register interest

Najib Rahman

Research Area: Integrative Physiology (Systems Biology)
Technology Exchange: Drug discovery and Medical statistics

I currently lead pleural trials and trials methodology at the Oxford Respiratory Trials Unit (ORTU). My personal research area is clinical studies in malignant and infectious pleural disease, for which I received MRC Training Fellowship funding to conduct my D Phil. This involved:

  • Completion of a phase IIb randomised controlled trial assessing novel intrapleural agents for efficient drainage in pleural infection (The Second Multi-centre Intrapleural Sepsis Trial (MIST2)). This trial involved the Medical Research Council CTU and the British Thoracic Society (11 centre UK double blind placebo controlled study). The study identified a novel enzyme combination treatment which improves radiological outcomes and was associated with reduced hospital stay (New England Journal of Medicine 2011)
  • A single centre phase I toxicity study assessing a novel pro-inflammatory (TLR pathway) pleurodesis agent (Lipoteichoic Acid-T in Malignant Pleural Effusion trial), which identified a potential new strategy for pleurodesis in malignant pleural effusion (Lancet Oncology 2008)
  • A Multicentre clinical trial addressing pragmatic questions in the treatment of malignant effusion (The First Therapeutic Intervention in Malignant Effusion Trial (TIME 1)) working with the MRC CTU. This study is a 2 x 2 factorial assessment of drain size and analgesia for malignant effusion pleurodesis, with projected completion of recruitment (n=320) in February 2011 and completion of follow up in June 2011.
  • Two studies assessing the diagnostic value and interventional safety of thoracic ultrasound in pleural disease (Thorax 2008 and 2010)
  • Novel diagnostic strategies to increase microbiological yield in pleural infection (prospective assessment of the use of blood culture bottles in the diagnosis of pleural infection, Thorax 2011).

Ongoing Research

Our current programme of research is focussed on practice changing pragmatic trials in specialised areas of respiratory medicine (pleural disease and sleep/ventilation). This includes:

  • A prospective multinational cohort study of risk factors, microbiology and outcome in pleural infection (MRC grant)
  • Prospective randomised assessment of the use of thoracic ultrasound in pleurodesis prediction for malignant effusion (funding decision awaited)
  • Three randomised multi-centre studies assessing optimal analgesia and drain size, the clinical value of indwelling pleural catheters and intrapleural fibrinolytic agents in the treatment of malignant pleural effusion (the Therapeutic Intervention in Malignant Effusion (TIME) Trials (1/2/3)). These are at various stages of completion, with one study in the analysis phase currently
  • The Pathogen Identification in Pneumonia and Pleural Infection (PIPAP) study, assessing molecular and novel radiological diagnostic techniques in thoracic infection
  • A definitive phase III study assessing intrapleural tPA and DNase for the treatment of pleural infection (MIST3) - currently in planning / funding stage
  • Detailed radiological description of pleural infection, and its correlates to microbiology and outcome
  • Development work using a number of novel biological agents to manipulate pleural fluid production / pleurodesis.

Oxford Respiratory Trials Unit based studies in pleural disease and sleep medicine over the last 5 years have demonstrated the feasibility of multi-centre (>200 patient) recruitment in the UK into pragmatic trials of pleural disease and sleep, and have discovered novel treatment mechanisms in both pleural infection (MIST2) and malignant pleural effusion (LTAT phase I study). The infrastructure necessary to conduct multi-centre studies is now present, and extension in to other disease areas is now planned.

Name Department Institution Country
John Stradling Experimental Medicine Division Oxford University, Churchill Hospital United Kingdom
Dr Fergus Gleeson Experimental Medicine Division Oxford University,
Professor Peter Robbins University of Oxford United Kingdom
Dr Fabien Maldonado Vanderbilt University United States
David Feller-Kopman Johns Hopkins United States
Lonny Yarmus Johns Hopkins United States
George Eapen MD Anderson Texas United States
Gregory P, Rahman NM, Lee YCG. 2019. Osler Centenary Papers: Management of pleural infection: Osler's final illness and recent advances. Postgrad Med J, 95 (1130), pp. 656-659. | Show Abstract | Read more

Sir William Osler's great work and achievements are extensively documented. Less well known is his prolonged battle with postinfluenza pneumonia, lung abscess and pleural infection that eventually led to his demise. At the age of 70, he was a victim of the global Spanish influenza epidemic, and subsequently developed pneumonia. In the era before antibiotics, he received supportive care and opium for symptom control. The infection extended to the pleura and he required repeated thoracentesis which failed to halt his deterioration. He proceeded to open surgical drainage involving rib resection. Unfortunately, he died shortly after the operation from massive pleuropulmonary haemorrhage. In this article, we review the events leading up to Osler's death and contrast his care 100 years ago with contemporary state-of-the-art management in pleural infection.

Lentz RJ, Shojaee S, Grosu HB, Rickman OB, Roller L, Pannu JK, DePew ZS, Debiane LG, Cicenia JC, Akulian J et al. 2019. The Impact of Gravity versus Suction-driven Therapeutic Thoracentesis on Pressure-related Complications: the GRAVITAS Multicenter Randomized Controlled Trial. Chest, | Show Abstract | Read more

BACKGROUND: Thoracentesis can be accomplished by active aspiration or drainage with gravity. We investigated whether gravity drainage could protect against negative-pressure related complications, such as chest discomfort, re-expansion pulmonary edema or pneumothorax, compared to active aspiration. METHODS: This prospective, multicenter single blinded randomized controlled trial allocated patients with large free-flowing effusions estimated ≥ 500 mL 1:1 to active aspiration or gravity drainage. Patients rated chest discomfort on 100 mm visual analog scales before, during, and after drainage. Thoracentesis was halted at complete evacuation or for persistent chest discomfort, intractable cough, or other complication. The primary outcome was overall procedural chest discomfort scored five minutes post-procedure. Secondary outcomes included measures of discomfort and breathlessness through 48 hours post-procedure. RESULTS: One hundred forty-two patients were randomized with 140 in the final analysis. Groups did not differ for the primary outcome (mean VAS score difference 5.3 mm, 95% CI -2.4 to 13.0, p = 0.17). Secondary outcomes of discomfort and dyspnea did not differ between groups. Comparable volumes were drained in both groups but procedure duration was significantly longer in the gravity arm (mean difference 7.4 minutes, 95% CI 10.2 to 4.6, p<0.001). There were no serious complications. CONCLUSIONS: Thoracentesis via active aspiration and gravity drainage both appear safe and result in comparable levels of procedural comfort and dyspnea improvement. Active aspiration requires less total procedural time.

Hassan M, Mercer RM, Maskell NA, Asciak R, McCracken DJ, Bedawi EO, Shaarawy H, El-Ganady A, Psallidas I, Miller RF, Rahman NM. 2019. Survival in patients with malignant pleural effusion undergoing talc pleurodesis. Lung Cancer, 137 pp. 14-18. | Show Abstract | Read more

OBJECTIVES: Recent observations indicate a potential survival benefit in patients with malignant pleural effusion (MPE) who achieve successful pleurodesis in comparison to patients who experience effusion recurrence post pleurodesis. This study aimed to explore this observation using two datasets of patients with MPE undergoing talc pleurodesis. MATERIALS AND METHODS: Dataset 1 comprised patients who underwent talc pleurodesis at Oxford Pleural Unit for MPE. Dataset 2 comprised patients enrolled in the TIME1 clinical trial. Pleurodesis success was defined as absence of need for further therapeutic procedures for MPE in the three months following pleurodesis. Data on various clinical, laboratory and radiological parameters were collected and survival was compared according to pleurodesis outcome (success vs. failure) after adjusting for the aforementioned parameters. RESULTS: Dataset 1 comprised 60 patients with mean age 74.1±10.3 years. The most common primary malignancies were mesothelioma, breast and lung cancer. 29 patients (48.3%) achieved pleurodesis. The adjusted odds ratio (aOR) for poor survival with pleurodesis failure was 2.85 (95% CI 1.08-7.50, =p 0.034). Dataset 2 comprised 259 patients from the TIME1 trial. The mean age was 70.8±10.3 and the most common primary malignancies were mesothelioma, lung and breast cancer. Pleurodesis was successful in 205 patients (79%). aOR for poor survival was 1.62 (95% CI 1.09-2.39, p = 0.015). CONCLUSION: Achieving pleurodesis seems to impart a survival benefit in patients with MPE. Further studies are required to explore factors that may contribute to this phenomenon and to address the difference in survival between pleurodesis and indwelling pleural catheter interventions.

Walker S, Mercer R, Maskell N, Rahman NM. 2019. Malignant pleural effusion management: keeping the flood gates shut. Lancet Respir Med, | Show Abstract | Read more

With no cure for malignant pleural effusion, efforts are focused on symptomatic management. Historically, this symptomatic management was achieved with the instillation of a sclerosant agent into the pleural space to achieve pleurodesis. The development of the tunnelled indwelling pleural catheter and ambulatory pleural drainage changed the management of malignant pleural effusion, not solely by offering an alternative management pathway, but by challenging how health-care providers view success in a palliative condition. Furthermore, with additional treatment options available, increased imperative exists to better characterise patients to enable a personalised approach to their care. We have done a review of the scientific literature and clinical trial registries to provide an overview of the current and ground-breaking research published in the past 10 years.

Bedawi EO, Rahman NM. 2019. Shining Light on Pleural Biopsy in Mesothelioma: Is It Time to Get "Smart"? Chest, 156 (4), pp. 643-644. | Read more

Fitzgerald DB, Waterer GW, Read CA, Fysh ET, Shrestha R, Stanley C, Muruganandan S, Lan NSH, Popowicz ND, Peddle-McIntyre CJ et al. 2019. Steroid therapy and outcome of parapneumonic pleural effusions (STOPPE): Study protocol for a multicenter, double-blinded, placebo-controlled randomized clinical trial. Medicine (Baltimore), 98 (43), pp. e17397. | Show Abstract | Read more

BACKGROUND: Community-acquired pneumonia (CAP) is a major global disease. Parapneumonic effusions often complicate CAP and range from uninfected (simple) to infected (complicated) parapneumonic effusions and empyema (pus). CAP patients who have a pleural effusion at presentation are more likely to require hospitalization, have a longer length of stay and higher mortality than those without an effusion. Conventional management of pleural infection, with antibiotics and chest tube drainage, fails in about 30% of cases. Several randomized controlled trials (RCT) have evaluated the use of corticosteroids in CAP and demonstrated some potential benefits. Importantly, steroid use in pneumonia has an acceptable safety profile with no adverse impact on mortality. A RCT focused on pediatric patients with pneumonia and a parapneumonic effusion demonstrated shorter time to recovery. The effects of corticosteroid use on clinical outcomes in adults with parapneumonic effusions have not been tested. We hypothesize that parapneumonic effusions develop from an exaggerated pleural inflammatory response. Treatment with systemic steroids may dampen the inflammation and lead to improved clinical outcomes. The steroid therapy and outcome of parapneumonic pleural effusions (STOPPE) trial will assess the efficacy and safety of systemic corticosteroid as an adjunct therapy in adult patients with CAP and pleural effusions. METHODS: STOPPE is a pilot multicenter, double-blinded, placebo-controlled RCT that will randomize 80 patients with parapneumonic effusions (2:1) to intravenous dexamethasone or placebo, administered twice daily for 48 hours. This exploratory study will capture a wide range of clinically relevant endpoints which have been used in clinical trials of pneumonia and/or pleural infection; including, but not limited to: time to clinical stability, inflammatory markers, quality of life, length of hospital stay, proportion of patients requiring escalation of care (thoracostomy or thoracoscopy), and mortality. Safety will be assessed by monitoring for the incidence of adverse events during the study. DISCUSSION: STOPPE is the first trial to assess the efficacy and safety profile of systemic corticosteroids in adults with CAP and pleural effusions. This will inform future studies on feasibility and appropriate trial endpoints. TRIAL REGISTRATION: ACTRN12618000947202 PROTOCOL VERSION:: version 3.00/26.07.18.

Kanellakis NI, Wrightson JM, Hallifax R, Bedawi EO, Mercer R, Hassan M, Asciak R, Hedley E, Dobson M, Dong T et al. 2019. Biological effect of tissue plasminogen activator (t-PA) and DNase intrapleural delivery in pleural infection patients. BMJ Open Respir Res, 6 (1), pp. e000440. | Show Abstract | Read more

Background: Pleural infection (PI) is a major global disease with an increasing incidence, and pleural fluid (PF) drainage is essential for the successful treatment. The MIST2 study demonstrated that intrapleural administration of tissue plasminogen activator (t-PA) and DNase, or t-PA alone increased the volume of drained PF. Mouse model studies have suggested that the volume increase is due to the interaction of the pleura with the t-PA via the monocyte chemoattractant protein 1 (MCP-1) pathway. We designed a study to determine the time frame of drained PF volume induction on intrapleural delivery of t-PA±DNase in humans, and to test the hypothesis that the induction is mediated by the MCP-1 pathway. Methods: Data and samples from the MIST2 study were used (210 PI patients randomised to receive for 3 days either: t-PA and DNase, t-PA and placebo, DNase and placebo or double placebo). PF MCP-1 levels were measured by ELISA. One-way and two-way analysis of variance (ANOVA) with Tukey's post hoc tests were used to estimate statistical significance. Pearson's correlation coefficient was used to assess linear correlation. Results: Intrapleural administration of t-PA±DNase stimulated a statistically significant rise in the volume of drained PF during the treatment period (days 1-3). No significant difference was detected between any groups during the post-treatment period (days 5-7). Intrapleural administration of t-PA increased MCP-1 PF levels during treatment; however, no statistically significant difference was detected between patients who received t-PA and those who did not. PF MCP-1 expression was not correlated to the drug given nor the volume of drained PF. Conclusions: We conclude that the PF volume drainage increment seen with the administration of t-PA does not appear to act solely via activation of the MCP-1 pathway.

Chen M, Doganay O, Matin T, McIntyre A, Rahman N, Bulte D, Gleeson F. 2019. Delayed ventilation assessment using fast dynamic hyperpolarised Xenon-129 magnetic resonance imaging. Eur Radiol, | Show Abstract | Read more

OBJECTIVES: To investigate the use of a fast dynamic hyperpolarised 129Xe ventilation magnetic resonance imaging (DXeV-MRI) method for detecting and quantifying delayed ventilation in patients with chronic obstructive pulmonary disease (COPD). METHODS: Three male participants (age range 31-43) with healthy lungs and 15 patients (M/F = 12:3, age range = 48-73) with COPD (stages II-IV) underwent spirometry tests, quantitative chest computed tomography (QCT), and DXeV-MRI at 1.5-Tesla. Regional delayed ventilation was captured by measuring the temporal signal change in each lung region of interest (ROI) in comparison to that in the trachea. In addition to its qualitative assessment through visual inspection by a clinical radiologist, delayed ventilation was quantitatively captured by calculating a covariance measurement of the lung ROI and trachea signals, and quantified using both the time delay, and the difference between the integrated areas covered by the signal-time curves of the two signals. RESULTS: Regional temporal ventilation, consistent with the expected physiological changes across a free breathing cycle, was demonstrated with DXeV-MRI in all patients. Delayed ventilation was observed in 13 of the 15 COPD patients and involved variable lung ROIs. This was in contrast to the control group, where no delayed ventilation was demonstrated (p = 0.0173). CONCLUSIONS: DXeV-MRI offers a non-invasive way of detecting and quantifying delayed ventilation in patients with COPD, and provides physiological information on regional pulmonary function during a full breathing cycle. KEY POINTS: • Dynamic xenon MRI allows for the non-invasive detection and measurement of delayed ventilation in COPD patients. • Dynamic xenon MRI during a free breathing cycle can provide unique information about pulmonary physiology and pulmonary disease pathophysiology. • With further validation, dynamic xenon MRI could offer a non-invasive way of measuring collateral ventilation which can then be used to guide lung volume reduction therapy (LVRT) for certain COPD patients.

Stanton AE, Evison M, Roberts M, Latham J, Clive AO, Batalla-Duran E, Bhatnagar R, Asciak R, Diggins B, Bintcliffe OJ et al. 2019. Training opportunities in thoracic ultrasound for respiratory trainees: are current guidelines practical? BMJ Open Respir Res, 6 (1), pp. e000390. | Show Abstract | Read more

Introduction: Respiratory trainees in the UK face challenges in meeting current Royal College of Radiologists (RCR) Level 1 training requirements for thoracic ultrasound (TUS) competence, specified as attending 'at least one session per week over a period of no less than 3 months, with approximately five scans per session performed by the trainee (under supervision of an experienced practitioner)'. We aimed to clarify where TUS training opportunities currently exist for respiratory registrars. Methods: Data were collected (over a 4-week period) to clarify the number of scans (and therefore volume of training opportunities) within radiology departments and respiratory services in hospitals in the South West, North West deaneries and Oxford. Results: 14 hospitals (including three tertiary pleural centres) provided data. Of 964 scans, 793 (82.3%) were conducted by respiratory teams who performed a mean of 17.7 scans per week, versus 3.1 TUS/week in radiology departments. There was no radiology session in any hospital with ≥5 TUS performed, whereas 8/14 (86%) of respiratory departments conducted such sessions. Almost half (6/14) of radiology departments conducted no TUS scans in the period surveyed. Conclusions: The currently recommended exposure of regularly attending a list or session to undertake five TUS is not achievable in radiology departments. The greatest volume of training opportunities exists within respiratory departments in a variety of scheduled and unscheduled settings. Revision of the competency framework in TUS, and where this is delivered, is required.

Smallwood N, Miller A, Walden A, Hew M, Tay TR, Rahman NM. 2019. Should point-of-care ultrasonography replace stethoscopes in acute respiratory failure? BMJ, 366 pp. l5225. | Read more

Chopra A, Judson MA, Doelken P, Maldonado F, Rahman NM, Huggins JT. 2019. The Relationship of Pleural Manometry With Postthoracentesis Chest Radiographic Findings in Malignant Pleural Effusion. Chest, | Show Abstract | Read more

BACKGROUND: Both elevated pleural elastance (E-PEL) and radiographic evidence of incomplete lung expansion following thoracentesis have been used to exclude patients with a malignant pleural effusion (MPE) from undergoing pleurodesis. This article reports on a cohort of patients with MPE in whom complete drainage was attempted with pleural manometry to determine the frequency of E-PEL and its relation with postthoracentesis radiographic findings. METHODS: Seventy consecutive patients with MPE who underwent therapeutic pleural drainage with pleural manometry were identified. The pressure/volume curves were constructed and analyzed to determine the frequency of E-PEL and the relation of PEL to the postthoracentesis chest radiographic findings. RESULTS: E-PEL and incomplete lung expansion were identified in 36 of 70 (51.4%) and 38 of 70 (54%) patients, respectively. Patients with normal PEL had an OR of 6.3 of having complete lung expansion compared with those with E-PEL (P = .0006). However, 20 of 70 (29%) patients exhibited discordance between postprocedural chest radiographic findings and the pleural manometry results. Among patients who achieved complete lung expansion on the postdrainage chest radiograph, 9 of 32 (28%) had an E-PEL. In addition, PEL was normal in 11 of 38 (34%) patients who had incomplete lung expansion as detected according to the postthoracentesis chest radiograph. CONCLUSIONS: E-PEL and incomplete lung expansion postthoracentesis are frequently observed in patients with MPE. Nearly one-third of the cohort exhibited discordance between the postprocedural chest radiographic findings and pleural manometry results. These findings suggest that a prospective randomized trial should be performed to compare both modalities (chest radiograph and pleural manometry) in predicting pleurodesis outcome.

Cargill TN, Hassan M, Corcoran JP, Harriss E, Asciak R, Mercer RM, McCracken DJ, Bedawi EO, Rahman NM. 2019. A systematic review of comorbidities and outcomes of adult patients with pleural infection. Eur Respir J, 54 (3), | Show Abstract | Read more

BACKGROUND: Pleural infection remains an important cause of mortality. This study aimed to investigate worldwide patterns of pre-existing comorbidities and clinical outcomes of patients with pleural infection. METHODS: Studies reporting on adults with pleural infection between 2000 and 2017 were identified from a search of Embase and MEDLINE. Articles reporting exclusively on tuberculous, fungal or post-pneumonectomy infection were excluded. Two reviewers assessed 20 980 records for eligibility. RESULTS: 211 studies met the inclusion criteria. 134 articles (227 898 patients, mean age 52.8 years) reported comorbidity and/or outcome data. The majority of studies were retrospective observational cohorts (n=104, 78%) and the most common region of reporting was East Asia (n=33, 24%) followed by North America (n=27, 20%). 85 articles (50 756 patients) reported comorbidity. The median (interquartile range (IQR)) percentage prevalence of any comorbidity was 72% (58-83%), with respiratory illness (20%, 16-32%) and cardiac illness (19%, 15-27%) most commonly reported. 125 papers (192 298 patients) reported outcome data. The median (IQR) length of stay was 19 days (13-27 days) and median in-hospital or 30-day mortality was 4% (IQR 1-11%). In regions with high-income economies (n=100, 74%) patients were older (mean 56.5 versus 42.5 years, p<0.0001), but there were no significant differences in prevalence of pre-existing comorbidity nor in length of hospital stay or mortality. CONCLUSION: Patients with pleural infection have high levels of comorbidity and long hospital stays. Most reported data are from high-income economy settings. Data from lower-income regions is needed to better understand regional trends and enable optimal resource provision going forward.

Grosu HB, Lu W, Ost DE, Vial MR, Hernandez M, Ghosh N, Noor L, Hasan AM, Bashoura L, Faiz S et al. 2019. Pleural Fluid Cytokine Levels at Baseline and Over Time are Associated With Time to IPC Removal: An Exploratory Study. J Bronchology Interv Pulmonol, | Show Abstract | Read more

BACKGROUND: The behavior of pleural fluid cytokine (PFCs) levels and their association with pleurodesis after indwelling pleural catheter (IPC) placement is unknown. OBJECTIVE: A prospective exploratory study was conducted to obtain preliminary data on PFC levels after IPC placement. METHODS: The PFC panel consisted of 4 cytokines [interleukin -8 (IL-8), vascular endothelial growth factor, total (but not activated) transforming growth factor betas, and basic fibroblast growth factor], measured across 5 time points (T0: insertion; T1: 24 to 48 h; T2: 72 to 96 h; T3: 1 wk; and T4: 2 wk). Profile plots were used to identify patterns of change of PFC levels. Correlation matrices for each PFC over time were computed, and area under the curve (AUC) categories were used to compare the cumulative incidence of IPC removal. Auto pleurodesis was defined as elective catheter removal because of decreased drainage within 90 days of insertion. RESULTS: A total of 22 patients provided complete data. Except for IL-8, the majority of PFCs demonstrated strong positive correlations across measurement time points. Patients with high AUCs for IL-8, basic fibroblast growth factor, and vascular endothelial growth factor had a higher cumulative incidence of IPC removal by 90 days than did patients with low AUCs. CONCLUSION: This is the first study to evaluate longitudinal changes of pleural cytokine levels with respect to the likelihood of IPC removal and provide early evidence that the cytokine profile may be associated with the outcome of pleurodesis induced by IPCs. However, this is an exploratory study and further studies are needed to assess if these findings can be validated in further studies.

Epelbaum O, Rahman NM. 2019. Contemporary approach to the patient with malignant pleural effusion complicating lung cancer. Ann Transl Med, 7 (15), pp. 352. | Show Abstract | Read more

Malignant pleural effusion (MPE) occurring in the patient with lung cancer can have profound prognostic and management implications. If clinically relevant, such an effusion first needs to be confirmed as malignant and then, in the majority of lung cancer patients, it will require a pleural intervention to relieve symptoms related to fluid accumulation. The field of pleural diseases in general, and pleural malignancy in particular, has undergone dynamic changes in recent years as the evidence base informing practice has grown by leaps and bounds. Both the diagnosis and management of MPE are dynamically changing disciplines in thoracic medicine. As commonly happens, emerging data have generated just as many questions as they have answered. The aim of the present review is to summarize the current knowledge about MPE resulting from lung cancer in a manner that is accessible to clinicians across medical specialties.

Walker AS, Budgell E, Laskawiec-Szkonter M, Sivyer K, Wordsworth S, Quaddy J, Santillo M, Krusche A, Roope LSJ, Bright N et al. 2019. Antibiotic Review Kit for Hospitals (ARK-Hospital): study protocol for a stepped-wedge cluster-randomised controlled trial. Trials, 20 (1), pp. 421. | Show Abstract | Read more

BACKGROUND: To ensure patients continue to get early access to antibiotics at admission, while also safely reducing antibiotic use in hospitals, one needs to target the continued need for antibiotics as more diagnostic information becomes available. UK Department of Health guidance promotes an initiative called 'Start Smart then Focus': early effective antibiotics followed by active 'review and revision' 24-72 h later. However in 2017, < 10% of antibiotic prescriptions were discontinued at review, despite studies suggesting that 20-30% of prescriptions could be stopped safely. METHODS/DESIGN: Antibiotic Review Kit for Hospitals (ARK-Hospital) is a complex 'review and revise' behavioural intervention targeting healthcare professionals involved in antibiotic prescribing or administration in inpatients admitted to acute/general medicine (the largest consumers of non-prophylactic antibiotics in hospitals). The primary study objective is to evaluate whether ARK-Hospital can safely reduce the total antibiotic burden in acute/general medical inpatients by at least 15%. The primary hypotheses are therefore that the introduction of the behavioural intervention will be non-inferior in terms of 30-day mortality post-admission (relative margin 5%) for an acute/general medical inpatient, and superior in terms of defined daily doses of antibiotics per acute/general medical admission (co-primary outcomes). The unit of observation is a hospital organisation, a single hospital or group of hospitals organised with one executive board and governance framework (National Health Service trusts in England; health boards in Northern Ireland, Wales and Scotland). The study comprises a feasibility study in one organisation (phase I), an internal pilot trial in three organisations (phase II) and a cluster (organisation)-randomised stepped-wedge trial (phase III) targeting a minimum of 36 organisations in total. Randomisation will occur over 18 months from November 2017 with a further 12 months follow-up to assess sustainability. The behavioural intervention will be delivered to healthcare professionals involved in antibiotic prescribing or administration in adult inpatients admitted to acute/general medicine. Outcomes will be assessed in adult inpatients admitted to acute/general medicine, collected through routine electronic health records in all patients. DISCUSSION: ARK-Hospital aims to provide a feasible, sustainable and generalisable mechanism for increasing antibiotic stopping in patients who no longer need to receive them at 'review and revise'. TRIAL REGISTRATION: ISRCTN Current Controlled Trials, ISRCTN12674243 . Registered on 10 April 2017.

Metintas M, Ak G, Metintas S, Yildirim H, Dündar E, Rahman N. 2019. Prospective Study of the Utility of Computed Tomography Triage of Pleural Biopsy Strategies in Patients With Pleural Diseases. J Bronchology Interv Pulmonol, 26 (3), pp. 210-218. | Show Abstract | Read more

BACKGROUND: This study aimed to prospectively evaluate the efficacy and reliability of a diagnostic workup, triaging pleural biopsy method according to baseline computerized tomography (CT) findings in the diagnosis of pleural diseases. METHODS: Patients with pleural pathology were divided into 3 arms according to findings on CT scan images. Arm A: patients with pleural thickening/lesion in addition to pleural effusion. These patients underwent CT scan-guided Abrams' needle pleural biopsy. Arm B: patients with pleural effusion alone or suspected benign asbestos pleurisy. This group underwent medical thoracoscopy (MT). Arm C: patients with only pleural thickening. This group underwent ultrasonography-guided cutting needle pleural biopsy. MT was planned in patients who did not have a specific diagnosis in the CT scan-guided Abrams' needle pleural biopsy group. When patients with a histopathologic diagnosis of fibrinous pleuritis after MT were assessed in terms of the risk factors for malignant pleural diseases, we offered a further invasive procedure. RESULTS: A total of 164 patients were enrolled in the study. Diagnostic sensitivity after the initial procedure was 90.2% in Arm A, 93.3% in Arm B, 95.2% in Arm C, and 92.4% in the entire workup. The negative predictive value of the entire workup was 90.4% for malignant pleural mesothelioma, 97.1% for metastatic malignant pleural diseases, and 100% for tuberculous pleurisy. Five cases who had a diagnosis of fibrinous pleuritis after MT were detected to have risk factors, 4 of which (80%) indicated malignant disease. Complication rates were low and acceptable. CONCLUSION: Use of CT scans to triage an appropriate pleural biopsy method is associated with high diagnostic success. We recommend that the proposed diagnostic workup in this study may be used as a diagnostic algorithm for pleural diseases that require a histopathologic analysis. Determination of risk factors predicting malignant disease in patients where fibrinous pleuritis is reported after MT would be useful for clinical practice.

Hassan M, Cargill T, Harriss E, Asciak R, Mercer RM, Bedawi EO, McCracken DJ, Psallidas I, Corcoran JP, Rahman NM. 2019. The microbiology of pleural infection in adults: a systematic review. Eur Respir J, 54 (3), | Show Abstract | Read more

BACKGROUND AND OBJECTIVES: Pleural infection is a major cause of morbidity and mortality among adults. Identification of the offending organism is key to appropriate antimicrobial therapy. It is not known whether the microbiological pattern of pleural infection is variable temporally or geographically. This systematic review aimed to investigate available literature to understand the worldwide pattern of microbiology and the factors that might affect such pattern. DATA SOURCES AND ELIGIBILITY CRITERIA: Ovid MEDLINE and Embase were searched between 2000 and 2018 for publications that reported on the microbiology of pleural infection in adults. Both observational and interventional studies were included. Studies were excluded if the main focus of the report was paediatric population, tuberculous empyema or post-operative empyema. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies of ≥20 patients with clear reporting of microbial isolates were included. The numbers of isolates of each specific organism/group were collated from the included studies. Besides the overall presentation of data, subgroup analyses by geographical distribution, infection setting (community versus hospital) and time of the report were performed. RESULTS: From 20 980 reports returned by the initial search, 75 articles reporting on 10 241 patients were included in the data synthesis. The most common organism reported worldwide was Staphylococcus aureus. Geographically, pneumococci and viridans streptococci were the most commonly reported isolates from tropical and temperate regions, respectively. The microbiological pattern was considerably different between community- and hospital-acquired infections, where more Gram-negative and drug-resistant isolates were reported in the hospital-acquired infections. The main limitations of this systematic review were the heterogeneity in the method of reporting of certain bacteria and the predominance of reports from Europe and South East Asia. CONCLUSIONS: In pleural infection, the geographical location and the setting of infection have considerable bearing on the expected causative organisms. This should be reflected in the choice of empirical antimicrobial treatment.

Kaul V, McCracken DJ, Rahman NM, Epelbaum O. 2019. Contemporary Approach to the Diagnosis of Malignant Pleural Effusion. Ann Am Thorac Soc, 16 (9), pp. 1099-1106. | Show Abstract | Read more

Advanced malignancy is a prevalent cause of exudative pleural effusion. The management of malignant pleural effusion (MPE) has been the subject of several recent randomized controlled trials and excellent reviews. Less attention has been focused on another controversial and challenging aspect of MPE: establishing the diagnosis. Before selecting the optimal management strategy, the presence of an MPE must first be correctly identified with an emphasis on minimizing invasiveness and discomfort in a patient with late-stage cancer. The aim of the present review is to summarize the current knowledge about MPE diagnostics and to propose an algorithm for the diagnosis of MPE in established or suspected malignancy.

Hassan M, Asciak R, Mercer RM, McCracken DJ, Tsikrika S, Shaarawy H, Elganady A, Wrightson JM, Rahman NM. 2019. Echogenic Swirling Seen on Ultrasound and Outcome of Pleurodesis in Malignant Pleural Effusion. Arch Bronconeumol, 55 (12), pp. 659-661. | Read more

Grendelmeier P, Rahman NM. 2019. What's the Score? Do Pleural Effusion Clinical Scoring Systems Help in Management of Disease? Semin Respir Crit Care Med, 40 (3), pp. 394-401. | Show Abstract | Read more

Pleural effusion is a common condition, affecting over 3,000 people per million population every year. More than 50 causes of pleural effusions are known, including pleural infection and malignant pleural disease. These conditions place a large burden on healthcare systems with one-fourth of patients with pleural infection having a length of hospital stay of more than 1 month. Malignant pleural effusion represents advanced malignant disease with a correspondingly high mortality. Prognostic models using clinical information in combination with blood or pleural fluid biomarkers predicting survival and other outcome measures are therefore a priority in improving clinical care, and potentially outcomes. Identifying patients with poor prognosis may help avoid discomfort and unnecessary interventions at the end of their lives, while, on the other hand, individuals with scores predicting a particularly good prognosis might be selected for more aggressive early treatment. Such scores must be based on data representing routine practice in a general hospital and variables chosen based on their clinical availability at clinical decision points (i.e., before treatment is instituted), making the findings widely applicable.

