register interest

Dr Chris S Garrard

Research Area: Genetics and Genomics
Scientific Themes: Genetics & Genomics and Immunology & Infectious Disease
Keywords: sepsis, genomics, Intensive care, pneumonia, peritonitis, UKCCG and GAinS
Web Links:

UK Critical Care Genomics (UKCCG) A consortium of 30 UK Intensive Care Units collaborating in genomic studies of host response to severe life threatening infection. Leads: Dr CS Garrard (NDM) and Prof Charles Hinds (St Bartholomew's Hospital, London) see: http://www.ukccg-gains.org/

UKCCG currently participating in 2 large, multi-centre genome association studies in the UK (Genomic Advances in Sepsis - GAinS) and in Europe (Genetics of Sepsis - GenOSept). Funded by the Sainsbury Charitable Fund and 6th Framework programme of Research and Development - European Union) these studies are actively recruiting patients with sepsis syndrome admitted to Intensive Care Units in the UK and Europe with admission diagnoses of community acquired pneumonia, faecal peritonitis (GAinS) pancreatitis or meningococcal disease (GenOSept).  See also:  https://clinicaltrials.gov/

Name Department Institution Country
Professor Charles Hinds Barts and The Royal London United Kingdom
Professor Adrian VS Hill Jenner Institute Oxford University, Old Road Campus Research Building United Kingdom
Mark Caulfield Barts and London School of Medicine, London United Kingdom
Professor Richard F Mott Wellcome Trust Centre for Human Genetics Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Charles Mein Bart's and the London, School of Medicine United Kingdom
Professor Julian C Knight Wellcome Trust Centre for Human Genetics Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Tridente A, Bion J, Mills GH, Gordon AC, Clarke GM, Walden A, Hutton P, Holloway PAH, Chiche JD, Stuber F et al. 2017. Derivation and validation of a prognostic model for postoperative risk stratification of critically ill patients with faecal peritonitis. Ann Intensive Care, 7 (1), pp. 96. | Show Abstract | Read more

BACKGROUND: Prognostic scores and models of illness severity are useful both clinically and for research. The aim of this study was to develop two prognostic models for the prediction of long-term (6 months) and 28-day mortality of postoperative critically ill patients with faecal peritonitis (FP). METHODS: Patients admitted to intensive care units with faecal peritonitis and recruited to the European GenOSept study were divided into a derivation and a geographical validation subset; patients subsequently recruited to the UK GAinS study were used for temporal validation. Using all 50 clinical and laboratory variables available on day 1 of critical care admission, Cox proportional hazards regression was fitted to select variables for inclusion in two prognostic models, using stepwise selection and nonparametric bootstrapping sampling techniques. Using Area under the receiver operating characteristic curve (AuROC) analysis, the performance of the models was compared to SOFA and APACHE II. RESULTS: Five variables (age, SOFA score, lowest temperature, highest heart rate, haematocrit) were entered into the prognostic models. The discriminatory performance of the 6-month prognostic model yielded an AuROC 0.81 (95% CI 0.76-0.86), 0.73 (95% CI 0.69-0.78) and 0.76 (95% CI 0.69-0.83) for the derivation, geographic and temporal external validation cohorts, respectively. The 28-day prognostic tool yielded an AuROC 0.82 (95% CI 0.77-0.88), 0.75 (95% CI 0.69-0.80) and 0.79 (95% CI 0.71-0.87) for the same cohorts. These AuROCs appeared consistently superior to those obtained with the SOFA and APACHE II scores alone. CONCLUSIONS: The two prognostic models developed for 6-month and 28-day mortality prediction in critically ill septic patients with FP, in the postoperative phase, enhanced the day one SOFA score's predictive utility by adding a few key variables: age, lowest recorded temperature, highest recorded heart rate and haematocrit. External validation of their predictive capability in larger cohorts is needed, before introduction of the proposed scores into clinical practice to inform decision making and the design of clinical trials.

Burnham KL, Davenport EE, Radhakrishnan J, Humburg P, Gordon AC, Hutton P, Svoren-Jabalera E, Garrard C, Hill AVS, Hinds CJ, Knight JC. 2017. Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia. Am J Respir Crit Care Med, 196 (3), pp. 328-339. | Show Abstract | Read more

RATIONALE: Heterogeneity in the septic response has hindered efforts to understand pathophysiology and develop targeted therapies. Source of infection, with different causative organisms and temporal changes, might influence this heterogeneity. OBJECTIVES: To investigate individual and temporal variations in the transcriptomic response to sepsis due to fecal peritonitis, and to compare these with the same parameters in community-acquired pneumonia. METHODS: We performed genome-wide gene expression profiling in peripheral blood leukocytes of adult patients admitted to intensive care with sepsis due to fecal peritonitis (n = 117) or community-acquired pneumonia (n = 126), and of control subjects without sepsis (n = 10). MEASUREMENTS AND MAIN RESULTS: A substantial portion of the transcribed genome (18%) was differentially expressed compared with that of control subjects, independent of source of infection, with eukaryotic initiation factor 2 signaling being the most enriched canonical pathway. We identified two sepsis response signature (SRS) subgroups in fecal peritonitis associated with early mortality (P = 0.01; hazard ratio, 4.78). We defined gene sets predictive of SRS group, and serial sampling demonstrated that subgroup membership is dynamic during intensive care unit admission. We found that SRS is the major predictor of transcriptomic variation; a small number of genes (n = 263) were differentially regulated according to the source of infection, enriched for IFN signaling and antigen presentation. We define temporal changes in gene expression from disease onset involving phagosome formation as well as natural killer cell and IL-3 signaling. CONCLUSIONS: The majority of the sepsis transcriptomic response is independent of the source of infection and includes signatures reflecting immune response state and prognosis. A modest number of genes show evidence of specificity. Our findings highlight opportunities for patient stratification and precision medicine in sepsis.

Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, Rautanen A, Gordon AC, Garrard C, Hill AV et al. 2016. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med, 4 (4), pp. 259-271. | Show Abstract | Read more

BACKGROUND: Effective targeted therapy for sepsis requires an understanding of the heterogeneity in the individual host response to infection. We investigated this heterogeneity by defining interindividual variation in the transcriptome of patients with sepsis and related this to outcome and genetic diversity. METHODS: We assayed peripheral blood leucocyte global gene expression for a prospective discovery cohort of 265 adult patients admitted to UK intensive care units with sepsis due to community-acquired pneumonia and evidence of organ dysfunction. We then validated our findings in a replication cohort consisting of a further 106 patients. We mapped genomic determinants of variation in gene transcription between patients as expression quantitative trait loci (eQTL). FINDINGS: We discovered that following admission to intensive care, transcriptomic analysis of peripheral blood leucocytes defines two distinct sepsis response signatures (SRS1 and SRS2). The presence of SRS1 (detected in 108 [41%] patients in discovery cohort) identifies individuals with an immunosuppressed phenotype that included features of endotoxin tolerance, T-cell exhaustion, and downregulation of human leucocyte antigen (HLA) class II. SRS1 was associated with higher 14 day mortality than was SRS2 (discovery cohort hazard ratio (HR) 2·4, 95% CI 1·3-4·5, p=0·005; validation cohort HR 2·8, 95% CI 1·5-5·1, p=0·0007). We found that a predictive set of seven genes enabled the classification of patients as SRS1 or SRS2. We identified cis-acting and trans-acting eQTL for key immune and metabolic response genes and sepsis response networks. Sepsis eQTL were enriched in endotoxin-induced epigenetic marks and modulated the individual host response to sepsis, including effects specific to SRS group. We identified regulatory genetic variants involving key mediators of gene networks implicated in the hypoxic response and the switch to glycolysis that occurs in sepsis, including HIF1α and mTOR, and mediators of endotoxin tolerance, T-cell activation, and viral defence. INTERPRETATION: Our integrated genomics approach advances understanding of heterogeneity in sepsis by defining subgroups of patients with different immune response states and prognoses, as well as revealing the role of underlying genetic variation. Our findings provide new insights into the pathogenesis of sepsis and create opportunities for a precision medicine approach to enable targeted therapeutic intervention to improve sepsis outcomes. FUNDING: European Commission, Medical Research Council (UK), and the Wellcome Trust.

Mills TC, Chapman S, Hutton P, Gordon AC, Bion J, Chiche JD, Holloway PA, Stüber F, Garrard CS, Hinds CJ et al. 2015. Variants in the Mannose-binding Lectin Gene MBL2 do not Associate With Sepsis Susceptibility or Survival in a Large European Cohort. Clin Infect Dis, 61 (5), pp. 695-703. | Show Abstract | Read more

BACKGROUND: Sepsis is an increasingly common condition, which continues to be associated with unacceptably high mortality. A large number of association studies have investigated susceptibility to, or mortality from, sepsis for variants in the functionally important immune-related gene MBL2. These studies have largely been underpowered and contradictory. METHODS: We genotyped and analyzed 4 important MBL2 single nucleotide polymorphisms (SNPs; rs5030737, rs1800450, rs1800451, and rs7096206) in 1839 European community-acquired pneumonia (CAP) and peritonitis sepsis cases, and 477 controls from the United Kingdom. We analyzed the following predefined subgroups and outcomes: 28-day and 6 month mortality from sepsis due to CAP or peritonitis combined, 28-day mortality from CAP sepsis, peritonitis sepsis, pneumococcal sepsis or sepsis in younger patients, and susceptibility to CAP sepsis or pneumococcal sepsis in the United Kingdom. RESULTS: There were no significant associations (all P-values were greater than .05 after correction for multiple testing) between MBL2 genotypes and any of our predefined analyses. CONCLUSIONS: In this large, well-defined cohort of immune competent adult patients, no associations between MBL2 genotype and sepsis susceptibility or outcome were identified.

