradling JR. 1989. Sleep apnoea and systemic hypertension. Thorax, 44 (12), pp. 984-989. | Read more

Stradling JR. 1989. Obstructive sleep apnoea and driving. BMJ, 298 (6678), pp. 904-905. | Read more

Warley A, Clarke M, Phillips T, Stradling J. 1989. Ventilatory response to an inhaled constant CO2 load and added dead space in healthy men, awake and asleep. Respir Physiol, 75 (2), pp. 183-191. | Show Abstract | Read more

Experiments were conducted in ten adult men to determine if rapid-eye-movement sleep (REMS) reduced the ventilatory response to two 'steady-state' respiratory loads compared to slow wave sleep (SWS). A constant addition of 150 (or 200) ml/min pure CO2 to the inspirate (7 subjects) and 230 ml of added dead space (5 subjects) were the two respiratory loads. Inspiratory ventilation was measured by pneumotachygraph for at least five continuous minutes in wakefulness, SWS and REMS. The increase in ventilation to both stimuli was equal in SWS and REMS with no suggestion of an impaired response during the latter: increases in ventilation during CO2 loading being 49 and 51%, SWS and REMS, respectively, and during additional dead space they were 53 and 59%, SWS and REMS, respectively. Following the addition of extra dead space, end tidal PCO2 levels did not rise significantly more during REMS compared to SWS (P greater than 0.5). These findings show that when ventilatory responses to CO2 are considered across the whole of REMS (including periods with and without actual eye-movements) then they do not appear to be blunted compared to SWS.

Higgins RM, Stradling JR, Lane DJ. 1988. Should ipratropium bromide be added to beta-agonists in treatment of acute severe asthma? Chest, 94 (4), pp. 718-722. | Show Abstract | Read more

In a double-blind randomized trial, 40 patients with acute severe asthma were given either nebulized salbutamol, 5 mg, or salbutamol, 5 mg mixed with ipratropium bromide 500 micrograms, on admission to hospital and again two hours later. There was no significant difference between the mean peak flows of the two treatment groups at any time. However, two hours after each treatment, there were fewer subjects in the ipratropium and salbutamol group whose peak flow rates had fallen back toward baseline levels than in the salbutamol only treatment group. Thus, although ipratropium did not improve the overall maximal bronchodilator response, it may have prolonged the duration of the response, which would be a clinically useful effect.

Warley AR, Mitchell JH, Stradling JR. 1988. Prevalence of nocturnal hypoxaemia amongst men with mild to moderate hypertension. Q J Med, 68 (256), pp. 637-644. | Show Abstract | Read more

Thirty men (aged 35-65) with untreated essential hypertension (BP greater than or equal to 140/90), confirmed by 24-h ambulatory monitoring, had overnight recordings of arterial oxygen saturation (SaO2) in their own homes. The overnight saturation records were compared with those from a group of 30 normotensive control subjects matched for age, height and weight. The groups did not exhibit significant differences in any of the following parameters of overnight oxygenation: median SaO2, lowest SaO2 or frequency of 3 or 4 per cent dips in SaO2. We conclude that essential hypertension is not associated with excessive arterial hypoxaemia such as might be due to a sleep apnoea syndrome.

Connaughton JJ, Catterall JR, Elton RA, Stradling JR, Douglas NJ. 1988. Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis, 138 (2), pp. 341-344. | Show Abstract | Read more

To determine whether studies of breathing and oxygenation during sleep are clinically useful, we have assessed whether the detection of excess nocturnal hypoxemia in patients with chronic obstructive pulmonary disease (COPD) is of prognostic importance. Ninety-seven patients with COPD were followed for 32 to 108 (median, 70) months after studies of overnight oxygenation. Significant relationships (p less than 0.001) were obtained between mean oxygen saturation (SaO2) asleep and awake. There was similarly a significant relationship between lowest SaO2 asleep and awake, but this relationship was improved by the inclusion of awake arterial carbon dioxide tension (PaCO2). The patients who were more hypoxic at night than predicted from these regression relationships had similar survivals to the patients who were less hypoxic at night than predicted, whether excess nocturnal hypoxia was defined in terms of mean or lowest SaO2 during sleep. In the 66 patients who did not subsequently receive long-term oxygen therapy, none of the indices of nocturnal oxygenation was related to survival, the only significant predictor of survival being daytime arterial oxygen tension (PaO2). For all 97 patients, both mean nocturnal SaO2 and lowest SaO2 during sleep were related to survival (p less than 0.05), and percent predicted vital capacity was also related to survival (p less than 0.05). Neither of the oxygen saturations during sleep significantly added to the more readily and cheaply measured percent predicted vital capacity in determining survival in these patients. Thus, in patients with COPD, excess nocturnal hypoxemia is not associated with an impaired prognosis, and so studies of oxygenation during sleep cannot be recommended in the routine clinical management of these patients.

STRADLING JR. 1988. SLEEP DISRUPTION IN DOWNS-SYNDROME BRITISH MEDICAL JOURNAL, 297 (6643), pp. 289-289.

Rozkovec A, Stradling JR, Shepherd G, MacDermot J, Oakley CM, Dollery CT. 1988. Prediction of favourable responses to long term vasodilator treatment of pulmonary hypertension by short term administration of epoprostenol (prostacyclin) or nifedipine. Br Heart J, 59 (6), pp. 696-705. | Show Abstract | Read more

Eighteen patients with moderate to severe pulmonary hypertension were studied, nine with intracardiac shunts and nine without. The effects of an incremental infusion of epoprostenol (prostacyclin) (0.5-8 ng/kg per minute) or sublingual nifedipine (20-30 mg) were compared with the response to three months' treatment with oral nifedipine. Both epoprostenol and sublingual nifedipine caused a fall in pulmonary vascular resistance and pressure and a rise in cardiac output. Patients with intracardiac shunts had higher systemic blood flows than those without shunts. Exercise in the shunt group was accompanied by systemic desaturation and hyperventilation. Analysis of individual results showed that the size of the response was inversely related to the severity of the pulmonary vascular disease. A good long term response to nifedipine seemed to be as readily predicted by the resting control values for haemodynamic variables as by values after short term treatment. A favourable response was likely if the pretreatment mean pulmonary artery pressure was less than 50 mm Hg, the ratio of total pulmonary to systemic resistance was less than 0.7, or the ratio of mean pulmonary artery pressure to systemic artery pressure was less than 0.6. Short term vasodilator protocols may do harm. If such studies are carried out, an adequate dose range must be tried before the long term efficacy of an individual drug can be forecast.

HIGGINS RM, STRADLING JR, LANE DJ. 1988. SHOULD NEBULIZED IPRATROPIUM BE ADDED TO SALBUTAMOL IN ACUTE SEVERE ASTHMA THORAX, 43 (3), pp. P249-P249.

WARLEY A, MORICE A, STRADLING JR. 1988. PLASMA-LEVELS OF ATRIAL NATRIURETIC PEPTIDE (ANP) IN OBSTRUCTIVE SLEEP-APNEA (OSA) THORAX, 43 (3), pp. P253-P254.

Warley AR, Stradling JR. 1988. Abnormal diurnal variation in salt and water excretion in patients with obstructive sleep apnoea. Clin Sci (Lond), 74 (2), pp. 183-185. | Show Abstract | Read more

1. In healthy individuals, sleep is associated with a fall in urine and sodium output. 2. Seven male patients with obstructive sleep apnoea exhibited a paradoxical rise in both urine and sodium output during the hours of sleep. 3. Continuous positive airway pressure applied via the nose abolished both the apnoea and the nocturnal rise in urine and sodium output, thereby restoring the diurnal pattern towards normal.

Stradling JR, Warley AR. 1988. Bilateral diaphragm paralysis and sleep apnoea without diurnal respiratory failure. Thorax, 43 (1), pp. 75-77. | Read more

WARLEY ARH, STRADLING JR. 1987. NOCTURIA IN OBSTRUCTIVE SLEEP-APNEA - EFFECT OF CONTINUOUS POSITIVE AIRWAY PRESSURE BULLETIN EUROPEEN DE PHYSIOPATHOLOGIE RESPIRATOIRE-CLINICAL RESPIRATORY PHYSIOLOGY, 23 pp. S421-S421.