Puchalski J, Rahman NM. 2019. Pleural Diseases. Semin Respir Crit Care Med, 40 (3), pp. 295-296. | Read more

Kapoor M, Storrar W, Balls L, Brown TP, Mansur A, Hedley E, Jones T, Roberts C, Shirkey B, Dutton S et al. 2019. Nocturnal temperature-controlled laminar airflow device for adults with severe allergic asthma: the LASER RCT. Health Technol Assess, 23 (29), pp. 1-140. | Show Abstract | Read more

BACKGROUND: Severe asthma exacerbations are costly to patients and the NHS, and occur frequently in severely allergic patients. OBJECTIVE: To ascertain whether or not nocturnal temperature-controlled laminar airflow (TLA) device usage over 12 months can reduce severe exacerbations and improve asthma control and quality of life compared with a placebo device, while being cost-effective and acceptable to adults with severe allergic asthma. DESIGN: A pragmatic, multicentre, randomised, double-blind, placebo-controlled, parallel-group, superiority trial with qualitative interviews. The trial included an internal pilot with qualitative focus groups. SETTING: Fourteen hospitals in the UK that manage patients with severe asthma. PARTICIPANTS: Adults (16-75 years) with severe, poorly controlled, exacerbation-prone asthma despite high-intensity treatment, and who are sensitised to a perennial indoor aeroallergen. INTERVENTION: Nocturnal, home-based TLA treatment using an Airsonett® (Airsonett AB, Ängelholm, Sweden) device. The comparator was a placebo device that was identical to the active device except that it did not deliver the laminar airflow. Participants were allocated 1 : 1 to TLA therapy or placebo, minimised by site, origin of case, baseline severe exacerbation frequency, maintenance oral corticosteroid use and pre-bronchodilator forced expiratory volume in 1 second. MAIN OUTCOME MEASURES: Primary outcome - frequency of severe asthma exacerbations occurring within the 12-month follow-up period, defined as worsening of asthma requiring systemic corticosteroids [≥ 30 mg of prednisolone or equivalent daily (or ≥ 50% increase in dose if on maintenance dose of ≥ 30 mg of prednisolone)] for ≥ 3 days. Secondary outcomes - changes in asthma control, lung function, asthma-specific and global quality of life for participants, adherence to the intervention, device acceptability, health-care resource use and cost-effectiveness. RESULTS: Between May 2014 and January 2016, 489 patients consented to participate in the trial, of whom 249 failed screening and 240 were randomised (n = 119 in the treatment group and n = 121 in the placebo group); all were analysed. In total, 202 participants (84%) reported use of the device for 9-12 months. Qualitative analyses showed high levels of acceptability. The mean [standard deviation (SD)] rate of severe exacerbations did not differ between groups [active 1.39 (1.57), placebo 1.48 (2.03); risk ratio 0.92, 95% CI 0.66 to 1.27; p = 0.616]. There were no significant differences in secondary outcomes for lung function, except for a reduction in mean daily peak expiratory flow [mean (SD) difference 14.7 l/minute (7.35 l/minute), 95% CI 0.32 to 29.1 l/minute; p = 0.045) for those in the active device group. There were no differences in asthma control or airway inflammation and no serious harms related to the device. No significant difference between the groups in quality-adjusted life-years gained over 1 year was observed. In addition, there was no difference in generic or disease-specific health-related quality of life overall, although statistically significant higher quality of life at month 6 was observed. Increases in quality of life were not sufficient to offset the annual costs associated with use of the TLA device. LIMITATIONS: Missing outcome data could have resulted in an underestimation of exacerbations and rendered the study inconclusive. CONCLUSIONS: Within the limits of the data, no consistent benefits of the active device were demonstrated, and the differences observed were not sufficient to make the device cost-effective. The types of patients who may benefit from the TLA device, and the reasons for large reductions in exacerbation frequency in severe asthma trials, which also incorporate other methods of recording exacerbations, need to be explored. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46346208. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 29. See the NIHR Journals Library website for further project information.

Luengo-Fernandez R, Penz E, Dobson M, Psallidas I, Nunn AJ, Maskell NA, Rahman NM. 2019. Cost-effectiveness of intrapleural use of tissue plasminogen activator and DNase in pleural infection: evidence from the MIST2 randomised controlled trial. Eur Respir J, 54 (2), | Show Abstract | Read more

The MIST2 (Second Multicentre Intrapleural Sepsis Trial) trial showed that combined intrapleural use of tissue plasminogen activator (t-PA) and recombinant human DNase was effective when compared with single agents or placebo. However, the treatment costs are significant and overall cost-effectiveness of combined therapy remains unclear.An economic evaluation of the MIST2 trial was performed to assess the cost-effectiveness of combined therapy. Costs included were those related to study medications, initial hospital stay and subsequent hospitalisations. Outcomes were measured in terms of life-years gained. All costs were reported in euro and in 2016 prices.Mean annual costs were lowest in the t-PA-DNase group (EUR 10 605 for t-PA, EUR 17 856 for DNase, EUR 13 483 for placebo and EUR 7248 for t-PA-DNase; p=0.209). Mean 1-year life expectancy was 0.988 for t-PA, 0.923 for DNase, and 0.969 for both placebo and t-PA-DNase (p=0.296). Both DNase and placebo were less effective, in terms of life-years gained, and more costly than t-PA. When placebo was compared with t-PA-DNase, the incremental cost per life-year gained of placebo was EUR 1.6 billion, with a probability of 0.85 of t-PA-DNase being cost-effective.This study demonstrates that combined t-PA-DNase is likely to be highly cost-effective. In light of this evidence, a definitive trial designed to facilitate a thorough economic evaluation is warranted to provide further evidence on the cost-effectiveness of this promising combined intervention.

Mercer RM, Corcoran JP, Porcel JM, Rahman NM, Psallidas I. 2019. Interpreting pleural fluid results . Clin Med (Lond), 19 (3), pp. 213-217. | Show Abstract | Read more

Interpreting pleural fluid results correctly requires an awareness of the possible aetiologies of a pleural effusion and an understanding of the reliability of the outcome of each investigation. All results must be interpreted within each different clinical context and knowledge of the pitfalls for each test is necessary when the diagnosis is unclear. This review aims to discuss the common aetiologies of a pleural effusion and some of the pitfalls in interpretation that can occur when the diagnosis is unclear.

Karpathiou G, Hathroubi S, Patoir A, Tiffet O, Casteillo F, Brun C, Forest F, Rahman NM, Peoc'h M, Froudarakis ME. 2019. Non-specific pleuritis: pathological patterns in benign pleuritis. Pathology, 51 (4), pp. 405-411. | Show Abstract | Read more

A pleural biopsy without granulomatous inflammation or tumour cells is interpreted as 'non-specific pleuritis' (NSP), a diagnosis without any specificity, often frustrating for physicians. However, varying histological features are found in NSPs with unknown significance. The aim of this study was to describe the detailed microscopic features of NSP and correlate them with the underlying aetiology. One hundred patients diagnosed with NSP after pleural biopsy were retrospectively evaluated. A benign cause of pleural effusion was attributed. Histological features evaluated were inflammation, fibrosis, vascular proliferation, haemorrhage, fibrin, oedema and mesothelial hyperplasia. A semi-quantitative scoring was applied. Bacterial-caused and autoimmune disease-associated NSPs showed a higher score followed by viral and drug-induced conditions, while pneumothorax and cardiac-induced NSPs showed a lower score (p<0.0001). The degree of fibrosis was higher in bacterial NSP, and the type of fibrosis was cellular in this group (p=0.006). Vascular proliferation differed between groups (p<0.0001), and was higher in bacterial NSP. Histological findings differ significantly between the varying aetiologies of NSP, and this may be used to suggest the cause of the effusion.

Beckert L, Brockway B, Simpson G, Southcott AM, Lee YCG, Rahman N, Light RW, Shoemaker S, Gillies J, Komissarov AA et al. 2019. Phase 1 trial of intrapleural LTI-01; single chain urokinase in complicated parapneumonic effusions or empyema. JCI Insight, 5 (10), | Show Abstract | Read more

BACKGROUND: Current dosing of intrapleural fibrinolytic therapy (IPFT) in adults with complicated parapneumonic effusion (CPE) / empyema is empiric, as dose-escalation trials have not previously been conducted. We hypothesized that LTI-01 (scuPA), which is relatively resistant to PA inhibitor-1 (PAI-1), would be well-tolerated. METHODS: This was an open-label, dose-escalation trial of LTI-01 IPFT at 50,000-800,000 IU daily for up to 3 days in adults with loculated CPE/empyema and failed pleural drainage. The primary objective was to evaluate safety and tolerability, and secondary objectives included assessments of processing and bioactivity of scuPA in blood and pleural fluid (PF), and early efficacy. RESULTS: LTI-01 was well tolerated with no bleeding, treatment-emergent adverse events or surgical referrals (n=14 subjects). uPA antigen increased in PFs at 3 hours after LTI-01 (p<0.01) but not in plasma. PF saturated active PAI-1, generated PAI-1-resistant bioactive complexes, increased PA and fibrinolytic activities and D-dimers. There was no systemic fibrinogenolysis, nor increments in plasma D-dimer. Decreased pleural opacities occurred in all but one subject. Both subjects receiving 800,000 IU required two doses to relieve pleural sepsis, with two other subjects similarly responding at lower doses. CONCLUSION: LTI-01 IPFT was well-tolerated at these doses with no safety concerns. Bioactivity of LTI-01 IPFT was confirmed, limited to PFs where its processing simulated that previously reported in preclinical studies. Preliminary efficacy signals including reduction of pleural opacity were observed.

Laskawiec-Szkonter M, Roberts M, Downer N, Mishra E, Rahman NM. 2019. The UK Pleural Society. Br J Hosp Med (Lond), 80 (4), pp. 186-187. | Read more

Merrick C, Sherrill T, Kanellakis NI, Asciak R, Stathopoulos GT, Maldonado F, Rahman NM, Blackwell T, Psallidas I. 2019. Novel mouse model of indwelling pleural catheter in mice with malignant pleural effusion. ERJ Open Res, 5 (2), | Show Abstract | Read more

This novel mouse model mimics malignant pleural effusion drainage using an indwelling pleural catheter in humans, and provides direct access to the pleural space potentially enabling the testing of intrapleural therapies in the treatment of MPE. bit.ly/2W2kzO0.

Shojaee S, Rahman N. 2019. Pleural Fluid for the Detection of Actionable Somatic Mutations: Have We Struck Oil Yet? J Bronchology Interv Pulmonol, 26 (2), pp. 78-80. | Read more

Hallifax R, Laskawiec-Szkonter M, Dobson M, Gerry S, Miller RF, Harvey JE, Rahman N. 2019. Randomised Ambulatory Management of Primary Pneumothorax (RAMPP): protocol of an open-label, randomised controlled trial. BMJ Open Respir Res, 6 (1), pp. e000403. | Show Abstract | Read more

Introduction: Pneumothorax is a common clinical problem. Primary spontaneous pneumothorax (PSP) occurs in otherwise fit young patients, but optimal management is not clearly defined and often results in a long hospital stay. Ambulatory treatment options are available, but the existing data on their efficacy are poor. The Randomised Ambulatory Management of Primary Pneumothorax trial is a multicentre, randomised controlled trial comparing ambulatory management with standard care, specifically designed to safely and effectively reduce hospital stay. Methods and analysis: 236 patients with PSP will be recruited from UK hospitals. Patients will be randomised 1:1 to treatment to either the 'Intervention' arm (ambulatory device; Rocket Pleural Vent) or the 'Control' arm (aspiration ± standard chest drain insertion). Patients will be followed up for a total of 12 months to assess recurrence rates. The primary outcome is total length of stay in hospital (including readmissions) up to 30 days postrandomisation. The secondary outcomes are pain and breathlessness scores, air leak measurement and radiological evidence (on CT scanning) of emphysema-like changes, compared with short-term and long-term outcomes, respectively, and health economic analysis. Ethics and dissemination: The trial has received ethical approval from the National Research Ethics Service Committee South-Central Oxford A (15/SC/0240). Trial registration number: ISRCTN79151659.

Asciak R, Hassan M, Mercer RM, Hallifax RJ, Wrightson JM, Psallidas I, Rahman NM. 2019. Prospective Analysis of the Predictive Value of Sonographic Pleural Fluid Echogenicity for the Diagnosis of Exudative Effusion. Respiration, 97 (5), pp. 451-456. | Show Abstract | Read more

BACKGROUND: Pleural effusion echogenicity on ultrasound has previously been suggested to allow identification of exudates. A case series suggested that homogenously echogenic effusions are always exudates. With modern imaging techniques and more advanced ultrasound technology, this may no longer be true. OBJECTIVES: This study aims to prospectively assess the predictive value of echogenicity in the identification of exudates. METHOD: Patients undergoing thoracic ultrasound before pleural fluid sampling were analysed prospectively (n = 140). Pleural fluid was classified as an exudate if both fluid total protein (TP) > 29 g/L and fluid lactate dehydrogenase (LDH) > 2/3 upper limit of normal serum LDH (which is 255 IU/L in females and 235 IU/L in males) were present. If only one of these criteria was met, the effusion was considered to have discordant biochemistry. RESULTS: Fifty-five (39%) patients had non-echogenic and 85 (61%) had echogenic effusions. Six (7.1%) patients with echogenic effusions had transudates; the median fluid TP for this group was 18.5 g/L (IQR 9.75) and median LDH 63.0 IU/L (IQR 40.3). The specificity of echogenicity identifying exudates from transudates, excluding patients with discordant biochemistry, was 57.1%, positive predictive value (PPV) 90.3%, sensitivity 65.1%, and negative predictive value (NPV) 21.0%. The specificity of echogenicity identifying exudates (including discordant biochemistry) from transudates was 57.1%, PPV 92.9%, sensitivity 62.7%, and NPV 14.5%. CONCLUSIONS: Echogenicity of a pleural effusion has a low specificity for identifying an underlying exudate, and the echogenic qualities of the fluid should not influence clinical decision-making.

Psallidas I, Rahman NM. 2019. Response. Chest, 155 (3), pp. 650-651. | Read more

Corcoran JP, Rahman NM. 2019. Response. Chest, 155 (3), pp. 649. | Read more

Lentz RJ, Lerner AD, Pannu JK, Merrick CM, Roller L, Walston C, Valenti S, Goddard T, Chen H, Huggins JT et al. 2019. Routine monitoring with pleural manometry during therapeutic large-volume thoracentesis to prevent pleural-pressure-related complications: a multicentre, single-blind randomised controlled trial. Lancet Respir Med, 7 (5), pp. 447-455. | Show Abstract | Read more

BACKGROUND: In patients with non-expandable lung, removal of pleural fluid can result in excessively negative pleural pressure, which is associated with chest discomfort, pneumothorax, and re-expansion pulmonary oedema. Pleural manometry is widely used to safeguard against pressure-related complications during thoracentesis despite little evidence to support the approach. We investigated whether monitoring of pleural pressure with manometry during thoracentesis could protect against complications compared with assessment of symptoms alone. METHODS: We did a prospective randomised single-blind trial involving patients with large pleural effusions at two academic medical centres in, Nashville, TN, and Baltimore, MD, USA. Eligible patients were adults with free-flowing effusions estimated to be at least 0·5 L who could remain seated throughout the procedure. Patients were randomly assigned 1:1 to receive thoracentesis guided by symptoms only (control) or by symptoms plus manometry at timepoints based on volume drained. The randomisation schedule was computer generated, used permuted blocks of four and six, and was stratified by participating institution. Patients, who were masked to study-group assignment, were asked to rate chest discomfort on 100 mm visual analogue scales before, during, and after drainage. In both groups drainage was discontinued before complete evacuation of pleural fluid if patients developed persistent chest discomfort, intractable cough, or other complications. In the manometry group, an additional criterion for stopping was if end-expiratory pleural pressure was lower than -20 cm H2O or declined by more than 10 cm H2O between two measurements to a value less than or equal to -10 cm H2O. The primary outcome was overall chest discomfort from before the start to after the procedure measured by patients 5 min after the end of drainage. Analysis was by modified intention to treat (ie, included all patients with any procedure or outcome data). This trial is registered with ClinicalTrials.gov, number NCT02677883. FINDINGS: Between March 4, 2016, and Sept 8, 2017, 191 patients were screened, of whom 128 were randomly assigned treatment and 124 were included in the final analysis (62 in each group). Four patients were excluded because of manometer malfunction (n=2), inability to access effusion due to pleural tumour burden (n=1), and inability to remain seated (n=1). Groups did not differ for the primary outcome (mean difference in chest discomfort score 2·4 mm, 95% CI -5·7 to 10·5, p=0·56). Six (10%) of 62 patients in the control group had asymptomatic pneumothorax ex vacuo compared with none in the manometry group (p=0·01). No serious complications occurred in either group. INTERPRETATION: Measurement of pleural pressure by manometry during large-volume thoracentesis does not alter procedure-related chest discomfort. Our findings do not support the routine use of this approach. FUNDING: Centurion Medical Products.

Asciak R, Mercer RM, Hallifax RJ, Hassan M, Bedawi E, McCracken D, Kanellakis NI, Wrightson JM, Psallidas I, Rahman NM. 2019. Does attempting talc pleurodesis affect subsequent indwelling pleural catheter (IPC)-related non-draining septated pleural effusion and IPC-related spontaneous pleurodesis? ERJ Open Res, 5 (1), pp. 00208-2018. | Show Abstract | Read more

Prior talc pleurodesis does not result in worsened outcomes from subsequent indwelling pleural catheter use, and patients should not be dissuaded from choosing talc as a primary treatment for recurrent pleural effusion. http://ow.ly/qAAC30mYmr3.

Bedawi EO, Hassan M, McCracken D, Rahman NM. 2019. Pleural infection: a closer look at the etiopathogenesis, microbiology and role of antibiotics. Expert Rev Respir Med, 13 (4), pp. 337-347. | Show Abstract | Read more

INTRODUCTION: Pleural infection is a condition that continues to pose a significant challenge to respiratory physicians. We hypothesize that the main barriers to progress include limited understanding of the etiopathogenesis, microbiology,and role of antibiotics in the pleural space. Areas covered: PubMed was searched for articles related to adult pleural infection using the terms 'pleural infection', 'empyema' and 'parapneumonic'. The search focused on relevant literature within the last 10 years, with any older citations used only to display context or lack of progress. Tuberculous pleural infection was excluded. We chose to give specific attention to the etiopathogenesis of pleural infection, including recent advances in diagnostics and biomarkers. We discuss our understanding of the pleural microbiome and rationalize the current use of antibiotics in treating this condition. Expert commentary: Understanding of key events in the development of this condition remains limited. The microbiology is unique compared to the lung, and highly variable. Higher culture yields from pleural biopsy may add new insights into the etiopathogenesis. There is little evidence into achievable effective antibiotic concentration within the pleura. Research into issues including the relevance of biofilm formation and significance of pleural thickening is necessary for treatment progress.

Brims F, Gunatilake S, Lawrie I, Marshall L, Fogg C, Qi C, Creech L, Holtom N, Killick S, Yung B et al. 2019. Early specialist palliative care on quality of life for malignant pleural mesothelioma: a randomised controlled trial. Thorax, 74 (4), pp. 354-361. | Show Abstract | Read more

PURPOSE: Malignant pleural mesothelioma (MPM) has a high symptom burden and poor survival. Evidence from other cancer types suggests some benefit in health-related quality of life (HRQoL) with early specialist palliative care (SPC) integrated with oncological services, but the certainty of evidence is low. METHODS: We performed a multicentre, randomised, parallel group controlled trial comparing early referral to SPC versus standard care across 19 hospital sites in the UK and one large site in Western Australia. Participants had newly diagnosed MPM; main carers were additionally recruited. INTERVENTION: review by SPC within 3 weeks of allocation and every 4 weeks throughout the study. HRQoL was assessed at baseline and every 4 weeks with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30. PRIMARY OUTCOME: change in EORTC C30 Global Health Status 12 weeks after randomisation. RESULTS: Between April 2014 and October 2016, 174 participants were randomised. There was no significant between group difference in HRQoL score at 12 weeks (mean difference 1.8 (95% CI -4.9 to 8.5; p=0.59)). HRQoL did not differ at 24 weeks (mean difference -2.0 (95% CI -8.6 to 4.6; p=0.54)). There was no difference in depression/anxiety scores at 12 weeks or 24 weeks. In carers, there was no difference in HRQoL or mood at 12 weeks or 24 weeks, although there was a consistent preference for care, favouring the intervention arm. CONCLUSION: There is no role for routine referral to SPC soon after diagnosis of MPM for patients who are cared for in centres with good access to SPC when required. TRIAL REGISTRATION NUMBER: ISRCTN18955704.

Reddy CB, DeCamp MM, Diekemper RL, Gould MK, Henry T, Iyer NP, Lee YCG, Lewis SZ, Maskell NA, Rahman NM et al. 2019. Summary for Clinicians: Clinical Practice Guideline for Management of Malignant Pleural Effusions. Ann Am Thorac Soc, 16 (1), pp. 17-21. | Read more

Cardillo G, Ricciardi S, Rahman N, Walker S, Maskell NA. 2019. Primary spontaneous pneumothorax: Time for surgery at first episode? Journal of Thoracic Disease, 11 pp. S1393-S1397. | Read more

Pietersen PI, Konge L, Madsen KR, Bendixen M, Maskell NA, Rahman N, Graumann O, Laursen CB. 2019. Development of and Gathering Validity Evidence for a Theoretical Test in Thoracic Ultrasound Respiration, | Show Abstract | Read more

© 2019 S. Karger AG, Basel. Background: Thoracic ultrasound (TUS) has a high diagnostic accuracy for many common pulmonary diseases, but theoretic knowledge in sonographic physics, thoracic anatomy and physiology, and sonopathologic patterns is required to develop competence. Objectives: The aims of the study were to develop and gather validity evidence for a theoretical test in TUS and to establish a pass/fail standard. Methods: Content was provided based on expert interviews, leading to the creation of 113 initial multiple-choice question (MCQ) items. Consensus was reached on 92 proceeding items through a Delphi process, and items were presented to physicians with different knowledge and experience in TUS. Answers were used for item statistics in order to select the items with the most optimal item discrimination and difficulty (i.e., level I items) to be included in the final test. Mean scores of the novice, intermediate and experienced groups were compared, and a pass/fail score was established using the contrasting groups' standard setting method. Results:Item statistics revealed 38 level I items, of which 30 were selected to be included in the final test. The internal consistency was high (Cronbach's alpha = 0.88). Differences in mean scores were 8.6 points (p < 0.001), 6.3 points (p = 0.01), and 14.9 points (p < 0.001) between novices and intermediates, intermediates and experienced, and novices and experienced, respectively. A pass/fail standard of 20 points was established. Conclusion: The established MCQ test can distinguish between physicians with different levels of competence in TUS and enables an objective, evidence-based approach for assessing the theoretical knowledge of trainees undergoing an educational programme in TUS.

McCracken DJ, Porcel JM, Rahman NM. 2018. Malignant Pleural Effusions: Management Options. Semin Respir Crit Care Med, 39 (6), pp. 704-712. | Show Abstract | Read more

Malignant pleural effusion (MPE) represents advanced metastatic malignancy and is associated with poor median survival. Incidence remains high and continues to rise, in part due to changing population demographics. This therefore represents a significant health care burden. Management is predominantly palliative in nature and multiple interventions are available within conventional treatment paradigms, all of which are proven to result in statistically significant patient benefit. This article further explores the methods available in the management of MPE along with the pitfalls, complications, and alternatives. Recent advances within the field are discussed with an exploration of likely future directions, including the role of ultrasound as a prospective predictor and the role of intrapleural fibrinolytic therapy.

McCracken DJ, Bedawi EO, Hassan M, Stavroulias D, Rahman NM. 2018. Secondary pneumothorax in end-stage lung disease complicated by noninvasive ventilation and a persistent air leak. Breathe (Sheff), 14 (4), pp. e119-e122. | Show Abstract | Read more

Pneumothorax is a well-recognised complication of end-stage COPD, but the management is often complex and may be complicated by other sequelae of advanced respiratory disease including the requirement for NIV http://ow.ly/vkoJ30mB4nZ.

Hassan M, Tsikrika S, Asciak R, Mercer RM, El-Ganady A, Rahman NM. 2019. Computed tomography abnormalities antedating mesothelioma diagnosis: a perspective on the natural history. Eur Respir J, 53 (2), pp. 1800935-1800935. | Read more

Hassan M, Tsikrika S, Rahman NM. 2019. Chest Wall Seroma Following Surgery for Malignant Pleural Effusion. Arch Bronconeumol, 55 (5), pp. 266. | Read more

McCracken DJ, Rahman NM. 2018. Management of Malignant Pleural Effusion Clinical Pulmonary Medicine, 25 (6), pp. 215-219. | Show Abstract | Read more

© 2018 Wolters Kluwer Health, Inc. Malignant pleural effusion is a common clinical problem with an increasing incidence that may be seen to complicate the management of almost all forms of cancer. It is associated with a very poor median survival leading to a palliative management approach. Several methods are available in the management of malignant pleural effusion including simple pleural aspiration, talc pleurodesis, or indwelling pleural catheters. Patient selection, however, remains difficult. The role for each management option, their indications, predictors of success, and factors influencing patient selection are all crucial considerations and are discussed here, as are the health economic impacts and future directions.

Bedawi EO, Yarmus L, Rahman NM. 2018. The ongoing struggle with empyema management: is surgery really the answer? J Thorac Dis, 10 (Suppl 33), pp. S4122-S4125. | Read more

Hallifax RJ, Laskawiec-Szkonter M, Rahman NM, RAMPP Trial collaborators. 2019. Predicting outcomes in primary spontaneous pneumothorax using air leak measurements. Thorax, 74 (4), pp. 410-412. | Show Abstract | Read more

The initial treatment regime for primary spontaneous pneumothorax (PSP) is generic and non-personalised, often involving a long hospital stay waiting for air leak to cease. This prospective study of 81 patients with PSP, who required drain insertion, captured daily digital air leak measurements and assessed failure of medical management against prespecified criteria. Patients with higher air leak at day 1 or 2 had significantly longer hospital stay. If air leak was ≥100 mL/min on day 1, the adjusted OR of treatment failure was 5.2 (95% CI 1.2 to 22.6, p=0.03), demonstrating that early digital air leak measurements could potentially predict future medical treatment failure. TRIAL REGISTRATION NUMBER: ISRCTN79151659.

Feller-Kopman DJ, Reddy CB, DeCamp MM, Diekemper RL, Gould MK, Henry T, Iyer NP, Lee YCG, Lewis SZ, Maskell NA et al. 2018. Management of Malignant Pleural Effusions. An Official ATS/STS/STR Clinical Practice Guideline. Am J Respir Crit Care Med, 198 (7), pp. 839-849. | Show Abstract | Read more

BACKGROUND: This Guideline, a collaborative effort from the American Thoracic Society, Society of Thoracic Surgeons, and Society of Thoracic Radiology, aims to provide evidence-based recommendations to guide contemporary management of patients with a malignant pleural effusion (MPE). METHODS: A multidisciplinary panel developed seven questions using the PICO (Population, Intervention, Comparator, and Outcomes) format. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the Evidence to Decision framework was applied to each question. Recommendations were formulated, discussed, and approved by the entire panel. RESULTS: The panel made weak recommendations in favor of: 1) using ultrasound to guide pleural interventions; 2) not performing pleural interventions in asymptomatic patients with MPE; 3) using either an indwelling pleural catheter (IPC) or chemical pleurodesis in symptomatic patients with MPE and suspected expandable lung; 4) performing large-volume thoracentesis to assess symptomatic response and lung expansion; 5) using either talc poudrage or talc slurry for chemical pleurodesis; 6) using IPC instead of chemical pleurodesis in patients with nonexpandable lung or failed pleurodesis; and 7) treating IPC-associated infections with antibiotics and not removing the catheter. CONCLUSIONS: These recommendations, based on the best available evidence, can guide management of patients with MPE and improve patient outcomes.

Hallifax RJ, Goldacre R, Landray MJ, Rahman NM, Goldacre MJ. 2018. Trends in the Incidence and Recurrence of Inpatient-Treated Spontaneous Pneumothorax, 1968-2016. JAMA, 320 (14), pp. 1471-1480. | Show Abstract | Read more

Importance: Spontaneous pneumothorax is a common disease known to have an unusual epidemiological profile, but there are limited contemporary population-based data. Objective: To estimate the incidence of hospital admissions for spontaneous pneumothorax, its recurrence and trends over time using large, longstanding hospitalization data sets in England. Design, Setting, and Participants: A population-based epidemiological study was conducted using an English national data set and an English regional data set, each spanning 1968 to 2016, and including 170 929 hospital admission records of patients 15 years and older. Final date of the study period was December 31, 2016. Exposures: Calendar year (for incidence) and readmission to hospital for spontaneous pneumothorax (for recurrence). Main Outcomes and Measures: Primary outcomes were rates of hospital admissions for spontaneous pneumothorax and recurrence, defined as a subsequent hospital readmission with spontaneous pneumothorax. Record-linkage was used to identify multiple admissions per person and comorbidity. Risk factors for recurrence over 5 years of follow-up were assessed using cumulative time-to-failure analysis and Cox proportional hazards regression. Results: From 1968 to 2016, there were 170 929 hospital admissions for spontaneous pneumothorax (median age, 44 years [IQR, 26-88]; 73.0% male). In 2016, there were 14.1 spontaneous pneumothorax admissions per 100 000 population 15 years and older (95% CI, 13.7-14.4), a significant increase compared with earlier years, up from 9.1 (95% CI, 8.1-10.1) in 1968. The population-based rate per 100 000 population 15 years and older was higher for males (20.8 [95% CI, 20.2-21.4]) than for females (7.6 [95% CI, 7.2-7.9]). Of patients with spontaneous pneumothorax, 60.8% (95% CI, 59.5%-62.0%) had chronic lung disease. Record-linkage analysis demonstrated that the overall increase in admissions over time could be due in part to an increase in repeat admissions, but there were also significant increases in the annual rate of first-known spontaneous pneumothorax admissions in some population subgroups, for example in women 65 years and older (annual percentage change from 1968 to 2016, 4.08 [95% CI, 3.33-4.82], P < .001). The probability of recurrence within 5 years was similar by sex (25.5% [95% CI, 25.1%-25.9%] for males vs 26.0% [95% CI, 25.3%-26.7%] for females), but there was variation by age group and presence of chronic lung disease. For example, the probability of readmission within 5 years among males aged 15 to 34 years with chronic lung disease was 39.2% (95% CI, 37.7%-40.7%) compared with 19.6% (95% CI, 18.2%-21.1%) in men 65 years and older without chronic lung disease. Conclusions and Relevance: This study provides contemporary information regarding the trends in incidence and recurrence of inpatient-treated spontaneous pneumothorax.

de Fonseka D, Underwood W, Stadon L, Rahman N, Edey A, Rogers C, Maskell NA. 2018. Randomised controlled trial to compare the diagnostic yield of positron emission tomography CT (PET-CT) TARGETed pleural biopsy versus CT-guided pleural biopsy in suspected pleural malignancy (TARGET trial). BMJ Open Respir Res, 5 (1), pp. e000270. | Show Abstract | Read more

Introduction: Pleural malignancy, particularly malignant pleural mesothelioma (MPM) is increasing in incidence due to the long latency period from exposure to asbestos to development of the disease. MPM can be challenging to diagnose. For patients presenting without a pleural effusion, CT-guided biopsy remains the primary choice of biopsy, but the diagnostic sensitivity of this investigation is 70%-75%. Therefore, a proportion of patients will go on to require further biopsies. If the first biopsy is non-diagnostic, the chances of further non-diagnostic biopsies are high in MPM. Methods: Target is a multicentre randomised controlled trial, aiming to recruit 78 patients over a 30-month period, from 10 centres in the UK. Patients will be randomised to either the standard arm which is a second CT-guided biopsy, or the interventional arm, a positron emission tomography-CT scan followed by a targeted CT-guided biopsy. Patients will be followed up for 12 months (patients recruited in the last 6 months of recruitment will have 6 months of follow-up). MPM biomarker mesothelin will be checked at baseline, 6 month and 12 month follow-up appointments where patients are able to attend these appointments. Ethics and dissemination: Ethical approval for this trial was granted by the South West-Exeter research and ethics committee (reference number 15/SW/0156). Results of the trial will be published in a peer-reviewed journal and presented at an international conference. Trial registration number: ISRCTN 14024829; Pre-results.

Corcoran JP, Hallifax RJ, Mercer RM, Yousuf A, Asciak R, Hassan M, Piotrowska HE, Psallidas I, Rahman NM. 2018. Thoracic Ultrasound as an Early Predictor of Pleurodesis Success in Malignant Pleural Effusion. Chest, 154 (5), pp. 1115-1120. | Show Abstract | Read more

BACKGROUND: Malignant pleural effusion (MPE) is common and imposes a significant burden on patients and health-care providers. Most patients require definitive treatment, usually drainage and chemical pleurodesis, to relieve symptoms and prevent fluid recurrence. Thoracic ultrasound (TUS) can identify the presence of pleural adhesions in other clinical scenarios, and could therefore have a role in predicting long-term pleurodesis success or failure in MPE. METHODS: Patients undergoing chest tube drainage and talc slurry pleurodesis for symptomatic MPE were recruited to a prospective observational cohort pilot study assessing whether TUS findings pre-talc and post-talc instillation predicted treatment outcome. Participants underwent TUS examination immediately before, and 24 h after talc slurry administration to derive pleural adherence scores for the affected hemithorax. The recorded TUS scans were additionally scored by two independent assessors blinded to the patient's clinical status. The primary outcome was pleurodesis success at 1-month and 3-month follow-up. RESULTS: Eighteen participants were recruited to the pilot study. Participants who suffered pleurodesis failure had a lower pleural adherence score at 24 h post-talc instillation than those who were successful (difference of 6.27; 95% CI, 3.94-8.59). TUS examination was acceptable to patients, while TUS scoring was highly consistent across all assessors (intraclass correlation coefficient, 0.762; 95% CI, 0.605-0.872). CONCLUSION: A TUS-derived pleural adherence score may facilitate early prediction of long-term outcomes following chemical pleurodesis, with implications for personalized care and decision making in MPE. Further research is needed to evaluate this novel finding. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT02625675; URL: www.clinicaltrials.gov.

