Imperial College London

ProfessorStephenBrett

Faculty of MedicineDepartment of Surgery & Cancer

Professor of Critical Care
 
 
 
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Contact

 

+44 (0)20 3313 4521stephen.brett Website

 
 
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Location

 

Hammersmith House 570Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

204 results found

Palmer E, Post B, Klapaukh R, Marra G, MacCallum NS, Brealey D, Ercole A, Jones A, Ashworth S, Watkinson P, Beale R, Brett SJ, Young JD, Black C, Rashan A, Martin D, Singer M, Harris Set al., 2019, The association between supra-physiologic arterial oxygen levels and mortality in critically ill patients: a multi-centre observational cohort study, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Rationale: There is conflicting evidence on harm related to exposure to supra-physiologic arterial oxygen tensions (hyperoxemia) in critically ill patients. Objectives: To examine the association between longitudinal exposure to hyperoxemia and mortality in patients admitted to intensive care units (ICUs) in 5 UK University Hospitals. Methods: Retrospective cohort of ICU admissions between 31st January 2014 - 31st December 2018, from the National Institute of Health Research Critical Care Health Informatics Collaborative (CC-HIC). Multivariable logistic regression modelled death in ICU by exposure to hyperoxemia. Measurements: Subsets with oxygen exposure windows of 0-1, 0-3, 0-5 and 0-7 days were evaluated, capturing 19,515, 10,525, 6,360 and 4,296 patients, respectively. Hyperoxemia dose was defined as the area between the PaO2 time curve and a boundary of 13.3 kPa (100 mmHg) divided by the hours of potential exposure (24, 72, 120, or 168 hours). Main Results: An association was found between exposure to hyperoxemia and ICU mortality [odds ratios (95% compatibility intervals); 1.15 (0.95-1.38), p = 0.15; 1.35 (1.04-1.74), p = 0.02; 1.5 (1.07-2.13), p = 0.02; and 1.74 (1.11-2.72), p = 0.02 for exposure windows of 0-1, 0-3, 0-5 and 0-7 days’ duration, respectively. However, a dose-response relationship was not observed. There was no evidence to support a differential effect between hyperoxemia and either a respiratory diagnosis or mechanical ventilation. Conclusions: An association between hyperoxemia and mortality was observed in our large, unselected multicenter cohort. The absence of a dose-response relationship weakens causal interpretation. Further experimental research is warranted to elucidate this important question.

Journal article

Wandrag L, Brett SJ, Frost G, Hickson M, To M, Loubo E, Jackson N, Umpleby M, Bountziouka Vet al., Leucine-enriched essential amino acid supplementation in mechanically ventilated trauma patients – a feasibility study, Trials, ISSN: 1745-6215

Background: Critically ill patients lose up to 2% muscle mass per day. We assessed the feasibility of administering a leucine-enriched essential amino acid (L-EAA) supplement to mechanically ventilated trauma patients with the aim of assessing the effect on skeletal muscle mass and function. Methods: A randomised feasibility study was performed over 6 months in intensive care (ICU), patients received 5g L-EAA five times per day in addition to standard feed (L-EAA group) or standard feed only (control group) up to 14 days. CRP, albumin, IL-6, IL-10, urinary 3-MH, nitrogen balance, protein turnover ([1-13C] leucine infusion), muscle depth change (ultrasound), functional change (Katz & Barthel indices) and muscle strength Medical Research Council (MRC) sum score to assess ICU Acquired Weakness, were measured sequentially.Results: Eight patients (9.5% of screened patients) were recruited over 6 months. L-EAA doses were provided on 91/124 (73%) occasions. Inflammatory and urinary marker data were collected; serial muscle depth measurements were lacking due to short length of stay. Protein turnover studies were performed on five occasions. MRC-sum score could not be performed as patients were not able to respond to the screening questions. The Katz & Barthel indices did not change. L-EAA delivery was achievable, but meaningful functional and muscle mass outcome measures require careful consideration in the design of a future RCT. Conclusion: L-EAA was practical to provide, but we found significant barriers to recruitment and measurement of the chosen outcomes which would need to be addressed in the design of a future, large randomised controlled trial.