Warley AR, Mitchell JH, Stradling JR. 1987. Evaluation of the Ohmeda 3700 pulse oximeter. Thorax, 42 (11), pp. 892-896. | Show Abstract | Read more

Arterial oxygen saturation values (Sao2) from 60% to 98% were measured by the Ohmeda 3700 pulse oximeter with the three types of probe available and compared with values of oxygen saturation estimated from direct arterial sampling (arterial oxygen and carbon dioxide tensions and pH) on 65 occasions. The response time of the oximeter was measured after a sudden rise in inspired oxygen concentration. Artefact rejection was assessed by arterial compression proximal to the probe site, and by simultaneous recordings of overnight Sao2 on opposite hands. The ability to recreate patterns of oscillating Sao2 from the data stored in the oximeter was also investigated. With the best probe system the oximeter measured Sao2, relative to arterial values estimated from Pao2, with a mean (SD) difference of -0.4% (1.8%). The response time was comparable with those of previous oximeters. It was not possible to generate artefactual dips in excess of 2% Sao2, and the dual overnight recordings rarely showed even small dips on one tracing alone. The stored data can recreate oscillating Sao2 signals with wavelengths down to about 35 seconds, but not below. The Ohmeda 3700 pulse oximeter appears to be suitable for unattended overnight recordings of Sao2.

Higgins RM, Stradling JR. 1987. Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am J Med, 83 (4), pp. 809-811. | Read more

Stradling JR, Kozar LF, Dark J, Kirby T, Andrey SM, Phillipson EA. 1987. Effect of acute diaphragm paralysis on ventilation in awake and sleeping dogs. Am Rev Respir Dis, 136 (3), pp. 633-637. | Show Abstract | Read more

The mechanisms responsible for hypoventilation during rapid-eye-movement (REM) sleep in patients with diaphragmatic weakness are not clear. Therefore, we studied the effects of unilateral (UDP) and bilateral (BDP) diaphragmatic paralysis on ventilation during wakefulness (W), slow-wave sleep (SWS), and REM sleep. Studies were performed in 3 trained dogs in which small silicone cuffs had been implanted surgically around the phrenic nerves. Reversible diaphragmatic paralysis was induced during wakefulness or sleep by bathing the phrenic nerves in local anesthetic injected through a catheter attached to the phrenic cuffs. The UDP reduced abdominal expansion and increased rib cage expansion, but had no effect on minute volume of ventilation (VI) or end-tidal PCO2 (PACO2). The BDP produced marked abdominal paradox, but did not reduce VI during W or SWS and had no effect on tidal volume or respiratory frequency. In contrast, during REM sleep, VI was decreased by an average of 21% mainly because of a fall in tidal volume, and PACO2 increased by 2.4 mm Hg compared with that during the intact state. Furthermore, addition of extra dead space to the breathing circuit, which was well tolerated in intact dogs, led to a progressive increase in PACO2 during BDP and to arousal from sleep. The findings indicate that acute BDP does not impair ventilation during quiet W or SWS, but reduces ventilation during REM sleep, supporting the concept that during REM sleep maintenance of ventilation is critically dependent on diaphragmatic compensation for intercostal and accessory muscle inhibition.

Stradling JR, England SJ, Harding R, Kozar LF, Andrey S, Phillipson EA. 1987. Role of upper airway in ventilatory control in awake and sleeping dogs. J Appl Physiol (1985), 62 (3), pp. 1167-1173. | Show Abstract | Read more

We examined the role of the upper airway in the regulation of the pattern of breathing in six adult dogs during wakefulness and sleep. The dogs breathed through a fenestrated endotracheal tube inserted through a tracheostomy. The tube was modified to allow airflow to be directed either through the nose or through the tracheostomy. When airflow was diverted from nose to tracheostomy there was an abrupt increase in the rate of expiratory airflow, resulting in prolongation of the end-expiratory pause but no change in overall expiratory duration or respiratory frequency. Furthermore, electromyogram recordings from implanted diaphragmatic and laryngeal muscle electrodes did not show any changes that could be interpreted as an attempt to delay expiratory airflow or increase end-expiratory lung volume. The effects of switching from nose to tracheostomy breathing could be reversed by adding a resistance to the endotracheal tube so as to approximate upper airway resistance. The findings indicate that under normal conditions in the adult dog upper airway receptors play little role in regulation of respiratory pattern and that the upper airway exerts little influence on the maintenance of end-expiratory lung volume.

STRADLING JR, COOKSON W, WARLEY ARH, LANE DJ. 1987. THE EFFECT OF NOCTURNAL HYPOXEMIA ON SURVIVAL OF PATIENTS WITH CHRONIC AIRWAYS OBSTRUCTION THORAX, 42 (3), pp. 216-217.

WARLEY ARH, STRADLING JR, MITCHELL J. 1987. THE OHMEDA 3700 PULSE OXIMETER - EVALUATION AND USE AS A SCREENING DEVICE FOR SLEEP HYPOXEMIA THORAX, 42 (3), pp. 216-216.

Stradling J. 1987. Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis, 135 (1), pp. 274. | Read more

WARLEY ARH, STRADLING JR. 1987. THE EFFECT OF FOMINOBEN ON RESTING VENTILATION AND HYPERCAPNIC AND HYPOXIC VENTILATORY RESPONSE IN HEALTHY-MEN CLINICAL SCIENCE, 72 pp. P7-P7.

STRADLING JR. 1987. THORACIC MEDICINE IN THE REGIONS - STUDY OF SLEEP AND BREATHING DISORDERS THORAX, 42 (1), pp. 79-79. | Read more

WARLEY ARH, THOMAS J, STRADLING JR. 1987. EFFECT OF CONTINUOUS POSITIVE AIRWAY PRESSURE (CPAP) ON DIURNAL SODIUM AND WATER-EXCRETION IN OBSTRUCTIVE SLEEP-APNEA (OSA) CLINICAL SCIENCE, 73 pp. P22-P22.

England SJ, Harding R, Stradling JR, Phillipson EA. 1986. Laryngeal muscle activities during progressive hypercapnia and hypoxia in awake and sleeping dogs. Respir Physiol, 66 (3), pp. 327-339. | Show Abstract | Read more

Laryngeal, intercostal and diaphragmatic muscle activities were recorded during progressive hypercapnia and hypoxia in dogs with chronically implanted electrodes. As ventilation increased during progressive chemoreceptor stimulation, inspiratory activity of the posterior cricoarytenoid muscle, a laryngeal abductor, and of the cricothyroid muscle were augmented. When expiratory flow rates reached 2-3 times resting levels, both of these muscles were also active during expiration and recruitment of the internal intercostal muscles was observed. The thyroarytenoid muscle, a laryngeal adductor, was active only rarely and no consistent activation of this muscle was observed with either hypercapnia or hypoxia. The patterns of muscle activation in response to respiratory stimulation were not different during wakefulness, slow wave sleep, and rapid eye movement sleep. The results indicate that the laryngeal muscles are activated during hypercapnia and hypoxia in a manner which reduces both inspiratory and expiratory airflow resistance regardless of sleep-wakefulness state.