Bhatnagar R, Keenan EK, Morley AJ, Kahan BC, Stanton AE, Haris M, Harrison RN, Mustafa RA, Bishop LJ, Ahmed L et al. 2018. Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion. N Engl J Med, 378 (14), pp. 1313-1322. | Show Abstract | Read more

BACKGROUND: Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. METHODS: Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. RESULTS: The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant between-group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. CONCLUSIONS: Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40 .).

de Fonseka D, Slade M, Blyth KG, Edwards J, Evison M, Roberts M, Rahman N, Woolhouse I, Maskell NA. 2018. An Inconvenient Truth Concerning Surgery for Mesothelioma. J Clin Oncol, 36 (26), pp. 2745-2746. | Read more

Asciak R, Hallifax RJ, Mercer RM, Hassan M, Bradley C, Corcoran JP, Wrightson JM, Psallidas I, Rahman NM. 2018. Activity and Outcomes From a Dedicated Pleural On-Call Service. Chest, 154 (3), pp. 717-718. | Read more

Shojaee S, Rahman N, Haas K, Kern R, Leise M, Alnijoumi M, Lamb C, Majid A, Akulian J, Maldonado F et al. 2019. Indwelling Tunneled Pleural Catheters for Refractory Hepatic Hydrothorax in Patients With Cirrhosis: A Multicenter Study. Chest, 155 (3), pp. 546-553. | Show Abstract | Read more

BACKGROUND: The outcome of indwelling pleural catheter (IPC) use in hepatic hydrothorax (HH) is unclear. This study aimed to review the safety and feasibility of the IPC in patients with refractory HH. METHODS: A retrospective multicenter study of patients with HH from January 2010 to December 2016 was performed. Inclusion criteria were refractory HH treated with an IPC and an underlying diagnosis of cirrhosis. Records were reviewed for patient demographics, operative reports, and laboratory values. The Kaplan-Meier method was used to estimate catheter time to removal. The Cox proportional hazard model was used to evaluate for independent predictors of pleurodesis and death. RESULTS: Seventy-nine patients were identified from eight institutions. Indication for IPC placement was palliation in 58 patients (73%) and bridge to transplant in 21 patients (27%). The median in situ dwell time of all catheters was 156 days (range, 16-1,978 days). Eight patients (10%) were found to have pleural space infection, five of whom also had catheter-site cellulitis. Two patients (2.5%) died secondary to catheter-related sepsis. Catheter removal secondary to spontaneous pleurodesis was achieved in 22 patients (28%). Median time from catheter insertion to pleurodesis was 55 days (range, 10-370 days). Older age was an independent predictor of mortality on multivariate analysis (hazard ratio, 1.05; P = .01). CONCLUSIONS: We present, to our knowledge, the first multicenter study examining outcomes related to IPC use in HH. Ten percent infection risk and 2.5% mortality were identified. IPC placement may be a reasonable clinical option for patients with refractory HH, but it is associated with significant adverse events in this morbid population.

Hassan M, Rana M, Rahman NM. 2018. A Patient With Effusion Undergoing Pleural Biopsy. Chest, 154 (2), pp. e37-e39. | Read more

Bibby AC, Dorn P, Psallidas I, Porcel JM, Janssen J, Froudarakis M, Subotic D, Astoul P, Licht P, Schmid R et al. 2019. ERS/EACTS statement on the management of malignant pleural effusions. Eur J Cardiothorac Surg, 55 (1), pp. 116-132. | Show Abstract | Read more

Malignant pleural effusions (MPE) are a common pathology, treated by respiratory physicians and thoracic surgeons alike. In recent years, several well-designed randomized clinical trials have been published that have changed the landscape of MPE management. The European Respiratory Society (ERS) and the European Association for Cardio-Thoracic Surgery (EACTS) established a multidisciplinary collaboration of clinicians with expertise in the management of MPE with the aim of producing a comprehensive review of the scientific literature. Six areas of interest were identified, including the optimum management of symptomatic MPE, management of trapped lung in MPE, management of loculated MPE, prognostic factors in MPE, whether there is a role for oncological therapies prior to intervention for MPE and whether a histological diagnosis is always required in MPE. The literature revealed that talc pleurodesis and indwelling pleural catheters effectively manage the symptoms of MPE. There was limited evidence regarding the management of trapped lung or loculated MPE. The LENT score was identified as a validated tool for predicting survival in MPE, with Brims' prognostic score demonstrating utility in mesothelioma prognostication. There was no evidence to support the use of oncological therapies as an alternative to MPE drainage, and the literature supported the use of tissue biopsy as the gold standard for diagnosis and treatment planning.Management options for malignant pleural effusions have advanced over the past decade, with high-quality randomized trial evidence informing practice in many areas. However, uncertainties remain and further research is required http://ow.ly/rNt730jOxOS.

Bedawi EO, Hassan M, Rahman NM. 2018. Recent developments in the management of pleural infection: A comprehensive review. Clin Respir J, 12 (8), pp. 2309-2320. | Show Abstract | Read more

OBJECTIVES: Pleural infection is a condition commonly encountered by the respiratory physician. This review aims to provide the reader with an update on the most recent data regarding the epidemiology, microbiology, and the management of pleural infection. DATA SOURCE: Medline was searched for articles related to pleural infection using the terms "pleural infection," "empyema," and "parapneumonic." The search was limited to the years 1997-2017. Only human studies and reports in English were included. RESULTS: A rise in the incidence of pleural infection is seen worldwide. Despite the improvement in healthcare practices, the mortality from pleural infection remains high. The role of oral microflora in the etiology of pleural infection is firmly established. A concise review of the recent insights on the pathogenesis of pleural infections is presented. A particular focus is made on the role of tPA, DNAse and similar substances and their interaction with inflammatory cells and how this affects the pathogenesis and treatment of pleural infection. CONCLUSION: Pleural infection is a common disease with significant morbidity and mortality, as well as a considerable economic burden. The role of medical management is expanding thanks to the widespread use of newer treatments.

Shojaee S, Khalid M, Kallingal G, Kang L, Rahman N. 2018. Repeat Thoracentesis in Hepatic Hydrothorax and Non-Hepatic Hydrothorax Effusions: A Case-Control Study. Respiration, 96 (4), pp. 330-337. | Show Abstract | Read more

BACKGROUND: Repeat thoracentesis for symptom control is offered to patients with refractory hepatic hydrothorax (HH) but the risk profile for this management strategy remains unclear. OBJECTIVES: This study aimed to compare complication frequency and nature during repeat thoracentesis in patients with and without HH. METHODS: Complication rates in patients undergoing repeat thoracentesis for symptom relief was compared between patients with HH and a control group (non-HH group) at a single center from 2010 to 2015. Records were reviewed for demographics, laboratory values, number of thoracentesis, and associated complications with each procedure. RESULTS: 82 patients with HH (274 thoracenteses) and 100 control patients (188 thoracenteses) were included. A complication was noted in 17/462 (0.03%) procedures in the entire cohort. There was a higher overall complication rate with repeat thoracentesis in the HH group (8 vs. 0%, p = 0.016, 95% CI = 1.5-14.6). In the HH group, the cumulative risk of complications increased with sequential thoracenteses; a complication occurring in the preceding intervention was the strongest predictor for subsequent complication (OR = 17.1, p = 0.0013) and more than 1 previous complication was associated with a 15-fold increased risk of a subsequent complication (p < 0.001). In multivariate analysis within the HH group, the Model for End-Stage Liver Disease (MELD) score was an independent predictor of hemothorax (OR = 1.19, 95% CI = 1.03-1.36, p = 0.012). CONCLUSIONS: Repeat thoracentesis is an overall low-risk procedure, although a higher complication rate is observed in HH compared with non-HH patients. The presence of a previous complication significantly increases the risk of future complications in the HH population.

Bibby AC, Dorn P, Psallidas I, Porcel JM, Janssen J, Froudarakis M, Subotic D, Astoul P, Licht P, Schmid R et al. 2018. ERS/EACTS statement on the management of malignant pleural effusions. Eur Respir J, 52 (1), pp. 1800349-1800349. | Show Abstract | Read more

Malignant pleural effusions (MPE) are a common pathology, treated by respiratory physicians and thoracic surgeons alike. In recent years, several well-designed randomised clinical trials have been published that have changed the landscape of MPE management. The European Respiratory Society (ERS) and the European Association for Cardio-Thoracic Surgery (EACTS) established a multidisciplinary collaboration of clinicians with expertise in the management of MPE with the aim of producing a comprehensive review of the scientific literature.Six areas of interest were identified, including the optimum management of symptomatic MPE, management of trapped lung in MPE, management of loculated MPE, prognostic factors in MPE, whether there is a role for oncological therapies prior to intervention for MPE and whether a histological diagnosis is always required in MPE.The literature revealed that talc pleurodesis and indwelling pleural catheters effectively manage the symptoms of MPE. There was limited evidence regarding the management of trapped lung or loculated MPE. The LENT score was identified as a validated tool for predicting survival in MPE, with Brims' prognostic score demonstrating utility in mesothelioma prognostication. There was no evidence to support the use of oncological therapies as an alternative to MPE drainage, and the literature supported the use of tissue biopsy as the gold standard for diagnosis and treatment planning.

Psallidas I, Kanellakis NI, Gerry S, Thézénas ML, Charles PD, Samsonova A, Schiller HB, Fischer R, Asciak R, Hallifax RJ et al. 2018. Development and validation of response markers to predict survival and pleurodesis success in patients with malignant pleural effusion (PROMISE): a multicohort analysis. Lancet Oncol, 19 (7), pp. 930-939. | Show Abstract | Read more

BACKGROUND: The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival. METHODS: In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation. FINDINGS: 17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0·78 [95% CI 0·72-0·83] for internal validation and 0·89 [0·84-0·93] for external validation of the clinical PROMISE score). INTERPRETATION: To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies. FUNDING: European Respiratory Society, Medical Research Funding-University of Oxford, Slater & Gordon Research Fund, and Oxfordshire Health Services Research Committee Research Grants.

Asciak R, Addala D, Karimjee J, Rana MS, Tsikrika S, Hassan MF, Mercer RM, Hallifax RJ, Wrightson JM, Psallidas I et al. 2018. Chest Drain Fall-Out Rate According to Suturing Practices: A Retrospective Direct Comparison. Respiration, 96 (1), pp. 48-51. | Show Abstract | Read more

BACKGROUND: Chest drains often become displaced and require replacement, adding unnecessary risks to patients. Simple measures such as suturing of the drain may reduce fall-out rates; however, there is no direct data to demonstrate this and no standardized recommended practice that is evidence based. OBJECTIVES: The study aimed to analyze the rate of chest drain fall out according to suturing practice. METHODS: Retrospective analysis of all chest drain insertions (radiology and pleural teams) in 2015-2016. Details of chest drain fall out were collected from patient electronic records. Drain "fall out" was pre-hoc defined as the drain tip becoming dislodged outside the pleural cavity unintentionally before a clinical decision was taken to remove the drain. RESULTS: A total of 369 chest drains were inserted: sutured (n = 106, 28.7%; 44 male [41.5%], median age 74 [interquartile range (IQR) 21] years), and unsutured (n = 263, 71.3%; 139 male [52.9%], median age 68 [IQR 21] years). Of the sutured drains, 7 (6.6%) fell out after a mean of 3.3 days (SD 2.6) compared to 39 (14.8%; p = 0.04) unsutured drains falling out after a mean of 2.7 days (SD 2.0; p = 0.8). CONCLUSIONS: Within the limits of this retrospective analysis, these results -suggest that suturing of drains is associated with lower fall-out rates.

Idell S, Rahman NM. 2018. Intrapleural Fibrinolytic Therapy for Empyema and Pleural Loculation: Knowns and Unknowns. Ann Am Thorac Soc, 15 (5), pp. 515-517. | Read more

Komissarov AA, Rahman N, Lee YCG, Florova G, Shetty S, Idell R, Ikebe M, Das K, Tucker TA, Idell S. 2018. Fibrin turnover and pleural organization: bench to bedside. Am J Physiol Lung Cell Mol Physiol, 314 (5), pp. L757-L768. | Show Abstract | Read more

Recent studies have shed new light on the role of the fibrinolytic system in the pathogenesis of pleural organization, including the mechanisms by which the system regulates mesenchymal transition of mesothelial cells and how that process affects outcomes of pleural injury. The key contribution of plasminogen activator inhibitor-1 to the outcomes of pleural injury is now better understood as is its role in the regulation of intrapleural fibrinolytic therapy. In addition, the mechanisms by which fibrinolysins are processed after intrapleural administration have now been elucidated, informing new candidate diagnostics and therapeutics for pleural loculation and failed drainage. The emergence of new potential interventional targets offers the potential for the development of new and more effective therapeutic candidates.

Bruce RM, Phan PA, Pacpaco E, Rahman NM, Farmery AD. 2018. The inspired sine-wave technique: A novel method to measure lung volume and ventilatory heterogeneity. Exp Physiol, 103 (5), pp. 738-747. | Show Abstract | Read more

NEW FINDINGS: What is the central question of this study? We present a new non-invasive medical technology, the inspired sine-wave technique, which involves inhalation of sinusoidally fluctuating concentrations of a tracer gas. The technique requires only passive patient cooperation and can monitor different cardiorespiratory variables, such as end-expired lung volume, ventilatory heterogeneity and pulmonary blood flow. What is the main finding and its importance? In this article, we demonstrate that the measurements of end-expired lung volume are repeatable and accurate, in comparison to whole-body plethysmography, and the technique is sensitive to the changes in ventilatory heterogeneity associated with advancing age. As such, it has the potential to provide clinically valuable information. ABSTRACT: The inspired sine-wave technique (IST) is a new method that can provide simple, non-invasive cardiopulmonary measurements. Over successive tidal breaths, the concentration of a tracer gas (i.e. nitrous oxide, N2 O) is sinusoidally modulated in inspired air. Using a single-compartment tidal-ventilation lung model, the resulting amplitude/phase of the expired sine wave allows estimation of end-expired lung volume (ELV), pulmonary blood flow and three indices for ventilatory heterogeneity (VH; ELV180 /FRCpleth , ELV180 /FRCpred and ELV60 /ELV180 ). This investigation aimed to determine the repeatability and agreement of ELV with FRCpleth and, as normal ageing results in well-established changes in pulmonary structure and function, whether the IST estimates of ELV and VH are age dependent. Forty-eight healthy never-smoker participants (20-86 years) underwent traditional pulmonary function testing (e.g. spirometry, body plethysmography) and the IST test, which consisted of 4 min of quiet breathing through a face mask while inspired N2 O concentrations were oscillated in a sine-wave pattern with a fixed mean (4%) and amplitude (3%) and a period of either 180 or 60 s. The ELV180 /FRCpleth and ELV180 /FRCpred were age dependent (average decreases of 0.58 and 0.48% year-1 ), suggesting an increase in VH with advancing age. The ELV showed a mean bias of -1.09 litres versus FRCpleth , but when normalized for the effects of age this bias reduced to -0.35 litres. The IST test has potential to provide clinically useful information necessitating further study (e.g. for mechanically ventilated or obstructive lung disease patients), but these findings suggest that the increases in VH with healthy ageing must be taken into account in clinical investigations.

Kalin A, Hassan M, Anderson M, Rahman N. 2018. Bilious pleuritis following transpulmonary radiofrequency ablation of liver metastases. Thorax, 73 (5), pp. 493-494. | Read more

Talwar A, Willaime JMY, Pickup LC, Enescu M, Boukerroui D, Hickes W, Rahman NM, Gooding MJ, Kadir T, Gleeson FV. 2018. Pulmonary nodules: Assessing the imaging biomarkers of malignancy in a "coffee-break". Eur J Radiol, 101 pp. 82-86. | Show Abstract | Read more

INTRODUCTION: Although nodule volumetry is a recognized biomarker of malignancy in pulmonary nodules (PNs), caution is needed in its interpretation because of variables such as respiratory volume variation and inter-scan variability of up to 25%. CT Texture Analysis (CTTA) is a potential independent biomarker of malignancy but inter-scan variability and respiratory volume variation has not been assessed. METHODS: In this prospective cohort study, 40 patients (20 with an indeterminate PN and 20 with pulmonary metastases) underwent two LDCTs within a 60-min period (the "Coffee-break") with the aim of assessing the repeatability of CTTA and semi-automated volume measurements. Texture features were extracted from each automatic contoured region surrounding the PN. Patients were also randomized to two inspiratory control groups: normal breath hold, and controlled lung volume to study the influence of inspiratory control on these measurements. RESULTS: The mean difference in volume between the two scans was 6.3%,SD:29.9%. The textural features displayed 95% CI below ±17.8%, and were less variable than nodule volume (95%CI ± 28.9%). All features had high repeatability, calculated by the concordance correlation coefficient, (0.84 ≤ CCC ≤ 0.99). All measurements were more repeatable for the controlled lung volume group than the normal breath-hold group. CONCLUSION: CTTA repeatability was comparable to automatic volumetric measurements, and appears to be improved using controlled volume breath holding.

Mercer RM, Hassan M, Rahman NM. 2018. The role of pleurodesis in respiratory diseases. Expert Rev Respir Med, 12 (4), pp. 323-334. | Show Abstract | Read more

INTRODUCTION: Pleurodesis is used to obliterate the pleural space, most commonly in patients with symptomatic malignant pleural effusions but also in patients with benign effusions or pneumothorax. Areas covered: Traditionally, chemical pleurodesis has been undertaken at thoracoscopy or using instillation of a slurry through a chest drain. The optimum method of achieving pleurodesis, whether surgical or medical, has yet to be proven. Evidence in the different disease areas will be reviewed, along with ongoing trial evidence, which may change practice. Expert commentary: Newer methods of achieving pleurodesis are being introduced. Studies have shown that instilling sclerosing agents via an indwelling pleural catheter or introducing drug-eluting catheters are safe and effective ways of inducing pleurodesis. There is evidence that pleurodesis might increase in survival, especially after pleural infection, possibly due to activation of the immune system. Multiple studies are currently underway to answer some of these questions and the future landscape may be very different from the present.

Hassan M, Asciak R, Rizk R, Shaarawy H, Gleeson FV, Rahman NM. 2018. Lung abscess or empyema? Taking a closer look. Thorax, 73 (9), pp. 887-889. | Read more

Marchetti G, McCracken DJ, Rahman NM. 2018. Endobronchial coil penetration into the pleural space. Thorax, 73 (9), pp. 890-891. | Read more

Psallidas I, Kanellakis NI, Bhatnagar R, Ravindran R, Yousuf A, Edey AJ, Mercer RM, Corcoran JP, Hallifax RJ, Asciak R et al. 2018. A Pilot Feasibility Study in Establishing the Role of Ultrasound-Guided Pleural Biopsies in Pleural Infection (The AUDIO Study). Chest, 154 (4), pp. 766-772. | Show Abstract | Read more

BACKGROUND: Pleural infection is a common complication of pneumonia associated with high mortality and poor clinical outcome. Treatment of pleural infection relies on the use of broad-spectrum antibiotics because reliable pathogen identification occurs infrequently. We performed a feasibility interventional clinical study assessing the safety and significance of ultrasound (US)-guided pleural biopsy culture to increase microbiological yield. In an exploratory investigation, the 16S ribosomal RNA technique was applied to assess its utility on increasing speed and accuracy vs standard microbiological diagnosis. METHODS: Twenty patients with clinically established pleural infection were recruited. Participants underwent a detailed US scan and US-guided pleural biopsies before chest drain insertion, alongside standard clinical management. Pleural biopsies and routine clinical samples (pleural fluid and blood) were submitted for microbiological analysis. RESULTS: US-guided pleural biopsies were safe with no adverse events. US-guided pleural biopsies increased microbiological yield by 25% in addition to pleural fluid and blood samples. The technique provided a substantially higher microbiological yield compared with pleural fluid and blood culture samples (45% compared with 20% and 10%, respectively). The 16S ribosomal RNA technique was successfully applied to pleural biopsy samples, demonstrating high sensitivity (93%) and specificity (89.5%). CONCLUSIONS: Our findings demonstrate the safety of US-guided pleural biopsies in patients with pleural infection and a substantial increase in microbiological diagnosis, suggesting potential niche of infection in this disease. Quantitative polymerase chain reaction primer assessment of pleural fluid and biopsy appears to have excellent sensitivity and specificity.

Asciak R, Rahman NM. 2018. Malignant Pleural Effusion: From Diagnostics to Therapeutics. Clin Chest Med, 39 (1), pp. 181-193. | Show Abstract | Read more

Malignant pleural effusion is a common complication of cancer and denotes a poor prognosis. It usually presents with dyspnea and a unilateral large pleural effusion. Thoracic computed tomography scans and ultrasound are helpful in distinguishing malignant from benign effusions. Pleural fluid cytology is diagnostic in about 60% of cases. In cytology-negative disease, pleural biopsies are helpful. Current management is palliative. Previously, first-line treatment for recurrent symptomatic malignant pleural effusion was chest drain insertion and talc pleurodesis, with indwelling pleural catheter insertion reserved for patients with trapped lung or failed talc pleurodesis. However, catheter insertion is an increasingly acceptable first-line treatment.

Woolhouse I, Bishop L, Darlison L, De Fonseka D, Edey A, Edwards J, Faivre-Finn C, Fennell DA, Holmes S, Kerr KM et al. 2018. British Thoracic Society Guideline for the investigation and management of malignant pleural mesothelioma. Thorax, 73 (Suppl 1), pp. i1-i30. | Read more

Corcoran JP, Rahman NM. 2018. Picking the winners: Outcome prediction in pleural disease. Respirology, 23 (6), pp. 558-559. | Show Abstract | Read more

© 2018 Asian Pacific Society of Respirology See related Article.

Mishra EK, Clive AO, Wills GH, Davies HE, Stanton AE, Al-Aloul M, Hart-Thomas A, Pepperell J, Evison M, Saba T et al. 2018. Randomized Controlled Trial of Urokinase versus Placebo for Nondraining Malignant Pleural Effusion. Am J Respir Crit Care Med, 197 (4), pp. 502-508. | Show Abstract | Read more

RATIONALE: Patients with malignant pleural effusion experience breathlessness, which is treated by drainage and pleurodesis. Incomplete drainage results in residual dyspnea and pleurodesis failure. Intrapleural fibrinolytics lyse septations within pleural fluid, improving drainage. OBJECTIVES: To assess the effects of intrapleural urokinase on dyspnea and pleurodesis success in patients with nondraining malignant effusion. METHODS: We conducted a prospective, double-blind, randomized trial. Patients with nondraining effusion were randomly allocated in a 1:1 ratio to intrapleural urokinase (100,000 IU, three doses, 12-hourly) or matched placebo. MEASUREMENTS AND MAIN RESULTS: Co-primary outcome measures were dyspnea (average daily 100-mm visual analog scale scores over 28 d) and time to pleurodesis failure to 12 months. Secondary outcomes were survival, hospital length of stay, and radiographic change. A total of 71 subjects were randomized (36 received urokinase, 35 placebo) from 12 U.K. centers. The baseline characteristics were similar between the groups. There was no difference in mean dyspnea between groups (mean difference, 3.8 mm; 95% confidence interval [CI], -12 to 4.4 mm; P = 0.36). Pleurodesis failure rates were similar (urokinase, 13 of 35 [37%]; placebo, 11 of 34 [32%]; adjusted hazard ratio, 1.2; P = 0.65). Urokinase was associated with decreased effusion size visualized by chest radiography (adjusted relative improvement, -19%; 95% CI, -28 to -11%; P < 0.001), reduced hospital stay (1.6 d; 95% CI, 1.0 to 2.6; P = 0.049), and improved survival (69 vs. 48 d; P = 0.026). CONCLUSIONS: Use of intrapleural urokinase does not reduce dyspnea or improve pleurodesis success compared with placebo and cannot be recommended as an adjunct to pleurodesis. Other palliative treatments should be used. Improvements in hospital stay, radiographic appearance, and survival associated with urokinase require further evaluation. Clinical trial registered with ISRCTN (12852177) and EudraCT (2008-000586-26).

Woolhouse I, Bishop L, Darlison L, de Fonseka D, Edey A, Edwards J, Faivre-Finn C, Fennell DA, Holmes S, Kerr KM et al. 2018. BTS guideline for the investigation and management of malignant pleural mesothelioma. BMJ Open Respir Res, 5 (1), pp. e000266. | Show Abstract | Read more

The full guideline for the investigation and management of malignant pleural mesothelioma is published in Thorax. The following is a summary of the recommendations and good practice points. The sections referred to in the summary refer to the full guideline.

Huggins JT, Maldonado F, Chopra A, Rahman N, Light R. 2018. Unexpandable lung from pleural disease. Respirology, 23 (2), pp. 160-167. | Show Abstract | Read more

Unexpandable lung is a common complication of malignant pleural effusions and inflammatory pleural diseases, such as pleural infection (e.g. empyema and complicated parapneumonic effusion) and noninfectious fibrinous pleuritis. Unexpandable lung due to pleural disease may be because of an active pleural process, and is referred to as malignant or inflammatory lung entrapment. An unexpandable lung may also be encountered in the setting of remote pleural inflammation resulting in a mature fibrous membrane overlying the visceral pleura preventing full expansion of the lung. This condition is termed trapped lung and may be understood as a form of defective healing of the pleural space. Trapped lung typically presents as a chronic, stable pleural effusion without evidence of active pleural disease. An unexpandable lung most often manifests itself as an inability of fully expanding the lung with pleural space drainage. Patients will either develop chest pain preventing complete drainage of the pleural space or develop a post-procedure pneumothorax. Pleural manometry and radiological imaging are useful in the assessment of an unexpandable lung. Pleural manometry can demonstrate abnormal lung expansion during drainage and imaging will demonstrate abnormal visceral pleural thickening found in trapped lung or malignant and inflammatory lung entrapment.

Matthews C, Freeman C, Sharples LD, Fox-Rushby J, Tod A, Maskell NA, Edwards JG, Coonar AS, Sivasothy P, Hughes V et al. 2019. MesoTRAP: a feasibility study that includes a pilot clinical trial comparing video-assisted thoracoscopic partial pleurectomy decortication with indwelling pleural catheter in patients with trapped lung due to malignant pleural mesothelioma designed to address recruitment and randomisation uncertainties and sample size requirements for a phase III trial. BMJ Open Respir Res, 6 (1), pp. e000368. | Show Abstract | Read more

Introduction: One of the most debilitating symptoms of malignant pleural mesothelioma (MPM) is dyspnoea caused by pleural effusion. MPM can be complicated by the presence of tumour on the visceral pleura preventing the lung from re-expanding, known as trapped lung (TL). There is currently no consensus on the best way to manage TL. One approach is insertion of an indwelling pleural catheter (IPC) under local anaesthesia. Another is video-assisted thoracoscopic partial pleurectomy/decortication (VAT-PD). Performed under general anaesthesia, VAT-PD permits surgical removal of the rind of tumour from the visceral pleura thereby allowing the lung to fully re-expand. Methods and analysis: MesoTRAP is a feasibility study that includes a pilot multicentre, randomised controlled clinical trial comparing VAT-PD with IPC in patients with TL and pleural effusion due to MPM. The primary objective is to measure the SD of visual analogue scale scores for dyspnoea following randomisation and examine the patterns of change over time in each treatment group. Secondary objectives include documenting survival and adverse events, estimating the incidence and prevalence of TL in patients with MPM, examining completion of alternative forms of data capture for economic evaluation and determining the ability to randomise 38 patients in 18 months. Ethics and dissemination: This study was approved by the East of England-Cambridge Central Research Ethics Committee and the Health Research Authority (reference number 16/EE/0370). We aim to publish the outputs of this work in international peer-reviewed journals compliant with an Open Access policy. Trial registration: NCT03412357.

Asciak R, Hallifax RJ, Mercer RM, Hassan M, Wigston C, Wrightson JM, Psallidas I, Rahman NM. 2019. The Hospital and Patient Burden of Indwelling Pleural Catheters: A Retrospective Case Series of 210 Indwelling Pleural Catheter Insertions. Respiration, 97 (1), pp. 70-77. | Show Abstract | Read more

BACKGROUND: Indwelling pleural catheters (IPC) offer an alternative to talc pleurodesis in recurrent effusion, especially in patients wishing to avoid hospitalization. Two randomized trials have demonstrated reduced time in hospital using IPCs versus talc pleurodesis in malignant pleural effusion (MPE). However, the impact of IPCs on hospital services and patients has not been well studied. OBJECTIVES: To analyze long-term outcomes of IPCs and understand the hospital burden in terms of requirement for hospital visits and contacts with healthcare, while the IPC was in situ. METHODS: IPC insertions in a tertiary pleural center were analyzed retrospectively. Reviews of patients with IPCs in situ considered "additional" to routine clinical follow-up were defined pre-hoc. RESULTS: A total of 202 cases were analyzed: 89.6% MPE group (n = 181) and 10.4% non-MPE group (n = 21). There were a median 3.0 (interquartile range [IQR] 3) and 2.0 (IQR 2) ipsilateral pleural procedures prior to each IPC insertion in non-MPE and MPE groups, respectively (p = 0.26), and a mean 1.3 (SD 1.7) planned IPC-related outpatient follow-up visits per patient. There were 2 (9.5%) and 14 (7.7%) IPC-related infections in non-MPE and MPE groups, respectively. Four (19.0%) and 44 (24.3%) patients required additional IPC-related reviews in non-MPE and MPE groups, respectively (p = 0.6), and these occurred within 250 days post IPC insertion. CONCLUSIONS: Although IPCs decrease initial length of hospital stay compared to talc pleurodesis via chest drain, IPCs are associated with significant hospital-visit burden, in addition to planned visits and regular home IPC drainages. IPC-using services need to be prepared for this additional work to run an IPC service effectively.

Editorial A. 2018. Clinical guidelines on diagnosis and management of patients with malignant pleural mesothelioma (part 1) Russian Pulmonology, 28 (5), pp. 531-557. | Show Abstract | Read more

<jats:p>Adopted from: Woolhouse I., Bishop L., Darlison L., De Fonseka D., Edey A., Edwards J., Faivre-Finn C., Fennell D.A., Holmes S., Kerr K.M., Nakas A., Peel T., Rahman N.M., Slade M., Steele J., Tsim S., Maskell N.A. British Thoracic Society Guideline for the investigation and management of malignant pleural mesothelioma. Thorax. 2018; 73 (Suppl. 1): i1–i30. DOI: 10.1136/thoraxjnl-2017-211321.</jats:p>

Evison M, Blyth KG, Bhatnagar R, Corcoran J, Saba T, Duncan T, Hallifax R, Ahmed L, West A, Pepperell JCT et al. 2018. Providing safe and effective pleural medicine services in the UK: an aspirational statement from UK pleural physicians. BMJ Open Respir Res, 5 (1), pp. e000307. | Show Abstract | Read more

Physicians face considerable challenges in ensuring safe and effective care for patients admitted to hospital with pleural disease. While subspecialty development has driven up standards of care, this has been tempered by the resulting loss of procedural experience in general medical teams tasked with managing acute pleural disease. This review aims to define a framework though which a minimum standard of care might be implemented. This review has been written by pleural clinicians from across the UK representing all types of secondary care hospital. Its content has been formed on the basis of literature review, national guidelines, National Health Service England policy and consensus opinion following a round table discussion. Recommendations have been provided in the broad themes of procedural training, out-of-hours management and pleural service specification. Procedural competences have been defined into descriptive categories: emergency, basic, intermediate and advanced. Provision of emergency level operators at all times in all trusts is the cornerstone of out-of-hours recommendations, alongside readily available escalation pathways. A proposal for minimum standards to ensure the safe delivery of pleural medicine have been described with the aim of driving local conversations and providing a framework for service development, review and risk assessment.

Editorial A. 2018. Clinical guidelines on diagnosis and management of patientsа with malignant pleural mesothelioma (рart 2) Russian Pulmonology, 28 (6), pp. 655-679. | Read more

Hassan M, Talwar A, Hallifax RJ, Corcoran JP, Psallidas I, Rahman NM. 2017. Tips and tricks in the management of pneumothorax: An update Minerva Pneumologica, 56 (4), pp. 235-248. | Show Abstract | Read more

Pneumothorax is the abnormal collection of air in the pleural space. This can occur spontaneously, following trauma to the chest or as a side effect of a medical procedure. In most of the times, diagnosing pneumothorax is feasible via a standard chest radiograph. The management strategies for pneumothorax vary from watchful observation to medical and/ or surgical intervention. At initial management, the necessity of drainage of the pleural air is dictated by the symptoms a patient is exhibiting, the size of the pneumothorax and the state of the underlying lung. In cases where recurrence of pneumothorax is foreseen, further procedures are required to decrease the risk of such recurrence. The following review discusses the epidemiology, pathophysiology and clinical presentation of pneumothorax. It also summarizes the most recent guidelines on management with a view on the new strategies that have not been adopted in guidelines.