Tridente A, Clarke GM, Walden A, Gordon AC, Hutton P, Chiche JD, Holloway PAH, Mills GH, Bion J, Stüber F et al. 2015. Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: Analysis of the GenOSept cohort Critical Care, 19 (1), | Show Abstract | Read more

© 2015 Tridente et al.; licensee BioMed Central. Introduction: Patients admitted to intensive care following surgery for faecal peritonitis present particular challenges in terms of clinical management and risk assessment. Collaborating surgical and intensive care teams need shared perspectives on prognosis. We aimed to determine the relationship between dynamic assessment of trends in selected variables and outcomes. Methods: We analysed trends in physiological and laboratory variables during the first week of intensive care unit (ICU) stay in 977 patients at 102 centres across 16 European countries. The primary outcome was 6-month mortality. Secondary endpoints were ICU, hospital and 28-day mortality. For each trend, Cox proportional hazards (PH) regression analyses, adjusted for age and sex, were performed for each endpoint. Results: Trends over the first 7 days of the ICU stay independently associated with 6-month mortality were worsening thrombocytopaenia (mortality: hazard ratio (HR) = 1.02; 95% confidence interval (CI), 1.01 to 1.03; P < 0.001) and renal function (total daily urine output: HR =1.02; 95% CI, 1.01 to 1.03; P < 0.001; Sequential Organ Failure Assessment (SOFA) renal subscore: HR = 0.87; 95% CI, 0.75 to 0.99; P = 0.047), maximum bilirubin level (HR = 0.99; 95% CI, 0.99 to 0.99; P = 0.02) and Glasgow Coma Scale (GCS) SOFA subscore (HR = 0.81; 95% CI, 0.68 to 0.98; P = 0.028). Changes in renal function (total daily urine output and renal component of the SOFA score), GCS component of the SOFA score, total SOFA score and worsening thrombocytopaenia were also independently associated with secondary outcomes (ICU, hospital and 28-day mortality). We detected the same pattern when we analysed trends on days 2, 3 and 5. Dynamic trends in all other measured laboratory and physiological variables, and in radiological findings, changes inrespiratory support, renal replacement therapy and inotrope and/or vasopressor requirements failed to be retained as independently associated with outcome in multivariate analysis. Conclusions: Only deterioration in renal function, thrombocytopaenia and SOFA score over the first 2, 3, 5 and 7 days of the ICU stay were consistently associated with mortality at all endpoints. These findings may help to inform clinical decision making in patients with this common cause of critical illness.

Tridente A, Clarke GM, Walden A, Gordon AC, Hutton P, Chiche JD, Holloway PA, Mills GH, Bion J, Stüber F et al. 2015. Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort. Crit Care, 19 (1), pp. 210. | Show Abstract | Read more

INTRODUCTION: Patients admitted to intensive care following surgery for faecal peritonitis present particular challenges in terms of clinical management and risk assessment. Collaborating surgical and intensive care teams need shared perspectives on prognosis. We aimed to determine the relationship between dynamic assessment of trends in selected variables and outcomes. METHODS: We analysed trends in physiological and laboratory variables during the first week of intensive care unit (ICU) stay in 977 patients at 102 centres across 16 European countries. The primary outcome was 6-month mortality. Secondary endpoints were ICU, hospital and 28-day mortality. For each trend, Cox proportional hazards (PH) regression analyses, adjusted for age and sex, were performed for each endpoint. RESULTS: Trends over the first 7 days of the ICU stay independently associated with 6-month mortality were worsening thrombocytopaenia (mortality: hazard ratio (HR) = 1.02; 95% confidence interval (CI), 1.01 to 1.03; P < 0.001) and renal function (total daily urine output: HR =1.02; 95% CI, 1.01 to 1.03; P < 0.001; Sequential Organ Failure Assessment (SOFA) renal subscore: HR = 0.87; 95% CI, 0.75 to 0.99; P = 0.047), maximum bilirubin level (HR = 0.99; 95% CI, 0.99 to 0.99; P = 0.02) and Glasgow Coma Scale (GCS) SOFA subscore (HR = 0.81; 95% CI, 0.68 to 0.98; P = 0.028). Changes in renal function (total daily urine output and renal component of the SOFA score), GCS component of the SOFA score, total SOFA score and worsening thrombocytopaenia were also independently associated with secondary outcomes (ICU, hospital and 28-day mortality). We detected the same pattern when we analysed trends on days 2, 3 and 5. Dynamic trends in all other measured laboratory and physiological variables, and in radiological findings, changes in respiratory support, renal replacement therapy and inotrope and/or vasopressor requirements failed to be retained as independently associated with outcome in multivariate analysis. CONCLUSIONS: Only deterioration in renal function, thrombocytopaenia and SOFA score over the first 2, 3, 5 and 7 days of the ICU stay were consistently associated with mortality at all endpoints. These findings may help to inform clinical decision making in patients with this common cause of critical illness.

Cited:

42

Scopus

Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, Chiche JD, Parks T, Chapman SJ, Davenport EE et al. 2015. Genome-wide association study of survival from sepsis due to pneumonia: An observational cohort study The Lancet Respiratory Medicine, 3 (1), pp. 53-60. | Show Abstract | Read more

© 2015 Rautanen et al. Open Access article distributed under the terms of CC-BY-NC-SA. Background: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. Methods: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. Findings: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10 -8 ). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10 -8 (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10 -9 , after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. Interpretation: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. Funding: European Commission and the Wellcome Trust.

Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, Chiche JD, Parks T, Chapman SJ, Davenport EE et al. 2015. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med, 3 (1), pp. 53-60. | Show Abstract | Read more

BACKGROUND: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING: European Commission and the Wellcome Trust.

Walden AP, Clarke GM, McKechnie S, Hutton P, Gordon AC, Rello J, Chiche JD, Stueber F, Garrard CS, Hinds CJ, ESICM/ECCRN GenOSept Investigators. 2014. Patients with community acquired pneumonia admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Crit Care, 18 (2), pp. R58. | Show Abstract | Read more

INTRODUCTION: Community acquired pneumonia (CAP) is the most common infectious reason for admission to the Intensive Care Unit (ICU). The GenOSept study was designed to determine genetic influences on sepsis outcome. Phenotypic data was recorded using a robust clinical database allowing a contemporary analysis of the clinical characteristics, microbiology, outcomes and independent risk factors in patients with severe CAP admitted to ICUs across Europe. METHODS: Kaplan-Meier analysis was used to determine mortality rates. A Cox Proportional Hazards (PH) model was used to identify variables independently associated with 28-day and six-month mortality. RESULTS: Data from 1166 patients admitted to 102 centres across 17 countries was extracted. Median age was 64 years, 62% were male. Mortality rate at 28 days was 17%, rising to 27% at six months. Streptococcus pneumoniae was the commonest organism isolated (28% of cases) with no organism identified in 36%. Independent risk factors associated with an increased risk of death at six months included APACHE II score (hazard ratio, HR, 1.03; confidence interval, CI, 1.01-1.05), bilateral pulmonary infiltrates (HR1.44; CI 1.11-1.87) and ventilator support (HR 3.04; CI 1.64-5.62). Haematocrit, pH and urine volume on day one were all associated with a worse outcome. CONCLUSIONS: The mortality rate in patients with severe CAP admitted to European ICUs was 27% at six months. Streptococcus pneumoniae was the commonest organism isolated. In many cases the infecting organism was not identified. Ventilator support, the presence of diffuse pulmonary infiltrates, lower haematocrit, urine volume and pH on admission were independent predictors of a worse outcome.

Tridente A, Clarke GM, Walden A, McKechnie S, Hutton P, Mills GH, Gordon AC, Holloway PAH, Chiche JD, Bion J et al. 2014. Patients with faecal peritonitis admitted to European intensive care units: An epidemiological survey of the GenOSept cohort Intensive Care Medicine, 40 (2), pp. 202-210. | Show Abstract | Read more

Introduction: Faecal peritonitis (FP) is a common cause of sepsis and admission to the intensive care unit (ICU). The Genetics of Sepsis and Septic Shock in Europe (GenOSept) project is investigating the influence of genetic variation on the host response and outcomes in a large cohort of patients with sepsis admitted to ICUs across Europe. Here we report an epidemiological survey of the subset of patients with FP. Objectives: To define the clinical characteristics, outcomes and risk factors for mortality in patients with FP admitted to ICUs across Europe. Methods: Data was extracted from electronic case report forms. Phenotypic data was recorded using a detailed, quality-assured clinical database. The primary outcome measure was 6-month mortality. Patients were followed for 6 months. Kaplan-Meier analysis was used to determine mortality rates. Cox proportional hazards regression analysis was employed to identify independent risk factors for mortality. Results: Data for 977 FP patients admitted to 102 centres across 16 countries between 29 September 2005 and 5 January 2011 was extracted. The median age was 69.2 years (IQR 58.3-77.1), with a male preponderance (54.3 %). The most common causes of FP were perforated diverticular disease (32.1 %) and surgical anastomotic breakdown (31.1 %). The ICU mortality rate at 28 days was 19.1 %, increasing to 31.6 % at 6 months. The cause of FP, pre-existing co-morbidities and time from estimated onset of symptoms to surgery did not impact on survival. The strongest independent risk factors associated with an increased rate of death at 6 months included age, higher APACHE II score, acute renal and cardiovascular dysfunction within 1 week of admission to ICU, hypothermia, lower haematocrit and bradycardia on day 1 of ICU stay. Conclusions: In this large cohort of patients admitted to European ICUs with FP the 6 month mortality was 31.6 %. The most consistent predictors of mortality across all time points were increased age, development of acute renal dysfunction during the first week of admission, lower haematocrit and hypothermia on day 1 of ICU admission. © 2013 Springer-Verlag Berlin Heidelberg and ESICM.

Mills TC, Rautanen A, Elliott KS, Parks T, Naranbhai V, Ieven MM, Butler CC, Little P, Verheij T, Garrard CS et al. 2014. IFITM3 and susceptibility to respiratory viral infections in the community. J Infect Dis, 209 (7), pp. 1028-1031. | Show Abstract | Read more

Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM 1,2, and 3) are viral restriction factors that mediate cellular resistance to several viruses. We have genotyped a possible splice-site altering single-nucleotide polymorphism (rs12252) in the IFITM3 gene in 34 patients with H1N1 influenza and severe pneumonia, and >5000 individuals comprising patients with community-acquired mild lower respiratory tract infection and matched controls of Caucasian ancestry. We found evidence of an association between rs12252 rare allele homozygotes and susceptibility to mild influenza (in patients attending primary care) but could not confirm a previously reported association between this single-nucleotide polymorphism and susceptibility to severe H1N1 infection.