Harding R, England SJ, Stradling JR, Kozar LF, Phillipson EA. 1986. Respiratory activity of laryngeal muscles in awake and sleeping dogs. Respir Physiol, 66 (3), pp. 315-326. | Show Abstract | Read more

Experiments were conducted in adult dogs to determine the respiratory activity of laryngeal muscles during wakefulness and sleep. We studied the EMG activity of three laryngeal muscles in five trained dogs, two of which were completely intact, and three of which had a previously-formed side-hole tracheal stoma. Pairs of electrodes were implanted chronically into the posterior cricoarytenoid muscle (PCA), a laryngeal dilator, cricothyroid (CT), and thyroarytenoid (TA), a laryngeal adductor. EMG electrodes were also inserted into the costal portion of the diaphragm. In wakefulness (W), slow wave sleep (SWS) and rapid eye movement (REM) sleep the EMGs of the PCA and CT muscles increased in intensity during diaphragm activation, with varying levels of basal activity during expiration. However, the greatest levels of inspiratory activity in PCA and CT during sleep were found in REM sleep, usually in the absence of augmented diaphragm EMG activity. This laryngeal muscle activity was associated with laryngeal dilation. There were also marked state-related changes in the level of activity of CT during expiration, suggestive of changes in the degree of expiratory adduction of the larynx. The adductor muscles (TA) were not active during expiration, except during alert W. There were no consistent differences in respiratory activity of the laryngeal muscles between the two intact dogs and those with a tracheal stoma (whether or not an endotracheal tube was in place), nor was laryngeal muscle activity affected by the subsequent creation of a tracheal stoma in the two intact dogs. The findings indicate that sleep-wakefulness state exerts important influences on the respiratory activity of laryngeal muscles in the adult dog.

Stradling JR. 1986. Hypercapnia during oxygen therapy in airways obstruction: a reappraisal. Thorax, 41 (12), pp. 897-902. | Read more

STRADLING JR, KOZAR L, ANDREY S, PHILLIPSON EA. 1986. STEADY-STATE RESPONSES TO HYPERCAPNIA AND ADDED DEADSPACE IN AWAKE AND SLEEPING DOGS THORAX, 41 (9), pp. 724-724.

STRADLING JR. 1986. POLYSOMNOGRAPHY OR SCREENING STUDIES FOR SLEEP-DISORDERED BREATHING BULLETIN EUROPEEN DE PHYSIOPATHOLOGIE RESPIRATOIRE-CLINICAL RESPIRATORY PHYSIOLOGY, 22 pp. S176-S176.

STRADLING JR, KOZAR L, ANDREY S, DARK J, KIRBY T, PHILLIPSON EA. 1986. EFFECT OF ACUTE DIAPHRAGM PARALYSIS ON VENTILATION IN AWAKE AND SLEEPING DOGS AMERICAN REVIEW OF RESPIRATORY DISEASE, 133 (4), pp. A249-A249.

PHILLIPSON EA, EGAN TM, KIRBY T, SAUNDERS NR, STRADLING JR, COOPER JD. 1986. PATTERN OF RESPIRATORY MUSCLE ACTIVATION BY PERIPHERAL AND CENTRAL CHEMORECEPTOR STIMULI FEDERATION PROCEEDINGS, 45 (4), pp. 1126-1126.

Stradling JR. 1986. Controversies in sleep-related breathing disorders. Lung, 164 (1), pp. 17-31. | Show Abstract | Read more

This review addresses some current controversies and issues of interest in sleep-related disorders of breathing. Abnormalities of respiratory control may influence the degree of obstructive sleep apnea but it is likely that abnormalities of pharyngeal size are of far greater significance. Central sleep apnea is a heterogeneous condition. Examples of all the causes one would postulate leading to cessation of drives to breathe do occur, hence appropriate therapies also vary. It is not yet known what aspect of, and how much, disordered breathing during sleep leads to morbidity, thus fixed definitions of normality are not helpful. Recurrent nocturnal asphyxia alone is unlikely to result in chronic respiratory failure. Associated diffuse airways obstruction or impaired respiratory muscle function is probably necessary before this complication arises. The recurent REM sleep-induced dips of Sao2 in patients with chronic airways obstruction may be due to physiological inhibition of accessory muscles of respiration. This leads to considerable hypoventilation and recurrent activation of an intact, but displaced, hypoxic drive, resulting in the characteristic oscillations of Sao2. © 1986 Springer-Verlag.

Stradling JR, Phillipson EA. 1986. Breathing disorders during sleep. Q J Med, 58 (225), pp. 3-18. | Read more

STRADLING JR, KOZAR L, DARK J, KIRBY T, ANDREY S, PHILLIPSON EA. 1986. THE EFFECT OF ACUTE BILATERAL DIAPHRAGM PARALYSIS ON BREATHING IN AWAKE AND ASLEEP DOGS CLINICAL SCIENCE, 70 pp. P63-P64.

Stradling JR, Chadwick GA, Quirk C, Phillips T. 1985. Respiratory inductance plethysmography: calibration techniques, their validation and the effects of posture. Bull Eur Physiopathol Respir, 21 (4), pp. 317-324. | Show Abstract

Respiratory inductance plethysmography (RIP) is used to measure ventilation from two measurements of body surface movements (rib-cage and abdomen) via the application of volume-motion (V-M) coefficients. The correct derivation of both V-M coefficients (calibration) is necessary because there are considerable spontaneous variations in relative contributions from these two compartments even during resting breathing. In order to fully test a calibration, deliberate changes in rib-cage (RC) to abdominal (AB) contribution must be made. We used this approach to test two single-posture calibration techniques, multiple linear regression (MLR) and isovolume (ISV). Ten normal subjects and nine patients with chronic airway obstruction (CAWO) were studied using quiet breathing throughout. We also studied the effects of changing posture on the constancy of the V-M coefficients. MLR proved a little more accurate (p = 0.03) in deriving the V-M coefficients than ISV in normal subjects, and ISV consistently underestimated the AB V-M coefficient relative to RC. No difference between the two techniques existed in patients with CAWO. Both MLR and ISV calibrations failed to give acceptable calibrations in some patients. When MLR calibration was used, a deliberate 20% change in relative compartmental contribution (RC-AB) induced mean errors in RIP estimations of tidal volume of 3.5 and 9.5% in normal subjects and patients respectively. When there were no deliberate changes in relative contribution, the 95% confidence limits of individual tidal volume estimates were +/- 6.6 and +/- 12% in normal subjects and patients respectively. MLR calibration provides a statistical estimate of its quality at the time of V-M coefficient derivation.(ABSTRACT TRUNCATED AT 250 WORDS)

Stradling JR, Chadwick GA, Frew AJ. 1985. Changes in ventilation and its components in normal subjects during sleep. Thorax, 40 (5), pp. 364-370. | Show Abstract | Read more

Non-invasive measurements were made of ventilation, its derivatives, the contributions of abdomen and rib cage and arterial oxygen saturation in six healthy normal men whilst awake and during sleep. Minute ventilation fell significantly during slow wave (SW) sleep and rapid eye movement (REM) sleep (awake = 6.3 1 min-1, SW sleep = 5.7 1 min-1, REM sleep = 5.4 1 min-1; p less than 0.04). Mean inspiratory flow also fell significantly but timing was unchanged. The abdominal (diaphragmatic) contribution to ventilation fell very significantly during SW sleep but returned to awake levels during REM sleep (awake 54%, SW sleep 38%, REM sleep 56%; p less than 0.007). There were also significant falls in arterial oxygen saturation during SW and REM sleep (awake 97.3%, SW sleep 96.5%, REM sleep 96.2%; p less than 0.002). These falls represent reductions in arterial oxygen tension similar to those seen in patients with chronic airways obstruction and can be accounted for entirely by the associated reduction in ventilation.

CHADWICK GA, STRADLING JR, FREW AJ. 1985. CHANGES IN VENTILATION AND ITS COMPONENTS IN NORMAL SUBJECTS DURING SLEEP THORAX, 40 (3), pp. 235-235.

CHADWICK GA, FOEX B, STRADLING JR. 1985. THORACOABDOMINAL MOTION IN COPD PATIENTS AND DURING INSPIRATORY LOADING IN NORMAL SUBJECTS BULLETIN EUROPEEN DE PHYSIOPATHOLOGIE RESPIRATOIRE-CLINICAL RESPIRATORY PHYSIOLOGY, 21 pp. 85-85.

CHADWICK GA, GLAZEBROOK K, STRADLING JR, LANE DJ. 1985. EFFECT OF INTERMITTENT POSITIVE PRESSURE BREATHING AND JET NEBULIZER ON THE BREATHING PATTERN THORAX, 40 (3), pp. 233-234.