Psallidas I, Piotrowska HEG, Yousuf A, Kanellakis NI, Kagithala G, Mohammed S, Clifton L, Corcoran JP, Russell N, Dobson M et al. 2017. Efficacy of sonographic and biological pleurodesis indicators of malignant pleural effusion (SIMPLE): protocol of a randomised controlled trial. BMJ Open Respir Res, 4 (1), pp. e000225. | Show Abstract | Read more

Introduction: Malignant pleural effusion (MPE) is common and currently in UK there are an estimated 50 000 new cases of MPE per year. Talc pleurodesis remains one of the most popular methods for fluid control. The value of thoracic ultrasound (TUS) imaging, before and after pleurodesis, in improving the quality and efficacy of care for patients with MPE remains unknown. Additionally, biomarkers of successful pleurodesis including measurement of pleural fluid proteins have not been validated in prospective studies.The SIMPLE trial is an appropriately powered, multicentre, randomised controlled trial designed to assess 'by the patient bedside' use of TUS imaging and pleural fluid analysis in improving management of MPE. Methods and analysis: 262 participants with a confirmed MPE requiring intervention will be recruited from hospitals in UK and The Netherlands. Participants will be randomised (1:1) to undergo either chest drain insertion followed by instillation of sterile talc, or medical thoracoscopy and simultaneous poudrage. The allocated procedure will be done while the patient is hospitalised, and within 3 days of randomisation. Following hospital discharge, participants will be followed up at 1, 3 and 12 months. The primary outcome measure is the length of hospital stay during initial hospitalisation. Ethics and dissemination: The trial has received ethical approval from the South Central-Oxford C Research Ethics Committee (Reference number 15/SC/0600). The Trial Steering Committee includes an independent chair and members, and a patient representative. The trial results will be published in a peer-reviewed journal and presented at international conferences. Trial registration number: ISRCTN: 16441661.

Corcoran JP, Culver EL, Anstey RM, Talwar A, Manganis CD, Cargill TN, Hallifax RJ, Psallidas I, Rahman NM, Barnes E. 2017. Thoracic involvement in IgG4-related disease in a UK-based patient cohort. Respir Med, 132 pp. 117-121. | Show Abstract | Read more

IgG4-related disease (IgG4-RD) is a multi-system fibro-inflammatory disorder with classical histopathological findings, often in the context of elevated serum IgG4 levels. The thoracic manifestations of IgG4-RD are numerous and can mimic several common and better known conditions. The objective of this study was to outline the frequency and nature of thoracic involvement in a prospective cohort of IgG4-RD patients who met defined diagnostic criteria. Over 40% of IgG4-RD patients had clinicoradiological and/or histological evidence of thoracic involvement, predominantly mediastinal lymphadenopathy, the majority associated with multi-system disease outside the chest. Thoracic involvement was associated with a higher serum IgG4 level, potentially representing greater disease activity or spread. Our data highlight the diverse nature of thoracic IgG4-RD, and the importance of knowledge and recognition of the condition among respiratory physicians who are likely to encounter this disease entity on an increasing basis.

Layton B, Illsley A, Rahman NM. 2017. Book Reviews Ultrasound Edited by Leslie M Scoutt , Ulrike M Hamper , Teresita L Angtuaco Oxford University Press 2017 Price £112.50 . Pp 696 ISBN 978 0 19 998810 5 Geriatric Rehabilitation: From Bedside to Curbside K Rao Poduri CRC Press 2017 Price £140 . Pp 678 ISBN 978 1 48221 122 1 Challenging Concepts in Respiratory Medicine Edited by Lucy Schomberg , Elizabeth Sage , Nicholas Hart Oxford University Press 2017 Price £49.99 . Pp 304 ISBN 978 0 19965 774 2. Br J Hosp Med (Lond), 78 (9), pp. 537. | Read more

Rahman NM. 2017. Challenging Concepts in Respiratory Medicine BRITISH JOURNAL OF HOSPITAL MEDICINE, 78 (9), pp. 537-537.

Psallidas I, Yousuf A, Talwar A, Hallifax RJ, Mishra EK, Corcoran JP, Ali N, Rahman NM. 2017. Assessment of patient-reported outcome measures in pleural interventions. BMJ Open Respir Res, 4 (1), pp. e000171. | Show Abstract | Read more

INTRODUCTION: There is a lack of data evaluating the clinical effect on symptoms of pleural intervention procedures. This has led to the development of patient-reported outcome measures (PROMs) to define what constitutes patient benefit. The primary aim of this paper was to prospectively assess the effect of pleural procedures on PROMs and investigate the relationship between symptom change and clinical factors. METHODS: We prospectively collected data as part of routine clinical care from 158 patients with pleural effusion requiring interventions. Specific questionnaires included two patient-reported scores (a seven-point Likert scale and a 100 mm visual analogue scale (VAS) to assess symptoms). RESULTS: Excluding diagnostic aspiration, the majority of patients (108/126, 85.7%) experienced symptomatic benefit from fluid drainage (mean VAS improvement 42.6 mm, SD 24.7, 95% CI 37.9 to 47.3). There was a correlation between symptomatic benefit and volume of fluid removed post aspiration. A negative association was identified between the number of septations seen on ultrasound and improvement in dyspnoea VAS score in patients treated with intercostal chest drain. CONCLUSION: The results of our study highlight the effect of pleural interventions from a patient's perspective. The outcomes defined have the potential to form the basis of a clinical useful tool to appraise the effect, compare the efficiency and identify the importance of pleural interventions to the patients.

Idell S, Florova G, Shetty S, Tucker T, Idell R, Koenig K, Azghani A, Rahman NM, Komissarov A. 2017. Precision-guided, Personalized Intrapleural Fibrinolytic Therapy for Empyema and Complicated Parapneumonic Pleural Effusions: The Case for the Fibrinolytic Potential. Clin Pulm Med, 24 (4), pp. 163-169. | Show Abstract | Read more

Complicated pleural effusions and empyema with loculation and failed drainage are common clinical problems. In adults, intrapleural fibrinolytic therapy is commonly used with variable results and therapy remains empiric. Despite the intrapleural use of various plasminogen activators; fibrinolysins, for about sixty years, there is no clear consensus about which agent is most effective. Emerging evidence demonstrates that intrapleural administration of plasminogen activators is subject to rapid inhibition by plasminogen activator inhibitor-1 and that processing of fibrinolysins is importantly influenced by other factors including the levels and quality of pleural fluid DNA. Current therapy for loculation that accompanies pleural infections also includes surgery, which is invasive and for which patient selection can be problematic. Most of the clinical literature published to date has used flat dosing of intrapleural fibrinolytic therapy in all subjects but little is known about how that strategy influences the processing of the administered fibrinolysin or how this influences outcomes. We developed a new test of pleural fluids ex vivo, which is called the Fibrinolytic Potential or FP, in which a dose of a fibrinolysin is added to pleural fluids ex vivo after which the fibrinolytic activity is measured and normalized to baseline levels. Testing in preclinical and clinical empyema fluids reveals a wide range of responses, indicating that individual patients will likely respond differently to flat dosing of fibrinolysins. The test remains under development but is envisioned as a guide for dosing of these agents, representing a novel candidate approach to personalization of intrapleural fibrinolytic therapy.

Penz E, Watt KN, Hergott CA, Rahman NM, Psallidas I. 2017. Management of malignant pleural effusion: challenges and solutions. Cancer Manag Res, 9 pp. 229-241. | Show Abstract | Read more

Malignant pleural effusion (MPE) is a sign of advanced cancer and is associated with significant symptom burden and mortality. To date, management has been palliative in nature with a focus on draining the pleural space, with therapies aimed at preventing recurrence or providing intermittent drainage through indwelling catheters. Given that patients with MPEs are heterogeneous with respect to their cancer type and response to systemic therapy, functional status, and pleural milieu, response to MPE therapy is also heterogeneous and difficult to predict. Furthermore, the impact of therapies on important patient outcomes has only recently been evaluated consistently in clinical trials and cohort studies. In this review, we examine patient outcomes that have been studied to date, address the question of which are most important for managing patients, and review the literature related to the expected value for money (cost-effectiveness) of indwelling pleural catheters relative to traditionally recommended approaches.

Corcoran JP, Hallifax RJ, Psallidas I, Rahman NM. 2017. Pleural Diseases: Saline Irrigation in Pleural Infection, Epidemiology of Pneumothorax, and Bevacizumab in Mesothelioma. Am J Respir Crit Care Med, 196 (3), pp. 382-385. | Read more

Corcoran JP, Tazi-Mezalek R, Maldonado F, Yarmus LB, Annema JT, Koegelenberg CFN, St Noble V, Rahman NM. 2017. State of the art thoracic ultrasound: intervention and therapeutics. Thorax, 72 (9), pp. 840-849. | Show Abstract | Read more

The use of thoracic ultrasound outside the radiology department and in everyday clinical practice is becoming increasingly common, having been incorporated into standards of care for many specialties. For the majority of practitioners, their experience of, and exposure to, thoracic ultrasound will be in its use as an adjunct to pleural and thoracic interventions, owing to the widely recognised benefits for patient safety and risk reduction. However, as clinicians become increasingly familiar with the capabilities of thoracic ultrasound, new directions for its use are being sought which might enhance practice and patient care. This article reviews the ways in which the advent of thoracic ultrasound is changing the approach to the investigation and treatment of respiratory disease from an interventional perspective. This will include the impact of thoracic ultrasound on areas including patient safety, diagnostic and therapeutic procedures, and outcome prediction; and will also consider potential future research and clinical directions.

Mercer RM, Psallidas I, Rahman NM. 2017. Ultrasound in the management of pleural disease. Expert Rev Respir Med, 11 (4), pp. 323-331. | Show Abstract | Read more

INTRODUCTION: Pleural disease encompasses a large range of conditions, is a common presentation to the acute medical take and often requires comprehensive investigation and treatment. Ultrasound is well recognised as a useful investigative tool in pleural disease especially in the field of pleural effusion, pleural thickening and interventional procedures. Thoracic ultrasound (TUS) has gained widespread use by physicians as evidence has shown a reduced rate of complications when performing pleural procedures with ultrasound guidance. Areas covered: This article will review studies assessing the role of TUS in the management of pleural disease and examine ongoing research into how TUS could advance our knowledge and understanding over the next decade. Expert commentary: Physician lead thoracic ultrasound has become commonplace over the last decade, and now represents a minimum standard of safety in conducting the majority of 'bedside' pleural procedures. The current evidence points to important diagnostic and procedural roles of the use of bedside thoracic ultrasound. In the future, research developments are likely to lead to the use of thoracic ultrasound in prognostication, targeted treatment and understanding pathogenesis in pleural disease.

Matin TN, Rahman N, Nickol AH, Chen M, Xu X, Stewart NJ, Doel T, Grau V, Wild JM, Gleeson FV. 2017. Chronic Obstructive Pulmonary Disease: Lobar Analysis with Hyperpolarized 129Xe MR Imaging. Radiology, 282 (3), pp. 857-868. | Show Abstract | Read more

Purpose To compare lobar ventilation and apparent diffusion coefficient (ADC) values obtained with hyperpolarized xenon 129 (129Xe) magnetic resonance (MR) imaging to quantitative computed tomography (CT) metrics on a lobar basis and pulmonary function test (PFT) results on a whole-lung basis in patients with chronic obstructive pulmonary disease (COPD). Materials and Methods The study was approved by the National Research Ethics Service Committee; written informed consent was obtained from all patients. Twenty-two patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II-IV) underwent hyperpolarized 129Xe MR imaging at 1.5 T, quantitative CT, and PFTs. Whole-lung and lobar 129Xe MR imaging parameters were obtained by using automated segmentation of multisection hyperpolarized 129Xe MR ventilation images and hyperpolarized 129Xe MR diffusion-weighted images after coregistration to CT scans. Whole-lung and lobar quantitative CT-derived metrics for emphysema and bronchial wall thickness were calculated. Pearson correlation coefficients were used to evaluate the relationship between imaging measures and PFT results. Results Percentage ventilated volume and average ADC at lobar 129Xe MR imaging showed correlation with percentage emphysema at lobar quantitative CT (r = -0.32, P < .001 and r = 0.75, P < .0001, respectively). The average ADC at whole-lung 129Xe MR imaging showed moderate correlation with PFT results (percentage predicted transfer factor of the lung for carbon monoxide [Tlco]: r = -0.61, P < .005) and percentage predicted functional residual capacity (r = 0.47, P < .05). Whole-lung quantitative CT percentage emphysema also showed statistically significant correlation with percentage predicted Tlco (r = -0.65, P < .005). Conclusion Lobar ventilation and ADC values obtained from hyperpolarized 129Xe MR imaging demonstrated correlation with quantitative CT percentage emphysema on a lobar basis and with PFT results on a whole-lung basis. © RSNA, 2016.

Arnold DT, De Fonseka D, Hamilton FW, Rahman NM, Maskell NA. 2017. Prognostication and monitoring of mesothelioma using biomarkers: a systematic review. Br J Cancer, 116 (6), pp. 731-741. | Show Abstract | Read more

BACKGROUND: Radiological markers of treatment response and prognostication in malignant pleural mesothelioma have limitations due to the morphology of the disease. Serum or pleural fluid biomarkers that could act as an adjunct to radiological assessment would be of significant value. The aim of this review was to collate and summarise the literature relating to this topic. METHODS: A systematic review was performed on the databases Pubmed and EMBASE to identify relevant studies. Two independent researchers read the abstracts and used the Quality in Prognostic Studies tool to assess the quality of the evidence. RESULTS: Forty-five studies were identified from the current literature. Twenty studies investigated the role of serum soluble mesothelin with majority suggesting that it has variable utility as a baseline test but when measured serially correlates with treatment response and prognosis. Several studies demonstrated that serum osteopontin correlated with survival at baseline. Other biomarkers have shown prognostic utility in individual studies but are yet to be reproduced in large cohort studies. CONCLUSIONS: From the available literature no serum or pleural fluid biomarker was identified that could be recommended currently for routine clinical practice. However, a falling serum soluble mesothelin might correlate with treatment response and improved survival.

Psallidas I, Corcoran JP, Fallon J, Bintcliffe O, Sivasothy P, Maskell N, Maldonado F, Pepperell J, Rahman NM. 2017. Provision of Day-Case Local Anesthetic Thoracoscopy: A Multicenter Review of Practice. Chest, 151 (2), pp. 511-512. | Read more

Hallifax RJ, Psallidas I, Rahman NM. 2017. Chest Drain Size: the Debate Continues. Curr Pulmonol Rep, 6 (1), pp. 26-29. | Show Abstract | Read more

PURPOSE OF REVIEW: Small-bore chest tubes are widely used in the management of common pleural disease. Guidelines suggest that patients with malignant pleural effusions, pneumothorax and pleural infection may be successfully managed with small-bore drains. However, good quality data is often lacking. This article reviews the evidence for the treatment efficacy and potential adverse effects of different chest tube sizes. RECENT FINDINGS: In a large randomised study, the small difference in pain scores between large and small drains was not clinically significant. However, small-bore chest tubes commonly suffer from blockage or inadvertent removal, and may not be as effective in providing successful pleurodesis for malignant pleural effusions. SUMMARY: Although they may be effective in managing pleural infection, and less painful than large drains, small bore drains may be less effective for pleurodesis.

Olfert JAP, Penz ED, Manns BJ, Mishra EK, Davies HE, Miller RF, Luengo-Fernandez R, Gao S, Rahman NM. 2017. Cost-effectiveness of indwelling pleural catheter compared with talc in malignant pleural effusion. Respirology, 22 (4), pp. 764-770. | Show Abstract | Read more

BACKGROUND AND OBJECTIVE: Malignant pleural effusion is associated with morbidity and mortality. A randomized controlled trial previously compared clinical outcomes and resource use with indwelling pleural catheter (IPC) and talc pleurodesis in this population. Using unpublished quality of life data, we estimate the cost-effectiveness of IPC compared with talc pleurodesis. METHODS: Healthcare utilization and costs were captured during the trial. Utility weights produced by the EuroQol Group five-dimensional three-level questionnaire and survival were used to determine quality-adjusted life-years (QALYs) gained. The incremental cost-effectiveness ratio (ICER) was calculated over the 1-year trial period. Sensitivity analysis used patient survival data and modelled additional nursing time required per week for catheter drainage. RESULTS: Utility scores, cost and QALYs gained did not differ significantly between groups. The ICER for IPC compared with talc was favorable at $US10 870 per QALY gained. IPC was less costly with a probability exceeding 95% of being cost-effective when survival was <14 weeks, and was more costly when 2-h nursing time per week was assumed for catheter drainage. CONCLUSION: IPC is cost-effective when compared with talc, although substantial uncertainty exists around this estimate. IPC appears most cost-effective in patients with limited survival. If significant nursing time is required for catheter drainage, IPC becomes less likely to be cost-effective. Either therapy may be considered as a first-line option in treating malignant pleural effusion in patients without history of prior pleurodesis, with consideration for patient survival, support and preferences.

Talwar A, Willaime JMY, Pickup LC, Enescu M, Boukerroui D, Hickes W, Gooding MJ, Rahman NM, Kadir T, Gleeson FV. 2016. PULMONARY NODULES: ASSESSING THE REPEATABILITY OF IMAGING BIOMARKERS OF MALIGNANCY THORAX, 71 (Suppl 3), pp. A94-A95. | Read more

Sivakumar P, Curley D, Rahman NM, Lee YCG, Feller-Kopman D, West A, Ahmed L. 2016. CLINICIANS' PERSPECTIVES OF HEALTH RELATED QUALITY OF LIFE AND PRIORITIES IN DECIDING MANAGEMENT FOR MALIGNANT PLEURAL EFFUSION THORAX, 71 (Suppl 3), pp. A86-A87. | Read more

Talwar A, Rahman NM, Kadir T, Pickup LC, Gleeson F. 2017. A retrospective validation study of three models to estimate the probability of malignancy in patients with small pulmonary nodules from a tertiary oncology follow-up centre. Clin Radiol, 72 (2), pp. 177.e1-177.e8. | Show Abstract | Read more

AIM: To estimate the probability of malignancy in small pulmonary nodules (PNs) based on clinical and radiological characteristics in a non-screening population that includes patients with a prior history of malignancy using three validated models. MATERIALS AND METHODS: Retrospective data on clinical and radiological characteristics was collected from the medical records of 702 patients (379 men, 323 women; range 19-94 years) with PNs ≤12 mm in diameter at a single centre. The final diagnosis was compared to the probability of malignancy calculated by one of three models (Mayo, VA, and McWilliams). Model accuracy was assessed by receiver operating characteristics (ROC). The models were calibrated by comparing predicted and observed rates of malignancy. RESULTS: The area under the ROC curve (AUC) was highest for the McWilliams model (0.82; 95% confidence interval [CI]: 0.78-0.91) and lowest for the Mayo model (0.58; 95% CI: 0.55-0.59). The VA model had an AUC of (0.62; 95% CI: 0.47-0.64). Performance of the models was significantly lower than that in the published literature. CONCLUSIONS: The accuracy of the three models is lower in a non-screening population with a high prevalence of prior malignancy compared to the papers that describe their development. To the authors' knowledge, this is the largest study to validate predictive models for PNs in a non-screening clinically referred patient population, and has potential implications for the implementation of predictive models.

Hallifax RJ, Yousuf A, Jones HE, Corcoran JP, Psallidas I, Rahman NM. 2017. Effectiveness of chemical pleurodesis in spontaneous pneumothorax recurrence prevention: a systematic review. Thorax, 72 (12), pp. 1121-1131. | Show Abstract | Read more

OBJECTIVES: Spontaneous pneumothorax is a common pathology. International guidelines suggest pleurodesis for non-resolving air leak or recurrence prevention at second occurrence. This study comprehensively reviews the existing literature regarding chemical pleurodesis efficacy. DESIGN: We systematically reviewed the literature to identify relevant randomised controlled trials (RCTs), case-control studies and case series. We described the findings of these studies and tabulated relative recurrence rates or ORs (in studies with control groups). Meta-analysis was not performed due to substantial clinical heterogeneity. RESULTS: Of 560 abstracts identified by our search strategy, 50 were included in our systematic review following screening. Recurrence rates in patients with chest tube drainage only were between 26.1% and 50.1%. Thoracoscopic talc poudrage (four studies (n=249)) provided recurrence rates of between 2.5% and 10.2% with the only RCT suggesting an OR of 0.10 compared with drainage alone. In comparison, talc administration during video-assisted thoracic surgery (VATS) from eight studies (n=2324) recurrence was between 0.0% and 3.2%, but the RCT did not demonstrate a significant difference compared with bleb/bullectomy alone. Minocycline appears similarly effective post-VATS (recurrence rates 0.0-2.9%). Prolonged air leak and recurrence prevention using tetracycline via chest drain (n=726) is likely to provide recurrence rates between 13.0% and 33.3% and autologous blood patch pleurodesis (n=270) between 15.6% and 18.2%. CONCLUSIONS: Chemical pleurodesis postsurgical treatment or via thoracoscopy appears to be most effective. Evidence for definitive success rates of each agent is limited by the small number of randomised trials or other comparative studies.

Mercer RM, Corcoran JP, Rahman NM. 2016. Modern Management of Malignant Pleural Effusions Clinical Pulmonary Medicine, 23 (6), pp. 265-272. | Show Abstract | Read more

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. The development of a malignant pleural effusion (MPE) is diagnostic of advanced incurable cancer, and is seen with increasing frequency as the population ages and patients with malignancy survive for longer after the diagnosis as a result of advances in oncological therapies. MPE is frequently associated with significant symptoms including dyspnea, malaise, and cough that have a negative impact on a patient's quality of life. Treatment is generally palliative, with the median survival after diagnosis varying from 3 to 12 months. There has been considerable progress in recent years with respect to the management of MPE, and both patients and clinicians are now faced with a wide range of therapeutic interventions, each of which has its own advantages. This review article aims to summarize the evidence that underpins our current understanding of MPE and its treatment, and offer an insight into how ongoing research may further impact patient care in the future.

Bintcliffe OJ, Lee GYC, Rahman NM, Maskell NA. 2016. The management of benign non-infective pleural effusions. Eur Respir Rev, 25 (141), pp. 303-316. | Show Abstract | Read more

The evidence base concerning the management of benign pleural effusions has lagged behind that of malignant pleural effusions in which recent randomised trials are now informing current clinical practice and international guidelines.The causes of benign pleural effusions are broad, heterogenous and patients may benefit from individualised management targeted at both treating the underlying disease process and direct management of the fluid. Pleural effusions are very common in a number of non-malignant pathologies, such as decompensated heart failure, and following coronary artery bypass grafting. Pleural fluid analysis forms an important basis of the diagnostic evaluation, and more specific assays and imaging modalities are helpful in specific subpopulations.Options for management beyond treatment of the underlying disorder, whenever possible, include therapeutically aspirating the fluid, talc pleurodesis and insertion of an indwelling pleural catheter. Randomised trials will inform clinicians in the future as to the risks and benefits of these options providing a guide as to how best to manage patient symptoms in this challenging clinical setting.

Komissarov AA, Florova G, Azghani AO, Buchanan A, Boren J, Allen T, Rahman NM, Koenig K, Chamiso M, Karandashova S et al. 2016. Dose dependency of outcomes of intrapleural fibrinolytic therapy in new rabbit empyema models. Am J Physiol Lung Cell Mol Physiol, 311 (2), pp. L389-L399. | Show Abstract | Read more

The incidence of empyema (EMP) is increasing worldwide; EMP generally occurs with pleural loculation and impaired drainage is often treated with intrapleural fibrinolytic therapy (IPFT) or surgery. A number of IPFT options are used clinically with empiric dosing and variable outcomes in adults. To evaluate mechanisms governing intrapleural fibrinolysis and disease outcomes, models of Pasteurella multocida and Streptococcus pneumoniae were generated in rabbits and the animals were treated with either human tissue (tPA) plasminogen activator or prourokinase (scuPA). Rabbit EMP was characterized by the development of pleural adhesions detectable by chest ultrasonography and fibrinous coating of the pleura. Similar to human EMP, rabbits with EMP accumulated sizable, 20- to 40-ml fibrinopurulent pleural effusions associated with extensive intrapleural organization, significantly increased pleural thickness, suppression of fibrinolytic and plasminogen-activating activities, and accumulation of high levels of plasminogen activator inhibitor 1, plasminogen, and extracellular DNA. IPFT with tPA (0.145 mg/kg) or scuPA (0.5 mg/kg) was ineffective in rabbit EMP (n = 9 and 3 for P. multocida and S. pneumoniae, respectively); 2 mg/kg tPA or scuPA IPFT (n = 5) effectively cleared S. pneumoniae-induced EMP collections in 24 h with no bleeding observed. Although intrapleural fibrinolytic activity for up to 40 min after IPFT was similar for effective and ineffective doses of fibrinolysin, it was lower for tPA than for scuPA treatments. These results demonstrate similarities between rabbit and human EMP, the importance of pleural fluid PAI-1 activity, and levels of plasminogen in the regulation of intrapleural fibrinolysis and illustrate the dose dependency of IPFT outcomes in EMP.

Clive AO, Taylor H, Dobson L, Wilson P, de Winton E, Panakis N, Pepperell J, Howell T, Stewart SA, Penz E et al. 2016. Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial. Lancet Oncol, 17 (8), pp. 1094-1104. | Show Abstract | Read more

BACKGROUND: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. METHODS: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. FINDINGS: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. INTERPRETATION: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. FUNDING: Research for Patient Benefit Programme from the UK National Institute for Health Research.

Bhatnagar R, Corcoran JP, Maldonado F, Feller-Kopman D, Janssen J, Astoul P, Rahman NM. 2016. Advanced medical interventions in pleural disease. Eur Respir Rev, 25 (140), pp. 199-213. | Show Abstract | Read more

The burden of a number of pleural diseases continues to increase internationally. Although many pleural procedures have historically been the domain of interventional radiologists or thoracic surgeons, in recent years, there has been a marked expansion in the techniques available to the pulmonologist. This has been due in part to both technological advancements and a greater recognition that pleural disease is an important subspecialty of respiratory medicine. This article summarises the important literature relating to a number of advanced pleural interventions, including medical thoracoscopy, the insertion and use of indwelling pleural catheters, pleural manometry, point-of-care thoracic ultrasound, and image-guided closed pleural biopsy. We also aim to inform the reader regarding the latest updates to more established procedures such as chemical pleurodesis, thoracentesis and the management of chest drains, drawing on contemporary data from recent randomised trials. Finally, we shall look to explore the challenges faced by those practicing pleural medicine, especially relating to training, as well as possible future directions for the use and expansion of advanced medical interventions in pleural disease.

Psallidas I, Rahman NM. 2016. Advances in pleural disease. Eur Respir Rev, 25 (140), pp. 108-109. | Read more

Rahman NM, Pepperell J, Rehal S. 2016. Incorrect Number of Patients in a Figure. JAMA, 315 (15), pp. 1661. | Read more

Rahman NM, Pepperell J, Rehal S. 2016. Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion (vol 314, pg 2641, 2015) JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 315 (15), pp. 1661-1661.

Rintoul RC, Rassl DM, Gittins J, Marciniak SJ, MesobanK collaborators. 2016. MesobanK UK: an international mesothelioma bioresource. Thorax, 71 (4), pp. 380-382. | Show Abstract | Read more

Malignant pleural mesothelioma causes the greatest societal burden of all the asbestos-related diseases. Progress in better understanding tumour biology will be facilitated by the availability of quality-assured annotated tissue. MesobanK has been created to establish a bioresource of pleural mesothelioma tissue linked to detailed anonymised clinical data. When complete, the bioresource will comprise a 750-patient tissue microarray and prospectively collected tissue, blood and pleural fluid from 300 patients with mesothelioma. Twenty-six new cell lines have also been developed. MesobanK meets all appropriate ethical and regulatory procedures and has recently opened to requests for tissue and data.

Corcoran JP, Hallifax RJ, Talwar A, Psallidas I, Rahman NM. 2016. Safe site selection for chest drain insertion by trainee physicians - Implications for medical training and clinical practice. Eur J Intern Med, 28 pp. e13-e15. | Read more

Corcoran JP, Acton L, Ahmed A, Hallifax RJ, Psallidas I, Wrightson JM, Rahman NM, Gleeson FV. 2016. Diagnostic value of radiological imaging pre- and post-drainage of pleural effusions. Respirology, 21 (2), pp. 392-395. | Show Abstract | Read more

Patients with an unexplained pleural effusion often require urgent investigation. Clinical practice varies due to uncertainty as to whether an effusion should be drained completely before diagnostic imaging. We performed a retrospective study of patients undergoing medical thoracoscopy for an unexplained effusion. In 110 patients with paired (pre- and post-drainage) chest X-rays and 32 patients with paired computed tomography scans, post-drainage imaging did not provide additional information that would have influenced the clinical decision-making process.

Storrar W, Fogg C, Brown T, Dennison P, Yu L-M, Dewey A, Luengo-Fernandez R, Dean T, Rahman N, Mansur A et al. 2016. Temperature-controlled laminar airflow in severe asthma for exacerbation reduction (The LASER Trial): study protocol for a randomised controlled trial. Trials, 17 (1), pp. 15. | Show Abstract | Read more

BACKGROUND: Asthma affects more than 5 million patients in the United Kingdom. Nearly 500,000 of these patients have severe asthma with severe symptoms and frequent exacerbations that are inadequately controlled with available treatments. The burden of severe asthma on the NHS is enormous, accounting for 80 % of the total asthma cost (£1 billion), with frequent exacerbations and expensive medications generating much of this cost. Of those patients with severe asthma, 70 % are sensitised to indoor aeroallergens, and the level of exposure to allergens determines the symptoms; patients exposed to high levels are therefore most at risk of exacerbations and hospital admissions. The LASER trial aims to assess whether a new treatment, temperature controlled laminar airflow (TLA) delivered by the Airsonett™ device, can reduce the frequency of exacerbations in patients with severe allergic asthma by reducing exposure to aeroallergens overnight. METHODS: This multicentre study is a placebo-controlled, blinded, randomised controlled, parallel group trial. A total of 222 patients with a new or current diagnosis of severe allergic asthma will be assigned with a random element in a 1:1 ratio to receive either an active device for one year or a placebo device. The primary outcome is the frequency of severe asthma exacerbations occurring over a 12-month period, defined in accordance with the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines. Secondary outcomes include changes in asthma control, lung function, asthma-specific and global quality of life for participants and their carers, adherence to intervention, healthcare resource use and costs, and cost-effectiveness. Qualitative interviews will be conducted to elicit participant's and their partner's perceptions of the treatment. DISCUSSION: Effective measures of allergen avoidance have, to date, proved elusive. The LASER trial aims to address this. The study will ascertain whether home-based nocturnal TLA usage over a 12-month period can reduce the frequency of exacerbations and improve asthma control and quality of life as compared to placebo, whilst being cost-effective and acceptable to adults with poorly controlled, severe allergic asthma. The results of this study will be widely applicable to the many patients with allergic asthma both in the UK and internationally. TRIAL REGISTRATION: Current controlled trials ISRCTN46346208 (Date assigned 22 January 2014).

Corcoran JP, Psallidas I, Ross CL, Hallifax RJ, Rahman NM. 2016. Always Worth Another Look? Thoracic Ultrasonography before, during, and after Pleural Intervention. Ann Am Thorac Soc, 13 (1), pp. 118-121. | Read more

Hallifax RJ, Corcoran JP, Psallidas I, Rahman NM. 2016. Medical thoracoscopy: Survey of current practice-How successful are medical thoracoscopists at predicting malignancy? Respirology, 21 (5), pp. 958-960. | Show Abstract | Read more

Use of medical thoracoscopy by respiratory physicians is increasing. This survey of experienced thoracoscopists was conducted to establish current practice of medical thoracoscopy and physicians' opinion of theoretical cases using 20 video clips. Results suggest an increasing trend towards day-case thoracoscopy but that caution is required when making diagnosis on macroscopic appearance: malignant and benign disease could only be differentiated in 59% of cases, and trapped lung is difficult to predict at thoracoscopy.

Rahman NM, Pepperell J, Rehal S, Saba T, Tang A, Ali N, West A, Hettiarachchi G, Mukherjee D, Samuel J et al. 2015. Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial. JAMA, 314 (24), pp. 2641-2653. | Show Abstract | Read more

IMPORTANCE: For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven. OBJECTIVE: To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion. DESIGN, SETTING, AND PARTICIPANTS: A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013. INTERVENTIONS: Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). MAIN OUTCOMES AND MEASURES: Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%). RESULTS: Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20). CONCLUSIONS AND RELEVANCE: Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN33288337.