Journal article

Wong JLC, Romano M, Kerry L, Kwong J, Low W, Brett S, Clements A, Beis K, Frankel Get al., OmpK36-mediated Carbapenem resistance attenuates ST258 Klebsiella pneumoniae in vivo, Nature Communications, ISSN: 2041-1723

Carbapenem-resistance in Klebsiella pneumoniae (KP) sequence type ST258 is mediated by carbapenemases (e.g. KPC-2) and loss or modification of the major non-selective porins OmpK35 and OmpK36. However, the mechanism underpinning OmpK36-mediated resistance and consequences of these changes on pathogenicity remain unknown. By solving the crystal structure of a clinical ST258 OmpK36 variant we provide direct structural evidence of pore constriction, mediated by a di-amino acid (Gly115-Asp116) insertion into loop 3, restricting diffusion of both nutrients (e.g. lactose) and Carbapenems. In the presence of KPC-2 this results in a 16-fold increase in MIC to Meropenem. Additionally, the Gly-Asp insertion impairs bacterial growth in lactose-containing medium and confers a significant in vivo fitness cost in a murine model of ventilator-associated pneumonia. Our data suggest that the continuous selective pressure imposed by widespread Carbapenem utilisation in hospital settings drives the expansion of KP expressing Gly-Asp insertion mutants, despite an associated fitness cost.

Journal article

Tatham KC, McAuley DF, Borthwick M, Henderson N, Bashevoy G, Brett SJet al., The National Institute for Health Research Critical Care Research Priority Setting Survey 2018, Journal of the Intensive Care Society, ISSN: 1751-1437

IntroductionDefining research priorities in intensive care is key todetermining appropriate allocation of funding. Several topics were identified from the recent James Lind Alliance (JLA) priority setting exerciseconducted with the Intensive Care Society(1). The JLA process included significant (and vital) patient/public contribution, but as a result may have failedto identify potential early-stage translational research topics, which are more likely identified by medical/academic members of relevant specialist intensive care groups. Theobjectiveof the present project was to complement the JLA project by generating an updated list of research prioritiesby facilitatingacademic research input.MethodAsurveywas conducted by the National Institute forHealth Research(NIHR)to identify the key research priorities from Intensive Care clinicians, including allied health professionals and academics, along with any evolving themes arising from translational research. Feasibility of all identified topics were then discussedand allocated to themesby ajoint clinical academics/NIHR focus group. ResultsThe survey was completed by 94 intensive care clinicians(including subspecialists),academicsand allied healthprofessions. In total203researchquestionswere identified, with the top fivethemesfocusing on:appropriate case selection (e.g.who and when to treat; 24%), ventilation(7%), sepsis (6%), delirium (5%) and rehabilitation (5%). DiscussionUtilising a methodology distinct from thatemployed by the JLAprocess, from a broad spectrum of intensive care clinicians/scientists,enabled identification of a variety of priority research areas. These topics cannowinform not only the investigator-led researchagenda, but will alsobe considered in due course by the NIHR for potential future funding calls.

Journal article

Kotfis K, Wittebole X, Jaschinski U, Sole-Violan J, Kashyap R, Leone M, Nanchal R, Fontes LE, Sakr Y, Vincent J-L, Tomas E, Bibonge EA, Charra B, Faroudy M, Doedens L, Farina Z, Adler D, Balkema C, Kok A, Alaya S, Gharsallah H, Muzha D, Temelkov A, Georgiev G, Simeonov G, Tsaryanski G, Georgiev S, Seliman A, Vrankovic S, Vucicevic Z, Gornik I, Barsic B, Husedzinovic I, Pavlik P, Manak J, Kieslichova E, Turek R, Fischer M, Valkova R, Dadak L, Dostal P, Malaska J, Hajek R, Zidkova A, Lavicka P, Starkopf J, Kheladze Z, Chkhaidze M, Kaloiani V, Medve L, Sarkany A, Kremer I, Marjanek Z, Tamasi P, Krupnova I, Vanags I, Liguts V, Pilvinis V, Vosylius S, Kekstas G, Balciunas M, Kolbusz A, Kubler A, Mielczarek B, Mikaszewska-Sokolewicz M, Kotfis K, Tamowicz B, Sulkowski W, Smuszkiewicz P, Pihowicz A, Trejnowska E, Hagau N, Filipescu D, Droc G, Lupu M, Nica A, Stoica R, Tomescu D, Constantinescu D, Zbaganu GV, Slavcovici A, Bagin V, Belsky D, Palyutin S, Shlyapnikov S, Bikkulova D, Gritsan A, Natalia G, Makarenko E, Kokhno V, Tolkach A, Kokarev E, Belotserkovskiy B, Zolotukhin K, Kulabukhov V, Soskic L, Palibrk I, Jankovic R, Jovanovic B, Pandurovic M, Bumbasirevic V, Uljarevic B, Surbatovic M, Ladjevic N, Slobodianiuk G, Sobona V, Cikova A, Gebhardtova A, Jun C, Yunbo S, Dong U, Feng S, Duan M, Xu Y, Xue X, Gao T, Xing X, Zhao X, Li C, Gengxihua G, Tan H, Xu J, Jiang L, Tiehe Q, Bingyu Q, Shi Q, Lv Z, Zhang L, Jingtao L, Zhen Z, Wang Z, Wang T, Yuhong L, Zhai Q, Chen Y, Wang C, Jiang W, Ruilan W, Chen Y, Xiaobo H, Ge H, Yan T, Yuhui C, Zhang J, Jian-Hong F, Zhu H, Huo F, Wang Y, Li C, Zhuang M, Ma Z, Sun J, Liuqingyue L, Yang M, Meng J, Ma S, Kang Y, Yu L, Peng Q, Wei Y, Zhang W, Sun R, Yeung A, Wan W, Sin K, Lee K, Wijanti M, Widodo U, Samsirun H, Sugiman T, Wisudarti C, Maskoen T, Hata N, Kobe Y, Nishida O, Miyazaki D, Nunomiya S, Uchino S, Kitamura N, Yamashita K, Hashimoto S, Fukushima H, Adib NN, Tai L, Tony B, Bigornia R, Palo J, Chatterjee S, Tan B, Kong A, Goh S, Leeet al., 2019, A worldwide perspective of sepsis epidemiology and survival according to age: Observational data from the ICON audit, JOURNAL OF CRITICAL CARE, Vol: 51, Pages: 122-132, ISSN: 0883-9441