CHADWICK GC, STRADLING JR. 1984. MECHANISM OF HYPEROXIA-INDUCED HYPERCAPNIA IN PATIENTS WITH CHRONIC AIRWAYS OBSTRUCTION CLINICAL SCIENCE, 67 pp. P9-P9.

Stradling JR, Nicholl CG, Cover D, Davies EE, Hughes JM, Pride NB. 1984. The effects of oral almitrine on pattern of breathing and gas exchange in patients with chronic obstructive pulmonary disease. Clin Sci (Lond), 66 (4), pp. 435-442. | Show Abstract | Read more

Almitrine at a low dose of 100 mg orally significantly raises PaO2 and lowers PaCO2 in patients with chronic obstructive pulmonary disease, compared with placebo, when they were breathing air or 28% oxygen. The estimated ideal alveolar-arterial PO2 difference was less after almitrine compared with placebo, when patients were breathing either air or 28% oxygen. After almitrine overall ventilation breathing air increased by 10% but this did not reach statistical significance. During 28% oxygen breathing almitrine hardly altered overall ventilation but the inspiratory duty cycle (Ti/Ttot.) decreased and mean inspiratory flow rate (VT/Ti) increased compared with placebo. These changes were significant on a paired t-test (P less than 0.05). Changes in both volume and pattern of breathing may explain the improved gas exchange in the lung after almitrine.

Stradling J. 1984. Respiratory physiology during labour. Midwife Health Visit Community Nurse, 20 (2), pp. 38-42.

STRADLING JR, CHADWICK GA. 1984. INACCURACIES IN THE USE OF BODY-SURFACE MOVEMENTS TO MEASURE VENTILATION QUANTITATIVELY DURING SLEEP BULLETIN EUROPEEN DE PHYSIOPATHOLOGIE RESPIRATOIRE-CLINICAL RESPIRATORY PHYSIOLOGY, 20 (5), pp. A12-A13.

CHADWICK GA, STRADLING JR. 1984. OBSERVATIONS ON THE MECHANISM OF HYPOXEMIA IN ACUTE MINOR PULMONARY-EMBOLISM BRITISH MEDICAL JOURNAL, 289 (6448), pp. 836-836. | Read more

STRADLING JR, CHADWICK GA, QUIRK C, PHILLIPS T. 1984. SIMPLIFYING THE USE OF RESPIRATORY INDUCTANCE PLETHYSMOGRAPHY THORAX, 39 (3), pp. 233-234.

Stradling JR, Nicholl CG, Cover D, Hughes JM. 1983. Speed of response and accuracy of two transcutaneous carbon dioxide monitors. Bull Eur Physiopathol Respir, 19 (4), pp. 407-410. | Show Abstract

Two instruments (Radiometer and Hewlett-Packard) for measuring transcutaneous carbon dioxide levels have been compared. Their warm-up times, speed of response and accuracy in predicting arterial PCO2 have been assessed in six normal subjects and ten patients with respiratory problems. They both performed well with similar accuracy in predicting PaCO2 [95% confidence limits +/- 0.9 kPa (6.7 mmHg)]. The warm-up time following application depended on actual PaCO2, but was approximately 10 min for normal subjects and 15 min in patients. Their response to step changes in PaCO2 was complete in approximately 6 min. Prior skin abrasion (essential for the Hewlett-Packard) increased the speed of response of the Radiometer considerably and this is the faster instrument. The Hewlett-Packard proved easier to use. These instruments are a significant advance in non-invasive monitoring.

Apps MC, Gillon JC, Stradling JR. 1983. Underdiagnosis of obstructive sleep apnea in Britain. Lancet, 1 (8332), pp. 1054. | Read more

Jones HA, Stradling JR, Clark JC, Davies EE, Rozkovec A. 1983. Quantitative measurement of intrapulmonary and extrapulmonary right-to-left shunt. J Appl Physiol Respir Environ Exerc Physiol, 54 (5), pp. 1434-1438. | Show Abstract | Read more

We have developed a new technique that enables the shunting of blood from the right to the left side of the circulation to be partitioned into a cardiac and a lung component. The effects of recirculation are minimal, and the method does not require on-line data analysis. Quantitative estimates of these components have been made in two normal dogs and in five patients with raised pulmonary arterial pressures, some of whom were known to have a patent foramen ovale. The results were compared with oxygen shunt measured during air breathing. A poorly soluble gas, nitrogen, radiolabelled with 13N in solution is injected first into a central vein while matched samples of blood are drawn from the pulmonary artery and the aorta. A second solution containing 13N is injected into the right ventricle and sampled from the aorta only. Standardized gamma-counting techniques were used to analyze both the injected radioactivity and the radioactivity in the samples. These two measurements enable us to calculate the total right-to-left shunt, the pulmonary shunt, and by subtraction the extrapulmonary cardiac shunt.

Stradling JR, Lane DJ. 1983. Nocturnal hypoxaemia in chronic obstructive pulmonary disease. Clin Sci (Lond), 64 (2), pp. 213-222. | Show Abstract | Read more

1. Day and night arterial oxygen saturation (Sao2) has been measured in forty-one patients with chronic obstructive pulmonary disease (COPD), mean FEV1 0.84 (range 0.4-1.4)litres, and with a range of daytime Sao2 values of 67-95%. 2. The mean and biggest falls in Sao2 at night were much greater in the patients with lower daytime saturations. However, when falls in arterial oxygen tension (Pao2) were estimated from the decreases in Sao2, there was no correlation between the estimated biggest fall in Pao2 and daytime Sao2 and only a weak correlation between estimated mean fall in Pao2 and daytime Sao2. 3. Measurement of ventilation in four hypoxaemic patients with COPD (range 60-90% Sao2) by respiratory inductance plethysmography showed that nocturnal hypoxaemic dips were accompanied by diminished ventilation, which was not always shown by nasal thermistors. 4. Because nocturnal hypoxaemic dips are transient the ideal alveolar-arterial oxygen difference, which assumes a constant respiratory exchange ratio, cannot be used to assess the mechanism of hypoxaemia. 5. Erythrocyte mass was strongly correlated with daytime Sao2 but this correlation was not significantly improved by including nocturnal hypoxaemia in the regression. 6. The results suggest that greater falls in Sao2 at night are related to lower initial Sao2 values and that the cause may be a reduction in ventilation.

Stradling JR, Nicholl CG, Cover D, Davies EE, Hughes JM, Pride NB. 1983. Pattern of breathing and gas exchange following oral almitrine bismesylate in patients with chronic obstructive pulmonary disease. Eur J Respir Dis Suppl, 126 (SUPPL. 126), pp. 255-264. | Show Abstract

Almitrine bismesylate (100 mg orally) significantly raised PaO2 and lowered PaCO2 in six patients with chronic obstructive pulmonary disease, compared to placebo, when they were breathing air or 28% oxygen. The estimated ideal alveolar arterial PO2 difference (AaDO2) was less after almitrine bismesylate compared to placebo, when patients were breathing either air or 28% oxygen. After almitrine bismesylate overall ventilation breathing air increased by 10% but this did not reach statistical significance. During 28% oxygen breathing, almitrine bismesylate hardly altered overall ventilation but the inspiratory duty cycle (TI/TTOT) decreased and mean inspiratory flow rate (VT/TI) increased compared to placebo. These changes were significant on a paired T test (P less than 0.05). The improvement in AaDO2 correlated with the rise in VT/TI (r = 0.67, P = 0.02) and thus we suggest that changes in both volume and pattern of breathing might explain the improved gas exchange in the lung after almitrine bismesylate .

NICHOLL CG, STRADLING JR, COVER D, HUGHES JMB. 1983. EVALUATION OF 2 TRANS-CUTANEOUS CARBON-DIOXIDE MONITORS THORAX, 38 (3), pp. 233-234.

STRADLING JR. 1983. TREATMENT OF OBSTRUCTIVE SLEEP-APNEA WITH NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE THORAX, 38 (3), pp. 237-238.