Porcel JM, Azzopardi M, Koegelenberg CF, Maldonado F, Rahman NM, Lee YCG. 2015. The diagnosis of pleural effusions Expert Review of Respiratory Medicine, 9 (6), pp. 801-815. | Show Abstract | Read more

© 2015 Taylor & Francis. Pleural effusions arise from a variety of systemic, inflammatory, infectious and malignant conditions. Their precise etiological diagnosis depends on a combination of medical history, physical examination, imaging tests and pertinent pleural fluid analyses; including specific biomarkers (e.g., natriuretic peptides for heart failure, adenosine deaminase for tuberculosis, or mesothelin for mesothelioma). Invasive procedures, such as pleuroscopic biopsies, may be required for persistently symptomatic effusions which remain undiagnosed after the analysis of one or more pleural fluid samples. However, whenever parietal pleural nodularity or thickening exist, image-guided biopsies should first be attempted. This review addresses the current diagnostic approach to pleural effusions secondary to heart failure, pneumonia, cancer, tuberculosis and other less frequent conditions.

Bintcliffe O, Maskell N, Rahman N. 2015. Initial management of spontaneous pneumothorax - Authors' reply. Lancet Respir Med, 3 (11), pp. e36. | Read more

Porcel JM, Azzopardi M, Koegelenberg CF, Maldonado F, Rahman NM, Lee YCG. 2015. The diagnosis of pleural effusions. Expert Rev Respir Med, 9 (6), pp. 801-815. | Show Abstract | Read more

Pleural effusions arise from a variety of systemic, inflammatory, infectious and malignant conditions. Their precise etiological diagnosis depends on a combination of medical history, physical examination, imaging tests and pertinent pleural fluid analyses; including specific biomarkers (e.g., natriuretic peptides for heart failure, adenosine deaminase for tuberculosis, or mesothelin for mesothelioma). Invasive procedures, such as pleuroscopic biopsies, may be required for persistently symptomatic effusions which remain undiagnosed after the analysis of one or more pleural fluid samples. However, whenever parietal pleural nodularity or thickening exist, image-guided biopsies should first be attempted. This review addresses the current diagnostic approach to pleural effusions secondary to heart failure, pneumonia, cancer, tuberculosis and other less frequent conditions.

Hallifax RJ, Rahman NM. 2015. Epidemiology of pneumothorax - Finally something solid out of thin air Thorax, 70 (10), pp. 921-922. | Read more

Wrightson JM, Wray JA, Street TL, Chapman SJ, Gleeson FV, Maskell NA, Peto TEA, Rahman NM, Crook DWM. 2015. Absence of Atypical Pathogens in Pleural Infection. Chest, 148 (3), pp. e102-e103. | Read more

Psallidas I, Helm EJ, Maskell NA, Yarmus L, Feller-Kopman DJ, Gleeson FV, Rahman NM. 2015. Iatrogenic injury to the intercostal artery: Aetiology, diagnosis and therapeutic intervention Thorax, 70 (8), pp. 802-804. | Read more

Hallifax RJ, Rahman NM. 2015. Epidemiology of pneumothorax--finally something solid out of thin air. Thorax, 70 (10), pp. 921-922. | Read more

Nickol AH, Frise MC, Cheng H-Y, McGahey A, McFadyen BM, Harris-Wright T, Bart NK, Curtis MK, Khandwala S, O'Neill DP et al. 2015. A cross-sectional study of the prevalence and associations of iron deficiency in a cohort of patients with chronic obstructive pulmonary disease. BMJ Open, 5 (7), pp. e007911. | Show Abstract | Read more

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Iron deficiency, with or without anaemia, is associated with other chronic conditions, such as congestive heart failure, where it predicts a worse outcome. However, the prevalence of iron deficiency in COPD is unknown. This observational study aimed to determine the prevalence of iron deficiency in COPD and associations with differences in clinical phenotype. SETTING: University hospital outpatient clinic. PARTICIPANTS: 113 adult patients (65% male) with COPD diagnosed according to GOLD criteria (forced expiratory volume in 1 s (FEV1): forced vital capacity (FVC) ratio <0·70 and FEV1 <80% predicted); with age-matched and sex-matched control group consisting of 57 healthy individuals. MAIN OUTCOME MEASURES: Prevalence of iron deficiency, defined as: any one or more of (1) soluble transferrin receptor >28.1 nmol/L; (2) transferrin saturation <16% and (3) ferritin <12 µg/L. Severity of hypoxaemia, including resting peripheral arterial oxygen saturation (SpO2) and nocturnal oximetry; C reactive protein (CRP); FEV1; self-reported exacerbation rate and Shuttle Walk Test performance. RESULTS: Iron deficiency was more common in patients with COPD (18%) compared with controls (5%). In the COPD cohort, CRP was higher in patients with iron deficiency (median 10.5 vs 4.0 mg/L, p<0.001), who were also more hypoxaemic than their iron-replete counterparts (median resting SpO2 92% vs 95%, p<0.001), but haemoglobin concentration did not differ. Patients with iron deficiency had more self-reported exacerbations and a trend towards worse exercise tolerance. CONCLUSIONS: Non-anaemic iron deficiency is common in COPD and appears to be driven by inflammation. Iron deficiency associates with hypoxaemia, an excess of exacerbations and, possibly, worse exercise tolerance, all markers of poor prognosis. Given that it has been shown to be beneficial in other chronic diseases, intravenous iron therapy should be explored as a novel therapeutic option in COPD.

Corcoran JP, Sivasothy PR, Rahman NM. 2015. Insertion of intercostal chest drains: who, where and when? Br J Hosp Med (Lond), 76 (7), pp. 376-377. | Read more

Bintcliffe OJ, Hallifax RJ, Edey A, Feller-Kopman D, Lee YCG, Marquette CH, Tschopp J-M, West D, Rahman NM, Maskell NA. 2015. Spontaneous pneumothorax: time to rethink management? Lancet Respir Med, 3 (7), pp. 578-588. | Show Abstract | Read more

There are substantial differences in international guidelines for the management of pneumothorax and much geographical variation in clinical practice. These discrepancies have, in part, been driven by a paucity of high-quality evidence. Advances in diagnostic techniques have increasingly allowed the identification of lung abnormalities in patients previously labelled as having primary spontaneous pneumothorax, a group in whom recommended management differs from those with clinically apparent lung disease. Pathophysiological mechanisms underlying pneumothorax are now better understood and this may have implications for clinical management. Risk stratification of patients at baseline could help to identify subgroups at higher risk of recurrent pneumothorax who would benefit from early intervention to prevent recurrence. Further research into the roles of conservative management, Heimlich valves, digital air-leak monitoring, and pleurodesis at first presentation might lead to an increase in their use in the future.

Corcoran JP, Wrightson JM, Belcher E, DeCamp MM, Feller-Kopman D, Rahman NM. 2015. Pleural infection: past, present, and future directions. Lancet Respir Med, 3 (7), pp. 563-577. | Show Abstract | Read more

Pleural space infections are increasing in incidence and continue to have high associated morbidity, mortality, and need for invasive treatments such as thoracic surgery. The mechanisms of progression from a non-infected, pneumonia-related effusion to a confirmed pleural infection have been well described in the scientific literature, but the route by which pathogenic organisms access the pleural space is poorly understood. Data suggests that not all pleural infections can be related to lung parenchymal infection. Studies examining the microbiological profile of pleural infection inform antibiotic choice and can help to delineate the source and pathogenesis of infection. The development of radiological methods and use of clinical indices to predict which patients with pleural infection will have a poor outcome, as well as inform patient selection for more invasive treatments, is particularly important. Randomised clinical trial and case series data have shown that the combination of an intrapleural tissue plasminogen activator and deoxyribonuclease therapy can potentially improve outcomes, but the use of this treatment as compared with surgical options has not been precisely defined, particularly in terms of when and in which patients it should be used.

Bibby AC, Clive AO, Slade GC, Morley AJ, Fallon J, Psallidas I, Pepperell JCT, Slade MG, Stanton AE, Rahman NM, Maskell NA. 2015. Survival in Patients With Malignant Pleural Effusions Who Developed Pleural Infection: A Retrospective Case Review From Six UK Centers. Chest, 148 (1), pp. 235-241. | Show Abstract | Read more

OBJECTIVE: Malignant pleural effusion (MPE) incidence is increasing, and prognosis remains poor. Indwelling pleural catheters (IPCs) relieve symptoms but increase the risk of pleural infection. We reviewed cases of pleural infection in patients with IPCs for MPE from six UK centers between January 1, 2005, and January 31, 2014. METHODS: Survival in patients with pleural infection was compared with 788 patients with MPE (known as the LENT [pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type] cohort) and with national statistics. RESULTS: Of 672 IPCs inserted, 25 (3.7%) became infected. Most patients (20 of 25) had mesothelioma or lung cancer. Median survival in the pleural infection cohort appeared longer than in the LENT cohort, although this result did not achieve significance (386 days vs 132 days; hazard ratio, 0.67; P = .07). Median survival with mesothelioma and pleural infection was twice as long as national estimates for mesothelioma survival (753 days vs < 365 days) and double the median survival of patients with mesothelioma in the LENT cohort (339 days; 95% CI, nonoverlapping). Survival with lung and breast cancer did not differ significantly between the groups. Sixty-one percent of patients experienced early infection. There was no survival difference between patients with early and late infection (P = .6). CONCLUSIONS: This small series of patients with IPCs for MPE suggests pleural infection may be associated with longer survival, particularly in patients with mesothelioma. Results did not achieve significance, and a larger study is needed to explore this relationship further and investigate whether the local immune response, triggered by infection, is able to modulate mesothelioma progression.

Treasure T, Hallifax RJ, Rahman N. 2016. Are we ready to go directly to videothoracoscopic surgery at a first presentation of primary spontaneous pneumothorax? Eur J Cardiothorac Surg, 49 (3), pp. 860-861. | Read more

Corcoran JP, Psallidas I, Wrightson JM, Hallifax RJ, Rahman NM. 2015. Pleural procedural complications: prevention and management. J Thorac Dis, 7 (6), pp. 1058-1067. | Show Abstract | Read more

Pleural disease is common with a rising case frequency. Many of these patients will be symptomatic and require diagnostic and/or therapeutic procedures. Patients with pleural disease present to a number of different medical specialties, and an equally broad range of clinicians are therefore required to have practical knowledge of these procedures. There is often underestimation of the morbidity and mortality associated with pleural interventions, even those regarded as being relatively straightforward, with potentially significant implications for processes relating to patient safety and informed consent. The advent of thoracic ultrasound (TUS) has had a major influence on patient safety and the number of physicians with the necessary skill set to perform pleural procedures. As the variety and complexity of pleural interventions increases, there is increasing recognition that early specialist input can reduce the risk of complications and number of procedures a patient requires. This review looks at the means by which complications of pleural procedures arise, along with how they can be managed or ideally prevented.

Hallifax RJ, Talwar A, Rahman NM. 2015. The role of computed tomography in assessing pleural malignancy prior to thoracoscopy. Curr Opin Pulm Med, 21 (4), pp. 368-371. | Show Abstract | Read more

PURPOSE OF REVIEW: Computed tomography (CT) scanning is part of the routine diagnostic work up of patients with suspected pleural malignancy but has a wide variation in the reported sensitivity and specificity. This review was to appraise the recent literature on the utility of CT scanning. RECENT FINDINGS: When investigating patients for suspected pleural malignancy, the sensitivity of a malignant CT report may be higher than previously reported (68%), but the specificity seems significantly lower (78%). The predictive value of CT scanning (on all patients with pleural effusions) may be increased using a CT scoring system. Recent meta-analyses of the utility of PET give differing opinions on the value of this imaging modality. Further work needs to be done to define its place in the diagnostic pathway. SUMMARY: CT scoring systems may allow further risk stratification. However, a low negative predictive value of a 'negative' CT scan could lead to false reassurance and missed malignancy. PET/CT does not currently appear to add additional diagnostic value. Pulmonary emboli should be considered in all patients being investigated for clinically suspected malignant pleural disease. Respiratory physicians should be mindful of rare or unusual presentations.

Hew M, Corcoran JP, Harriss EK, Rahman NM, Mallett S. 2015. The diagnostic accuracy of chest ultrasound for CT-detected radiographic consolidation in hospitalised adults with acute respiratory failure: a systematic review. BMJ Open, 5 (5), pp. e007838. | Show Abstract | Read more

OBJECTIVES: (1) Summarise chest ultrasound accuracy to diagnose radiological consolidation, referenced to chest CT in patients with acute respiratory failure (ARF). (2) Directly compared ultrasound with chest X-ray. SETTING: Hospitalised patients. PARTICIPANTS: Studies were eligible if adult participants in respiratory failure underwent chest ultrasound to diagnose consolidation referenced to CT. Exclusion: (1) not primary study, (2) not respiratory failure, (3) not chest ultrasound, (4) not consolidation, (5) translation unobtainable, (6) unable to extract data, (7) unable to obtain paper. 4 studies comprising 224 participants met inclusion. OUTCOME MEASURES: As planned, paired forest plots display 95% CIs of sensitivity and specificity for ultrasound and chest X-ray. Sensitivity and specificity from each study are plotted in receiver operator characteristics space. Meta-analysis was planned if studies were sufficiently homogeneous and numerous (≥4). Although this numerical requirement was met, meta-analysis was prevented by heterogeneous units of analysis between studies. RESULTS: All studies were in intensive care, with either a high risk of selection bias or high applicability concerns. Studies had unclear or high risk of bias related to use of ultrasound. Only 1 study clearly performed ultrasound within 24 h of respiratory failure diagnosis. Ultrasound sensitivity ranged from 0.91 (95% CI 0.81 to 0.97) to 1.00 (95% CI 0.95 to 1.00). Specificity ranged from 0.78 (95% CI 0.52 to 0.94) to 1.00 (0.99 to 1.00). In two studies, chest X-ray had lower sensitivity than ultrasound, but there were insufficient patients to compare specificity. CONCLUSIONS: Four small studies suggest ultrasound is highly sensitive and specific for consolidation in ARF, but high risk of bias and concerns about applicability in all studies may have inflated diagnostic accuracy. Further robustly designed studies are needed to define the role of ultrasound in this setting. TRIAL REGISTRATION NUMBER: http://www.crd.york.ac.uk/PROSPERO/ (CRD42013006472).

Psallidas I, Helm EJ, Maskell NA, Yarmus L, Feller-Kopman DJ, Gleeson FV, Rahman NM. 2015. Iatrogenic injury to the intercostal artery: aetiology, diagnosis and therapeutic intervention. Thorax, 70 (8), pp. 802-804. | Read more

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.

Corcoran JP, Hallifax RJ, Talwar A, Psallidas I, Sykes A, Rahman NM. 2015. Intercostal chest drain insertion by general physicians: attitudes, experience and implications for training, service and patient safety. Postgrad Med J, 91 (1075), pp. 244-250. | Show Abstract | Read more

BACKGROUND: Intercostal chest drain (ICD) insertion is considered a core skill for the general physician. Recent guidelines have highlighted the risks of this procedure, while UK medical trainees have reported a concurrent decline in training opportunities and confidence in their procedural skills. OBJECTIVES: We explored clinicians' attitudes, experience and knowledge relating to pleural interventions and ICD insertion in order to determine what changes might be needed to maintain patient safety and quality of training. METHODS: Consultants and trainees delivering general medical services across five hospitals in England were invited to complete a questionnaire survey over a 5-week period in July and August 2014. RESULTS: 117 general physicians (32.4% of potential participants; comprising 31 consultants, 48 higher specialty trainees, 38 core trainees) responded. Respondents of all grades regarded ICD insertion as a core procedural skill. Respondents were asked to set a minimum requirement for achieving and maintaining independence at ICD insertion; however, only 25% of higher specialty trainees reported being able to attain this self-imposed standard. A knowledge gap was also revealed, with trainees managing clinical scenarios correctly in only 51% of cases. CONCLUSIONS: Given the disparity between clinical reality and what is expected of the physician-in-training, it is unclear whether ICD insertion can remain a core procedural skill for general physicians. Consideration should be given to how healthcare providers and training programmes might address issues relating to clinical experience and knowledge given the implications for patient safety and service provision.

Hooper CE, Lyburn ID, Searle J, Darby M, Hall T, Hall D, Morley A, White P, Rahman NM, De Winton E et al. 2015. The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication. Br J Cancer, 112 (7), pp. 1175-1182. | Show Abstract | Read more

BACKGROUND: Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care. METHODS: Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months. FINDINGS: Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272-576) days vs NLR⩾4, 257 (IQR 147-490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001). INTERPRETATION: Neutrophil-lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.

Arnold DT, Hooper CE, Morley A, White P, Lyburn ID, Searle J, Darby M, Hall T, Hall D, Rahman NM et al. 2015. The effect of chemotherapy on health-related quality of life in mesothelioma: results from the SWAMP trial. Br J Cancer, 112 (7), pp. 1183-1189. | Show Abstract | Read more

BACKGROUND: The effect of chemotherapy on health-related quality of life (HRQoL) in malignant pleural mesothelioma (MPM) is poorly understood. Patient-individualised prognostication and prediction of treatment response from chemotherapy is useful but little evidence exists to guide practice. METHOD: Consecutive patients with MPM who were fit for first-line chemotherapy with pemetrexed and cisplatin\carboplatin were recruited and followed up for a minimum of 12 months. This study focussed on the HRQoL outcomes of these patients using the EQ-5D, EORTC QLQ-C30 and LC13. RESULTS: Seventy-three patients were recruited of which 58 received chemotherapy and 15 opted for best supportive care (BSC). Compliance with HRQoL questionnaires was 98% at baseline. The chemotherapy group maintained HRQoL compared with the BSC group whose overall HRQoL fell (P=0.006) with worsening dyspnoea and pain. The impact of chemotherapy was irrespective of histological subtype although those with non-epithelioid disease had worse HRQoL at later time points (P=0.012). Additionally, those with a falling mesothelin or improvement on modified-RECIST CT at early follow-up had a better HRQoL at 16 weeks. CONCLUSIONS: HRQoL was maintained following chemotherapy compared with a self-selected BSC group. Once chemotherapy is initiated, a falling mesothelin or improved RECIST CT findings infer a quality-of-life advantage.

Hew M, Corcoran J, Harriss E, Rahman N, Mallett S. 2015. THE DIAGNOSTIC ACCURACY OF CHEST ULTRASOUND FOR CT-DETECTED RADIOGRAPHIC CONSOLIDATION IN HOSPITALISED ADULTS WITH ACUTE RESPIRATORY FAILURE: A SYSTEMATIC REVIEW RESPIROLOGY, 20 (5), pp. 108-108. | Show Abstract | Read more

Objectives: (1) Summarise chest ultrasound accuracy to diagnose radiological consolidation, referenced to chest CT in patients with acute respiratory failure (ARF). (2) Directly compared ultrasound with chest X-ray. Setting: Hospitalised patients. Participants: Studies were eligible if adult participants in respiratory failure underwent chest ultrasound to diagnose consolidation referenced to CT. Exclusion: (1) not primary study, (2) not respiratory failure, (3) not chest ultrasound, (4) not consolidation, (5) translation unobtainable, (6) unable to extract data, (7) unable to obtain paper. 4 studies comprising 224 participants met inclusion. Outcome measures: As planned, paired forest plots display 95% CIs of sensitivity and specificity for ultrasound and chest X-ray. Sensitivity and specificity from each study are plotted in receiver operator characteristics space. Meta-analysis was planned if studies were sufficiently homogeneous and numerous (≥4). Although this numerical requirement was met, meta-analysis was prevented by heterogeneous units of analysis between studies. Results: All studies were in intensive care, with either a high risk of selection bias or high applicability concerns. Studies had unclear or high risk of bias related to use of ultrasound. Only 1 study clearly performed ultrasound within 24 h of respiratory failure diagnosis. Ultrasound sensitivity ranged from 0.91 (95% CI 0.81 to 0.97) to 1.00 (95% CI 0.95 to 1.00). Specificity ranged from 0.78 (95% CI 0.52 to 0.94) to 1.00 (0.99 to 1.00). In two studies, chest X-ray had lower sensitivity than ultrasound, but there were insufficient patients to compare specificity. Conclusions: Four small studies suggest ultrasound is highly sensitive and specific for consolidation in ARF, but high risk of bias and concerns about applicability in all studies may have inflated diagnostic accuracy. Further robustly designed studies are needed to define the role of ultrasound in this setting.

Bhatnagar R, Kahan BC, Morley AJ, Keenan EK, Miller RF, Rahman NM, Maskell NA. 2015. The efficacy of indwelling pleural catheter placement versus placement plus talc sclerosant in patients with malignant pleural effusions managed exclusively as outpatients (IPC-PLUS): study protocol for a randomised controlled trial. Trials, 16 (1), pp. 48. | Show Abstract | Read more

BACKGROUND: Malignant pleural effusions (MPEs) remain a common problem, with 40,000 new cases in the United Kingdom each year and up to 250,000 in the United States. Traditional management of MPE usually involves an inpatient stay with placement of a chest drain, followed by the instillation of a pleural sclerosing agent such as talc, which aims to minimise further fluid build-up. Despite a good success rate in studies, this approach can be expensive, time-consuming and inconvenient for patients. More recently, an alternative method has become available in the form of indwelling pleural catheters (IPCs), which can be inserted and managed in an outpatient setting. It is currently unknown whether combining talc pleurodesis with IPCs will provide improved pleural symphysis rates over those of IPCs alone. METHODS/DESIGN: IPC-PLUS is a patient-blind, multicentre randomised controlled trial (RCT) comparing the combination of talc with an IPC to the use of an IPC alone for inducing pleurodesis in MPEs. The primary outcome is successful pleurodesis at five weeks post-randomisation. This study will recruit 154 patients, with an interim analysis for efficacy after 100 patients, and aims to help to define the future gold standard for outpatient management of patients with symptomatic MPEs. DISCUSSION: IPC-PLUS is the first RCT to examine the practicality and utility of talc administered via an IPC. The study remains in active recruitment and has the potential to significantly alter how patients requiring pleurodesis for MPE are approached in the future. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN73255764 ) on 23 August 2012.

Corcoran JP, Psallidas I, Hallifax RJ, Talwar A, Sykes A, Rahman NM. 2015. Ultrasound-guided pneumothorax induction prior to local anaesthetic thoracoscopy. Thorax, 70 (9), pp. 906-908. | Show Abstract | Read more

Local anaesthetic thoracoscopy (LAT) is performed by a growing number of respiratory physicians in the context of an expanding population with pleural disease. Most LATs occur in patients with moderate to large effusions where the presence of fluid allows safe access to the pleural space. Patients with little or no fluid, but other features concerning for pleural disease, are usually investigated by surgical means. Advanced LAT practitioners can also provide this service through pneumothorax induction, although there is little published data on the safety or efficacy of this technique. We present data from a series of 77 consecutive patients in whom ultrasound-guided pneumothorax induction and LAT were attempted. 67 procedures (87.0%) were successful, with the most common histopathological diagnoses being chronic pleuritis (58.2%) and mesothelioma (16.4%). No adverse events were reported secondary to the procedure. These findings demonstrate the utility of this approach and should inform future practice and guidelines.

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Hallifax R, Haris M, Corcoran JP, Leyakathalikhan S, Brown E, Srikantharaja D, Manuel A, Gleeson FV, Munavvar M, Rahman NM. 2015. Role of CT in assessing pleural malignancy prior to thoracoscopy Thorax, 70 (2), pp. 192-193. | Show Abstract | Read more

© 2015, BMJ Publishing Group. All rights reserved. The definitive diagnosis of pleural malignancy depends upon histological confirmation by pleural biopsy. CT is reported to have a high sensitivity and specificity for the diagnosis of malignant pleural disease, and is part of the routine diagnostic workup of these patients. The aim of this study was to assess the sensitivity and specificity of CT in detecting pleural malignancy prior to definitive histology obtained via thoracoscopy in a large cohort of patients with suspected malignant pleural disease. Retrospective review of thoracoscopies between January 2008 and January 2013 at two UK tertiary referral centres: Oxford and Preston. The histological results were compared with the CT reported diagnosis before the procedure. CT scan reports were assessed by independent respiratory physicians as to whether the radiologist concluded evidence of malignant pleural disease or benign features only. 211 (57%) of 370 patients included in the analysis had malignant disease: CT scans were reported as 'malignant' in 144, giving a sensitivity of 68% (95% CI 62% to 75%). Of the 159 patients with benign disease, 124 had CT scans reported as benign: specificity 78% (72% to 84%). The positive predictive value of a malignant CT report was 80% (75% to 86%), with a negative predictive value of 65% (58% to 72%). A significant proportion of patients being investigated for malignant disease will have malignancy despite a negative CT report. The use of CT alone in determining which patients should have invasive pleural biopsies should be re-evaluated, and further studies to define the diagnostic pathway are now required.

Clive AO, Wilson P, Taylor H, Morley AJ, de Winton E, Panakis N, Rahman N, Pepperell J, Howell T, Batchelor TJP et al. 2015. Protocol for the surgical and large bore procedures in malignant pleural mesothelioma and radiotherapy trial (SMART Trial): an RCT evaluating whether prophylactic radiotherapy reduces the incidence of procedure tract metastases. BMJ Open, 5 (1), pp. e006673. | Show Abstract | Read more

INTRODUCTION: Patients with malignant pleural mesothelioma (MPM) may develop painful 'procedure tract metastasis' (PTM) at the site of previous pleural interventions. Prophylactic radiotherapy has been used to minimise this complication; however, three small randomised trials have shown conflicting results regarding its effectiveness. The surgical and large bore procedures in malignant pleural mesothelioma and radiotherapy trial (SMART Trial) is a suitably powered, multicentre, randomised controlled trial, designed to evaluate the efficacy of prophylactic radiotherapy within 42 days of pleural instrumentation in preventing the development of PTM in MPM. METHODS AND ANALYSIS: 203 patients with a histocytologically proven diagnosis of MPM, who have undergone a large bore pleural intervention (thoracic surgery, large bore chest drain, indwelling pleural catheter or local anaesthetic thoracoscopy) in the previous 35 days, will be recruited from UK hospitals. Patients will be randomised (1:1) to receive immediate radiotherapy (21 Gy in 3 fractions over 3 working days within 42 days of the pleural intervention) or deferred radiotherapy (21 Gy in 3 fractions over 3 working days given if a PTM develops). Patients will be followed up for 12 months. The primary outcome measure is the rate of PTM until death or 12 months (whichever is sooner), as defined by the presence of a clinically palpable nodule of at least 1 cm diameter felt within 7 cm of the margins of the procedure site as confirmed by two assessors. Secondary outcome measures include chest pain, quality of life, analgaesic requirements, healthcare utilisation and safety (including radiotherapy toxicity). ETHICS AND DISSEMINATION: The trial has received ethical approval from the Southampton B Research Ethics Committee (11/SC/0408). There is a Trial Steering Committee, including independent members and a patient and public representative. The trial results will be published in a peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN72767336.

Corcoran JP, Culver EL, Psallidas I, Hallifax RJ, Davies SJ, Bateman AC, Barnes E, Rahman NM. 2015. A 63-year-old man with a recurrent right-sided pleural effusion. Thorax, 70 (5), pp. 504-507. | Read more

Psallidas I, Corcoran JP, Rahman NM. 2014. Management of parapneumonic effusions and empyema. Semin Respir Crit Care Med, 35 (6), pp. 715-722. | Show Abstract | Read more

Pleural infection remains a common and serious respiratory condition with important implications for patients and health-care services. This review will cover the management of pleural infection including medical treatment, the role of intrapleural agents and surgical treatment. We discuss the directions that future research in this important area might take. Increasing incidence of pleural infection has been reported worldwide without a clear explanation. The pathogens responsible for pleural infection differ from those in pneumonia. Proper antibiotic selection and pleural fluid drainage remain the cornerstones of treatment. There is no evidence in adult pleural infection to support the routine use of intrapleural fibrinolytics to alter clinically meaningful outcomes; however, combined intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) therapy may have a future role. The role of medical thoracoscopy remains unproven. Surgical referral should be considered in patients who fail to respond to standard medical management after 5 to 7 days. Despite advances in microbiology, medical management, and surgery, the mortality of pleural infection at one year remains approximately 20% for the last two decades. Future studies are required to validate predictive scores for patients' stratification (RAPID score) and the role of fibrinolytics (combination of tPA plus DNase). Surgical drainage remains a vital treatment option, but ongoing research is required to define the group of patients who would benefit most and when, in the disease course, this treatment should be offered.

Kahan BC, Cro S, Doré CJ, Bratton DJ, Rehal S, Maskell NA, Rahman N, Jairath V. 2014. Reducing bias in open-label trials where blinded outcome assessment is not feasible: strategies from two randomised trials. Trials, 15 (1), pp. 456. | Show Abstract | Read more

BACKGROUND: Blinded outcome assessment is recommended in open-label trials to reduce bias, however it is not always feasible. It is therefore important to find other means of reducing bias in these scenarios. METHODS: We describe two randomised trials where blinded outcome assessment was not possible, and discuss the strategies used to reduce the possibility of bias. RESULTS: TRIGGER was an open-label cluster randomised trial whose primary outcome was further bleeding. Because of the cluster randomisation, all researchers in a hospital were aware of treatment allocation and so could not perform a blinded assessment. A blinded adjudication committee was also not feasible as it was impossible to compile relevant information to send to the committee in a blinded manner. Therefore, the definition of further bleeding was modified to exclude subjective aspects (such as whether symptoms like vomiting blood were severe enough to indicate the outcome had been met), leaving only objective aspects (the presence versus absence of active bleeding in the upper gastrointestinal tract confirmed by an internal examination).TAPPS was an open-label trial whose primary outcome was whether the patient was referred for a pleural drainage procedure. Allowing a blinded assessor to decide whether to refer the patient for a procedure was not feasible as many clinicians may be reluctant to enrol patients into the trial if they cannot be involved in their care during follow-up. Assessment by an adjudication committee was not possible, as the outcome either occurred or did not. Therefore, the decision pathway for procedure referral was modified. If a chest x-ray indicated that more than a third of the pleural space filled with fluid, the patient could be referred for a procedure; otherwise, the unblinded clinician was required to reach a consensus on referral with a blinded assessor. This process allowed the unblinded clinician to be involved in the patient's care, while reducing the potential for bias. CONCLUSIONS: When blinded outcome assessment is not possible, it may be useful to modify the outcome definition or method of assessment to reduce the risk of bias. TRIAL REGISTRATION TRIGGER: ISRCTN85757829. Registered 26 July 2012.TAPPS: ISRCTN47845793. Registered 28 May 2012.

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Kahan BC, Cro S, Doré CJ, Bratton DJ, Rehal S, Maskell NA, Rahman N, Jairath V. 2014. Reducing bias in open-label trials where blinded outcome assessment is not feasible: Strategies from two randomised trials Trials, 15 (1), | Show Abstract | Read more

© 2014 Kahan et al. Background: Blinded outcome assessment is recommended in open-label trials to reduce bias, however it is not always feasible. It is therefore important to find other means of reducing bias in these scenarios. Methods: We describe two randomised trials where blinded outcome assessment was not possible, and discuss the strategies used to reduce the possibility of bias. Results: TRIGGER was an open-label cluster randomised trial whose primary outcome was further bleeding. Because of the cluster randomisation, all researchers in a hospital were aware of treatment allocation and so could not perform a blinded assessment. A blinded adjudication committee was also not feasible as it was impossible to compile relevant information to send to the committee in a blinded manner. Therefore, the definition of further bleeding was modified to exclude subjective aspects (such as whether symptoms like vomiting blood were severe enough to indicate the outcome had been met), leaving only objective aspects (the presence versus absence of active bleeding in the upper gastrointestinal tract confirmed by an internal examination). Conclusions: When blinded outcome assessment is not possible, it may be useful to modify the outcome definition or method of assessment to reduce the risk of bias. Trial registration: TRIGGER: ISRCTN85757829. Registered 26 July 2012.

Hallifax RJ, Corcoran JP, Rahman NM. 2014. Response. Chest, 146 (5), pp. e179. | Read more

Hallifax RJ, Corcoran JP, Rahman NM. 2014. Response. Chest, 146 (5), pp. e172. | Read more

Bhatnagar R, Laskawiec-Szkonter M, Piotrowska HEG, Kahan BC, Hooper CE, Davies HE, Harvey JE, Miller RF, Rahman NM, Maskell NA. 2014. Evaluating the efficacy of thoracoscopy and talc poudrage versus pleurodesis using talc slurry (TAPPS trial): protocol of an open-label randomised controlled trial. BMJ Open, 4 (11), pp. e007045. | Show Abstract | Read more

INTRODUCTION: The management of recurrent malignant pleural effusions (MPE) can be challenging. Various options are available, with the most efficacious and widely used being talc pleurodesis. Talc can either be applied via a chest drain in the form of slurry, or at medical thoracoscopy using poudrage. Current evidence regarding which method is most effective is conflicting and often methodologically flawed. The TAPPS trial is a suitably powered, multicentre, open-label, randomised controlled trial designed to compare the pleurodesis success rate of medical thoracoscopy and talc poudrage with chest drain insertion and talc slurry. METHODS AND ANALYSIS: 330 patients with a confirmed MPE requiring intervention will be recruited from UK hospitals. Patients will be randomised (1:1) to undergo either small bore (<14 Fr) Seldinger chest drain insertion followed by instillation of sterile talc (4 g), or to undergo medical thoracoscopy and simultaneous poudrage (4 g). The allocated procedure will be performed as an inpatient within 3 days of randomisation taking place. Following discharge, patients will be followed up at regular intervals for 6 months. The primary outcome measure is pleurodesis failure rates at 3 months. Pleurodesis failure is defined as the need for further pleural intervention for fluid management on the side of the trial intervention. ETHICS AND DISSEMINATION: The trial has received ethical approval from the National Research Ethics Service Committee North West-Preston (12/NW/0467). There is a trial steering committee which includes independent members and a patient and public representative. The trial results will be published in a peer-reviewed journal and presented at international conferences, as well as being disseminated via local and national charities and patient groups. All participants who wish to know the study results will also be contacted directly on their publication. TRIAL REGISTRATION NUMBER: ISRCTN47845793.