Tridente A, Clarke GM, Walden A, McKechnie S, Hutton P, Mills GH, Gordon AC, Holloway PA, Chiche JD, Bion J et al. 2014. Patients with faecal peritonitis admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Intensive Care Med, 40 (2), pp. 202-210. | Show Abstract | Read more

INTRODUCTION: Faecal peritonitis (FP) is a common cause of sepsis and admission to the intensive care unit (ICU). The Genetics of Sepsis and Septic Shock in Europe (GenOSept) project is investigating the influence of genetic variation on the host response and outcomes in a large cohort of patients with sepsis admitted to ICUs across Europe. Here we report an epidemiological survey of the subset of patients with FP. OBJECTIVES: To define the clinical characteristics, outcomes and risk factors for mortality in patients with FP admitted to ICUs across Europe. METHODS: Data was extracted from electronic case report forms. Phenotypic data was recorded using a detailed, quality-assured clinical database. The primary outcome measure was 6-month mortality. Patients were followed for 6 months. Kaplan-Meier analysis was used to determine mortality rates. Cox proportional hazards regression analysis was employed to identify independent risk factors for mortality. RESULTS: Data for 977 FP patients admitted to 102 centres across 16 countries between 29 September 2005 and 5 January 2011 was extracted. The median age was 69.2 years (IQR 58.3-77.1), with a male preponderance (54.3%). The most common causes of FP were perforated diverticular disease (32.1%) and surgical anastomotic breakdown (31.1%). The ICU mortality rate at 28 days was 19.1%, increasing to 31.6% at 6 months. The cause of FP, pre-existing co-morbidities and time from estimated onset of symptoms to surgery did not impact on survival. The strongest independent risk factors associated with an increased rate of death at 6 months included age, higher APACHE II score, acute renal and cardiovascular dysfunction within 1 week of admission to ICU, hypothermia, lower haematocrit and bradycardia on day 1 of ICU stay. CONCLUSIONS: In this large cohort of patients admitted to European ICUs with FP the 6 month mortality was 31.6%. The most consistent predictors of mortality across all time points were increased age, development of acute renal dysfunction during the first week of admission, lower haematocrit and hypothermia on day 1 of ICU admission.

Tridente A, Clarke GM, Walden A, McKechnie SR, Hutton P, Martynoga R, Mills GH, Gordon AC, Stueber F, Garrard C, Hinds C. 2011. EPIDEMIOLOGY OF FAECAL PERITONITIS IN THE GENOSEPT COHORT INTENSIVE CARE MEDICINE, 37 pp. S199-S199.

Walden AP, Garrard CS, Salmon J. 2010. Sustained effects of thoracocentesis on oxygenation in mechanically ventilated patients. Respirology, 15 (6), pp. 986-992. | Show Abstract | Read more

BACKGROUND AND OBJECTIVE: No consensus exists as to the benefit of pleural drainage in mechanically ventilated patients with conflicting data concerning the effects on gas exchange. We determined the effects on gas exchange over a 48-hour period of draining, by thoracocentesis, large volume pleural effusions. METHODS: A total of 15 thoracocenteses were performed in 10 mechanically ventilated patients with ultrasound evidence of pleural effusions predicted to be greater than 800 mL in volume. Gas exchange, mixed expired CO2, dynamic lung compliance, ventilator settings before procedure and at 30 min, 4, 8, 24 and 48 h were determined. Data were analysed using paired t-tests and repeated-measure anova. RESULTS: Following thoracocentesis there was a 40% increase in the PaO(2) from 82.0 +/- 10.6 mm Hg to 115.2 +/- 31.1 mm Hg (P < 0.05) with a 34% increase in the P:F ratio from 168.9 +/- 55.9 mm Hg to 237.8 +/- 72.6 mm Hg (P < 0.05). These effects were maintained for a period of 48 h. There was a correlation between the amount of fluid drained and the effects on oxygenation with an increase in the PaO(2) of 4 mm Hg for each 100 mL of pleural fluid drained. A-a gradients continued to improve over the course of the study together with a reduction in the dead space fraction and improved dynamic compliance. CONCLUSIONS: Drainage of large pleural effusions in mechanically ventilated patients leads to a significant improvement in gas exchange, and these effects are sustained for 48 h after the procedure supporting a role in the discontinuation of mechanical ventilation.

Determann RM, Millo JL, Garrard CS, Schultz MJ. 2006. Bronchoalveolar levels of plasminogen activator inhibitor-1 and soluble tissue factor are sensitive and specific markers of pulmonary inflammation. Intensive Care Med, 32 (6), pp. 946-947. | Read more

Gordon AC, Waheed U, Hansen TK, Hitman GA, Garrard CS, Turner MW, Klein NJ, Brett SJ, Hinds CJ. 2006. Mannose-binding lectin polymorphisms in severe sepsis: relationship to levels, incidence, and outcome. Shock, 25 (1), pp. 88-93. | Show Abstract | Read more

Mannose-binding lectin (MBL) genetic polymorphisms result in deficiency of the encoded protein and increased susceptibility to infection, especially in children and the immunocompromised. The objective of this study was to investigate the relationship between MBL-2 exon 1 and promoter -221 polymorphisms, plasma levels of the encoded protein, and the incidence and outcome of severe sepsis and septic shock. One hundred seventy-four white adult patients with severe sepsis or septic shock were recruited in a prospective multicenter study across eight intensive care units in the South of England, UK. Genotype and haplotype frequencies were compared between normal population controls and patients, and between survivors and nonsurvivors. Plasma levels of encoded protein were related to genotype and outcome. The exon 1 polymorphisms (A/O or O/O) were significantly more common in the patients with severe sepsis and septic shock than in normal healthy adults (54.6% vs. 39.7%, P = 0.001), and there was a significant difference in haplotype frequency between controls and septic patients (P < 0.0001). There was no significant difference in MBL-2 genotype or haplotype frequency between survivors and nonsurvivors. There was a strong relationship between MBL-2 haplotype and plasma MBL concentration (P < 0.001). Individual plasma levels were variable and increased between days 1 and 7. The mortality rate was higher in those with MBL levels <1000 microg/L than in those patients with levels >1000 microg/L (47.2 vs. 22.2%, P = 0.05). We conclude that genetic polymorphisms resulting in mannose-binding lectin deficiency are associated with increased susceptibility to sepsis. The close relationship between polymorphic variants and plasma MBL concentration persists during sepsis but individual levels vary widely. Lower circulating MBL levels are associated with a poor outcome.

Determann RM, Millo JL, Gibot S, Korevaar JC, Vroom MB, van der Poll T, Garrard CS, Schultz MJ. 2005. Serial changes in soluble triggering receptor expressed on myeloid cells in the lung during development of ventilator-associated pneumonia. Intensive Care Med, 31 (11), pp. 1495-1500. | Show Abstract | Read more

OBJECTIVE: To determine the diagnostic role of soluble triggering receptor expressed on myeloid cells (sTREM)-1 in non-directed bronchial lavage fluid in ventilator-associated pneumonia (VAP). DESIGN: Non-directed bronchial lavage fluid and plasma were collected on alternate days in critically ill mechanically ventilated patients from the start of ventilatory support until complete weaning from the ventilator. Soluble TREM-1 levels were measured by an enzyme-linked immunosorbent assay. SETTING: A general adult medical and surgical university hospital intensive care unit. PATIENTS: Nine patients who developed VAP and 19 patients who did not develop VAP (controls). RESULTS: Plasma levels of sTREM-1 did not change significantly in either patient group. While in controls concentrations of sTREM-1 in non-directed bronchial lavage fluid did not change significantly over time, in patients who developed VAP levels of sTREM-1 in non-directed bronchial lavage fluid increased towards the diagnosis of VAP. A cut-off value for non-directed bronchial lavage fluid sTREM-1 levels of 200 pg/ml on the day of VAP had a diagnostic sensitivity of 75% and a specificity of 84%. Sensitivity increased when taking into account all sTREM-1 levels higher than 200 pg/ml from the 6-day period before the day of diagnosis that were preceded by an increase of at least 100 pg/ml (sensitivity 88%, specificity 84%). CONCLUSIONS: Soluble TREM-1 is a potential biomarker of VAP.

Choi G, Schultz MJ, Levi M, van der Poll T, Millo JL, Garrard CS. 2005. Protein C in pneumonia. Thorax, 60 (8), pp. 705-706. | Read more

Gordon AC, Lagan AL, Aganna E, Cheung L, Peters CJ, McDermott MF, Millo JL, Welsh KI, Holloway P, Hitman GA et al. 2004. TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study. Genes Immun, 5 (8), pp. 631-640. | Show Abstract | Read more

Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis. Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results. This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock. A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia. Plasma levels of TNF (P = 0.02), sTNFRSF1A (P = 0.005) and sTNFRSF1B (P = 0.01) were significantly higher in those who died on ICU compared to those who survived. There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R = 0.51, P < 0.001; sTNFRSF1B R = 0.53, P < 0.001), and in particular with the degree of renal dysfunction. In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome. The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.

Schultz MJ, Millo J, Levi M, Hack CE, Weverling GJ, Garrard CS, van der Poll T. 2004. Local activation of coagulation and inhibition of fibrinolysis in the lung during ventilator associated pneumonia. Thorax, 59 (2), pp. 130-135. | Show Abstract | Read more

BACKGROUND: Fibrin deposition is a hallmark of pneumonia. To determine the kinetics of alterations in local coagulation and fibrinolysis in relation to ventilator associated pneumonia (VAP), a single centre prospective study of serial changes in pulmonary and systemic thrombin generation and fibrinolytic activity was conducted in patients at risk for VAP. METHODS: Non-directed bronchial lavage (NBL) was performed on alternate days in patients expected to require mechanical ventilation for more than 5 days. A total of 28 patients were studied, nine of whom developed VAP. RESULTS: In patients who developed VAP a significant increase in thrombin generation was observed in the airways, as reflected by a rise in the levels of thrombin-antithrombin complexes in NBL fluid accompanied by increases in soluble tissue factor and factor VIIa concentrations. The diagnosis of VAP was preceded by a decrease in fibrinolytic activity in NBL fluid. Indeed, before VAP was diagnosed clinically, plasminogen activator activity levels in NBL fluid gradually declined, which appeared to be caused by a sharp increase in NBL fluid levels of plasminogen activator inhibitor 1. CONCLUSION: VAP is characterised by a shift in the local haemostatic balance to the procoagulant side, which precedes the clinical diagnosis of VAP.