STRADLING JR, NICHOLL CG, COVER D, DAVIES EE, HUGHES JMB, PRIDE NB. 1983. THE EFFECTS OF ALMITRINE ON RESTING VENTILATION AND GAS-EXCHANGE IN PATIENTS WITH CHRONIC AIRWAYS OBSTRUCTION CLINICAL SCIENCE, 64 (2), pp. P48-P48.

NUNN P, WANG YT, MYERS M, STRADLING JR, HUGHES JMB. 1983. EFFECTS OF ALMITRINE ON INTERREGIONAL DISTRIBUTION OF VENTILATION AND PERFUSION IN CHRONIC-BRONCHITIS THORAX, 38 (3), pp. 234-234.

Stradling JR, Nicholl CG, Cover D, Hughes JMB. 1983. Speed of response and accuracy of two transcutaneous carbon dioxide monitors Clinical Respiratory Physiology, 19 (4), pp. 407-410. | Show Abstract

Two instruments (Radiometer and Hewlett-Packard) for measuring transcutaneous carbon dioxide levels have been compared. Their warm-up times, speed of response and accuracy in predicting arterial PCO2have been assessed in six normal subjects and ten patients with respiratory problems. They both performed well with similar accuracy in predicting PaCO2[95% confidence limits ± 0.9 kPa (6.7 mmHg)]. The warm-up time following application depended on actual PaCO2but was approximately 10 min for normal subjects and 15 min in patients. Their response to step changes in PaCO2was complete in approximately 6 min. Prior skin abrasion (essential for the Hewlett-Packard) increased the speed of response of the Radiometer considerably and this is the faster instrument. The Hewlett-Packard proved easier to use. These instruments are a significant advance in non-invasive monitoring.

Stradling JR, Barnes P, Pride NB. 1982. The effects of almitrine on the ventilatory response to hypoxia and hypercapnia in normal subjects. Clin Sci (Lond), 63 (4), pp. 401-404. | Show Abstract | Read more

1. Almitrine at a dose of 0.5 mg h-1 kg-1 given intravenously over 2 h had no effect on resting ventilation in normal males. 2. There was a small, but insignificant, rise in the hypercapnic drive to breathe as compared with placebo. 3. A large rise in the hypoxic drive to breathe was seen in response to almitrine. 4. These findings support the claim that almitrine has its action on ventilation via the peripheral chemoreceptors. 5. No correlation between blood levels of almitrine and the rise in hypoxic response was seen.

Stradling JR. 1982. The accuracy of the Hewlett-Packard 47201A ear oximeter below 50% saturation. Bull Eur Physiopathol Respir, 18 (5), pp. 791-794. | Show Abstract

The Hewlett-Packard 47201A ear oximeter has been shown to measure arterial oxygen saturation (SaO2) above 50% SaO2 with an accuracy of +/- 5%. Below 50% SaO2, the oximeter underestimates arterial saturation in a predictable way, thus allowing a correction factor to be used: true SaO2 = (oximeter reading + 50)/2.

Stradling JR. 1982. Obstructive sleep apnoea syndrome. Br Med J (Clin Res Ed), 285 (6341), pp. 528-530. | Read more

Stradling JR. 1982. Avoidance of tracheostomy in sleep apnoea syndrome. Br Med J (Clin Res Ed), 285 (6339), pp. 407-408. | Show Abstract | Read more

Obstructive sleep apnoea (the Pickwickian syndrome) as a cause of daytime hypersomnolence, intellectual deterioration, and eventual respiratory failure with cor pulmonale and death is well recognized. Tracheostomy may be life saving and is the treatment of choice in some centres, although other methods have been tried with limited success. It is, however, a drastic treatment with medical and psychological implications and if possible should be avoided. We suspect in this patient that the considerably deviated nasal septum, and possibly the tonsils, acted as added upstream resistance. The reduction of this resistance was enough to prevent actual apnoea, although not the snoring. His subsequent weight loss further reduced the tendency to pharyngeal collapse and abolished the snoring. This case suggests that tracheostomy and other complex operations for sleep apnoea may not be necessary.

Stradling JR, Bolton P. 1982. Upper airways obstruction as cause of pulmonary oedema. Lancet, 1 (8285), pp. 1353-1354. | Read more

ROZKOVEC A, MINTY K, STRADLING J, SHEPHERD G, MACDERMOT J, OAKLEY CM, DOLLERY CT, HUGHES JMB. 1982. VALUE OF ACUTE VASODILATOR STUDIES IN MANAGEMENT OF PRIMARY PULMONARY-HYPERTENSION CIRCULATION, 66 (4), pp. 49-49.

ROZKOVEC A, STRADLING J, SHEPHERD G, WILDE S, MACDERMOT J, OAKLEY CM, DOLLERY CT. 1982. VARIABLE RESPONSE TO VASODILATOR THERAPY IN PRIMARY PULMONARY-HYPERTENSION BULLETIN EUROPEEN DE PHYSIOPATHOLOGIE RESPIRATOIRE-CLINICAL RESPIRATORY PHYSIOLOGY, 18 (4), pp. P98-P98.

ROZKOVEC A, STRADLING J, MINTY K, SHEPHERD G, OAKLEY CM. 1982. Hydralazine in pulmonary hypertension. N Engl J Med, 307 (19), pp. 1214-1216. | Show Abstract | Read more

To the Editor: The symptomatic fall in blood pressure with one ensuing death after administration of hydralazine to 13 patients with pulmonary hypertension recently described by Packer et al.1 is alarming. Only some patients with severe pulmonary hypertension still have a lung bed capable of dilatation.2 In those who do not, cardiac output is limited by high pulmonary vascular resistance,2,3 and the only effect of an unselective vasodilator is to cause systemic hypotension. The adverse results obtained with hydralazine strongly argue for an initial assessment of the potential reversibility of high pulmonary vascular resistance, using either a selective pulmonary. © 1982, Massachusetts Medical Society. All rights reserved.

STRADLING JR, TURNER SL, BARNES P, BRIDE NB. 1982. THE EFFECTS OF ALMITRINE ON RESTING VENTILATION AND HYPOXIC AND HYPERCAPNIC DRIVES TO VENTILATION IN NORMAL SUBJECTS CLINICAL SCIENCE, 62 (2), pp. P6-P6.

STRADLING JR, LANE DJ, HUGHES JMB. 1982. NOCTURNAL VERSUS DAYTIME HYPOXEMIA IN CHRONIC AIRWAY-OBSTRUCTION BULLETIN EUROPEEN DE PHYSIOPATHOLOGIE RESPIRATOIRE-CLINICAL RESPIRATORY PHYSIOLOGY, 18 (6), pp. P158-P158.

Stradling JR, Huddart S, Arnold AG. 1981. Sleep apnoea syndrome caused by neurofibromatosis and superior vena caval obstruction. Thorax, 36 (8), pp. 634-635. | Show Abstract | Read more

Superior vena caval (SVC) obstruction is usually caused by malignant conditions but benign causes have been reported in as many as 26% of cases. We describe a patient with mediastinal neurofibromata who developed SVC obstruction, upper airways oedema, and gross sleep apnoea syndrome. We can find no previously documented cases of sleep apnoea caused by SVC obstruction.

Stradling JR, Lane DJ. 1981. Development of secondary polycythaemia in chronic airways obstruction. Thorax, 36 (5), pp. 321-325. | Read more

STRADLING JR, LEE S, MARSHALL R, LANE DJ, HUDDART S. 1981. NOCTURNAL HYPOXIA IN CHRONIC AIRWAYS OBSTRUCTION THORAX, 36 (3), pp. 224-225.