Corcoran JP, Hallifax RJ, Bettinson HV, Psallidas I, Rahman NM. 2016. Tuberculous pleuritis secondary to Mycobacterium bovis in a veterinarian. Clin Respir J, 10 (4), pp. 500-503. | Show Abstract | Read more

Mycobacterium bovis is a rare cause of tuberculosis in humans, but should be considered in individuals at risk secondary to medical comorbidities (notably immunocompromise) or occupational exposure. Most cases are secondary to reactivation of latent infection in elderly individuals although cases of primary infection still occur, usually involving animal-to-human transmission. Pleural fluid culture in the context of suspected tuberculous pleuritis is frequently negative and pleural biopsy significantly increases the likelihood of confirming the diagnosis histologically and microbiologically. Although thoracoscopic biopsies are the reference standard, closed pleural biopsies are an appropriate and more accessible alternative in the majority of cases - these should be done under direct ultrasound guidance to maximise diagnostic yield. Treatment for M. bovis infection is with prolonged combination anti-tuberculous therapy, using an alternative to pyrazinamide as the organism is inherently resistant to this drug.

Bhatnagar R, Reid ED, Corcoran JP, Bagenal JD, Pope S, Clive AO, Zahan-Evans N, Froeschle PO, West D, Rahman NM et al. 2014. Indwelling pleural catheters for non-malignant effusions: a multicentre review of practice. Thorax, 69 (10), pp. 959-961. | Show Abstract | Read more

Indwelling pleural catheters (IPCs) are commonly used in the management of malignant pleural effusion (MPE). There is little data on their use in non-malignant conditions. All IPC insertions for non-malignant cases from five large UK centres were found using prospectively maintained databases. Data were collected on 57 IPC insertions. The commonest indications were hepatic hydrothorax (33%) and inflammatory pleuritis (26%). The mean weekly fluid output was 2.8 L (SD 2.52). 48/57 (84%) patients had no complications. Suspected pleural infection was documented in 2 (3.5%) cases. 33% (19/57) of patients underwent 'spontaneous' pleurodesis at a median time of 71 days. Patients with hepatic disease achieved pleurodesis significantly less often than those with non-hepatic disease (p=0.03). These data support the use of IPCs in select cases of non-malignant disease when maximal medical therapy has failed.

Psallidas I, Corcoran JP, Hallifax RJ, Rahman NM. 2014. Image of the month: A misleading chest X-ray--not all opacification is effusion. Clin Med (Lond), 14 (5), pp. 556-557. | Read more

Hallifax RJ, Corcoran JP, Ahmed A, Nagendran M, Rostom H, Hassan N, Maruthappu M, Psallidas I, Manuel A, Gleeson FV, Rahman NM. 2014. Physician-based ultrasound-guided biopsy for diagnosing pleural disease. Chest, 146 (4), pp. 1001-1006. | Show Abstract | Read more

BACKGROUND: Definitive diagnosis of pleural disease (particularly malignancy) depends upon histologic proof obtained via pleural biopsy or positive pleural fluid cytology. Image-guided sampling is now standard practice. Local anesthetic thoracoscopy has a high diagnostic yield for malignant and nonmalignant disease, but is not always possible in frail patients, if pleural fluid is heavily loculated, or where the lung is adherent to the chest wall. Such cases can be converted during the same procedure as attempted thoracoscopy to cutting-needle biopsy. This study aimed to determine the diagnostic yield of a physician-led service in both planned biopsies and cases of failed thoracoscopy. METHODS: This study was a retrospective review of all ultrasound-guided, cutting-needle biopsies performed at the Oxford Centre for Respiratory Medicine between January 2010 and July 2013. Histologic results were assessed for the yield of pleural tissue, final diagnosis, and clinical follow-up in nonmalignant cases. RESULTS: Fifty ultrasound-guided biopsies were undertaken. Overall, 47 (94.0%) successfully obtained sufficient tissue for histologic diagnosis. Of the 50 biopsy procedures, 13 were conducted after failed thoracoscopy (5.2% of 252 attempted thoracoscopies over the same time period); of these 13, 11 (84.6%) obtained sufficient tissue. Thirteen of 50 biopsy specimens (26.0%) demonstrated pleural malignancy on histology (despite previous negative pleural fluid cytology), while 34 specimens (68.0%) were diagnosed as benign. Of the benign cases, 10 were pleural TB, two were sarcoidosis, and 22 were benign pleural thickening. There was one "false negative" of mesothelioma (median follow-up, 16 months). CONCLUSIONS: Within this population, physician-based, ultrasound-guided, cutting-needle pleural biopsy obtained pleural tissue successfully in a high proportion of cases, including those of failed thoracoscopy.

Halim MU, Maruthappu M, Christian A, Giles MF, Manuel A, Rahman NM. 2015. The pulmonary embolism severity index: underused despite its clinical merits. J Emerg Med, 48 (5), pp. 609. | Read more

Gunatilake S, Brims FJH, Fogg C, Lawrie I, Maskell N, Forbes K, Rahman N, Morris S, Ogollah R, Gerry S et al. 2014. A multicentre non-blinded randomised controlled trial to assess the impact of regular early specialist symptom control treatment on quality of life in malignant mesothelioma (RESPECT-MESO): study protocol for a randomised controlled trial. Trials, 15 (1), pp. 367. | Show Abstract | Read more

BACKGROUND: Malignant pleural mesothelioma is an incurable cancer caused by exposure to asbestos. The United Kingdom has the highest death rate from mesothelioma in the world and this figure is increasing. Median survival is 8 to 12 months, and most patients have symptoms at diagnosis. The fittest patients may be offered chemotherapy with palliative intent. For patients not fit for systemic anticancer treatment, best supportive care remains the mainstay of management. A study from the United States examining advanced lung cancer showed that early specialist palliative care input improved patient health related quality of life and depression symptoms 12 weeks after diagnosis. While mesothelioma and advanced lung cancer share many symptoms and have a poor prognosis, oncology and palliative care services in the United Kingdom, and many other countries, vary considerably compared to the United States. The aim of this trial is to assess whether regular early symptom control treatment provided by palliative care specialists can improve health related quality of life in patients newly diagnosed with mesothelioma. METHODS: This multicentre study is an non-blinded, randomised controlled, parallel group trial. A total of 174 patients with a new diagnosis of malignant pleural mesothelioma will be minimised with a random element in a 1:1 ratio to receive either 4 weekly regular early specialist symptom control care, or standard care. The primary outcome is health related quality of life for patients at 12 weeks. Secondary outcomes include health related quality of life for patients at 24 weeks, carer health related quality of life at 12 and 24 weeks, patient and carer mood at 12 and 24 weeks, overall survival and analysis of healthcare utilisation and cost. DISCUSSION: Current practice in the United Kingdom is to involve specialist palliative care towards the final weeks or months of a life-limiting illness. This study aims to investigate whether early, regular specialist care input can result in significant health related quality of life gains for patients with mesothelioma and if this change in treatment model is cost-effective. The results will be widely applicable to many institutions and patients both in the United Kingdom and internationally. TRIAL REGISTRATION: Current controlled trials ISRCTN18955704. Date ISRCTN assigned: 31 January 2014.

Corcoran JP, Rahman NM. 2014. Response. Chest, 146 (3), pp. e105-e106. | Read more

Corcoran JP, Rahman NM. 2014. Response. Chest, 146 (2), pp. e71-e72. | Read more

Corcoran JP, Psallidas I, Barker G, Sykes A, Hallifax RJ, Gleeson FV, Rahman NM. 2014. Reexpansion pulmonary edema following local anesthetic thoracoscopy: correlation and evolution of radiographic and ultrasonographic findings. Chest, 146 (2), pp. e34-e37. | Show Abstract | Read more

Local anesthetic (medical) thoracoscopy is used with increasing frequency by pulmonologists worldwide for both diagnostic and therapeutic purposes, notably in comorbid patients who may not be physiologically robust enough for general anesthesia. Understanding the complications that can arise and how to manage them is crucial for any physician performing this procedure. Reexpansion pulmonary edema is a rare but recognized complication of draining pleural effusions and pneumothoraces that has not been described previously in association with physician-led thoracoscopy. This case provides an opportunity for an overview of what is known about this unusual but potentially fatal condition. Data correlating ultrasonographic, radiographic, and clinical progression are also presented to highlight the potential usefulness of ultrasonography in identifying lung parenchymal abnormalities such as extravascular lung water.

Hallifax RJ, Haris M, Corcoran JP, Leyakathalikhan S, Brown E, Srikantharaja D, Manuel A, Gleeson FV, Munavvar M, Rahman NM. 2015. Role of CT in assessing pleural malignancy prior to thoracoscopy. Thorax, 70 (2), pp. 192-193. | Show Abstract | Read more

The definitive diagnosis of pleural malignancy depends upon histological confirmation by pleural biopsy. CT is reported to have a high sensitivity and specificity for the diagnosis of malignant pleural disease, and is part of the routine diagnostic workup of these patients. The aim of this study was to assess the sensitivity and specificity of CT in detecting pleural malignancy prior to definitive histology obtained via thoracoscopy in a large cohort of patients with suspected malignant pleural disease. Retrospective review of thoracoscopies between January 2008 and January 2013 at two UK tertiary referral centres: Oxford and Preston. The histological results were compared with the CT reported diagnosis before the procedure. CT scan reports were assessed by independent respiratory physicians as to whether the radiologist concluded evidence of malignant pleural disease or benign features only. 211 (57%) of 370 patients included in the analysis had malignant disease: CT scans were reported as 'malignant' in 144, giving a sensitivity of 68% (95% CI 62% to 75%). Of the 159 patients with benign disease, 124 had CT scans reported as benign: specificity 78% (72% to 84%). The positive predictive value of a malignant CT report was 80% (75% to 86%), with a negative predictive value of 65% (58% to 72%). A significant proportion of patients being investigated for malignant disease will have malignancy despite a negative CT report. The use of CT alone in determining which patients should have invasive pleural biopsies should be re-evaluated, and further studies to define the diagnostic pathway are now required.

Penz ED, Mishra EK, Davies HE, Manns BJ, Miller RF, Rahman NM. 2014. Comparing cost of indwelling pleural catheter vs talc pleurodesis for malignant pleural effusion. Chest, 146 (4), pp. 991-1000. | Show Abstract | Read more

BACKGROUND: Malignant pleural effusion is associated with short life expectancy and significant morbidity. A randomized controlled trial comparing indwelling pleural catheters (IPCs) with talc pleurodesis found that IPCs reduced in-hospital time and the need for additional procedures but were associated with excess adverse events. METHODS: Using data from the clinical trial, we compared costs associated with use of IPCs and with talc pleurodesis. Resource use and adverse events were captured through case report forms over the 1-year trial follow-up. Costs for outpatient and inpatient visits, diagnostic imaging, nursing, and doctor time were obtained from the UK National Health Service reference costs and University of Kent's Unit Costs of Health and Social Care 2011 and inflated to 2013 using the UK Consumer Price Index. Procedure supply costs were obtained from the manufacturer. Difference in mean costs was compared using nonparametric bootstrapping. All costs were converted to US dollars using the Organisation for Economic Co-operation and Development Purchasing Power Parity Index. RESULTS: Overall mean cost (SD) for managing patients with IPCs and talc pleurodesis was $4,993 ($5,529) and $4,581 ($4,359), respectively. The incremental mean cost difference was $401, with 95% CI of -$1,387 to $2,261. The mean cost related to ongoing drainage in the IPC group was $1,011 ($732) vs $57 ($213) in the talc pleurodesis group (P = .001). This included the cost of drainage bottles, dressing changes in the first month, and catheter removal. There was no significant difference in cost of the initial intervention or adverse events between the groups. For patients with survival < 14 weeks, IPC is significantly less costly than talc pleurodesis, with mean cost difference of -$1,719 (95% CI, -$3,376 to -$85). CONCLUSIONS: There is no significant difference in the mean cost of managing patients with IPCs compared with talc pleurodesis. For patients with limited survival, IPC appears less costly. TRIAL REGISTRY: isrctn.org; No.: ISRCTN87514420; URL: www.isrctn.org.

Rahman NM, Kahan BC, Miller RF, Gleeson FV, Nunn AJ, Maskell NA. 2014. A clinical score (RAPID) to identify those at risk for poor outcome at presentation in patients with pleural infection. Chest, 145 (4), pp. 848-855. | Show Abstract | Read more

BACKGROUND: Pleural infection is associated with a high morbidity and mortality. Development of a validated clinical risk score at presentation to identify those at high risk of dying would enable patient triage and may help formulate early management strategies. METHODS: A clinical risk score was derived based on data from patients entering the multicenter UK pleural infection trial (first Multicenter Intrapleural Sepsis Trial [MIST1], n=411). From 22 baseline clinical characteristics, model selection was undertaken to find variables predictive of poor clinical outcome. Outcomes were mortality at 3 months (primary), need for surgical intervention at 3 months, and time from randomization to discharge. The derived scoring system RAPID (renal, age, purulence, infection source, and dietary factors) was validated using patients enrolled in the subsequent MIST2 trial (n=191). RESULTS: Age, urea, albumin, hospital-acquired infection, and nonpurulence predicted poor outcome. Patients were stratified into low-risk (0-2), medium-risk (3-4), and high-risk (5-7) groups. Using the low-risk group as a reference, a RAPID score of 3 to 4 and >4 was associated with an OR of 24.4 (95% CI, 3.1-186.7; P=.002) and 192.4 (95% CI, 25.0-1480.4; P<.001), respectively, for death at 3 months. In the validation cohort (MIST2), a medium-risk RAPID score was nonsignificantly associated with mortality (OR, 3.2; 95% CI, 0.8-13.2; P=.11), and a high-risk score was associated with increased mortality (OR, 14.1; 95% CI, 3.5-56.8; P<.001). Hospitalization duration was associated with increasing RAPID score (score 0-2: median duration=7, interquartile range 6-13; score>5: median duration=15, interquartile range 9-28, P=.08). CONCLUSIONS: The RAPID score may permit risk stratification of patients with pleural infection at presentation.

Corcoran JP, Rahman NM. 2014. Point: should fibrinolytics be routinely administered intrapleurally for management of a complicated parapneumonic effusion? Yes. Chest, 145 (1), pp. 14-17. | Read more

Corcoran JP, Rahman NM. 2014. Rebuttal from Drs Corcoran and Rahman. Chest, 145 (1), pp. 20-21. | Read more

Talwar A, Hallifax RJ, Corcoran JP, Psallidas I, Rahman NM. 2014. Tips and tricks in the management of pneumothorax: A review Minerva Pneumologica, 53 (4), pp. 155-165. | Show Abstract

Pneumothorax is defined as air within the pleural cavity. Tuberculosis was the predominant cause in the 19<sup>th</sup> century, but there are now an established number of aetiological causes of pneumothorax. Primary spontaneous pneumothorax (PSP) and secondary spontaneous pneumothorax (SSP) should be thought of as distinct entities with varied treatment and prognosis. Pneumothoraces are often diagnosed on clinical history and confirmed 'with a chest radiograph. With more advanced radiological techniques, these have complemented the understanding and management of more complex cases. In terms of management, high quality evidence supporting the basis of clinical decisions is very limited. Treatment varies widely even at a local level and is often based on best practice and expert opinion. In this review, we present and discuss the epidemiology, pathophysiology, clinical presentation, imaging techniques, and management (both conservative and interventional) of pneumothorax. Some brief tips will be given for management of pneumothorax in pregnancy and cystic fibrosis.

Castle L, Sykes A, Rahman NM, Belcher E, Black E, Breen D, Moore A. 2014. Is MediastINOScopy A Necessity After Ebus-Tbna Staging In Patients With Non-Small Cell Lung Cancer AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 189

Hallifax RJ, Corcoran JP, Rahman NM. 2014. Post-Thoracoscopy Lung Re-Expansion: Pilot Data Using Digital Suction Device AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 189

Hallifax RJ, Corcoran JP, Rahman NM. 2014. Predicting Pneumothorax Outcome By Air Leak Measurement: Pilot Using Digital Suction Device AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 189

Hallifax RJ, Corcoran JP, Rahman NM. 2013. POST-THORACOSCOPY LUNG RE-EXPANSION: PILOT DATA USING DIGITAL SUCTION DEVICE THORAX, 68 (Suppl 3), pp. A43-A43. | Read more

Hallifax RJ, Corcoran JP, Rahman NM. 2013. PREDICTING PNEUMOTHORAX OUTCOME BY AIR LEAK MEASUREMENT: PILOT USING DIGITAL SUCTION DEVICE THORAX, 68 (Suppl 3), pp. A174-A175. | Read more

Hallifax RJ, Corcoran J, Shah KA, Rahman NM. 2013. Ameloblastoma: unusual cause of chest wall mass and effusion. BMJ case reports, 2013

Corcoran JP, Hallifax R, Rahman NM. 2013. Advances in the management of pleural disease. Expert Rev Respir Med, 7 (5), pp. 499-513. | Show Abstract | Read more

Pleural disease affects over 3000 people per million population annually. Consequently, it represents a significant proportion of the respiratory physician's workload and can present to clinicians of all backgrounds in primary and secondary care. Pleural effusions have been reported in association with over 50 different conditions; some related to specific pulmonary pathologies, but many being manifestations of multisystem disease. The burden that conditions such as pleural infection; malignant pleural disease; and pneumothorax impose on patients and health care systems is enormous and growing. As such, a clear understanding of these key conditions is crucial to any physician regardless of the specialty. This article addresses a number of areas relating to pleural disease, providing an overview of the diagnostic and therapeutic advances that have been made in our understanding of pleural pathology in recent years. The directions that future research in this important area of respiratory medicine might take will also be discussed.

Hallifax RJ, Corcoran J, Shah KA, Rahman NM. 2013. Ameloblastoma: unusual cause of chest wall mass and effusion. BMJ Case Rep, 2013 (sep25 1), pp. bcr2013200971-bcr2013200971. | Read more

Hallifax RJ, Corcoran JP, Rostom H, Hassan NM, Nagendran M, Manuel A, Rahman NM. 2013. Ultrasound-guided cutting-needle biopsy for diagnosing pleural disease: Experience in Oxford EUROPEAN RESPIRATORY JOURNAL, 42

Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, Mandal S, Martin J, Mills J, Navani N et al. 2013. British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE. Thorax, 68 Suppl 1 (Suppl 1), pp. i1-i44. | Show Abstract | Read more

Monitoring, precautions and complications All patients undergoing bronchoscopy should have heart rate, respiratory rate, blood pressure and oxygen saturation recorded repeatedly, including before, during and after the procedure. (Grade D) . All bronchoscopy units should undertake periodic audit of bronchoscopic performance, including efficacy, complications and patient satisfaction surveys. (Good practice point . All Trusts should have a 'safe sedation policy', and ensure all bronchoscopy unit staff, including trainees, receive appropriate training.

Hew M, Rahman N. 2013. Preventing intercostal vessel trauma: ultrasound to the rescue once more? Respirology, 18 (6), pp. 891-892. | Read more

Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, Mandal S, Martin J, Mills J, Navani N et al. 2013. Summary of the British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults. Thorax, 68 (8), pp. 786-787. | Show Abstract | Read more

Flexible bronchoscopy is an essential, established and expanding tool in respiratory medicine. Its practice, however, needs to be safe, effective and for the right indications to maximise clinical utility. This guideline is based on the best available evidence and is a revised update of the British Thoracic Society guideline on diagnostic flexible bronchoscopy.

Fysh ETH, Tremblay A, Feller-Kopman D, Mishra EK, Slade M, Garske L, Clive AO, Lamb C, Boshuizen R, Ng BJ et al. 2013. Clinical outcomes of indwelling pleural catheter-related pleural infections: an international multicenter study. Chest, 144 (5), pp. 1597-1602. | Show Abstract | Read more

BACKGROUND: Indwelling pleural catheters (IPCs) offer effective control of malignant pleural effusions (MPEs). IPC-related infection is uncommon but remains a major concern. Individual IPC centers see few infections, and previous reports lack sufficient numbers and detail. This study combined the experience of 11 centers from North America, Europe, and Australia to describe the incidence, microbiology, management, and clinical outcomes of IPC-related pleural infection. METHODS: This was a multicenter retrospective review of 1,021 patients with IPCs. All had confirmed MPE. RESULTS: Only 50 patients (4.9%) developed an IPC-related pleural infection; most (94%) were successfully controlled with antibiotics (62% IV). One death (2%) directly resulted from the infection, whereas two patients (4%) had ongoing infectious symptoms when they died of cancer progression. Staphylococcus aureus was the causative organism in 48% of cases. Infections from gram-negative organisms were associated with an increased need for continuous antibiotics or death (60% vs 15% in gram-positive and 25% mixed infections, P = .02). The infections in the majority (54%) of cases were managed successfully without removing the IPC. Postinfection pleurodesis developed in 31 patients (62%), especially those infected with staphylococci (79% vs 45% with nonstaphylococcal infections, P = .04). CONCLUSIONS: The incidence of IPC-related pleural infection was low. The overall mortality risk from pleural infection in patients treated with IPC was only 0.29%. Antibiotics should cover S aureus and gram-negative organisms until microbiology is confirmed. Postinfection pleurodesis is common and often allows removal of IPC. Heterogeneity in management is common, and future studies to define the optimal treatment strategies are needed.

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.

Helm EJ, Rahman NM, Talakoub O, Fox DL, Gleeson FV. 2013. Course and variation of the intercostal artery by CT scan. Chest, 143 (3), pp. 634-639. | Show Abstract | Read more

BACKGROUND: It is conventionally taught that the intercostal artery is shielded in the intercostal groove of the superior rib. The continuous course and variability of the intercostal artery, and factors that may influence them, have not been described in a large number of arteries in vivo. METHODS: Maximal intensity projection reformats in the coronal plane were produced from CT scan pulmonary angiograms to identify the posterolateral course of the intercostal artery (seventh to 11th rib spaces). A novel semiautomated computer segmentation algorithm was used to measure distances between the lower border of the superior rib, the upper border of the inferior rib, and the position of the intercostal artery when exposed in the intercostal space. The position and variability of the artery were analyzed for association with clinical factors. RESULTS: Two hundred ninety-eight arteries from 47 patients were analyzed. The mean lateral distance from the spine over which the artery was exposed within the intercostal space was 39 mm, with wide variability (SD, 10 mm; 10th-90th centile, 28-51 mm). At 3 cm lateral distance from the spine, 17% of arteries were shielded by the superior rib, compared with 97% at 6 cm. Exposed artery length was not associated with age, sex, rib space, or side. The variability of arterial position was significantly associated with age (coefficient, 0.91; P < .001) and rib space number (coefficient, - 2.60; P < .001). CONCLUSIONS: The intercostal artery is exposed within the intercostal space in the first 6 cm lateral to the spine. The variability of its vertical position is greater in older patients and in more cephalad rib spaces.

Corcoran JP, Hallifax R, Rahman NM. 2013. New therapeutic approaches to pleural infection. Curr Opin Infect Dis, 26 (2), pp. 196-202. | Show Abstract | Read more

PURPOSE OF REVIEW: Pleural infection is a common and serious clinical problem that because of its high morbidity and mortality imposes a significant burden on clinicians, healthcare resources and patients of all ages. Defining the optimal management strategy for pleural infection remains a cause for research and debate. This review considers the areas of interest including bacteriology and antibiotic selection, intrapleural fibrinolytics and the role of surgery. RECENT FINDINGS: Pleural infection is increasing in the adult and paediatric populations without clear explanation and with clinical and financial consequences. The bacteriology of pleural infection is recognized as being unique from parenchymal lung infection with implications for its treatment. Although established in paediatric management, intrapleural fibrinolytics remain of uncertain benefit in adults, though the novel combination of tissue plasminogen activator and deoxyribonuclease used in the MIST2 study offers cause for optimism. Surgery remains a key intervention in pleural infection, but its precise role is unclear with no robust evidence to show when and in whom it should be optimally utilized. SUMMARY: The high mortality in adults from pleural infection despite advances in clinical knowledge, diagnostics and therapeutics highlights the need for ongoing research. Future studies are required to focus on improving the clinical outcomes, with the identification of those patients at greatest risk of poor outcomes at presentation and most likely to benefit from more radical treatment a priority to allow the delivery of individualized care.

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

Penz ED, Mishra EK, Davies HE, Manns BJ, Miller RF, Kahan BC, Rahman NM. 2013. Comparing The Cost Of Talc Pleurodesis Vs. Indwelling Pleural Catheter For Malignant Pleural Effusions: A Detailed Cost Analysis Done Alongside A Randomized Clinical Trial AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 187

Mishra EK, Corcoran J, Hallifax R, Rahman NM. 2013. Minimal Important Difference For The Visual Analogue Scale For Dyspnoea AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 187

Komissarov AA, Florova G, Schaefer C, Rahman NM, Lee YCG, Idell S. 2013. Pleural Fluids Collected During The Second Multicenter Intrapleural Sepsis Trial (mist2) Demonstrate Highly Variable Fibrinolytic Potential Prior To The Treatment And Endogenous Fibrinolytic Activity Depletion During Intrapleural Fibrinolytic Therapy AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 187

Wrightson JM, Bateman KM, Hooper C, Gleeson FV, Rahman NM, Maskell NA. 2012. Development and efficacy of a 1-d thoracic ultrasound training course. Chest, 142 (5), pp. 1359-1361. | Read more

Fysh ETH, Wrightson JM, Lee YCG, Rahman NM. 2012. Complications of Removal of Indwelling Pleural Catheters: Response Chest, 142 (4), pp. 1071-1072. | Read more

Fysh ETH, Wrightson JM, Lee YCG, Rahman NM. 2012. Complications of Removal of Indwelling Pleural Catheters Response CHEST, 142 (4), pp. 1071-1072. | Read more

Davies HE, Mishra EK, Kahan BC, Wrightson JM, Stanton AE, Guhan A, Davies CWH, Grayez J, Harrison R, Prasad A et al. 2012. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA, 307 (22), pp. 2383-2389. | Show Abstract | Read more

CONTEXT: Malignant pleural effusion causes disabling dyspnea in patients with a short life expectancy. Palliation is achieved by fluid drainage, but the most effective first-line method has not been determined. OBJECTIVE: To determine whether indwelling pleural catheters (IPCs) are more effective than chest tube and talc slurry pleurodesis (talc) at relieving dyspnea. DESIGN: Unblinded randomized controlled trial (Second Therapeutic Intervention in Malignant Effusion Trial [TIME2]) comparing IPC and talc (1:1) for which 106 patients with malignant pleural effusion who had not previously undergone pleurodesis were recruited from 143 patients who were treated at 7 UK hospitals. Patients were screened from April 2007-February 2011 and were followed up for a year. INTERVENTION: Indwelling pleural catheters were inserted on an outpatient basis, followed by initial large volume drainage, education, and subsequent home drainage. The talc group were admitted for chest tube insertion and talc for slurry pleurodesis. MAIN OUTCOME MEASURE: Patients completed daily 100-mm line visual analog scale (VAS) of dyspnea over 42 days after undergoing the intervention (0 mm represents no dyspnea and 100 mm represents maximum dyspnea; 10 mm represents minimum clinically significant difference). Mean difference was analyzed using a mixed-effects linear regression model adjusted for minimization variables. RESULTS: Dyspnea improved in both groups, with no significant difference in the first 42 days with a mean VAS dyspnea score of 24.7 in the IPC group (95% CI, 19.3-30.1 mm) and 24.4 mm (95% CI, 19.4-29.4 mm) in the talc group, with a difference of 0.16 mm (95% CI, −6.82 to 7.15; P = .96). There was a statistically significant improvement in dyspnea in the IPC group at 6 months, with a mean difference in VAS score between the IPC group and the talc group of −14.0 mm (95% CI, −25.2 to −2.8 mm; P = .01). Length of initial hospitalization was significantly shorter in the IPC group with a median of 0 days (interquartile range [IQR], 0-1 day) and 4 days (IQR, 2-6 days) for the talc group, with a difference of −3.5 days (95% CI, −4.8 to −1.5 days; P < .001). There was no significant difference in quality of life. Twelve patients (22%) in the talc group required further pleural procedures compared with 3 (6%) in the IPC group (odds ratio [OR], 0.21; 95% CI, 0.04-0.86; P = .03). Twenty-one of the 52 patients in the catheter group experienced adverse events vs 7 of 54 in the talc group (OR, 4.70; 95% CI, 1.75-12.60; P = .002). CONCLUSION: Among patients with malignant pleural effusion and no previous pleurodesis, there was no significant difference between IPCs and talc pleurodesis at relieving patient-reported dyspnea. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN87514420.

Rahman NM. 2012. Intrapleural agents for pleural infection: fibrinolytics and beyond. Curr Opin Pulm Med, 18 (4), pp. 326-332. | Show Abstract | Read more

PURPOSE OF REVIEW: Pleural infection is a common, increasing clinical problem with a high morbidity and mortality. Medical management of pleural infection often fails, requiring invasive thoracic surgery to drain infected pleural collections, and for many years intrapleural agents have been assessed to reduce the need for surgical drainage and improve clinical outcomes. Randomized trials assessing intrapleural fibrinolytic agents have given conflicting results, and recent evidence provides important information on the role of intrapleural agents in the treatment of pleural infection, and the possible biology associated with infection progression in these patients. RECENT FINDINGS: Pleural infection is increasing in both the adult and paediatric populations. The combined previous evidence assessing intrapleural fibrinolytics alone in pleural infection suggests lack of efficacy for clinically important outcomes. The Multi-Centre Intrapleural Sepsis Trial 2 (MIST2) study provides the first evidence of a novel treatment combination [intrapleural tissue plasminogen activator (tPA) combined with intrapleural deoxyribonuclease (DNase)], which significantly improves the chest radiograph compared with either agent alone or placebo, and has potentially important benefits to important clinical outcomes (need for surgery and hospital stay). The precise mechanism of action of combination fibrinolytic and DNase in pleural infection is speculative. SUMMARY: Fibrinolytic therapy alone has not been proven to be of use in the treatment of pleural infection. The MIST2 study provides clear-cut evidence demonstrating improved chest radiographs, and highly suggestive secondary outcomes suggesting improved clinically important outcomes, using a combination of intrapleural tPA and DNase. This novel treatment combination may represent an important step in our understanding and treatment of pleural infection; however, larger clinical studies specifically addressing important clinical outcomes and further laboratory research describing the potential mechanisms of action are now required.

Fysh ETH, Wrightson JM, Lee YCG, Rahman NM. 2012. Fractured indwelling pleural catheters. Chest, 141 (4), pp. 1090-1094. | Show Abstract | Read more

Indwelling pleural catheters (IPCs) are increasingly used in the management of malignant pleural effusions. IPCs are designed to be secured in situ indefinitely; however, in selected patients, IPCs can be removed when drainage ceases. This case series reports complications of removal of IPCs that resulted in fractured catheters or necessitated deliberate severing of the catheters. From the combined data of two pleural centers, 61 of 170 IPCs inserted (35.9%) were removed. In six cases (9.8%), the removals were complicated, leading to fracture or iatrogenic severing of the IPC. Although four patients had catheter fragments retained within the pleural space, none developed any complications (eg, pain or infection) (median follow-up, 459 days; range, 113-1,119 days), despite two patients undergoing subsequent chemotherapy. Clinicians should be aware that IPC removal can be problematic, but retained fragments are safe, and aggressive retrieval is unnecessary.

Bhatnagar R, Rahman NM. 2012. The palliation of malignant pleural effusions. Br J Hosp Med (Lond), 73 (1), pp. 4-5. | Read more

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.