Millo JL, Schultz MJ, Williams C, Weverling GJ, Ringrose T, Mackinlay CI, van der Poll T, Garrard CS. 2004. Compartmentalisation of cytokines and cytokine inhibitors in ventilator-associated pneumonia. Intensive Care Med, 30 (1), pp. 68-74. | Show Abstract | Read more

OBJECTIVE: To examine whether cytokine concentrations change in the pulmonary compartment during the development of ventilator-associated pneumonia (VAP). DESIGN: Non-directed bronchial lavage (NBL) was performed every 48 h in critically ill mechanically ventilated patients. Serial measurements of the cytokines tumor necrosis factor (TNF) alpha, interleukin (IL)-1alpha, IL-1beta, IL-6, and IL-10 and the cytokine inhibitors soluble TNFalpha receptor type I (sTNFalphaRI), IL-1 receptor antagonist (IL-1Ra) and soluble IL-1 receptor II (sIL-1RII) were performed on the NBL fluid and matching plasma samples by ELISA. SETTING: An adult medical and surgical university hospital intensive care unit. PATIENTS: Nine patients who developed VAP and nineteen patients who did not develop VAP served as controls. INTERVENTIONS: None. RESULTS: Plasma concentrations of the measured cytokines and cytokine inhibitors did not change significantly in any patients. In control patients, NBL fluid concentrations of sIL-1RII decreased significantly over time (P=0.01). In patients who developed VAP, NBL fluid concentrations of TNFalpha, sTNFalphaRI, IL-1alpha, and IL-1beta increased significantly (P=0.002, P=0.03, P=0.04 and P=0.02, respectively). Furthermore, NBL fluid/plasma concentration ratios for TNFalpha, sTNFalphaRI, IL-1alpha, IL-1Ra and IL-6 increased significantly as VAP developed (P=0.001, P=0.001, P=0.04, P=0.03, and P=0.04, respectively). CONCLUSION: Our results suggest that the production of important cytokines and cytokine inhibitors is compartmentalised within the lung in critically ill mechanically ventilated patients who develop VAP.

Roche RJ, Farmery AD, Garrard CS. 2003. Outcome for cardiothoracic surgical patients requiring multidisciplinary intensive care. Eur J Anaesthesiol, 20 (9), pp. 719-725. | Show Abstract | Read more

BACKGROUND AND OBJECTIVE: Patients who require multidisciplinary intensive care after cardiac surgery have a poor prognosis. The aim was to investigate factors in the mortality of this group of patients at 6 months. METHODS: A retrospective analysis was made of the 6-month mortality rate in 301 adults who required admission to a multidisciplinary intensive care unit following cardiac surgery from 1991 to 1997. Mortality was correlated with clinical and patient characteristic variables. RESULTS: The intensive care mortality rate was 34% and at 6 months after patients' discharge from intensive care it was 51%. There were positive correlations with death at 6 months for ventricular failure (odds ratio of death 3.4, P = 0.002), sepsis (odds ratio 3.0, P = 0.004) and age over 80 yr (odds ratio of death 9.2, P = 0.034). Patients who had undergone isolated coronary artery graft surgery (odds ratio of death 0.28, P = 0.036) or thoracic surgery (odds ratio of death 0.22, P = 0.042) had better 6-month outcomes. Patients with respiratory or renal failure in the absence of ventricular failure or sepsis had a 6-month mortality rate of 36%; but the lower mortality rate did not achieve statistical significance. CONCLUSIONS: The 6-month mortality rate of 51% in a group of patients requiring multidisciplinary intensive care after cardiac surgery is consistent with previous studies; mortality was particularly high in extreme old age and in patients referred with sepsis or ventricular failure. Those patients with uncomplicated respiratory or renal failure had a better outcome than the group as a whole.

Phipps P, Garrard CS. 2003. The pulmonary physician in critical care . 12: Acute severe asthma in the intensive care unit. Thorax, 58 (1), pp. 81-88. | Show Abstract | Read more

Most deaths from acute asthma occur outside hospital, but the at-risk patient may be recognised on the basis of prior ICU admission and asthma medication history. Patients who fail to improve significantly in the emergency department should be admitted to an HDU or ICU for observation, monitoring, and treatment. Hypoxia, dehydration, acidosis, and hypokalaemia render the severe acute asthmatic patient vulnerable to cardiac dysrrhythmia and cardiorespiratory arrest. Mechanical ventilation may be required for a small proportion of patients for whom it may be life saving. Aggressive bronchodilator (continuous nebulised beta agonist) and anti-inflammatory therapy must continue throughout the period of mechanical ventilation. Recognised complications of mechanical ventilation include hypotension, barotrauma, and nosocomial pneumonia. Low ventilator respiratory rates, long expiratory times, and small tidal volumes help to prevent hyperinflation. Volatile anaesthetic agents may produce bronchodilation in patients resistant to beta agonists. Fatalities in acute asthmatics admitted to HDU/ICU are rare.

Millo JL, Schultz MJ, Van der Poll T, Garrard CS. 2001. Compartmentalised cytokine production due to ventilator-associated pneumonia CRITICAL CARE MEDICINE, 29 (12), pp. A107-A107.

MacKenzie IM, Garrard CS, Young JD. 2001. Indices of nitric oxide synthesis and outcome in critically ill patients. Anaesthesia, 56 (4), pp. 326-330. | Show Abstract | Read more

We measured the concentrations of serum nitrates/nitrites and plasma cyclic guanosine monophosphate as markers of nitric oxide synthesis in patients with or without septic shock for 5 days following admission to intensive care. We found that nitrate/nitrite concentrations, when corrected for the effect of renal failure, were significantly higher in patients with septic shock, both on admission and in the final samples drawn. In a logistic regression analysis, the rate of change of nitrate/nitrite concentration was associated with survival to day 28 (falling in survivors). The concentration of cyclic guanosine monophosphate when corrected for the confounding effects of renal function and platelet count, was only associated with the septic shock group on admission.

Garrard CS. 2000. Human-computer interactions: can computers improve the way doctors work? Schweiz Med Wochenschr, 130 (42), pp. 1557-1563. | Show Abstract

As medicine becomes more complex and the knowledge base expands, the integration of computer systems into clinical practice would appear to be an inescapable necessity rather than an option. The issues of security and reliability have largely been solved by industrial and business applications of computer technology. The larger challenge lies in designing convenient, efficient and acceptable interfaces between the clinician and computer for data input and presentation. In the future, decision making algorithms are likely to assist the clinician in diagnosis and management to a degree that should significantly improve clinical effectiveness.

Bailey CM, Thompson-Fawcett MW, Kettlewell MG, Garrard C, Mortensen NJ. 2000. Laparostomy for severe intra-abdominal infection complicating colorectal disease. Dis Colon Rectum, 43 (1), pp. 25-30. | Show Abstract | Read more

PURPOSE: The aim of this study was to evaluate the use of laparostomy in the management of patients with severe intra-abdominal infection resulting from colorectal disease. METHODS: Seven patients, four with inflammatory bowel disease, two with colorectal carcinoma, and one with diverticular perforation, underwent laparostomy during a six-year period for postoperative, severe, intra-abdominal infection. RESULTS: The median age was 42 years, the mean Acute Physiology and Chronic Health Evaluation II score was 22.7, and the observed mortality was 28.6 percent (2/7 patients). In one patient the laparostomy was closed at 11 days; in all the others the wound was left to heal by granulation and contraction, and two of these later required reconstructive surgery. The median follow-up was three years and seven months. CONCLUSION: Laparostomy is an effective and practical method of managing patients with severe intra-abdominal infection as a result of colorectal disease.

Ringrose T, Garrard C. 1999. Suboptimal ward care of critically ill patients. Doctors don't review patients that nurses identify as highly dependent. BMJ, 318 (7175), pp. 52.

Garrard C, Young D. 1998. Suboptimal care of patients before admission to intensive care. is caused by a failure to appreciate or apply the ABCs of life support. BMJ, 316 (7148), pp. 1841-1842.

Evans KD, Benham SW, Garrard CS. 1998. A comparison of handwritten and computer-assisted prescriptions in an intensive care unit. Crit Care, 2 (2), pp. 73-78. | Show Abstract | Read more

BACKGROUND: We conducted a prospective comparative study to evaluate the potential benefit of computer-assisted prescribing (CAP). We compared the accuracy, completeness and time use of CAP with that of conventional handwritten prescribing at the intensive care unit (ICU) of the John Radcliffe Hospital, Oxford, UK. RESULTS: Twenty-five clinicians and 2409 drug entries were evaluated for accuracy, completeness, legibility and time spent prescribing. One hundred and twenty-eight handwritten and 110 CAP charts were monitored. One hundred percent of CAP charts were complete compared to 47% of handwritten charts.Drug prescriptions were divided into three categories: intravenous fluids, intravenous infusions and intermittent drugs. Percentage of correct entries in each category were 64%, 47.5% and 90% for handwritten, compared to 48%, 32% and 90% for CAP charts, respectively.The mean time taken to prescribe was 20 s for hand written prescribing and 55 s for CAP. CONCLUSIONS: Computer-assisted prescriptions were more complete, signed and dated than handwritten prescriptions. Errors in prescribing, including failure to discontinue a drug were not reduced by CAP. Handwritten prescribing was quicker than CAP. Simple enhancements of the computer software could be introduced which might overcome these deficiencies. CAP was successfully integrated into clinical practice in the ICU.