Stradling JR. 1980. Apnea alarms. Lancet, 1 (8179), pp. 1197. | Read more

Stradling JR, Lane DJ. 1980. Polycythaemia vera and central sleep apnoea. Br Med J, 280 (6211), pp. 404. | Read more

Stradling JR. 1978. Heparin and infusion phlebitis. Br Med J, 2 (6146), pp. 1195-1196. | Read more

Stradling JR. 1976. Letter: Quality control of "dextrostix". Lancet, 2 (7987), pp. 690-691. | Read more

Manuel AR, Hart N, Stradling JR. 2016. Correlates of obesity-related chronic ventilatory failure. BMJ Open Respir Res, 3 (1), pp. e000110. | Show Abstract | Read more

INTRODUCTION: Only a third of obese patients develop chronic ventilatory failure. This cross-sectional study assessed multiple factors potentially associated with chronic ventilatory failure. MATERIALS/PATIENTS AND METHODS: Participants had a body mass index (BMI) >30 kg/m(2), with or without chronic ventilatory failure (awake arterial partial pressure of carbon dioxide >6 kPa or base excess (BE) ≥2 mmols/L). Factors investigated were grouped into domains: (1) obesity measures, (2) pulmonary function, (3) respiratory and non-respiratory muscle strength, (4) sleep study derivatives, (5) hypoxic and hypercapnic responses, and (6) some hormonal, nutritional and inflammatory measures. RESULTS: 71 obese participants (52% male) were studied over 27 months, 52 (SD 9) years and BMI 47 (range 32-74) kg/m(2). The best univariate correlates of BE from each domain were: (1) dual-energy X-ray absorptiometry measurement of visceral fat (r=+0.50, p=0.001); (2) supine forced expiratory volume in 1 s (r=-0.40, p=0.001); (3) sniff maximum pressure (r=-0.28, p=0.02); (4) mean overnight arterial oxygen saturation (r=-0.50, p<0.001); (5) ventilatory response to 15% O2 breathing (r=-0.28, p=0.02); and (6) vitamin D (r=-0.30, p=0.01). In multivariate analysis, only visceral fat and ventilatory response to hypoxia remained significant. CONCLUSIONS: We have confirmed that in the obese, BMI is a poor correlate of chronic ventilatory failure, and the best independent correlates are visceral fat and hypoxic ventilatory response. TRIAL REGISTRATION NUMBER: NCT01380418.

Schwarz EI, Martinez-Lozano Sinues P, Bregy L, Gaisl T, Garcia Gomez D, Gaugg MT, Suter Y, Stebler N, Nussbaumer-Ochsner Y, Bloch KE et al. 2016. Effects of CPAP therapy withdrawal on exhaled breath pattern in obstructive sleep apnoea. Thorax, 71 (2), pp. 110-117. | Show Abstract | Read more

BACKGROUND: Obstructive sleep apnoea (OSA) is highly prevalent and associated with cardiovascular and metabolic changes. OSA is usually diagnosed by polysomnography which is time-consuming and provides little information on the patient's phenotype thus limiting a personalised treatment approach. Exhaled breath contains information on metabolism which can be analysed by mass spectrometry within minutes. The objective of this study was to identify a breath profile in OSA recurrence by use of secondary-electrospray-ionization-mass spectrometry (SESI-MS). METHODS: Patients with OSA effectively treated with CPAP were randomised to either withdraw treatment (subtherapeutic CPAP) or continue therapeutic CPAP for 2 weeks. Exhaled breath analysis by untargeted SESI-MS was performed at baseline and 2 weeks after randomisation. The primary outcome was the change in exhaled molecular breath pattern. RESULTS: 30 patients with OSA were randomised and 26 completed the trial according to the protocol. CPAP withdrawal led to a recurrence of OSA (mean difference in change of oxygen desaturation index between groups +30.3/h; 95% CI 19.8/h,40.7/h, p<0.001) which was accompanied by a significant change in 62 exhaled features (16 metabolites identified). The panel of discriminating mass-spectral features allowed differentiation between treated and untreated OSA with a sensitivity of 92.9% and a specificity of 84.6%. CONCLUSION: Exhaled breath analysis by SESI-MS allows rapid and accurate detection of OSA recurrence. The technique has the potential to characterise an individual's metabolic response to OSA and thus makes a comprehensible phenotyping of OSA possible. TRIAL REGISTRATION NUMBER: NCT02050425 (registered at ClinicalTrials.gov).

McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Davies RJ, Nunn AJ, Stradling JR, Riha RL, Morrell MJ. 2015. A multicentre randomised controlled trial and economic evaluation of continuous positive airway pressure for the treatment of obstructive sleep apnoea syndrome in older people: PREDICT. Health Technol Assess, 19 (40), pp. 1-188. | Show Abstract | Read more

BACKGROUND: The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnoea syndrome (OSAS) have been established in middle-aged people. In older people there is a lack of evidence. OBJECTIVE: To determine the clinical efficacy of CPAP in older people with OSAS and to establish its cost-effectiveness. DESIGN: A randomised, parallel, investigator-blinded multicentre trial with within-trial and model-based cost-effectiveness analysis. METHODS: Two hundred and seventy-eight patients, aged ≥ 65 years with newly diagnosed OSAS [defined as oxygen desaturation index at ≥ 4% desaturation threshold level for > 7.5 events/hour and Epworth Sleepiness Scale (ESS) score of ≥ 9] recruited from 14 hospital-based sleep services across the UK. INTERVENTIONS: CPAP with best supportive care (BSC) or BSC alone. Autotitrating CPAP was initiated using standard clinical practice. BSC was structured advice on minimising sleepiness. COPRIMARY OUTCOMES: Subjective sleepiness at 3 months, as measured by the ESS (ESS mean score: months 3 and 4) and cost-effectiveness over 12 months, as measured in quality-adjusted life-years (QALYs) calculated using the European Quality of Life-5 Dimensions (EQ-5D) and health-care resource use, information on which was collected monthly from patient diaries. SECONDARY OUTCOMES: Subjective sleepiness at 12 months (ESS mean score: months 10, 11 and 12) and objective sleepiness, disease-specific and generic quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, cardiovascular risk factors and events at 3 and 12 months. RESULTS: Two hundred and seventy-eight patients were randomised to CPAP (n = 140) or BSC (n = 138) over 27 months and 231 (83%) patients completed the trial. Baseline ESS score was similar in both groups [mean (standard deviation; SD) CPAP 11.5 (3.3), BSC 11.4 (4.2)]; groups were well balanced for other characteristics. The mean (SD) in ESS score at 3 months was -3.8 (0.4) in the CPAP group and -1.6 (0.3) in the BSC group. The adjusted treatment effect of CPAP compared with BSC was -2.1 points [95% confidence interval (CI) -3.0 to -1.3 points; p < 0.001]. At 12 months the effect was -2.0 points (95% CI -2.8 to -1.2 points; p < 0.001). The effect was greater in patients with increased CPAP use or higher baseline ESS score. The number of QALYs calculated using the EQ-5D was marginally (0.005) higher with CPAP than with BSC (95% CI -0.034 to 0.044). The average cost per patient was £1363 (95% CI £1121 to £1606) for those allocated to CPAP and £1389 (95% CI £1116 to £1662) for those allocated to BSC. On average, costs were lower in the CPAP group (mean -£35; 95% CI -£390 to £321). The probability that CPAP was cost-effective at thresholds conventionally used by the NHS (£20,000 per QALY gained) was 0.61. QALYs calculated using the Short Form questionnaire-6 Dimensions were 0.018 higher in the CPAP group (95% CI 0.003 to 0.034 QALYs) and the probability that CPAP was cost-effective was 0.96. CPAP decreased objective sleepiness (p = 0.02), increased mobility (p = 0.03) and reduced total and low-density lipoprotein cholesterol (p = 0.05, p = 0.04, respectively) at 3 months but not at 12 months. In the BSC group, there was a fall in systolic blood pressure of 3.7 mmHg at 12 months, which was not seen in the CPAP group (p = 0.04). Mood, functionality, nocturia, accidents, cognitive function and cardiovascular events were unchanged. There were no medically significant harms attributable to CPAP. CONCLUSION: In older people with OSAS, CPAP reduces sleepiness and is marginally more cost-effective than BSC over 12 months. Further work is required in the identification of potential biomarkers of sleepiness and those patients at increased risk of cognitive impairment. Early detection of which could be used to inform the clinician when in the disease cycle treatment is needed to avert central nervous system sequelae and to assist patients decision-making regarding treatment and compliance. Treatment adherence is also a challenge in clinical trials generally, and adherence to CPAP therapy in particular is a recognised concern in both research studies and clinical practice. Suggested research priorities would include a focus on optimisation of CPAP delivery or support and embracing the technological advances currently available. Finally, the improvements in quality of life in trials do not appear to reflect the dramatic changes noted in clinical practice. There should be a greater focus on patient centred outcomes which would better capture the symptomatic improvement with CPAP treatment and translate these improvements into outcomes which could be used in health economic analysis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN90464927. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 40. See the NIHR Journals Library website for further project information.