Rahman NM, Gleeson FV. 2011. Lung, pleura and chest wall 2 pp. 1005-1021. | Read more

Rahman NM, Maskell NA, Nunn AJ. 2011. Tissue Plasminogen Activator and DNase in Empyema REPLY NEW ENGLAND JOURNAL OF MEDICINE, 365 (20), pp. 1936-1937. | Read more

Bachmayer K. 2011. Tissue plasminogen activator and DNase in empyema. N Engl J Med, 365 (20), pp. 1936. | Read more

Franklin JM, Rahman N, Gleeson FV. 2011. The clinician's response to a report of an incidental pulmonary embolism detected on multidetector CT. Postgrad Med J, 87 (1033), pp. 746-749. | Show Abstract | Read more

BACKGROUND: The prevalence of incidental pulmonary emboli (PE) detected on contrast enhanced CT performed for other reasons is approximately 2.5%. The treatment decisions based upon the discovery of incidental PE have been less well reported. The purpose of this study was to report the clinician's response to, and consequences of, the finding of incidental PE on contrast enhanced CT. METHODS: Retrospective cohort study. Patients with incidental PE detected on a contrast enhanced CT were retrospectively identified at a single institution between 1 January 2009 and 31 December 2009. Case note review was performed to assess clinicians' responses to this finding. Patients with synchronous venous thromboembolism, unrecognised symptoms or factors preventing response assessment were excluded from this analysis. Patient and PE characteristics, treatment, and outcomes related to treatment and non-treatment were recorded. RESULTS: There were 73 patients with incidental PE: 52 were in the proximal pulmonary arteries and 21 were distal. 16 patients were excluded from the treatment analysis. 52 of 57 (91.2%) patients were treated with therapeutic anticoagulation. There were 2 (3.8%) serious adverse events related to treatment. 5 (8.8%) patients were not treated; 2 (40%) developed recurrent venous thromboembolism. Treatment of incidental PE was not significantly associated with patient age, PE risk factors or PE location. A smaller proportion of single incidental PE were treated than multiple incidental PE (p=0.047). CONCLUSION: There is morbidity associated with both treatment and non-treatment of incidental PE. However, despite the uncertainty about the natural history and clinical significance of incidental PE, the majority of patients at the authors' institution received prompt anticoagulation.

Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CWH, Ali N, Kinnear W et al. 2011. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med, 365 (6), pp. 518-526. | Show Abstract | Read more

BACKGROUND: More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial. METHODS: We conducted a blinded, 2-by-2 factorial trial in which 210 patients with pleural infection were randomly assigned to receive one of four study treatments for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events. RESULTS: The mean (±SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (-29.5±23.3% vs. -17.2±19.6%; difference, -7.9%; 95% confidence interval [CI], -13.4 to -2.4; P=0.005); the change observed with t-PA alone and with DNase alone (-17.2±24.3 and -14.7±16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P=0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P=0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P=0.006); the hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups. CONCLUSIONS: Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective. (Funded by an unrestricted educational grant to the University of Oxford from Roche UK and by others; Current Controlled Trials number, ISRCTN57454527.).

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Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CWH, Ali N, Kinnear W et al. 2011. Intrapleural use of tissue plasminogen activator and DNase in pleural infection New England Journal of Medicine, 365 (6), pp. 518-526. | Show Abstract | Read more

BACKGROUND: More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial. METHODS: We conducted a blinded, 2-by-2 factorial trial in which 210 patients with pleural infection were randomly assigned to receive one of four study treatments for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events. RESULTS: The mean (±SD) change in pleural opacity was greater in the t-PA-DNase group thanin the placebo group (-29.5±23.3% vs. -17.2±19.6%; difference, -7.9%; 95% confidenceinterval [CI], -13.4 to -2.4; P = 0.005); the change observed with t-PA alone and with DNase alone (-17.2±24.3 and -14.7±16.4%, respectively) was not significantly differentfrom that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P = 0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P = 0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P = 0.006); the hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups. CONCLUSIONS: Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective. (Funded by an unrestricted educational grant to the University of Oxford from Roche UK and by others; Current Controlled Trials number, ISRCTN57454527.) Copyright © 2011 Massachusetts Medical Society.

Rahman NM, Maskell NA. 2011. Pleural infection on the increase but with a better evidence base to inform clinical care. Thorax, 66 (8), pp. 649-650. | Read more

Menzies SM, Rahman NM, Wrightson JM, Davies HE, Shorten R, Gillespie SH, Davies CWH, Maskell NA, Jeffrey AA, Lee YCG, Davies RJO. 2011. Blood culture bottle culture of pleural fluid in pleural infection. Thorax, 66 (8), pp. 658-662. | Show Abstract | Read more

BACKGROUND: Pleural infection is common, and has a >30% major morbidity and mortality-particularly when infection is caused by Gram-negative, Staphylococcus aureus or mixed aerobic pathogens. Standard pleural fluid culture is negative in ∼40% of cases. Culturing pleural fluid in blood culture bottles may increase microbial yield, and is cheap and easy to perform. OBJECTIVES: To determine whether inoculating pleural fluid into blood culture bottles increases the culture positivity of pleural infection over standard laboratory culture, and to assess the optimum volume of inoculum to introduce. METHODS: 62 patients with pleural infection were enrolled. Pairs of aerobic and anaerobic blood culture bottles were inoculated at the bedside with 2, 5 or 10 ml of pleural fluid, and two pleural fluid specimens were sent for standard culture. Pleural fluid from nine control patients was cultured to test for 'false-positive' results. RESULTS: The addition of blood culture bottle culture to standard culture increased the proportion of patients with identifiable pathogens by 20.8% (20/53 (37.7%) to 31/53 (58.5%) (difference 20.8%, 95% CI difference 8.9% to 20.8%, p<0.001)). The second standard culture did not similarly improve the culture positivity (19/49 (38.8%) to 22/49 (44.9%) (difference 6.1%, 95% CI difference -2.5% to 6.1%, p=0.08)). The culture inoculum volume did not influence bacterial isolation frequency. The control fluids were culture negative. CONCLUSIONS: Blood culture bottle culture of infected pleural fluid increases microbial yield when used in addition to standard culture. This technique should be part of routine care.

Slade MG, Rahman NM, Stanton AE, Curry L, Slade GC, Clelland CA, Gleeson FV. 2011. Improving standards in flexible bronchoscopy for lung cancer. Eur Respir J, 37 (4), pp. 895-901. | Show Abstract | Read more

Can the detection rate of flexible bronchoscopy for lung cancer be increased by a series of simple quality improvement measures? Bronchoscopy-associated clinical parameters were prospectively recorded between 2001 and 2007 in patients with suspected lung malignancy. The detection rate of bronchoscopy, diagnostic yield of each biopsy modality and the possible impact of different service-improvement measures were assessed. 746 bronchoscopies were performed in 704 patients. The detection rate of bronchoscopy for malignancy was 83.6%, and increased over time (67.3% detection rate in 2001 (95% CI 52.9-79.7), 89.7% detection rate in 2007 (95% CI 81.3-95.2); p<0.001). Detection rate increased for bronchoscopically visible (75.0% in 2001 to 94.5% in 2007) and non-visible tumours (41.7% in 2001 to 81.2% in 2007; p<0.001 for both analyses). Prior computed tomography availability was associated with a higher diagnostic yield that did not reach statistical significance. Logistic regression analysis identified tumour visibility, year of study, use of transbronchial needle aspiration and pathologist identity as independent predictors of a positive diagnosis. A significant increase in bronchoscopic detection rate for malignancy occurred in association with a number of simple improvement measures.

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Morel A, Mishra E, Medley L, Rahman NM, Wrightson J, Talbot D, Davies RJO. 2011. Chemotherapy should not be withheld from patients with an indwelling pleural catheter for malignant pleural effusion Thorax, 66 (5), pp. 448-449. | Read more

Rahman NM, Maskell NA. 2011. Pleural infection on the increase but with a better evidence base to inform clinical care Thorax, 66 (8), pp. 649-650. | Read more

Cited:

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Menzies SM, Rahman NM, Wrightson JM, Davies HE, Shorten R, Gillespie SH, Davies CWH, Maskell NA, Jeffrey AA, Lee YCG, Davies RJO. 2011. Blood culture bottle culture of pleural fluid in pleural infection Thorax, 66 (8), pp. 658-662. | Show Abstract | Read more

Background: Pleural infection is common, and has a >30% major morbidity and mortality - particularly when infection is caused by Gram-negative, Staphylococcus aureus or mixed aerobic pathogens. Standard pleural fluid culture is negative in ∼40% of cases. Culturing pleural fluid in blood culture bottles may increase microbial yield, and is cheap and easy to perform. Objectives: To determine whether inoculating pleural fluid into blood culture bottles increases the culture positivity of pleural infection over standard laboratory culture, and to assess the optimum volume of inoculum to introduce. Methods: 62 patients with pleural infection were enrolled. Pairs of aerobic and anaerobic blood culture bottles were inoculated at the bedside with 2, 5 or 10 ml of pleural fluid, and two pleural fluid specimens were sent for standard culture. Pleural fluid from nine control patients was cultured to test for 'false-positive' results. Results: The addition of blood culture bottle culture to standard culture increased the proportion of patients with identifiable pathogens by 20.8% (20/53 (37.7%) to 31/53 (58.5%) (difference 20.8%, 95% CI difference 8.9% to 20.8%, p<0.001)). The second standard culture did not similarly improve the culture positivity (19/49 (38.8%) to 22/49 (44.9%) (difference 6.1%, 95% CI difference -2.5% to 6.1%, p=0.08)). The culture inoculum volume did not influence bacterial isolation frequency. The control fluids were culture negative. Conclusions: Blood culture bottle culture of infected pleural fluid increases microbial yield when used in addition to standard culture. This technique should be part of routine care.

Rahman NM, Dobson M, Davies RJO. 2011. Setting up a respiratory trials unit. Respirology, 16 (1), pp. 64-68. | Show Abstract | Read more

Clinical trials are essential in advancing our knowledge and treatment of patients with respiratory disease. Conducting well-designed clinical studies which accurately and reliably answer important clinical questions is challenging. The expertise required to deliver such studies is increasingly concentrated in clinical trials units. This article will describe some of the challenges associated with clinical studies and the methods and personnel involved in a clinical trials unit.

Sharp Collaborative Group. 2010. Study of Heart and Renal Protection (SHARP): randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease. Am Heart J, 160 (5), pp. 785-794.e10. | Show Abstract | Read more

BACKGROUND: Lowering low-density lipoprotein (LDL) cholesterol with statin therapy has been shown to reduce the incidence of atherosclerotic events in many types of patient, but it remains uncertain whether it is of net benefit among people with chronic kidney disease (CKD). METHODS: Patients with advanced CKD (blood creatinine ≥ 1.7 mg/dL [≥ 150 μmol/L] in men or ≥ 1.5 mg/dL [ ≥ 130 μmol/L] in women) with no known history of myocardial infarction or coronary revascularization were randomized in a ratio of 4:4:1 to ezetimibe 10 mg plus simvastatin 20 mg daily versus matching placebo versus simvastatin 20 mg daily (with the latter arm rerandomized at 1 year to ezetimibe 10 mg plus simvastatin 20 mg daily vs placebo). The key outcome will be major atherosclerotic events, defined as the combination of myocardial infarction, coronary death, ischemic stroke, or any revascularization procedure. RESULTS: A total of 9,438 CKD patients were randomized, of whom 3,056 were on dialysis. Mean age was 61 years, two thirds were male, one fifth had diabetes mellitus, and one sixth had vascular disease. Compared with either placebo or simvastatin alone, allocation to ezetimibe plus simvastatin was not associated with any excess of myopathy, hepatic toxicity, or biliary complications during the first year of follow-up. Compared with placebo, allocation to ezetimibe 10 mg plus simvastatin 20 mg daily yielded average LDL cholesterol differences of 43 mg/dL (1.10 mmol/L) at 1 year and 33 mg/dL (0.85 mmol/L) at 2.5 years. Follow-up is scheduled to continue until August 2010, when all patients will have been followed for at least 4 years. CONCLUSIONS: SHARP should provide evidence about the efficacy and safety of lowering LDL cholesterol with the combination of ezetimibe and simvastatin among a wide range of patients with CKD.

Rahman NM, Davies RJO. 2010. Relearning an old lesson: stopping trials early. Thorax, 65 (10), pp. 851-853. | Read more

Morel A, Mishra E, Medley L, Rahman NM, Wrightson J, Talbot D, Davies RJO. 2011. Chemotherapy should not be withheld from patients with an indwelling pleural catheter for malignant pleural effusion. Thorax, 66 (5), pp. 448-449. | Read more

Rahman NM, Davies RJO. 2010. Occlusion and Malposition of Small-Bore Chest Tubes for Pleural Infection Response CHEST, 138 (3), pp. 760-761. | Read more

Wrightson JM, Rahman NM, Novak T, Huggett JF, Maskell NA, Zumla A, Miller RF, Davies RJO. 2011. Pneumocystis jirovecii in pleural infection: a nucleic acid amplification study. Thorax, 66 (5), pp. 450-451. | Read more

Rahman NM, Ali NJ, Brown G, Chapman SJ, Davies RJO, Downer NJ, Gleeson FV, Howes TQ, Treasure T, Singh S et al. 2010. Local anaesthetic thoracoscopy: British Thoracic Society Pleural Disease Guideline 2010. Thorax, 65 Suppl 2 (Suppl 2), pp. ii54-ii60. | Read more

Rahman NM, Singanayagam A, Davies HE, Wrightson JM, Mishra EK, Lee YCG, Benamore R, Davies RJO, Gleeson FV. 2010. Diagnostic accuracy, safety and utilisation of respiratory physician-delivered thoracic ultrasound. Thorax, 65 (5), pp. 449-453. | Show Abstract | Read more

BACKGROUND Thoracic ultrasound-guided pleural procedures are associated with fewer adverse events than 'blind' procedures for patients with pleural effusion. Ultrasound is increasingly practised by respiratory physicians but there has been no prospective assessment of its safety and diagnostic accuracy when delivered by respiratory physicians. METHODS The activity level, safety and diagnostic accuracy of thoracic ultrasound delivered by respiratory physicians were prospectively assessed. Diagnostic accuracy was assessed using a stepwise pragmatic approach (recording if pleural fluid was obtained or effusion was present on another radiological modality). In the absence of the above, ultrasound clips were reviewed by a blinded radiologist. The number of ultrasounds referred to radiologists and adverse events within 1 week were recorded. The complication rate was compared with the published literature. RESULTS 960 ultrasound scans occurred over a 3 year period. The activity of the service increased over time, as a result of increased use of interventional ultrasound. The referral rate to radiology remained constant over the study period (mean proportion 4.0%). Physician-delivered ultrasound correctly identified the presence/absence of pleural fluid in 951 of 955 evaluable scans (99.6% CI 98.9% to 99.9%). The major complication rate was 3/558=0.5% (95% CI 0.1% to 1.6%), which compared favourably with the identified published literature. CONCLUSION Respiratory physician-delivered thoracic ultrasound appears to be safe and effective in the diagnosis/intervention of pleural effusion, and is associated with a major complication rate comparable with that of published studies. Continued liaison with the radiology service has here been demonstrated as a requirement for a physician-based service.

Rahman N, Hitchcock R. 2010. Case report of paediatric oxalate urolithiasis and a review of enteric hyperoxaluria. J Pediatr Urol, 6 (2), pp. 112-116. | Show Abstract | Read more

The formation of renal calculi secondary to enteric hyperoxaluria is rare in the paediatric population. We present the case of an 8-year-old boy who had short bowel syndrome resulting in enteric hyperoxaluria which led to the development of urolithiasis and bilateral ureteric strictures, both of which resolved with medical management. We also review the literature on enteric hyperoxaluria.

Davies HE, Nicholson JE, Rahman NM, Wilkinson EM, Davies RJO, Lee YCG. 2010. Outcome of patients with nonspecific pleuritis/fibrosis on thoracoscopic pleural biopsies. Eur J Cardiothorac Surg, 38 (4), pp. 472-477. | Show Abstract | Read more

OBJECTIVE: Medical thoracoscopy is recommended in the investigation of patients with exudative pleural effusions, especially when pleural fluid analysis is uninformative. The histological finding of 'nonspecific pleuritis/fibrosis' is common in thoracoscopic biopsies and presents a great uncertainty for clinicians and patients as the long-term outcome of these patients is unclear, and anxieties about undiagnosed malignancy persist. METHOD: A retrospective case-note study of 142 patients who underwent medical thoracoscopy over a 58-month period in a tertiary referral centre with a high incidence of mesothelioma. Patients with 'nonspecific pleuritis/fibrosis' were followed up until death or for a mean (±SD) period of 21.3 (±12.0) months. RESULTS: A definitive histological diagnosis was achieved in 98 (69%) patients. A total of 44 (31%) patients had 'nonspecific pleuritis/fibrosis'. Five (12%) were subsequently diagnosed with malignant pleural disease after a mean interval of 9.8 (±4.6) months. All five patients had histologically confirmed mesothelioma. In 26 patients with 'nonspecific pleuritis/fibrosis', no cause for the pleural effusion was discovered. The false-negative rate of thoracoscopic biopsy for the detection of pleural malignancy was 5%, with a diagnostic sensitivity of 95% and negative predictive value of 90%. Pleural effusion recurrence was more frequently associated with a false-negative pleural biopsy result. However, there was no correlation with other patient characteristics or the thoracoscopist's prediction based on macroscopic appearances. CONCLUSION: Thoracoscopic pleural biopsy is valuable in the diagnosis of pleural malignancies. Patients with 'nonspecific pleuritis/fibrosis' require follow-up as a malignant diagnosis (especially mesothelioma) may eventually be established in approximately 12% of cases.

Rahman N, Chouhan J, Gould S, Joseph V, Grant H, Hitchcock R, Johnson P, Lakhoo K. 2010. Rectal biopsy for Hirschsprung's disease--are we performing too many? Eur J Pediatr Surg, 20 (2), pp. 95-97. | Show Abstract | Read more

BACKGROUND: Rectal biopsy is considered the gold standard for the diagnosis of Hirschsprung's disease. The aim of this study was to evaluate the outcome of rectal biopsies performed in our institution, and to determine whether we are performing an adequate number of biopsies in patients presenting with features suggestive of this disease. METHODS: A retrospective analysis was conducted of patients who underwent rectal biopsy to exclude Hirschsprung's disease over a seven year period between 2000 and 2006. The histological diagnosis of Hirschsprung's disease was made using haematoxylin and eosin as well as acetylcholinesterase on frozen section. Patients were grouped into three age categories: neonates (group A), infants (group B) and those over 1 year of age (group C). The results of the biopsies were compared between groups. RESULTS: A total of 668 patients underwent rectal biopsy. 18 samples were insufficient. Based on the histological studies of 650 suitable samples, 73 (11%) were positive and 577 (89%) were negative for Hirschsprung's disease. Of the 73 positive biopsies, 34 (47%) were from group A, 20 (27%) from group B and 19 (26%) from group C. The percentage of positive biopsies was much higher in group A with 29% (34 out of 118) compared to group B with 15% (20 out of 135) and group C with 5% (19 out of 395). Three complications of minor rectal bleeding occurred. CONCLUSIONS: With 3 complications and 18 insufficient samples out of 668, rectal biopsy is a safe procedure and remains the gold standard for the diagnosis of Hirschsprung's disease, despite the large number of negative biopsies. Contrary to some reports in the literature which question the need for rectal biopsy in those presenting after the neonatal period, 53% of our positive diagnoses were made in children presenting after this period, with 19 positive biopsies out of 395 (5%) performed in children above the age of 1 year.

Morel A, Mishra EK, Medley L, Rahman NM, Wrightson JM, Talbot DC, Davies RJ. 2010. Chemotherapy does not increase the risk of pleural infection in patients managed with an indwelling pleural catheter for malignant pleural effusion LUNG CANCER, 67 pp. S6-S7. | Read more

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Rahman NM, Maskell NA, Davies CWH, Hedley EL, Nunn AJ, Gleeson FV, Davies RJO. 2010. The relationship between chest tube size and clinical outcome in pleural infection Chest, 137 (3), pp. 536-543. | Show Abstract | Read more

Background: The optimal choice of chest tube size for the treatment of pleural infection is unknown, with only small cohort studies reported describing the efficacy and adverse events of different tube sizes. Methods: A total of 405 patients with pleural infection were prospectively enrolled into a multicenter study investigating the utility of fibrinolytic therapy. The combined frequency of death and surgery, and secondary outcomes (hospital stay, change in chest radiograph, and lung function at 3 months) were compared in patients receiving chest tubes of differing size (χ2, t test, and logistic regression analyses as appropriate). Pain was studied in detail in 128 patients. Results: There was no significant difference in the frequency with which patients either died or required thoracic surgery in patients receiving chest tubes of varying sizes (<10F, number dying or needing surgery 21/58 [36%]; size 10-14F, 75/208 [36%]; size 15-20F, 28/70 [40%]; size > 20F, 30/69 [44%]; χ2trend, 1 degrees of freedom [df ] = 1.21, P = .27), nor any difference in any secondary outcome. Pain scores were substantially higher in patients receiving (mainly blunt dissection inserted) larger tubes (<10F, median pain score 6 [range 4-7]; 10-14F, 5 [4-6]; 15-20F, 6 [5-7]; >20F, 6 [6-8]; χ2, 3 df = 10.80, P =.013, Kruskal-Wallis; χ2trend, 1 df = 6.3, P =.014). Conclusions: Smaller, guide-wire-inserted chest tubes cause substantially less pain than blunt-dissection-inserted larger tubes, without any impairment in clinical outcome in the treatment of pleural infection. These results suggest that smaller size tubes may be the initial treatment of choice for pleural infection, and randomized studies are now required. Trial registration: MIST1 trial ISRCTN number: 39138989. © 2010 American College of Chest Physicians.

Rahman NM, Davies RJO. 2010. Occlusion and Malposition of Small-Bore Chest Tubes for Pleural Infection: Response Chest, 138 (3), pp. 760-761. | Read more

Qureshi NR, Rahman NM, Gleeson FV. 2009. Thoracic ultrasound in malignant pleural effusion: a real world perspective Reply THORAX, 64 (11), pp. 1005-1005. | Read more

Rahman NM, Maskell NA, Davies CWH, Hedley EL, Nunn AJ, Gleeson FV, Davies RJO. 2010. The relationship between chest tube size and clinical outcome in pleural infection. Chest, 137 (3), pp. 536-543. | Show Abstract | Read more

BACKGROUND: The optimal choice of chest tube size for the treatment of pleural infection is unknown, with only small cohort studies reported describing the efficacy and adverse events of different tube sizes. METHODS: A total of 405 patients with pleural infection were prospectively enrolled into a multicenter study investigating the utility of fibrinolytic therapy. The combined frequency of death and surgery, and secondary outcomes (hospital stay, change in chest radiograph, and lung function at 3 months) were compared in patients receiving chest tubes of differing size (chi(2), t test, and logistic regression analyses as appropriate). Pain was studied in detail in 128 patients. RESULTS: There was no significant difference in the frequency with which patients either died or required thoracic surgery in patients receiving chest tubes of varying sizes ( < 10F, number dying or needing surgery 21/58 [36%]; size 10-14F, 75/208 [36%]; size 15-20F, 28/70 [40%]; size > 20F, 30/69 [44%]; chi(2)trend, 1 degrees of freedom [df] = 1.21, P = .27), nor any difference in any secondary outcome. Pain scores were substantially higher in patients receiving (mainly blunt dissection inserted) larger tubes ( < 10F, median pain score 6 [range 4-7]; 10-14F, 5 [4-6]; 15-20F, 6 [5-7]; > 20F, 6 [6-8]; chi(2), 3 df = 10.80, P = .013, Kruskal-Wallis; chi(2)trend, 1 df = 6.3, P = .014). CONCLUSIONS: Smaller, guide-wire-inserted chest tubes cause substantially less pain than blunt-dissection-inserted larger tubes, without any impairment in clinical outcome in the treatment of pleural infection. These results suggest that smaller size tubes may be the initial treatment of choice for pleural infection, and randomized studies are now required. TRIAL REGISTRATION: MIST1 trial ISRCTN number: 39138989.

Davies HE, Sadler RS, Bielsa S, Maskell NA, Rahman NM, Davies RJO, Ferry BL, Lee YCG. 2009. Clinical impact and reliability of pleural fluid mesothelin in undiagnosed pleural effusions. Am J Respir Crit Care Med, 180 (5), pp. 437-444. | Show Abstract | Read more

RATIONALE: Serum mesothelin is a new biomarker for the diagnosis of mesothelioma. Patients with mesothelioma commonly present with pleural effusions. To define the clinical utility of mesothelin quantification in pleural fluid, we assessed its additional value over pleural fluid cytology and its short-term reproducibility and reliability after pleural inflammatory processes, including pleurodesis. OBJECTIVES: To assess the diagnostic role of pleural fluid mesothelin and the effect of common clinical factors that may influence measurement accuracy. METHODS: Mesothelin was quantified in 424 pleural fluid and 64 serum samples by ELISA. Fluid was collected prospectively from 167 patients who presented with pleural effusions for investigation. Serial pleural fluid samples were obtained from patients (n = 33) requiring repeated drainage. Mesothelin levels were also measured in patients (n = 32) prepleurodesis and postpleurodesis. MEASUREMENTS AND MAIN RESULTS: Pleural fluid mesothelin concentrations were significantly higher in patients with mesothelioma (n = 24) relative to those with metastatic carcinomas (n = 67) and benign effusions (n = 75): median (interquartile range, 25th-75th percentile) = 40.3 (18.3-68.1) versus 6.1 (1.5-13.2) versus 3.7 (0.0-12.4) nM, respectively, P < 0.0001. Mesothelin measurement was superior to cytological examination in the diagnosis and exclusion of mesothelioma (sensitivity, 71 vs. 35%; specificity, 89 vs. 100%; negative predictive value, 95 vs. 82%, respectively). In patients with "suspicious" cytology, pleural fluid mesothelin was 100% specific for mesothelioma, and in cytology-negative effusions (n = 105) offered a negative predictive value of 94%. Intraindividual reproducibility of pleural fluid mesothelin was excellent: mean (+/-SD) variation, -0.15 (+/-8.41) nM in samples collected within 7 days from patients with mesothelioma. Measurements remained reliable after pleurodesis and were not affected by the presence of bacteria. CONCLUSIONS: Pleural fluid mesothelin provides additional diagnostic value relative to cytological examination. Mesothelin measurements are reproducible and not affected by inflammatory pleural processes.

Qureshi NR, Rahman NM, Gleeson FV. 2009. Thoracic ultrasound: an important skill for respiratory physicians Reply THORAX, 64 (9), pp. 826-826. | Read more

Rahman NM, Munavvar M. 2009. Investigation of the patient with pleural effusion (2) Response CLINICAL MEDICINE, 9 (4), pp. 401-401.

Choudhry MS, Rahman N, Boyd P, Lakhoo K. 2009. Duodenal atresia: associated anomalies, prenatal diagnosis and outcome. Pediatr Surg Int, 25 (8), pp. 727-730. | Show Abstract | Read more

BACKGROUND: The diagnosis of duodenal atresia is commonly made prenatally, either as an isolated lesion or due to its association with other chromosomal abnormalities (Robertson et al. in Semin Perinatol 18:182-195, 1994; Hemming and Rankin in J Prenat Diagn 27:1205-1211, 2007). The aim of this study was to describe the prevalence of associated anomalies, prenatal diagnostic accuracy and survival of cases of congenital duodenal atresia in our institution. METHODS: All cases of duodenal atresia registered with our local congenital anomaly register over a 10-year period, 1995-2004 inclusive, were studied, including those resulting in termination of pregnancies, stillbirths, intrauterine deaths and neonatal deaths. To ensure high-case ascertainment, data were cross checked with prenatal ultrasound, cytogenetic laboratory, pathology department and neonatal surgical data base. Data were analysed for associated anomalies, accuracy of prenatal diagnosis and neonatal outcomes. RESULTS: A total of 65 patients were initially diagnosed as having duodenal atresia, of these 4 were subsequently excluded (1 postnatal normal bowel and 3 high jejunal atresias). In the remaining 61 cases, 35 (57%) had an association with other congenital abnormalities and 26 (43%) were isolated anomalies. Thirty-five were male and 26 female (M:F = 1.4:1). Twenty-one out of 29 (72%) patients prenatally diagnosed, compared with 14 out of 32 (44%) patients diagnosed postnatally had associated anomalies. Duodenal atresia was suspected on routine prenatal ultrasonography at 20-week gestation in 33 cases and confirmed in 29 (48%) cases with 4 false-positive diagnoses (1 normal bowel and 3 high jejunal atresias). No prenatal diagnosis was made in 32 (52%) babies. Of the 61 cases, 53 were live births with 2 early neonatal deaths (1 cardiac and 1 VACTERL), 5 terminations, 2 intrauterine deaths and 1 stillbirth (Fig. 3). Overall neonatal survival was 96% (51 cases). Mortality in the group diagnosed prenatally was 34 % (10 cases). CONCLUSION: This study shows an overall increased association of duodenal atresia with Down's syndrome. In the group diagnosed prenatally, mortality as well as the association with other congenital anomalies was found to be higher. We have demonstrated a greater prenatal diagnostic accuracy, but confirm postnatal outcomes similar to previous studies.

Wrightson JM, Helm EJ, Rahman NM, Gleeson FV, Davies RJO. 2009. Pleural procedures and pleuroscopy. Respirology, 14 (6), pp. 796-807. | Show Abstract | Read more

Pleural procedures are commonly performed by physicians from a range of specialities. These procedures vary in complexity, from relatively straightforward pleural aspiration to more challenging procedures such as pleuroscopy. After appropriate training, even complex pleural procedures have a low risk of complications. Nevertheless, an appreciation of procedural risks is essential for physician training and forms the crux of a valid patient consent process. This review presents a systematic evaluation of the potential complications of common pleural procedures.

Rahman N, Lakhoo K. 2009. Patent processus vaginalis: a window to the abdomen. Afr J Paediatr Surg, 6 (2), pp. 116-117. | Show Abstract | Read more

A patent processus vaginalis (PPV) allows a communication between the peritoneum and scrotum. Hydrocoele is the usual presentation of a PPV in children. However, with intraabdominal pathology the patent PPV may provide the first clue to the mischief within the abdomen. We present here two unusual cases associated with a PPV and migration of intraabdominal contents from the abdomen to the scrotum.

Mishra EK, Rahman NM. 2009. Factors influencing the measurement of pleural fluid pH. Curr Opin Pulm Med, 15 (4), pp. 353-357. | Show Abstract | Read more

PURPOSE OF REVIEW: Pleural fluid pH measurement is important in the management of patients with exudative pleural effusions, especially in guiding treatment of parapneumonic effusions. Common variations in the method used to sample pleural fluid affect the accuracy of the value obtained. This article reviews the effects of these variations. RECENT FINDINGS: Pleural fluid pH is decreased by exposure to acidic fluids, such as retention of local anesthetic or heparin in the syringe or sampling following infiltration of local anesthetic. Exposure of the sample to air leads to an increase in pH. If immediate analysis is not possible, delay of up to 4 h does not cause a significant change in pH, even when the sample is kept at room temperature. It is essential that a blood gas analyzer is used to obtain accurate pH measurement.These factors have less effect on the glucose concentration, which may be used to guide management if an accurate pH value is not available. SUMMARY: Several common variables in collection method can lead to a clinically significant alteration in the pH value obtained. An evidence-based method for sampling and handling pleural fluid in order to obtain an accurate pH measurement is described.

Seville R, Riha RL, Rahman N. 2009. Pleural infection Respiratory Medicine CME, 2 (3), pp. 107-110. | Show Abstract | Read more

Pleural infection is a relatively common complication of pneumonia with a broad aetiology. Parapneumonic effusions caused by an infection of the pleural membranes occur in 40-57% of cases of pneumonia. A variable percentage (10-20%) of parapneumonic effusions progresses to empyema (pus) and/or abscess formation (encapsulation). Pleural infection is associated with significant morbidity and mortality. Diagnosis requires a multidisciplinary approach which may include respiratory physicians, thoracic surgeons, microbiologists and radiologists. Rigorous and prompt treatment with antibiotics, good clinical care and timely drainage of effusions remain the cornerstones of effective management. © 2009 Elsevier Ltd. All rights reserved.

Rahman NM, Munavvar M. 2009. Investigation of the patient with pleural effusion. Clin Med (Lond), 9 (2), pp. 174-178. | Read more

Rahman N, Lakhoo K. 2009. Comparison between open and thoracoscopic resection of congenital lung lesions. J Pediatr Surg, 44 (2), pp. 333-336. | Show Abstract | Read more

PURPOSE: This study compares the outcome between thoracoscopic and thoracotomy resection of congenital lung lesions. METHODS: From November 2005 to August 2007, 14 consecutive cases of video-assisted thoracoscopic (VATS) lung resections have been performed in our institution. A retrospective review comparing these cases to the previous open thoracotomies for lung resection was performed. Intraoperative and early postoperative results were compared. RESULTS: The mean age for VATS resection was 10 months compared with 7 months for thoracotomy. There were no major intraoperative complications. One case was converted from thoracoscopy to thoracotomy, and there was one anesthetic failed attempt of VATS resection, which was then performed open. Seven VATS resections and 6 thoracotomies were for congenital cystic adenomatous malformations. Intraoperative chest drains were used for all VATS resections but only 10 of the 14 thoracotomies, one of which developed a tension pneumothorax within hours of discharge. Perioperative outcomes including time to removal of chest drain, length of postoperative intravenous opioid requirement, and hospital stay were similar for both groups. Three had postoperative complications. Operative time was significantly lower in the thoracotomy group (124 minutes compared with 170 minutes, P < .05). The subgroup of congenital lobar emphysema had a particularly prolonged VATS resection time of 220 vs 155 minutes (P < .05). The thoracotomy group was more likely to receive adjuvant regional anesthesia (12 of 14 compared with 5 of 14). CONCLUSIONS: Thoracoscopic resection of lung lesions results in longer operative time but is a safe and feasible alternative to open thoracotomy. Congenital lobar emphysema is a subgroup more challenging thoracoscopically, and it is recommended that these should be preselected for open surgery.