Young JD, Mackenzie IM, Garrard CS. 1997. Nitric oxide production. Intensive Care Med, 23 (6), pp. 710.

Mortensen N, Garrard CS. 1996. Colorectal surgery comes in from the cold. N Engl J Med, 334 (19), pp. 1263-1264. | Read more

Chakraverty R, Davidson S, Peggs K, Stross P, Garrard C, Littlewood TJ. 1996. The incidence and cause of coagulopathies in an intensive care population. Br J Haematol, 93 (2), pp. 460-463. | Show Abstract | Read more

We studied 235 patients admitted to an adult intensive care unit in order to determine the incidence and cause of coagulation disturbances. Clinical coagulopathy, defined as bleeding unexplained by local or surgical factors, was identified in 13.6% of patients. Laboratory evidence of coagulopathy was more common: a prothrombin time (PT) ratio > or = 1.5 was found in 66% of patients and a platelet count <100 x 10(9)/l in 38% of patients. Both factors were predictive of excessive bleeding and poor outcome. In a retrospective analysis of plasmas from 45 of the above patients who had PT ratios > or = 1.5 the most common cause was vitamin K deficiency (20%).

Bernardi L, Radaelli A, Solda PL, Coats AJ, Reeder M, Calciati A, Garrard CS, Sleight P. 1996. Autonomic control of skin microvessels: assessment by power spectrum of photoplethysmographic waves. Clin Sci (Lond), 90 (5), pp. 345-355. | Show Abstract | Read more

1. Although it is well known that the microvessels of the skin constantly undergo spontaneous variations in volume, the significance of these rhythmic changes remains uncertain. 2. In 10 healthy males and in 15 patients in intensive care, we assessed the origin of the autonomic influences on spontaneous fluctuations in the microcirculation of the skin, obtained by an infra-red photoplethysmographic device; we used spectral analysis techniques to compare these fluctuations (which were recorded simultaneously in two sites) with those of blood pressure, in order to test the presence of autonomic control of any synchronous fluctuations in these different measurements from the cardiovascular system. In order to minimize mechanical fluctuations caused by occasional slow breaths, rather than nervously mediated fluctuations in skin blood flow, respiration was controlled at 15 breaths/min (0.25 Hz). 3. Spontaneous infra-red photoplethysmographic fluctuations were observed in different body areas (left index finger and left ear lobe, right and left index finger), and all were evident at 0.1 Hz, as well as respiration-related components at 0.25 Hz. Active standing increased the power of the 0.1 Hz fluctuations (sympathetic activity) in both blood pressure (from 62.7 +/- 7.1 to 79.2 +/- 3.7 normalized units, P < 0.05) and IRP (finger: from 68.5 +/- 6.4 to 86.9 +/- 3.4 normalized units, P < 0.05; ear: from 59.0 +/- 5.9 to 88.1 +/- 2.0, P < 0.01). There was a high (> 0.5) coherence between the fluctuations obtained in blood pressure, in IRP signals obtained simultaneously at the finger and at the ear, and in R-R interval. This synchronization between the oscillations in all these signals, which were unrelated to the respiratory frequency or to the pulse rate, suggests a common neural, non-local origin. The phase between IRP and blood pressure was positive in the 0.1 Hz region (+1.65 +/- 0.41 radians, i.e. IRP was leading blood pressure, showing that 0.1 Hz fluctuations were not passively transmitted to the skin microvessels from large arteries) and negative in the 0.25 Hz region (-0.74 +/- 0.19 radians, P < 0.01 compared with phase in the 0.1 Hz region, i.e. IRP was lagging behind blood pressure, suggesting possible passive transmission to the skin microvessels of blood pressure fluctuations caused by respiration). Fluctuations at lower frequency were observed in all IRP recordings, suggesting a local origin for these. Intra-arterial and IRP fluctuations were compared in the 15 intensive care patients and gave similar results. 4. The skin microcirculation is thus not only under local control, but also reflects changes in sympathetic activity; the effect of these changes on the skin microcirculation can be easily evaluated by the spectral analysis of the IRP signal obtained simultaneously in multiple areas, in conjunction with the spectra of R-R interval and blood pressure.

Mackenzie IM, Ekangaki A, Young JD, Garrard CS. 1996. Effect of renal function on serum nitrogen oxide concentrations. Clin Chem, 42 (3), pp. 440-444. | Show Abstract

Nitric oxide is too short-lived to measure in vivo, but its production can be estimated by measuring its stable oxidation products, nitrites and nitrates, in serum. Renal elimination of these ions has been demonstrated, but the effect of renal function on their concentrations in serum is currently unknown. We evaluated serum and urine nitrates + nitrites as serum nitrogen oxides (sNOx), nitrogen oxide (NOx) clearance, and creatinine clearance in 71 patients on the Intensive Therapy Unit. The correlation between sNOx and plasma creatinine was strong and highly significant (P <0.001). These results suggest that renal function has a significant effect on sNOx concentrations. Studies in which the sNOx concentration is used as an index of nitric oxide production can therefore be interpreted only if renal function has been taken into account.

Garrard CS, A'Court CD. 1995. The diagnosis of pneumonia in the critically ill. Chest, 108 (2 Suppl), pp. 17S-25S. | Read more

Piepoli M, Garrard CS, Kontoyannis DA, Bernardi L. 1995. Autonomic control of the heart and peripheral vessels in human septic shock. Intensive Care Med, 21 (2), pp. 112-119. | Show Abstract | Read more

OBJECTIVE: Circulating endotoxin impairs the sympathetic regulation of the cardiovascular system in animals. We studied the changes in the autonomic control of the heart and circulation during septic shock in humans. DESIGN: 12 patients (age 43.0 +/- 6, 17-83 years) were investigated during septic shock (mean duration: 3.5 +/- 0.5 days) and during recovery, fluctuations in R-R interval, invasive arterial pressure (AP) and peripheral arteriolar circulation (PC, photoplethysmography) were evaluated by spectral analysis as a validated noninvasive measure of sympathovagal tone. Apache II score was adopted as the disease severity index. Low frequency components (0.03-0.15 Hz) of the frequency spectra were expressed as relative to the overall variability (LFnu) for each cardiovascular variable. RESULTS: LFnu were low or absent during shock but, in the 10 patients who recovered, increased by the time of discharge (post-shock). R-R LFnu increased from 17 +/- 6 to 47 +/- 9 (p < 0.03), AP LFnu from 6 +/- 3 to 35 +/- 4 (p < 0.02) and PC LFnu from 18 +/- 3 to 66 +/- 4 (p < 0.001). Apache II fell from 23.1 +/- 1, at admission, to 14.8 +/- 1.8 at discharge (p < 0.005). Two patients died showing no LFnu increase. CONCLUSION: Reduced LF components of the variability of cardiovascular signals are characteristic of septic shock, confirming the presence of abnormal autonomic control. Restored sympathetic (LF) modulation seems to be associated with a favourable prognosis.

Howell SJ, Wanigasekera V, Young JD, Gavaghan D, Sear JW, Garrard CS. 1995. Effects of propofol and thiopentone, and benzodiazepine premedication on heart rate variability measured by spectral analysis. Br J Anaesth, 74 (2), pp. 168-173. | Show Abstract | Read more

We studied the effects of temazepam premedication and induction of anaesthesia with thiopentone or propofol on the heart rate power spectrum in 47 patients undergoing elective minor surgery. Eighteen patients received temazepam 20 mg orally as premedication. There was a significant reduction in high frequency power and total power, and an increase in the ratio of low to high frequency power after induction of anaesthesia with either propofol or thiopentone. Patients who had received temazepam premedication had significantly greater low frequency, high frequency and total power than those who were not premedicated. There was no significant difference between premedicated and unpremedicated patients in the ratio of low to ventilatory frequency power.

Mackenzie IM, Young JD, Garrard CS. 1994. Serum nitrates as markers of postoperative morbidity. Lancet, 344 (8919), pp. 410. | Read more

Fisher CJ, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ, Rackow EC, Shapiro MJ, Greenman RL. 1994. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA, 271 (23), pp. 1836-1843. | Show Abstract | Read more

OBJECTIVE: To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome. STUDY DESIGN: Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. POPULATION: A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo. OUTCOME MEASURE: Twenty-eight-day all-cause mortality. RESULTS: There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n = 893; generalized Wilcoxon statistic, P = .22) or among patients with shock at study entry (n = 713; generalized Wilcoxon statistic, P = .23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n = 563; linear dose-response, P = .009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n = 580; linear dose-response, P = .005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n = 411; linear dose-response, P = .002). CONCLUSIONS: There was not a statistically significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater.

Gordon AC, Pryn S, Collin J, Gray DW, Hands L, Garrard C. 1994. Outcome in patients who require renal support after surgery for ruptured abdominal aortic aneurysm. Br J Surg, 81 (6), pp. 836-838. | Show Abstract | Read more

Over a 3-year period haemofiltration and dialysis was provided for 18 patients who developed renal failure after operation for ruptured abdominal aortic aneurysm (AAA). Four of the patients underwent operation elsewhere and were transferred when renal failure was diagnosed. The median duration of renal support in the 11 survivors was 24 days, while the seven patients who died received support for a median of 11 days. By 3 months after operation eight of the 11 survivors were independent of dialysis. Renal support was life saving in eight of 91 patients operated on in Oxford for ruptured AAA and reduced the 30-day operative mortality rate from a potential 47 per cent to an actual 38 per cent. Haemofiltration and haemodialysis for acute renal failure after surgery for ruptured aortic aneurysm is clinically justified and results in the long-term survival of most patients.