Stradling JR, Schwarz EI, Schlatzer C, Manuel AR, Lee R, Antoniades C, Kohler M. 2015. Biomarkers of oxidative stress following continuous positive airway pressure withdrawal: data from two randomised trials. Eur Respir J, 46 (4), pp. 1065-1071. | Show Abstract | Read more

There is conflicting evidence whether intermittent hypoxia in obstructive sleep apnoea (OSA) influences oxidative stress. We hypothesised that withdrawal of continuous positive airway pressure (CPAP) from patients with OSA would raise markers of oxidative stress.59 patients with CPAP-treated moderate-to-severe OSA (oxygen desaturation index (ODI) >20 events·h(-1)) were randomised 1:1 to either stay on CPAP (n=30) or change to sham CPAP (n=29) for 2 weeks. Using samples from two similar studies at two sites, we measured early morning blood malondialdehyde (MDA, a primary outcome in one study and a secondary outcome in the other), lipid hydroperoxides, total antioxidant capacity, superoxide generation from mononuclear cells and urinary F2-isoprostane. We also measured superoxide dismutase as a marker of hypoxic preconditioning. "Treatment" effects (sham CPAP versus CPAP) were calculated via linear regression.Sham CPAP provoked moderate-to-severe OSA (mean ODI 46 events·h(-1)), but blood markers of oxidative stress did not change significantly (MDA "treatment" effect (95% CI) -0.02 (-0.23 to +0.19) μmol·L(-1)). Urinary F2-isoprostane fell significantly by ~30% (-0.26 (-0.42 to -0.10) ng·mL(-1)) and superoxide dismutase increased similarly (+0.17 (+0.02 to +0.30) ng·mL(-1)).We found no direct evidence of increased oxidative stress in patients experiencing a return of their moderate-to-severe OSA. The fall in urinary F2-isoprostane and rise in superoxide dismutase implies that hypoxic preconditioning may have reduced oxidative stress.

Craig S, Kylintireas I, Kohler M, Nicoll D, Bratton DJ, Nunn AJ, Leeson P, Neubauer S, Stradling JR. 2015. Effect of CPAP on Cardiac Function in Minimally Symptomatic Patients with OSA: Results from a Subset of the MOSAIC Randomized Trial. J Clin Sleep Med, 11 (9), pp. 967-973. | Show Abstract | Read more

STUDY OBJECTIVES: Minimally symptomatic obstructive sleep apnea (OSA) is highly prevalent, and the effects of continuous positive airway pressure (CPAP) on myocardial function in these patients are unknown. The MOSAIC randomized, controlled trial of CPAP for minimally symptomatic OSA assessed the effect of CPAP on myocardial function in a subset of patients. METHODS: Two centers taking part in the MOSAIC trial randomized 238 patients in parallel to 6 months of CPAP (120) or standard care (118). Of these, 168 patients had echocardiograms, and 68 patients had a cardiac magnetic resonance scan (CMR). A larger group (314) from 4 centers had brain natriuretic peptide (BNP) measured. RESULTS: Mean (SD) baseline oxygen desaturation index (ODI) and Epworth sleepiness score (ESS) were 13.5 (13.2), and 8.4 (4.0), respectively. CPAP significantly reduced ESS and ODI. Baseline LV ejection fraction (LVEF) was well preserved (60.4%). CPAP had no significant effect on echo-derived left atrial (LA) area (-1.0 cm2, 95% CI -2.6 to +0.6, p = 0.23) or early to late left ventricular filling velocity (E/A) ratio (-0.01, 95% CI -0.07 to +0.05, p = 0.79). There was a small change in echo-derived LV end diastolic volume (EDV) with CPAP (-5.9 mL, 95% CI -10.6 to -1.2, p = 0.015). No significant changes were detected by CMR on LV mass index (+1.1 g/m(2), 95% CI -5.9 to +8.0, p = 0.76) or LVEF (+0.8%, 95% CI -1.2 to +2.8, p = 0.41). CPAP did not affect BNP levels (p = 0.16). CONCLUSIONS: Six months of CPAP therapy does not change cardiac functional or structural parameters measured by echocardiogram or CMR in patients with minimally symptomatic mild-to-moderate OSA. CLINICAL TRIAL REGISTRATION: ISRCTN 34164388 (http://isrctn.org).

Stradling JR, Craig SE, Kohler M, Nicoll D, Ayers L, Nunn AJ, Bratton DJ. 2015. Markers of inflammation: data from the MOSAIC randomised trial of CPAP for minimally symptomatic OSA. Thorax, 70 (2), pp. 181-182. | Show Abstract | Read more

UNLABELLED: The Multi-centre Obstructive Sleep Apnoea Interventional Cardiovascular (MOSAIC) trial compared 6 months of CPAP therapy, versus no CPAP, in 391 patients with minimally symptomatic obstructive sleep apnoea (OSA). We now report some exploratory outcomes, markers of systemic inflammation (interleukin 6 (IL-6), IL-10, C reactive protein, tumour necrosis factor). We found no consistent changes (all p values >0.13). TRIAL REGISTRATION NUMBER: ISRCTN 34164388.

Manuel ARG, Hart N, Stradling JR. 2015. Is a raised bicarbonate, without hypercapnia, part of the physiologic spectrum of obesity-related hypoventilation? Chest, 147 (2), pp. 362-368. | Show Abstract | Read more

BACKGROUND: Obesity hypoventilation syndrome (OHS) conventionally includes awake hypercapnia, but an isolated raised bicarbonate, even in the absence of awake hypercapnia, may represent evidence of "early" OHS. We investigated whether such individuals exhibit certain features characteristic of established OHS. METHODS: Obese subjects (BMI > 30 kg/m(2)) were identified from a variety of sources and divided into those with (1) normal blood gas measurements and normal acid-base balance, (2) an isolated raised base excess (BE) (≥ 2 mmol/L), and (3) awake hypercapnia (> 6 kPa; ie, established OHS). Two-point ventilatory responses to hypoxia and hypercapnia were performed. Polygraphic sleep studies were done to identify intermittent and prolonged hypoxia. RESULTS: Seventy-one subjects (BMI, 47.2; SD, 9.8; age, 52.1 years; SD, 8.8 years) were recruited into three groups (33, 22, and 16 respectively). The Paco2 and BE values were 5.15, 5.42, 6.62 kPa, and +0.12, +3.01, +4.78 mmol/L, respectively. For nearly all the ventilatory response and sleep study measures, group 2 (with only an isolated raised BE) represented an intermediate group, and for some of the measures they were more similar to the third group with established OHS. CONCLUSIONS: These data suggest that obese individuals with a raised BE, despite normocapnia while awake, should probably be regarded as having early obesity-related hypoventilation. This has important implications for clinical management as well as randomized controlled treatment trials, as they may represent a group with a more reversible disease process. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01380418; URL: www.clinicaltrials.gov.