Qureshi NR, Rahman NM, Gleeson FV. 2009. Thoracic ultrasound in the diagnosis of malignant pleural effusion. Thorax, 64 (2), pp. 139-143. | Show Abstract | Read more

BACKGROUND: Malignant pleural effusion (MPE) is a common clinical problem with described investigation pathways. While thoracic ultrasound (TUS) has been shown to be accurate in pleural fluid detection, its use in the diagnosis of malignant pleural disease has not been assessed. A study was undertaken to assess the diagnostic accuracy of TUS in differentiating malignant and benign pleural disease. METHODS: 52 consecutive patients with suspected MPE underwent TUS and contrast-enhanced CT (CECT). TUS was used to assess pleural surfaces using previously published CT imaging criteria for malignancy, diaphragmatic thickness/nodularity, effusion size/nature and presence of hepatic metastasis (in right-sided effusions). A TUS diagnosis of malignant or benign disease was made blind to clinical data/other investigations by a second blinded operator using anonymised TUS video clips. The TUS diagnosis was compared with the definitive clinical diagnosis and in addition to the diagnosis found at CECT. RESULTS: A definitive malignant diagnosis was based on histocytology (30/33; 91%) and clinical/CT follow-up (3/33; 9%). Benign diagnoses were based on negative histocytology and follow-up over 12 months in 19/19 patients. TUS correctly diagnosed malignancy in 26/33 patients (sensitivity 73%, specificity 100%, positive predictive value 100%, negative predictive value 79%) and benign disease in 19/19. Pleural thickening >1 cm, pleural nodularity and diaphragmatic thickening >7 mm were highly suggestive of malignant disease. CONCLUSION: TUS is useful in differentiating malignant from benign pleural disease in patients presenting with suspected MPE and may become an important adjunct in the diagnostic pathway.

Rahman NM, Munavvar M. 2009. In response to both Clinical Medicine, Journal of the Royal College of Physicians of London, 9 (4), pp. 401.

Wrightson JM, Rahman NM, Novak T, Huggett JF, Miller RF, Davies RJO. 2009. Polymerase Chain Reaction (PCR) Demonstrates No Evidence of Pneumocystis jirovecii in Pleural Infection. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179

Rahman NM, Davies HE, Wrightson JM, Singanayagam A, Singanayagam A, Benamore R, Gleeson FV, Davies RJO. 2009. Activity, Efficacy and Safety of a Physician-Based Thoracic Ultrasound (PBUS) Service. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179

Davies HE, Sadler RS, Bielsa S, Maskell NA, Rahman NM, Davies RJO, Ferry BL, Lee YCG. 2009. The Clinical Role and Reliability of Pleural Fluid Mesothelin in Undiagnosed Pleural Effusions. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179

Qureshi NR, Rahman NM, Gleeson FV. 2009. Authors' reply Thorax, 64 (11), pp. 1005-1005. | Read more

Qureshi NR, Rahman NM, Gleeson FV. 2009. Authors' reply Thorax, 64 (9), pp. 826-826. | Read more

Rahman NM, Davies HE, Salzberg M, Truog P, Midgely R, Kerr D, Clelland C, Hedley EL, Lee YCG, Davies RJO. 2008. Use of lipoteichoic acid-T for pleurodesis in malignant pleural effusion: a phase I toxicity and dose-escalation study. Lancet Oncol, 9 (10), pp. 946-952. | Show Abstract | Read more

BACKGROUND: Bacterial infection of the pleural space often causes adherence of the pleural membranes by fibrous tissue, probably mediated by inflammation initiated by bacterial cell-wall motifs, including lipoteichoic acid-T (LTA-T). We postulated that therapeutically administered LTA-T might produce a similar effect, achieving control of malignant pleural effusion (pleurodesis). METHODS: Patients with histocytologically proven symptomatic malignant pleural effusions were included in this phase I toxicity and dose-escalation study, An indwelling pleural catheter was placed in the pleural effusion to drain the fluid fully. A control dose of intrapleural saline was administered after complete drainage (day 1) and pleural-fluid production was recorded for 7 days. On day 7 a single dose of intrapleural LTA-T (increasing in each patient) was administered and pleural-fluid production was monitored for a further 7 days. Long-term fluid control was recorded. This study is registered as an International Standard Randomised Controlled Trial, ISRCTN44367564. FINDINGS: Between November, 2004, and November, 2005, 14 patients were enrolled on the trial at the Oxford Centre for Respiratory Medicine (Oxford, UK). 13 of 14 patients received escalated doses of LTA-T. A dose-limiting toxic effect (ie, systemic inflammation) occurred at 3000 microg, and a therapeutic dose of 750-1500 microg was established. Toxic effects were mild and had no consistent pattern at the therapeutic dose. Pleural-fluid production decreased significantly after a dose of at least 750 microg LTA-T, compared with saline control (mean fluid production after saline control 1244 mL [SD 933], mean fluid production after LTA-T 394 mL [SD 375], mean difference -850 mL [SD 699], p=0.028), and six of seven (86%) patients achieved pleural-fluid control at 1 month with no further intervention. INTERPRETATION: The toxic effects of intrapleural LTA-T seem to be mild and favourable when compared with the toxicity profiles of standard pleurodesis agents. There is early evidence of LTA-T-induced pleurodesis efficacy, suggesting that this might be a viable therapeutic strategy for the control of malignant pleural effusion.

Rahman NM, Mishra EK, Davies HE, Davies RJO, Lee YCG. 2008. Clinically important factors influencing the diagnostic measurement of pleural fluid pH and glucose. Am J Respir Crit Care Med, 178 (5), pp. 483-490. | Show Abstract | Read more

RATIONALE: Accurate pleural fluid pH and glucose measurement is a key component in the diagnosis and management of patients with pleural effusion. Standardized methods of pleural fluid collection have not been defined. OBJECTIVES: To assess the effect of common clinical factors that may distort measurement accuracy of pleural fluid pH and glucose. METHODS: Ninety-two exudative pleural aspirates were collected in commercially available blood gas syringes. MEASUREMENTS AND MAIN RESULTS: Samples were analyzed immediately using a blood gas analyzer. The effects of residual air, lidocaine, heparin, and delay in analysis (24 h) on pH and glucose measurement accuracy were assessed. Pleural fluid pH was significantly increased by residual air (mean +/- SD, 0.08 +/- 0.07; 95% confidence interval [CI], 0.06 to 0.09; P < 0.001) and significantly decreased by residual lidocaine (0.2 ml; mean change in pH, -0.15 +/- 0.09; 95% CI, -0.13 to -0.18; P < 0.001) and residual heparin (mean change in pH, -0.02 +/- 0.05; 95% CI, -0.01 to -0.04; P = 0.027). Pleural fluid pH was stable at room temperature for 1 hour and significantly increased at 4 (mean +/- SD, 0.03 +/- 0.07; 95% CI, 0.01 to 0.04; P = 0.003) and 24 hours (0.05 +/- 0.12; 95% CI, 0.03 to 0.08; P < 0.001). Pleural fluid glucose concentration was not clinically significantly altered by residual air, lidocaine (up to 0.4 ml), or 24-hour analysis delay. CONCLUSIONS: Accuracy of measured pleural pH is critically dependent on sample collection method. Residual air, lidocaine, and analysis delay significantly alter pH and may impact on clinical management. Pleural fluid glucose concentration is not significantly influenced by these factors. Protocols defining appropriate sampling and analysis methods are needed.

Rahman NM, Davies RJO, Gleeson FV. 2008. Pleural interventions: management of acute and chronic pneumothorax. Semin Respir Crit Care Med, 29 (4), pp. 427-440. | Show Abstract | Read more

Pneumothorax is a common clinical entity that may present to a wide variety of medical specialties. Primary pneumothorax (in the presence of no known underlying lung disease) and secondary pneumothorax (in known lung disease) are distinct entities with varied etiology, treatment, and prognosis. Diagnosis is usually based on clinical history and basic radiology, but more advanced radiological techniques may be required in certain circumstances. There is relatively little evidence on which to base management decisions in patients with pneumothoraces, and many important aspects of management (e.g., aspiration vs intercostal drainage, chest drain size, use of suction) are often based on best practice and expert opinion. The etiology of pneumothorax will often inform the clinician whether a more conservative or more invasive approach is required. Radiological intervention techniques are valuable in the treatment of complicated pneumothoraces and in certain clinical situations.

Rahman NM, Gleeson FV. 2008. Image-guided pleural biopsy. Curr Opin Pulm Med, 14 (4), pp. 331-336. | Show Abstract | Read more

PURPOSE OF REVIEW: Pleural diseases are a common and increasing clinical problem. Establishing accurate diagnosis is an essential step in management of these patients, and approximately 40% of pleural effusions will remain undiagnosed after initial diagnostic thoracocentesis. Obtaining pleural tissue (by blind, image-guided or thoracoscopic pleural biopsy) is therefore a key procedure. Recent evidence provides important information on the relative value of each of these techniques. RECENT FINDINGS: For the diagnosis of malignant pleural disease, both thoracoscopic and image-guided biopsy have a far higher diagnostic yield than blind pleural biopsy. Cutting needle biopsies have a higher diagnostic yield in malignancy (and especially mesothelioma) compared with fine needle aspiration. The complication rate of image-guided biopsy is low. Rates of biopsy site tract invasion by mesothelioma may be lower using smaller biopsy ports, as used for image-guided pleural biopsy. SUMMARY: Blind pleural biopsy should no longer be conducted for the study of malignant pleural disease if facilities for other techniques are available. Image-guided and thoracoscopic biopsies have similarly high diagnostic rates, and are complementary techniques used in different clinical situations. Further studies assessing biopsy tract site invasion from mesothelioma with different biopsy techniques are required.

Davies HE, Rahman NM, Parker RJ, Davies RJO. 2008. Use of indwelling pleural catheters for chronic pleural infection. Chest, 133 (2), pp. 546-549. | Show Abstract | Read more

Recurrent, chronic pleural infection creates difficult management issues. Surgical drainage is currently recommended for patients who have failed initial "medical treatment" (ie, tube thoracostomy and antibiotic therapy), but the options for patients not fit for surgery are limited. Prolonged closed tube drainage may be an option in this group, although concerns exist regarding the efficacy and risk of catheter blockage. Long-term indwelling pleural catheters are increasingly used for the treatment of recurrent malignant pleural effusion. Pleural infection is recognized as a complication and is cited as a contraindication to insertion of an indwelling pleural drain within the product literature. We report two patients with empyema in a fixed pleural space in whom the insertion of an ambulatory catheter produced successful drainage. Long-term indwelling pleural catheters may have a role in maintaining the drainage of a chronically infected pleural space that is not readily treated in other ways.

Janes SM, Rahman NM, Davies RJO, Lee YCG. 2007. Catheter-tract metastases associated with chronic indwelling pleural catheters. Chest, 131 (4), pp. 1232-1234. | Show Abstract | Read more

Indwelling pleural catheters are increasingly being used for ambulatory treatment of malignant pleural effusion, particularly for patients unsuitable for pleurodesis. These catheters are often left in situ for the rest of the patient's life. Tumor metastasis along the tract between pleura and skin surface is a potential complication in patients with chronic indwelling pleural catheters that has seldom been reported. We describe four cases of catheter-tract metastasis that developed between 3 weeks and 9 months after catheter insertion. Catheter-tract metastasis occurred in two patients with mesothelioma despite prophylactic irradiation at time of insertion, and in two patients with metastatic adenocarcinoma. All cases were successfully treated using external-beam radiotherapy without necessitating catheter removal. A retrospective audit in our center showed that catheter-tract metastasis occurred in 6.7% of 45 patients treated with indwelling pleural catheters for malignant pleural effusions. Both clinicians and patients should be aware of this potential complication.

Rahman NM, Davies RJO, Gleeson FV. 2007. Investigating suspected malignant pleural effusion. BMJ, 334 (7586), pp. 206-207. | Read more

Rahman NM, Gleeson FV. 2006. New directions in the treatment of infected pleural effusion. Clin Radiol, 61 (9), pp. 719-722. | Show Abstract | Read more

The optimum management of patients with parapneumonic effusion and empyema remains uncertain. This article will review the evidence and current opinion on the pathophysiology of this disease, the role of fibrinolytic therapy, and the use of modern surgical techniques.

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Rahman NM, Chapman SJ, Davies RJO. 2006. The approach to the patient with a parapneumonic effusion CLINICS IN CHEST MEDICINE, 27 (2), pp. 253-+. | Read more

Rahman NM, Chapman SJ, Davies RJO. 2006. The approach to the patient with a parapneumonic effusion. Clin Chest Med, 27 (2), pp. 253-266. | Show Abstract | Read more

Parapneumonic effusion is a common clinical problem, and those that go on to develop pleural infection have high morbidity and mortality. The process of pleural infection evolution involves changes in pleural physiology that are increasingly being elucidated and understood. The microbiology of pleural infection has changed over recent years, with clear differences emerging between hospital- and community-acquired infections. Using biochemical surrogates of infection, chest drainage can be undertaken rationally for those who do not respond to antibiotics alone. Recent data suggest that fibrinolytics do not influence outcomes in pleural infection. The optimal type and timing of surgery remain controversial.

Rahman NM, Chapman SJ, Davies RJO. 2006. Diagnosis and management of infectious pleural effusion. Treat Respir Med, 5 (5), pp. 295-304. | Show Abstract | Read more

Pleural infection remains a common illness, with a high morbidity and mortality. The development of frank empyema from a simple exudative pleural effusion is a result of biochemical changes within the pleural space in response to bacterial invasion. These changes can be used in the diagnosis of pleural infection and used to predict which patients will require intercostal drainage for resolution of infection. Recent large trials in empyema have further advanced our knowledge of microbiologic patterns, informing important decisions about empiric antibacterial therapy. Diagnosis of pleural infection relies on high clinical suspicion in association with clinical features, radiology, and pleural fluid characteristics. Treatment of pleural infection is based upon accurate and often empiric choice of antibacterial agents, intercostal drainage in certain contexts, and appropriate surgical referral. Intrapleural thrombolytic therapy is not currently recommended for the treatment of pleural infection, on the basis of evidence from the largest randomized trial in empyema to date.

Rahman NM, Chapman SJ, Davies RJO. 2004. Pleural effusion: a structured approach to care. Br Med Bull, 72 (1), pp. 31-47. | Show Abstract | Read more

The accumulation of fluid in the pleural space is a common manifestation of a wide range of disease. This review provides a structured approach to the investigation of the patient with a pleural effusion. This should allow an accurate diagnosis to be made with the minimum number of invasive and time-consuming investigations.

Marlow L, Lee A, Hedley E, Grocott M, Steiner M, Young D, Rahman N, Snowden C, Pattinson KTS. Findings of a feasibility study of pre-operative pulmonary rehabilitation to reduce post-operative pulmonary complications in people with chronic obstructive pulmonary disease scheduled for major abdominal surgery. | Show Abstract | Read more

<jats:p>Background: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of complications and death following surgery. Pulmonary complications are particularly prominent. Pulmonary rehabilitation is a course of physical exercise and education that helps people with COPD manage their condition. Although proven to improve health outcomes in patients with stable COPD, it has never been formally tested as a pre-surgical intervention in patients scheduled for non-cardiothoracic surgery. If a beneficial effect were to be demonstrated, pulmonary rehabilitation for pre-surgical patients with COPD might be rapidly implemented across the National Health Service, as pulmonary rehabilitation courses are already well established across much of the United Kingdom (UK). Methods: We performed a feasibility study to test study procedures and barriers to identification and recruitment to a randomised controlled trial testing whether pulmonary rehabilitation, delivered before major abdominal surgery in a population of people with COPD, would reduce the incidence of post-operative pulmonary complications. This study was run in two UK centres (Oxford and Newcastle upon Tyne). Results: We determined that a full randomised controlled trial would not be feasible, due to failure to identify and recruit participants. We identified an unmet need to identify more effectively patients with COPD earlier in the surgical pathway. Service evaluations suggested that barriers to identification and recruitment would likely be the same across other UK hospitals. Conclusions: Although pulmonary rehabilitation is a potentially beneficial intervention to prevent post-operative pulmonary complications, a randomised controlled trial is unlikely to recruit sufficient participants to answer our study question conclusively at the present time, when spirometry is not automatically conducted in all patients planned for surgery. As pulmonary rehabilitation is a recommended treatment for all people with COPD, alternative study methods combined with earlier identification of candidate patients in the surgical pathway should be considered. Trial registration: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="isrctn" xlink:href="29696295">ISRCTN 29696295</jats:ext-link>, http://www.isrctn.com/<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="isrctn" xlink:href="29696295">ISRCTN29696295</jats:ext-link>, registered 31st August 2017</jats:p>

Bhatnagar R, Keenan EK, Morley AJ, Kahan BC, Stanton AE, Haris M, Harrison RN, Mustafa RA, Bishop LJ, Ahmed L et al. 2018. Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion. N Engl J Med, 378 (14), pp. 1313-1322. | Show Abstract | Read more

BACKGROUND: Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. METHODS: Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. RESULTS: The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant between-group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. CONCLUSIONS: Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40 .).

Psallidas I, Kanellakis NI, Gerry S, Thézénas ML, Charles PD, Samsonova A, Schiller HB, Fischer R, Asciak R, Hallifax RJ et al. 2018. Development and validation of response markers to predict survival and pleurodesis success in patients with malignant pleural effusion (PROMISE): a multicohort analysis. Lancet Oncol, 19 (7), pp. 930-939. | Show Abstract | Read more

BACKGROUND: The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival. METHODS: In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation. FINDINGS: 17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0·78 [95% CI 0·72-0·83] for internal validation and 0·89 [0·84-0·93] for external validation of the clinical PROMISE score). INTERPRETATION: To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies. FUNDING: European Respiratory Society, Medical Research Funding-University of Oxford, Slater & Gordon Research Fund, and Oxfordshire Health Services Research Committee Research Grants.

Psallidas I, Kanellakis NI, Bhatnagar R, Ravindran R, Yousuf A, Edey AJ, Mercer RM, Corcoran JP, Hallifax RJ, Asciak R et al. 2018. A Pilot Feasibility Study in Establishing the Role of Ultrasound-Guided Pleural Biopsies in Pleural Infection (The AUDIO Study). Chest, 154 (4), pp. 766-772. | Show Abstract | Read more

BACKGROUND: Pleural infection is a common complication of pneumonia associated with high mortality and poor clinical outcome. Treatment of pleural infection relies on the use of broad-spectrum antibiotics because reliable pathogen identification occurs infrequently. We performed a feasibility interventional clinical study assessing the safety and significance of ultrasound (US)-guided pleural biopsy culture to increase microbiological yield. In an exploratory investigation, the 16S ribosomal RNA technique was applied to assess its utility on increasing speed and accuracy vs standard microbiological diagnosis. METHODS: Twenty patients with clinically established pleural infection were recruited. Participants underwent a detailed US scan and US-guided pleural biopsies before chest drain insertion, alongside standard clinical management. Pleural biopsies and routine clinical samples (pleural fluid and blood) were submitted for microbiological analysis. RESULTS: US-guided pleural biopsies were safe with no adverse events. US-guided pleural biopsies increased microbiological yield by 25% in addition to pleural fluid and blood samples. The technique provided a substantially higher microbiological yield compared with pleural fluid and blood culture samples (45% compared with 20% and 10%, respectively). The 16S ribosomal RNA technique was successfully applied to pleural biopsy samples, demonstrating high sensitivity (93%) and specificity (89.5%). CONCLUSIONS: Our findings demonstrate the safety of US-guided pleural biopsies in patients with pleural infection and a substantial increase in microbiological diagnosis, suggesting potential niche of infection in this disease. Quantitative polymerase chain reaction primer assessment of pleural fluid and biopsy appears to have excellent sensitivity and specificity.

Clive AO, Taylor H, Dobson L, Wilson P, de Winton E, Panakis N, Pepperell J, Howell T, Stewart SA, Penz E et al. 2016. Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial. Lancet Oncol, 17 (8), pp. 1094-1104. | Show Abstract | Read more

BACKGROUND: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. METHODS: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. FINDINGS: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. INTERPRETATION: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. FUNDING: Research for Patient Benefit Programme from the UK National Institute for Health Research.

Rahman NM, Pepperell J, Rehal S, Saba T, Tang A, Ali N, West A, Hettiarachchi G, Mukherjee D, Samuel J et al. 2015. Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial. JAMA, 314 (24), pp. 2641-2653. | Show Abstract | Read more

IMPORTANCE: For treatment of malignant pleural effusion, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided because they may reduce pleurodesis efficacy. Smaller chest tubes may be less painful than larger tubes, but efficacy in pleurodesis has not been proven. OBJECTIVE: To assess the effect of chest tube size and analgesia (NSAIDs vs opiates) on pain and clinical efficacy related to pleurodesis in patients with malignant pleural effusion. DESIGN, SETTING, AND PARTICIPANTS: A 2×2 factorial phase 3 randomized clinical trial among 320 patients requiring pleurodesis in 16 UK hospitals from 2007 to 2013. INTERVENTIONS: Patients undergoing thoracoscopy (n = 206; clinical decision if biopsy was required) received a 24F chest tube and were randomized to receive opiates (n = 103) vs NSAIDs (n = 103), and those not undergoing thoracoscopy (n = 114) were randomized to 1 of 4 groups (24F chest tube and opioids [n = 28]; 24F chest tube and NSAIDs [n = 29]; 12F chest tube and opioids [n = 29]; or 12F chest tube and NSAIDs [n = 28]). MAIN OUTCOMES AND MEASURES: Pain while chest tube was in place (0- to 100-mm visual analog scale [VAS] 4 times/d; superiority comparison) and pleurodesis efficacy at 3 months (failure defined as need for further pleural intervention; noninferiority comparison; margin, 15%). RESULTS: Pain scores in the opiate group (n = 150) vs the NSAID group (n = 144) were not significantly different (mean VAS score, 23.8 mm vs 22.1 mm; adjusted difference, -1.5 mm; 95% CI, -5.0 to 2.0 mm; P = .40), but the NSAID group required more rescue analgesia (26.3% vs 38.1%; rate ratio, 2.1; 95% CI, 1.3-3.4; P = .003). Pleurodesis failure occurred in 30 patients (20%) in the opiate group and 33 (23%) in the NSAID group, meeting criteria for noninferiority (difference, -3%; 1-sided 95% CI, -10% to ∞; P = .004 for noninferiority). Pain scores were lower among patients in the 12F chest tube group (n = 54) vs the 24F group (n = 56) (mean VAS score, 22.0 mm vs 26.8 mm; adjusted difference, -6.0 mm; 95% CI, -11.7 to -0.2 mm; P = .04) and 12F chest tubes vs 24F chest tubes were associated with higher pleurodesis failure (30% vs 24%), failing to meet noninferiority criteria (difference, -6%; 1-sided 95% CI, -20% to ∞; P = .14 for noninferiority). Complications during chest tube insertion occurred more commonly with 12F tubes (14% vs 24%; odds ratio, 1.91; P = .20). CONCLUSIONS AND RELEVANCE: Use of NSAIDs vs opiates resulted in no significant difference in pain scores but was associated with more rescue medication. NSAID use resulted in noninferior rates of pleurodesis efficacy at 3 months. Placement of 12F chest tubes vs 24F chest tubes was associated with a statistically significant but clinically modest reduction in pain but failed to meet noninferiority criteria for pleurodesis efficacy. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN33288337.

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.

Hooper CE, Lyburn ID, Searle J, Darby M, Hall T, Hall D, Morley A, White P, Rahman NM, De Winton E et al. 2015. The South West Area Mesothelioma and Pemetrexed trial: a multicentre prospective observational study evaluating novel markers of chemotherapy response and prognostication. Br J Cancer, 112 (7), pp. 1175-1182. | Show Abstract | Read more

BACKGROUND: Robust markers that predict prognosis and detect early treatment response in malignant pleural mesothelioma (MPM) would enhance patient care. METHODS: Consecutive patients with MPM who were considered fit for first-line chemotherapy were prospectively recruited. Patients of similar performance status opting for best supportive care were included as a comparator group. Baseline and interval CT, PET-CT and serum markers (mesothelin, fibulin-3 and neutrophil-lymphocyte ratio (NLR)) were obtained, and patients followed up for a minimum 12 months. FINDINGS: Seventy-three patients were recruited (58 chemotherapy/15 comparator arm). Baseline TGV (total glycolytic volume on PET-CT) was an independent predictor of worse overall survival (OS) (P=0.001). Change in interval TGV(baseline/after two cycles of chemotherapy) did not predict OS or chemotherapy response on CT. Baseline NLR<4 was an independent predictor of better OS (median survival 453 (IQR 272-576) days vs NLR⩾4, 257 (IQR 147-490), P=0.002). Although baseline serum mesothelin did not predict OS, a falling level at 8 weeks significantly predicted longer time to progression (TTP) (P<0.001). INTERPRETATION: Neutrophil-lymphocyte ratio and baseline TGV predict prognosis in malignant pleural mesothelioma (MPM), but PET-CT is unhelpful in monitoring chemotherapy response. Serum mesothelin is a useful early treatment response marker when measured serially during chemotherapy and may have a role in evaluating patients' treatment response.

Corcoran JP, Psallidas I, Hallifax RJ, Talwar A, Sykes A, Rahman NM. 2015. Ultrasound-guided pneumothorax induction prior to local anaesthetic thoracoscopy. Thorax, 70 (9), pp. 906-908. | Show Abstract | Read more

Local anaesthetic thoracoscopy (LAT) is performed by a growing number of respiratory physicians in the context of an expanding population with pleural disease. Most LATs occur in patients with moderate to large effusions where the presence of fluid allows safe access to the pleural space. Patients with little or no fluid, but other features concerning for pleural disease, are usually investigated by surgical means. Advanced LAT practitioners can also provide this service through pneumothorax induction, although there is little published data on the safety or efficacy of this technique. We present data from a series of 77 consecutive patients in whom ultrasound-guided pneumothorax induction and LAT were attempted. 67 procedures (87.0%) were successful, with the most common histopathological diagnoses being chronic pleuritis (58.2%) and mesothelioma (16.4%). No adverse events were reported secondary to the procedure. These findings demonstrate the utility of this approach and should inform future practice and guidelines.

Hallifax RJ, Corcoran JP, Ahmed A, Nagendran M, Rostom H, Hassan N, Maruthappu M, Psallidas I, Manuel A, Gleeson FV, Rahman NM. 2014. Physician-based ultrasound-guided biopsy for diagnosing pleural disease. Chest, 146 (4), pp. 1001-1006. | Show Abstract | Read more

BACKGROUND: Definitive diagnosis of pleural disease (particularly malignancy) depends upon histologic proof obtained via pleural biopsy or positive pleural fluid cytology. Image-guided sampling is now standard practice. Local anesthetic thoracoscopy has a high diagnostic yield for malignant and nonmalignant disease, but is not always possible in frail patients, if pleural fluid is heavily loculated, or where the lung is adherent to the chest wall. Such cases can be converted during the same procedure as attempted thoracoscopy to cutting-needle biopsy. This study aimed to determine the diagnostic yield of a physician-led service in both planned biopsies and cases of failed thoracoscopy. METHODS: This study was a retrospective review of all ultrasound-guided, cutting-needle biopsies performed at the Oxford Centre for Respiratory Medicine between January 2010 and July 2013. Histologic results were assessed for the yield of pleural tissue, final diagnosis, and clinical follow-up in nonmalignant cases. RESULTS: Fifty ultrasound-guided biopsies were undertaken. Overall, 47 (94.0%) successfully obtained sufficient tissue for histologic diagnosis. Of the 50 biopsy procedures, 13 were conducted after failed thoracoscopy (5.2% of 252 attempted thoracoscopies over the same time period); of these 13, 11 (84.6%) obtained sufficient tissue. Thirteen of 50 biopsy specimens (26.0%) demonstrated pleural malignancy on histology (despite previous negative pleural fluid cytology), while 34 specimens (68.0%) were diagnosed as benign. Of the benign cases, 10 were pleural TB, two were sarcoidosis, and 22 were benign pleural thickening. There was one "false negative" of mesothelioma (median follow-up, 16 months). CONCLUSIONS: Within this population, physician-based, ultrasound-guided, cutting-needle pleural biopsy obtained pleural tissue successfully in a high proportion of cases, including those of failed thoracoscopy.

Rahman NM, Kahan BC, Miller RF, Gleeson FV, Nunn AJ, Maskell NA. 2014. A clinical score (RAPID) to identify those at risk for poor outcome at presentation in patients with pleural infection. Chest, 145 (4), pp. 848-855. | Show Abstract | Read more

BACKGROUND: Pleural infection is associated with a high morbidity and mortality. Development of a validated clinical risk score at presentation to identify those at high risk of dying would enable patient triage and may help formulate early management strategies. METHODS: A clinical risk score was derived based on data from patients entering the multicenter UK pleural infection trial (first Multicenter Intrapleural Sepsis Trial [MIST1], n=411). From 22 baseline clinical characteristics, model selection was undertaken to find variables predictive of poor clinical outcome. Outcomes were mortality at 3 months (primary), need for surgical intervention at 3 months, and time from randomization to discharge. The derived scoring system RAPID (renal, age, purulence, infection source, and dietary factors) was validated using patients enrolled in the subsequent MIST2 trial (n=191). RESULTS: Age, urea, albumin, hospital-acquired infection, and nonpurulence predicted poor outcome. Patients were stratified into low-risk (0-2), medium-risk (3-4), and high-risk (5-7) groups. Using the low-risk group as a reference, a RAPID score of 3 to 4 and >4 was associated with an OR of 24.4 (95% CI, 3.1-186.7; P=.002) and 192.4 (95% CI, 25.0-1480.4; P<.001), respectively, for death at 3 months. In the validation cohort (MIST2), a medium-risk RAPID score was nonsignificantly associated with mortality (OR, 3.2; 95% CI, 0.8-13.2; P=.11), and a high-risk score was associated with increased mortality (OR, 14.1; 95% CI, 3.5-56.8; P<.001). Hospitalization duration was associated with increasing RAPID score (score 0-2: median duration=7, interquartile range 6-13; score>5: median duration=15, interquartile range 9-28, P=.08). CONCLUSIONS: The RAPID score may permit risk stratification of patients with pleural infection at presentation.

Du Rand IA, Blaikley J, Booton R, Chaudhuri N, Gupta V, Khalid S, Mandal S, Martin J, Mills J, Navani N et al. 2013. British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE. Thorax, 68 Suppl 1 (Suppl 1), pp. i1-i44. | Show Abstract | Read more

Monitoring, precautions and complications All patients undergoing bronchoscopy should have heart rate, respiratory rate, blood pressure and oxygen saturation recorded repeatedly, including before, during and after the procedure. (Grade D) . All bronchoscopy units should undertake periodic audit of bronchoscopic performance, including efficacy, complications and patient satisfaction surveys. (Good practice point . All Trusts should have a 'safe sedation policy', and ensure all bronchoscopy unit staff, including trainees, receive appropriate training.

Helm EJ, Rahman NM, Talakoub O, Fox DL, Gleeson FV. 2013. Course and variation of the intercostal artery by CT scan. Chest, 143 (3), pp. 634-639. | Show Abstract | Read more

BACKGROUND: It is conventionally taught that the intercostal artery is shielded in the intercostal groove of the superior rib. The continuous course and variability of the intercostal artery, and factors that may influence them, have not been described in a large number of arteries in vivo. METHODS: Maximal intensity projection reformats in the coronal plane were produced from CT scan pulmonary angiograms to identify the posterolateral course of the intercostal artery (seventh to 11th rib spaces). A novel semiautomated computer segmentation algorithm was used to measure distances between the lower border of the superior rib, the upper border of the inferior rib, and the position of the intercostal artery when exposed in the intercostal space. The position and variability of the artery were analyzed for association with clinical factors. RESULTS: Two hundred ninety-eight arteries from 47 patients were analyzed. The mean lateral distance from the spine over which the artery was exposed within the intercostal space was 39 mm, with wide variability (SD, 10 mm; 10th-90th centile, 28-51 mm). At 3 cm lateral distance from the spine, 17% of arteries were shielded by the superior rib, compared with 97% at 6 cm. Exposed artery length was not associated with age, sex, rib space, or side. The variability of arterial position was significantly associated with age (coefficient, 0.91; P < .001) and rib space number (coefficient, - 2.60; P < .001). CONCLUSIONS: The intercostal artery is exposed within the intercostal space in the first 6 cm lateral to the spine. The variability of its vertical position is greater in older patients and in more cephalad rib spaces.

Characterising Cancer Specific Cytotoxic T cells in patients with Metastasis Pleural Effusion

Cancer individuals are characterized by dysfunctional anti-tumor T-cell responses. The importance of Tumor Specific T cell Reponses in controlling the cancer development has been highlighted by the recent success of rrecent exiting results from clinical trials with antibodies targeting these inhibitory receptors, such as PD-1 and CTLA4. However only proportion of the patients responded to currently available immune-checkpoint blockage therapy. In depth understanding of cancer specific T cell ...

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