A'Court CH, Garrard CS, Crook D, Bowler I, Conlon C, Peto T, Anderson E. 1993. Microbiological lung surveillance in mechanically ventilated patients, using non-directed bronchial lavage and quantitative culture. Q J Med, 86 (10), pp. 635-648. | Show Abstract | Read more

We surveyed bronchial microflora by alternate-day, non-directed bronchial lavage (NBL) in 150 patients requiring mechanical ventilation on an intensive care unit. This simple technique uses a 20 ml non-bronchoscopic lung lavage, then quantitative bacterial culture. NBL bacteriological findings were identical to those obtained by same-day bronchoscopic broncho-alveolar lavage on 16/20 occasions. Using serial NBLs, the bronchial bacterial population was characterized during 65 episodes of pneumonia defined by clinical and retrospective criteria. Mean bacterial colony counts increased significantly during the 2 days preceding the clinical onset of pneumonia, from < or = 10(3) cfu/ml to > or = 10(5) cfu/ml (p < 0.05). In 51 patients showing a clinical response to antibiotic treatment, mean colony counts fell significantly after antibiotic initiation (p < 0.05). By contrast, in 14 patients who showed progressive clinical deterioration or relapse, there was no significant fall in NBL counts, and serial NBLs revealed antibiotic resistance or superinfection. The surveillance data altered clinical management in 42% of patients. Positive NBLs guided the choice of antibiotics, whilst negative NBLs encouraged the withholding of antibiotics, or detection of alternative pathology. We propose routine bacteriological lung surveillance of mechanically ventilated patients using this simple, inexpensive and safe technique.

FINFER S, GARRARD C. 1993. PRESSURE-CONTROLLED VENTILATION IN ASTHMA BRITISH JOURNAL OF HOSPITAL MEDICINE, 50 (5), pp. 281-281.

Finfer SR, Garrard CS. 1993. Ventilatory support in asthma. Br J Hosp Med, 49 (5), pp. 357-360. | Show Abstract

Mechanical ventilation in acute asthma is associated with significant morbidity and mortality, and maximal medical therapy should prevent it being used inappropriately. We review current standards of medical therapy in acute asthma, the indications for mechanical ventilation and its management.

Fisher CJ, Opal SM, Dhainaut JF, Stephens S, Zimmerman JL, Nightingale P, Harris SJ, Schein RM, Panacek EA, Vincent JL. 1993. Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group. Crit Care Med, 21 (3), pp. 318-327. | Show Abstract | Read more

OBJECTIVES: To determine the safety, pharmacokinetics, and activity of an anti-tumor necrosis factor (TNF)-alpha monoclonal antibody in severe sepsis. DESIGN: Open-label, prospective, phase II multicenter trial with escalating doses of a murine monoclonal antibody (CB0006). SETTING: Twelve academic medical center intensive care units in the United States and Europe. PATIENTS: Eighty patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy in addition to the anti-TNF antibody. INTERVENTIONS: Patients were treated intravenously with one of four dosing regimens with CB0006: 0.1 mg/kg, 1.0 mg/kg, 10 mg/kg or two doses of 1 mg/kg 24 hrs apart. MEASUREMENTS AND MAIN RESULTS: The murine monoclonal anti-TNF antibody was well tolerated despite the development of anti-murine antibodies in 98% of patients. No survival benefit was found for the total study population, but patients with increased circulating TNF concentrations at study entry appeared to benefit by the high dose anti-TNF antibody treatment. Increased interleukin (IL)-6 levels predicted a fatal outcome (p = .003), but TNF levels were not found to be a prognostic indicator. TNF levels were higher (206.7 +/- 60.7 vs. 85.9 +/- 26.1 pg/mL; p < .001) and outcome was poor (41% vs. 71% survival; p = .007) in patients who were in shock at study entry when compared with septic patients not in shock. CONCLUSIONS: The murine anti-TNF-alpha monoclonal antibody CB0006 has proven to be safe in this clinical trial and may prove to be useful in septic patients with increased circulating TNF concentrations. Further studies are needed to determine efficacy and the ultimate clinical utility of this immunotherapeutic agent in sepsis.

Garrard CS, Kontoyannis DA, Piepoli M. 1993. Spectral analysis of heart rate variability in the sepsis syndrome. Clin Auton Res, 3 (1), pp. 5-13. | Show Abstract | Read more

Sympathetic and parasympathetic activity was evaluated on 39 occasions in 17 patients with the sepsis syndrome, by measurement of the variation in resting heart rate using frequency spectrum analysis. Heart rate was recorded by electrocardiography and respiratory rate by impedance plethysmography. The sepsis syndrome was established on the basis of established clinical and physiological criteria. Subjects were studied, whenever possible, during the period of sepsis and during recovery. Spectral density of the beat-to-beat heart rate was measured within the low frequency band 0.04 to 0.10 Hz (low frequency power, LFP) modulated by sympathetic and parasympathetic activity, and within a 0.12 Hz band width at the respiratory frequency mode (respiratory frequency power, RFP) modulated by parasympathetic activity. Results were expressed as the total variability (total area beneath the power spectrum), as the spectral components normalized to the total power (LFPn, RFPn) or as the ratio of LFP/RFP. During the sepsis syndrome, total heart rate variability and the sympathetically mediated component, LFPn were significantly lower than during the following recovery phase (ANOVA, p < 0.0001, p < 0.01 respectively). Both APACHE II (Acute Physiological and Chronic Health Evaluation) and TISS (Therapeutic Intervention Scoring System) scores showed an inverse correlation with total heart rate variability, logLFP, LFPn and the LFP/RFP ratio (p < 0.002 to 0.0001). Sympathetically mediated heart rate variability was significantly lower during the sepsis syndrome and was inversely proportional to disease severity.

A'Court C, Garrard CS. 1992. Nosocomial pneumonia in the intensive care unit: mechanisms and significance. Thorax, 47 (6), pp. 465-473. | Read more

Garrard CS, Seidler A, McKibben A, McAlpine LE, Gordon D. 1992. Spectral analysis of heart rate variability in bronchial asthma. Clin Auton Res, 2 (2), pp. 105-111. | Show Abstract | Read more

Sympathetic and parasympathetic activity was evaluated in ten healthy controls, nine asymptomatic, untreated asthmatic subjects and ten asthmatic patients during treatment for acute asthma, by measurement of the variation in resting heart rate using frequency spectrum analysis. Heart rate was recorded by ECG and respiratory rate by impedance plethysmography. Spectral density of the beat-to-beat heart rate was measured within the low frequency band 0.04 to 0.10 Hz (low frequency power) modulated by sympathetic and parasympathetic activity, and within a 0.12 Hz band width at the respiratory frequency mode (respiratory frequency power) modulated by parasympathetic activity. Acute asthmatics had higher heart rates than either of the other two groups; this was probably related to the effects of beta-adrenoceptor agonist medication. Sympathetically mediated heart rate variability (normalized low frequency power) was significantly lower in both asymptomatic (p less than 0.002) and acute (p less than 0.02) asthma subjects compared to controls. This is consistent with altered sympathetic/parasympathetic regulation of heart rate in subjects with bronchial asthma.

Warrell DA, Phillips RE, Garrard CS. 1991. Intensive care unit management of severe malaria Clinical Intensive Care, 2 (2), pp. 86-96.

Garrard CS, Crook DWM. 1991. Nosocomial pneumonia in the critically III Current Anaesthesia & Critical Care, 2 (3), pp. 155-160. | Show Abstract | Read more

Despite the large body of published work emphasising the importance of nosocomial pneumonia its true significance with respect to mortality is difficult to assess. This partially stems from the limitations imposed by clinical diagnostic criteria and from the interpretation of multivariate analyses which in themselves can only confirm correlations and associations. Two key questions need to be resolved. First, what is the true incidence of nosocomial pneumonia? Microbiological data would suggest the incidence to be much lower than previously suspected and this view is supported by the relative rarity of severe lung infections manifested as lung cavitation, empyema or bacteraemia. Second, what is the true mortality attributable to nosocomial pneumonia? Clinical studies need to examine the mode of death and not just confirm the presence of pneumonia at the time of death. Only in cases where overwhelming lung infection leads to an inability to maintain respiratory or haemodynamic homeostasis can death be genuinely attributed to nosocomial pneumonia. Clinical experience suggests that the attributable mortality is low, an impression that is reinforced by the relatively small impact of selective decontamination of the digestive tract (SDD) upon survival in patients with nosocomial pneumonia. Until these questions are answered satisfactorily it is appropriate to take reasonable measures to prevent nosocomial pneumonia but to embark on antibiotic therapy only when there is supportive microbiological evidence or in the presence of clinically indisputable lung infection. © 1991 Longman Group UK Ltd.

Garrard CS, Lane DJ. 1981. Pattern of carbon dioxide stimulated breathing in patients with chronic airway obstruction. Thorax, 36 (2), pp. 130-134. | Show Abstract | Read more

The pattern of stimulated breathing during carbon dioxide inhalation was studied in a group of 21 patients with severe irreversible airways obstruction (mean FEV1 = 0.9 litre, mean FEV1/FVC% = 50%). Carbon dioxide rebreathing experiments were performed, the ventilatory response being defined in terms of total ventilation (V) and CO2 sensitivity (S). Breathing pattern was defined by the changes in tidal volume (delta VT) and respiratory frequency (delta f) and the maximum VT achieved (VTmax). Contrary to some previous studied no significant relationship could be demonstrated between the severity of airway obstruction (FEV1/FVC%, Raw) and the ventilatory response to rebreathing (V, S, delta VT, delta f, VTmax). However, measurements of dynamic lung volume (FEV1, FVC, IC) were found to be significantly correlated with the breathing pattern variables (delta VT, delta f, VTmax). Resting PaO2 and PaCO2 were significantly correlated with delta VT but not delta f. Results indicate that the degree of airway obstruction does not dictate the ventilatory or breathing pattern response to carbon dioxide induced hyperpnoea. In contrast it is the restriction of dynamic lung volume, by limiting the VT response, that appears to determine the ventilatory and breathing pattern response in patients with severe airway obstruction.

GARRARD C, LANE D. 1979. EXERCISE BREATHING PATTERN IN PATIENTS WITH OBSTRUCTIVE LUNG-DISEASE AMERICAN REVIEW OF RESPIRATORY DISEASE, 119 (4), pp. 311-311.