Bratton DJ, Stradling JR, Barbé F, Kohler M. 2014. Effect of CPAP on blood pressure in patients with minimally symptomatic obstructive sleep apnoea: a meta-analysis using individual patient data from four randomised controlled trials. Thorax, 69 (12), pp. 1128-1135. | Show Abstract | Read more

BACKGROUND: CPAP reduces blood pressure (BP) in patients with symptomatic obstructive sleep apnoea (OSA). Whether the same benefit is present in patients with minimally symptomatic OSA is unclear, thus a meta-analysis of existing trial data is required. METHODS: The electronic databases Medline, Embase and trial registries were searched. Trials were eligible if they included patients with minimally symptomatic OSA, had randomised them to receive CPAP or either sham-CPAP or no CPAP, and recorded BP at baseline and follow-up. Individual participant data were obtained. Primary outcomes were absolute change in systolic and diastolic BP. FINDINGS: Five eligible trials were found (1219 patients) from which data from four studies (1206 patients) were obtained. Mean (SD) baseline systolic and diastolic BP across all four studies was 131.2 (15.8) mm Hg and 80.9 (10.4) mm Hg, respectively. There was a slight increase in systolic BP of 1.1 mm Hg (95% CI -0.2 to 2.3, p=0.086) and a slight reduction in diastolic BP of 0.8 mm Hg (95% CI -1.6 to 0.1, p=0.083), although the results were not statistically significant. There was some evidence of an increase in systolic BP in patients using CPAP <4 h/night (1.5 mm Hg, 95% CI -0.0 to 3.1, p=0.052) and reduction in diastolic BP in patients using CPAP >4 h/night (-1.4 mm Hg, 95% CI -2.5 to -0.4, p=0.008). CPAP treatment reduced both subjective sleepiness (p<0.001) and OSA severity (p<0.001). INTERPRETATION: Although CPAP treatment reduces OSA severity and sleepiness, it seems not to have a beneficial effect on BP in patients with minimally symptomatic OSA, except in patients who used CPAP for >4 h/night.

Rossi VA, Schwarz EI, Bloch KE, Stradling JR, Kohler M. 2014. Is continuous positive airway pressure necessarily an everyday therapy in patients with obstructive sleep apnoea? Eur Respir J, 43 (5), pp. 1387-1393. | Show Abstract | Read more

There are limited data on the evolution of obstructive sleep apnoea (OSA) during continuous positive airway pressure (CPAP) therapy and whether this treatment is required every night. 125 OSA patients with an original oxygen desaturation index (ODI) >10 events per hour, established on CPAP, were asked to withdraw CPAP for four nights and performed ambulatory nocturnal pulse oximetry on the fourth night of CPAP withdrawal. An ODI >10 events per hour during pulse oximetry was considered to indicate persistent OSA. Patients not experiencing recurrence of OSA underwent repeat ambulatory pulse oximetry after a further 2-week period off CPAP. In 71% of the patients, OSA recurred after four nights of CPAP withdrawal (group 1); thus, OSA did not recur in 29% (group 2). 55% of group 2 had an ODI >10 events per hour after 2 weeks off CPAP; thus, 45% remained without a recurrence. In multivariate analysis, higher original ODI, longer duration of CPAP therapy, current smoking status and larger neck circumference were independently associated with a higher ODI after four nights of CPAP withdrawal (all p<0.05). Following CPAP withdrawal, a third of CPAP-treated patients do not experience significant recurrence of oxygen desaturations after 4 days and ∼10% do not after 2 weeks. Thus, a significant proportion of patients may be able to stop CPAP for short periods.

Rossi VA, Winter B, Rahman NM, Yu L-M, Fallon J, Clarenbach CF, Bloch KE, Stradling JR, Kohler M. 2013. The effects of Provent on moderate to severe obstructive sleep apnoea during continuous positive airway pressure therapy withdrawal: a randomised controlled trial. Thorax, 68 (9), pp. 854-859. | Show Abstract | Read more

OBJECTIVES: The aim of this study was to test the effectiveness of Provent, an expiratory nasal resistance valve, to prevent the recurrence of OSA following CPAP withdrawal. DESIGN: Randomised, partially blinded, parallel, placebo-controlled trial. SETTING: Outpatient sleep clinics in the UK (Oxford) and Switzerland (Zurich). PARTICIPANTS: 67 patients with OSA receiving CPAP were randomised to one of three groups for 2 weeks: continuing CPAP, Provent or placebo Provent. MAIN OUTCOME MEASURES: Primary outcomes included for Provent versus placebo Provent, OSA severity (oxygen desaturation index (ODI), apnoea-hypopnoea index (AHI)) and Epworth Sleepiness Scale (ESS) score. Secondary outcomes for Provent versus placebo Provent included ODI from ambulatory pulse oximetry and blood pressure (BP). For CPAP versus Provent, or CPAP versus placebo Provent, secondary outcomes included ODI/AHI, ESS and BP. RESULTS: 63 patients were included in the per protocol analysis. OSA recurred in the Provent (ODI 35.8, SD 17.4) and placebo Provent (ODI 28.2, SD 18.3) groups, and there was no significant difference in ODI, AHI and ESS between Provent and placebo Provent at 2 weeks (mean difference ODI -1.0, 95% CI -10.0 to +12.0, p=0.85; AHI +3.2, 95% CI -7.7 to +14.1, p=0.52; and ESS -1.4, 95% CI -4.1 to +1.4, p=0.33). ODI from ambulatory pulse-oximetry and BP at 2 weeks were not different in the Provent versus placebo Provent groups. ODI, AHI and BP, but not ESS, were significantly higher in the Provent and placebo Provent groups compared with CPAP. CONCLUSIONS: Provent cannot be recommended as an alternative short-term therapy for patients with moderate to severe OSA already on CPAP. TRIALREGNO: NCT01332175.

Kohler M, Craig S, Pepperell JCT, Nicoll D, Bratton DJ, Nunn AJ, Leeson P, Stradling JR. 2013. CPAP improves endothelial function in patients with minimally symptomatic OSA: results from a subset study of the MOSAIC trial. Chest, 144 (3), pp. 896-902. | Show Abstract | Read more

BACKGROUND: Minimally symptomatic OSA is a highly prevalent disorder, and the effects of CPAP on vascular function in these patients are unknown. This trial aimed to investigate whether CPAP improves vascular function in minimally symptomatic OSA. METHODS: In two centers taking part in the MOSAIC (Multicentre Obstructive Sleep Apnoea Interventional Cardiovascular) trial, 253 patients with minimally symptomatic OSA were randomized to 6 months of CPAP or standard care. Two hundred eight patients attended their follow-up visit within the predefined time window and had complete measurements of arterial stiffness (augmentation index [AIx]), and 64 patients had endothelial function measurements by brachial artery flow-mediated dilatation (FMD). Multivariable analyses adjusting for baseline measurements and minimization factors were performed to assess the effect of CPAP treatment on FMD (% dilatation) and AIx (% augmentation) compared with standard care. RESULTS: The mean ± SD baseline oxygen desaturation index and Epworth Sleepiness Score (ESS) of the 208 patients (age 58 ± 7.3 years, 31 women) were 13.7 ± 12.8 events/h and 8.3 ± 4.2, respectively. There was no CPAP treatment effect on arterial stiffness (AIx, -1.4%; 95% CI, -3.6 to +0.9%; P = .23), but CPAP improved endothelial function (FMD, +2.1%; 95% CI, +1.0 to +3.2%; P &lt; .0001). CPAP reduced daytime sleepiness (ESS, -2.2; 95% CI, -3.0 to -1.5; P &lt; .0001) compared with standard care. There was a larger improvement in FMD in patients using CPAP for &gt; 4 h/night than those who used it less (P = .013). CONCLUSIONS: CPAP improves endothelial function, but not arterial stiffness, in minimally symptomatic OSA. Thus, minimally symptomatic OSA may be a cardiovascular risk factor. TRIAL REGISTRY: ISRCTN Register; No.: ISRCTN 34164388; URL: http://isrctn.org.

Craig SE, Kohler M, Nicoll D, Bratton DJ, Nunn A, Davies R, Stradling J. 2012. Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial. Thorax, 67 (12), pp. 1090-1096. | Show Abstract | Read more

BACKGROUND: Continuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious. METHODS: This multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status. RESULTS: Of 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2 : 39 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components. CONCLUSIONS: In patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.

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