Garrard CS, Lane DJ. 1979. The pattern of breathing in patients with chronic airflow obstruction. Clin Sci (Lond), 56 (3), pp. 215-221. | Show Abstract | Read more

1. The pattern of breathing in 12 patients with severe irreversible airflow obstruction has been studied during ventilatory stimulation by rebreathing CO2. Mean maximum tidal volume response was only 1.23 +/- 0.30 litres (mean +/- SD); this represented 65% of mean measured vital capacity and 82% of mean measured inspiratory capacity. During the course of rebreathing mean total breath duration was reduced from 3.48 +/- 0.93 to 2.44 +/- 0.48 s. 2. End-expiratory thoracic gas volume (FRC) was elevated at rest in all subjects and increased significantly by a further 0.50 +/- 1.90 litres during ventilatory stimulation in 10 of the 12 subjects. The maximum increase in FRC was proportional to the degree of airflow obstruction afforded by the airways in each subject. 3. It is suggested that the increase in FRC during ventilatory stimulation is responsible for the diminished tidal volume response and is an important determinant of breathing pattern and symptomatology in patients with airflow obstruction.

GARRARD C, LANE D. 1978. PATTERN OF BREATHING IN PATIENTS WITH AIRWAYS OBSTRUCTION AMERICAN REVIEW OF RESPIRATORY DISEASE, 117 (4), pp. 340-340.

Garrard CS, Lane DJ. 1978. The pattern of stimulated breathing in man during non-elastic expiratory loading. J Physiol, 279 (JUN), pp. 17-29. | Show Abstract | Read more

1. The pattern of breathing expressed as the relationship between tidal volume and the components of breath interval was studied in normal subjects during CO2 rebreathing, both under unloaded conditions and following the introduction of a non-elastic expiratory resistance. 2. Under unloaded conditions end-expiratory thoracic gas volume (FRC) measured plethysmographically did not alter during the course of the rebreathing experiment. Maximum tidal volume attained (VT, max.) was equal to or just less than the inspiratory capacity of the subject measured at rest. Expiratory reserve volume was not encroached upon even at the highest levels of ventilation. 3. Under loaded conditions the pattern of breathing was altered. VT, max. was diminished in all subjects and FRC showed a progressive rise during rebreathing which was proportional to the resistive load afforded by the artificial resistance. There were no consistent differences in the components of breath duration either at rest or on maximal ventilatory stimulation between the loaded and unloaded states. 4. It is suggested that the pattern of breathing adopted under conditions of expiratory non-elastic loading is influenced more by the secondary effects of breathing at an elevated lung volume, than by the effect of the non-elastic load per se.

GARRARD C, LANE D. 1976. PATTERN OF BREATHING DURING CO2 STIMULATION IN AIRWAYS OBSTRUCTION BULLETIN EUROPEEN DE PHYSIOPATHOLOGIE RESPIRATOIRE-CLINICAL RESPIRATORY PHYSIOLOGY, 12 (6), pp. P241-P241.

GARRARD C, LITTLER W, REDMAN C. 1976. PULMONARY-FUNCTION IN PREGNANCY CLINICAL SCIENCE AND MOLECULAR MEDICINE, 50 (2), pp. P23-P24.

Garrard CS, Lane DJ. 1975. Proceedings: The pattern of stimulated breathing in man during non-elastic expiratory loading. J Physiol, 251 (1), pp. 40P-41P.

LANE D, GARRARD C. 1975. PULMONARY MECHANICS IN RELATION TO BREATHING EXERCISES BULLETIN DE PHYSIO-PATHOLOGIE RESPIRATOIRE, 11 (3), pp. P182-P182.

GARRARD C, LANE D, WILLIS L, NICHOLS P. 1975. REHABILITATION OF PATIENTS WITH DISABLING CHRONIC AIR-FLOW OBSTRUCTION WITH OUTPATIENTS TECHNIQUES BULLETIN DE PHYSIO-PATHOLOGIE RESPIRATOIRE, 11 (3), pp. P175-P176.

GARRARD C, LANE D. 1973. REGULATION OF RESPIRATORY PATTERN BULLETIN DE PHYSIO-PATHOLOGIE RESPIRATOIRE, 9 (5), pp. 1267-1268.

Mills TC, Chapman S, Hutton P, Gordon AC, Bion J, Chiche JD, Holloway PA, Stüber F, Garrard CS, Hinds CJ et al. 2015. Variants in the Mannose-binding Lectin Gene MBL2 do not Associate With Sepsis Susceptibility or Survival in a Large European Cohort. Clin Infect Dis, 61 (5), pp. 695-703. | Show Abstract | Read more

BACKGROUND: Sepsis is an increasingly common condition, which continues to be associated with unacceptably high mortality. A large number of association studies have investigated susceptibility to, or mortality from, sepsis for variants in the functionally important immune-related gene MBL2. These studies have largely been underpowered and contradictory. METHODS: We genotyped and analyzed 4 important MBL2 single nucleotide polymorphisms (SNPs; rs5030737, rs1800450, rs1800451, and rs7096206) in 1839 European community-acquired pneumonia (CAP) and peritonitis sepsis cases, and 477 controls from the United Kingdom. We analyzed the following predefined subgroups and outcomes: 28-day and 6 month mortality from sepsis due to CAP or peritonitis combined, 28-day mortality from CAP sepsis, peritonitis sepsis, pneumococcal sepsis or sepsis in younger patients, and susceptibility to CAP sepsis or pneumococcal sepsis in the United Kingdom. RESULTS: There were no significant associations (all P-values were greater than .05 after correction for multiple testing) between MBL2 genotypes and any of our predefined analyses. CONCLUSIONS: In this large, well-defined cohort of immune competent adult patients, no associations between MBL2 genotype and sepsis susceptibility or outcome were identified.

Tridente A, Clarke GM, Walden A, Gordon AC, Hutton P, Chiche JD, Holloway PA, Mills GH, Bion J, Stüber F et al. 2015. Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort. Crit Care, 19 (1), pp. 210. | Show Abstract | Read more

INTRODUCTION: Patients admitted to intensive care following surgery for faecal peritonitis present particular challenges in terms of clinical management and risk assessment. Collaborating surgical and intensive care teams need shared perspectives on prognosis. We aimed to determine the relationship between dynamic assessment of trends in selected variables and outcomes. METHODS: We analysed trends in physiological and laboratory variables during the first week of intensive care unit (ICU) stay in 977 patients at 102 centres across 16 European countries. The primary outcome was 6-month mortality. Secondary endpoints were ICU, hospital and 28-day mortality. For each trend, Cox proportional hazards (PH) regression analyses, adjusted for age and sex, were performed for each endpoint. RESULTS: Trends over the first 7 days of the ICU stay independently associated with 6-month mortality were worsening thrombocytopaenia (mortality: hazard ratio (HR) = 1.02; 95% confidence interval (CI), 1.01 to 1.03; P < 0.001) and renal function (total daily urine output: HR =1.02; 95% CI, 1.01 to 1.03; P < 0.001; Sequential Organ Failure Assessment (SOFA) renal subscore: HR = 0.87; 95% CI, 0.75 to 0.99; P = 0.047), maximum bilirubin level (HR = 0.99; 95% CI, 0.99 to 0.99; P = 0.02) and Glasgow Coma Scale (GCS) SOFA subscore (HR = 0.81; 95% CI, 0.68 to 0.98; P = 0.028). Changes in renal function (total daily urine output and renal component of the SOFA score), GCS component of the SOFA score, total SOFA score and worsening thrombocytopaenia were also independently associated with secondary outcomes (ICU, hospital and 28-day mortality). We detected the same pattern when we analysed trends on days 2, 3 and 5. Dynamic trends in all other measured laboratory and physiological variables, and in radiological findings, changes in respiratory support, renal replacement therapy and inotrope and/or vasopressor requirements failed to be retained as independently associated with outcome in multivariate analysis. CONCLUSIONS: Only deterioration in renal function, thrombocytopaenia and SOFA score over the first 2, 3, 5 and 7 days of the ICU stay were consistently associated with mortality at all endpoints. These findings may help to inform clinical decision making in patients with this common cause of critical illness.

Cited:

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Scopus

Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, Chiche JD, Parks T, Chapman SJ, Davenport EE et al. 2015. Genome-wide association study of survival from sepsis due to pneumonia: An observational cohort study The Lancet Respiratory Medicine, 3 (1), pp. 53-60. | Show Abstract | Read more

© 2015 Rautanen et al. Open Access article distributed under the terms of CC-BY-NC-SA. Background: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. Methods: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. Findings: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10 -8 ). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10 -8 (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10 -9 , after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. Interpretation: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. Funding: European Commission and the Wellcome Trust.

Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, Chiche JD, Parks T, Chapman SJ, Davenport EE et al. 2015. Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med, 3 (1), pp. 53-60. | Show Abstract | Read more

BACKGROUND: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING: European Commission and the Wellcome Trust.

Walden AP, Clarke GM, McKechnie S, Hutton P, Gordon AC, Rello J, Chiche JD, Stueber F, Garrard CS, Hinds CJ, ESICM/ECCRN GenOSept Investigators. 2014. Patients with community acquired pneumonia admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Crit Care, 18 (2), pp. R58. | Show Abstract | Read more

INTRODUCTION: Community acquired pneumonia (CAP) is the most common infectious reason for admission to the Intensive Care Unit (ICU). The GenOSept study was designed to determine genetic influences on sepsis outcome. Phenotypic data was recorded using a robust clinical database allowing a contemporary analysis of the clinical characteristics, microbiology, outcomes and independent risk factors in patients with severe CAP admitted to ICUs across Europe. METHODS: Kaplan-Meier analysis was used to determine mortality rates. A Cox Proportional Hazards (PH) model was used to identify variables independently associated with 28-day and six-month mortality. RESULTS: Data from 1166 patients admitted to 102 centres across 17 countries was extracted. Median age was 64 years, 62% were male. Mortality rate at 28 days was 17%, rising to 27% at six months. Streptococcus pneumoniae was the commonest organism isolated (28% of cases) with no organism identified in 36%. Independent risk factors associated with an increased risk of death at six months included APACHE II score (hazard ratio, HR, 1.03; confidence interval, CI, 1.01-1.05), bilateral pulmonary infiltrates (HR1.44; CI 1.11-1.87) and ventilator support (HR 3.04; CI 1.64-5.62). Haematocrit, pH and urine volume on day one were all associated with a worse outcome. CONCLUSIONS: The mortality rate in patients with severe CAP admitted to European ICUs was 27% at six months. Streptococcus pneumoniae was the commonest organism isolated. In many cases the infecting organism was not identified. Ventilator support, the presence of diffuse pulmonary infiltrates, lower haematocrit, urine volume and pH on admission were independent predictors of a worse outcome.

Tridente A, Clarke GM, Walden A, McKechnie S, Hutton P, Mills GH, Gordon AC, Holloway PAH, Chiche JD, Bion J et al. 2014. Patients with faecal peritonitis admitted to European intensive care units: An epidemiological survey of the GenOSept cohort Intensive Care Medicine, 40 (2), pp. 202-210. | Show Abstract | Read more

Introduction: Faecal peritonitis (FP) is a common cause of sepsis and admission to the intensive care unit (ICU). The Genetics of Sepsis and Septic Shock in Europe (GenOSept) project is investigating the influence of genetic variation on the host response and outcomes in a large cohort of patients with sepsis admitted to ICUs across Europe. Here we report an epidemiological survey of the subset of patients with FP. Objectives: To define the clinical characteristics, outcomes and risk factors for mortality in patients with FP admitted to ICUs across Europe. Methods: Data was extracted from electronic case report forms. Phenotypic data was recorded using a detailed, quality-assured clinical database. The primary outcome measure was 6-month mortality. Patients were followed for 6 months. Kaplan-Meier analysis was used to determine mortality rates. Cox proportional hazards regression analysis was employed to identify independent risk factors for mortality. Results: Data for 977 FP patients admitted to 102 centres across 16 countries between 29 September 2005 and 5 January 2011 was extracted. The median age was 69.2 years (IQR 58.3-77.1), with a male preponderance (54.3 %). The most common causes of FP were perforated diverticular disease (32.1 %) and surgical anastomotic breakdown (31.1 %). The ICU mortality rate at 28 days was 19.1 %, increasing to 31.6 % at 6 months. The cause of FP, pre-existing co-morbidities and time from estimated onset of symptoms to surgery did not impact on survival. The strongest independent risk factors associated with an increased rate of death at 6 months included age, higher APACHE II score, acute renal and cardiovascular dysfunction within 1 week of admission to ICU, hypothermia, lower haematocrit and bradycardia on day 1 of ICU stay. Conclusions: In this large cohort of patients admitted to European ICUs with FP the 6 month mortality was 31.6 %. The most consistent predictors of mortality across all time points were increased age, development of acute renal dysfunction during the first week of admission, lower haematocrit and hypothermia on day 1 of ICU admission. © 2013 Springer-Verlag Berlin Heidelberg and ESICM.

Mills TC, Rautanen A, Elliott KS, Parks T, Naranbhai V, Ieven MM, Butler CC, Little P, Verheij T, Garrard CS et al. 2014. IFITM3 and susceptibility to respiratory viral infections in the community. J Infect Dis, 209 (7), pp. 1028-1031. | Show Abstract | Read more

Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM 1,2, and 3) are viral restriction factors that mediate cellular resistance to several viruses. We have genotyped a possible splice-site altering single-nucleotide polymorphism (rs12252) in the IFITM3 gene in 34 patients with H1N1 influenza and severe pneumonia, and >5000 individuals comprising patients with community-acquired mild lower respiratory tract infection and matched controls of Caucasian ancestry. We found evidence of an association between rs12252 rare allele homozygotes and susceptibility to mild influenza (in patients attending primary care) but could not confirm a previously reported association between this single-nucleotide polymorphism and susceptibility to severe H1N1 infection.

Tridente A, Clarke GM, Walden A, McKechnie S, Hutton P, Mills GH, Gordon AC, Holloway PA, Chiche JD, Bion J et al. 2014. Patients with faecal peritonitis admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Intensive Care Med, 40 (2), pp. 202-210. | Show Abstract | Read more

INTRODUCTION: Faecal peritonitis (FP) is a common cause of sepsis and admission to the intensive care unit (ICU). The Genetics of Sepsis and Septic Shock in Europe (GenOSept) project is investigating the influence of genetic variation on the host response and outcomes in a large cohort of patients with sepsis admitted to ICUs across Europe. Here we report an epidemiological survey of the subset of patients with FP. OBJECTIVES: To define the clinical characteristics, outcomes and risk factors for mortality in patients with FP admitted to ICUs across Europe. METHODS: Data was extracted from electronic case report forms. Phenotypic data was recorded using a detailed, quality-assured clinical database. The primary outcome measure was 6-month mortality. Patients were followed for 6 months. Kaplan-Meier analysis was used to determine mortality rates. Cox proportional hazards regression analysis was employed to identify independent risk factors for mortality. RESULTS: Data for 977 FP patients admitted to 102 centres across 16 countries between 29 September 2005 and 5 January 2011 was extracted. The median age was 69.2 years (IQR 58.3-77.1), with a male preponderance (54.3%). The most common causes of FP were perforated diverticular disease (32.1%) and surgical anastomotic breakdown (31.1%). The ICU mortality rate at 28 days was 19.1%, increasing to 31.6% at 6 months. The cause of FP, pre-existing co-morbidities and time from estimated onset of symptoms to surgery did not impact on survival. The strongest independent risk factors associated with an increased rate of death at 6 months included age, higher APACHE II score, acute renal and cardiovascular dysfunction within 1 week of admission to ICU, hypothermia, lower haematocrit and bradycardia on day 1 of ICU stay. CONCLUSIONS: In this large cohort of patients admitted to European ICUs with FP the 6 month mortality was 31.6%. The most consistent predictors of mortality across all time points were increased age, development of acute renal dysfunction during the first week of admission, lower haematocrit and hypothermia on day 1 of ICU admission.

Tridente A, Clarke GM, Walden A, McKechnie SR, Hutton P, Martynoga R, Mills GH, Gordon AC, Stueber F, Garrard C, Hinds C. 2011. EPIDEMIOLOGY OF FAECAL PERITONITIS IN THE GENOSEPT COHORT INTENSIVE CARE MEDICINE, 37 pp. S199-S199.

Determann RM, Millo JL, Garrard CS, Schultz MJ. 2006. Bronchoalveolar levels of plasminogen activator inhibitor-1 and soluble tissue factor are sensitive and specific markers of pulmonary inflammation. Intensive Care Med, 32 (6), pp. 946-947. | Read more

Gordon AC, Waheed U, Hansen TK, Hitman GA, Garrard CS, Turner MW, Klein NJ, Brett SJ, Hinds CJ. 2006. Mannose-binding lectin polymorphisms in severe sepsis: relationship to levels, incidence, and outcome. Shock, 25 (1), pp. 88-93. | Show Abstract | Read more

Mannose-binding lectin (MBL) genetic polymorphisms result in deficiency of the encoded protein and increased susceptibility to infection, especially in children and the immunocompromised. The objective of this study was to investigate the relationship between MBL-2 exon 1 and promoter -221 polymorphisms, plasma levels of the encoded protein, and the incidence and outcome of severe sepsis and septic shock. One hundred seventy-four white adult patients with severe sepsis or septic shock were recruited in a prospective multicenter study across eight intensive care units in the South of England, UK. Genotype and haplotype frequencies were compared between normal population controls and patients, and between survivors and nonsurvivors. Plasma levels of encoded protein were related to genotype and outcome. The exon 1 polymorphisms (A/O or O/O) were significantly more common in the patients with severe sepsis and septic shock than in normal healthy adults (54.6% vs. 39.7%, P = 0.001), and there was a significant difference in haplotype frequency between controls and septic patients (P < 0.0001). There was no significant difference in MBL-2 genotype or haplotype frequency between survivors and nonsurvivors. There was a strong relationship between MBL-2 haplotype and plasma MBL concentration (P < 0.001). Individual plasma levels were variable and increased between days 1 and 7. The mortality rate was higher in those with MBL levels <1000 microg/L than in those patients with levels >1000 microg/L (47.2 vs. 22.2%, P = 0.05). We conclude that genetic polymorphisms resulting in mannose-binding lectin deficiency are associated with increased susceptibility to sepsis. The close relationship between polymorphic variants and plasma MBL concentration persists during sepsis but individual levels vary widely. Lower circulating MBL levels are associated with a poor outcome.

Determann RM, Millo JL, Gibot S, Korevaar JC, Vroom MB, van der Poll T, Garrard CS, Schultz MJ. 2005. Serial changes in soluble triggering receptor expressed on myeloid cells in the lung during development of ventilator-associated pneumonia. Intensive Care Med, 31 (11), pp. 1495-1500. | Show Abstract | Read more

OBJECTIVE: To determine the diagnostic role of soluble triggering receptor expressed on myeloid cells (sTREM)-1 in non-directed bronchial lavage fluid in ventilator-associated pneumonia (VAP). DESIGN: Non-directed bronchial lavage fluid and plasma were collected on alternate days in critically ill mechanically ventilated patients from the start of ventilatory support until complete weaning from the ventilator. Soluble TREM-1 levels were measured by an enzyme-linked immunosorbent assay. SETTING: A general adult medical and surgical university hospital intensive care unit. PATIENTS: Nine patients who developed VAP and 19 patients who did not develop VAP (controls). RESULTS: Plasma levels of sTREM-1 did not change significantly in either patient group. While in controls concentrations of sTREM-1 in non-directed bronchial lavage fluid did not change significantly over time, in patients who developed VAP levels of sTREM-1 in non-directed bronchial lavage fluid increased towards the diagnosis of VAP. A cut-off value for non-directed bronchial lavage fluid sTREM-1 levels of 200 pg/ml on the day of VAP had a diagnostic sensitivity of 75% and a specificity of 84%. Sensitivity increased when taking into account all sTREM-1 levels higher than 200 pg/ml from the 6-day period before the day of diagnosis that were preceded by an increase of at least 100 pg/ml (sensitivity 88%, specificity 84%). CONCLUSIONS: Soluble TREM-1 is a potential biomarker of VAP.

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