Journal article

Nagendran M, Russell JA, Brett S, Perkins GD, Hajjar L, Mason AJ, Ashby D, Gordon Aet al., 2019, Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials, Intensive Care Medicine, Vol: 45, Pages: 844-855, ISSN: 0342-4642

PurposeWe performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups.MethodsOur pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses.ResultsFour trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86–1.12] or serious adverse events (RR 1.02, 95% CI 0.82–1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%–3.2%] but fewer arrhythmias (ARD − 2.8%, 95% CI − 0.2% to − 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74–0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion).ConclusionsVasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use.

Journal article

Kemp HI, Laycock H, Costello A, Brett SJet al., Chronic pain in critical care survivors: a narrative review, British Journal of Anaesthesia, ISSN: 1471-6771

Chronic pain is an important problem after critical care admission. Estimates of the prevalence of chronic pain in the year after discharge range from 14% to 77% depending on the type of cohort, the tool used to measure pain, and the time point when pain was assessed. The majority of data available come from studies using health-related quality of life tools, although some have included pain-specific tools. Nociceptive, neuropathic, and nociplastic pain can occur in critical care survivors, but limited information about the aetiology, body site, and temporal trajectory of pain is currently available. Older age, pre-existing pain, and medical co-morbidity have been associated with pain after critical care admission. No trials were identified of interventions to target chronic pain in survivors specifically. Larger studies, using pain-specific tools, over an extended follow-up period are required to confirm the prevalence, identify risk factors, explore any association between acute and chronic pain in this setting, determine the underlying pathological mechanisms, and inform the development of future analgesic interventions.

Journal article

Omassoli J, Hill NE, Woods DR, Delves SK, Fallowfield JL, Brett SJ, Wilson D, Corbett RW, Allsopp AJ, Stacey MJet al., 2019, Variation in renal responses to exercise in the heat with progressive acclimatisation, Journal of Science and Medicine in Sport, ISSN: 1440-2440

ObjectivesTo investigate changes in renal status from exercise in the heat with acclimatisation and to evaluate surrogates markers of Acute Kidney Injury.DesignProspective observational cohort study.Methods20 male volunteers performed 60 min standardised exercise in the heat, at baseline and on four subsequent occasions during a 23-day acclimatisation regimen. Blood was sampled before and after exercise for serum creatinine, copeptin, interleukin-6, normetanephrine and cortisol. Fractional excretion of sodium was calculated for corresponding urine samples. Ratings of Perceived Exertion were reported every 5 min during exercise. Acute Kidney Injury was defined as serum creatinine rise ≥26.5 μmol L−1 or fall in estimated glomerular filtration rate >25%. Predictive values of each candidate marker for developing Acute Kidney Injury were determined by ROC analysis.ResultsFrom baseline to Day 23, serum creatinine did not vary at rest, but showed a significant (P < 0.05) reduction post-exercise (120 [102, 139] versus 102 [91, 112] μmol L−1). Acute Kidney Injury was common (26/100 exposures) and occurred most frequently in the unacclimatised state. Log-normalised fractional excretion of sodium showed a significant interaction (exercise by acclimatization day), with post-exercise values tending to rise with acclimatisation. Ratings of Perceived Exertion predicted AKI (AUC 0.76, 95% confidence interval 0.65–0.88), performing at least as well as biochemical markers.ConclusionsHeat acclimatization is associated with reduced markers of renal stress and AKI incidence, perhaps due to improved regional perfusion. Acclimatisation and monitoring Ratings of Perceived Exertion are practical, non-invasive measures that could help to reduce renal injury from exercise in the heat.

Journal article

Grailey K, Bryden D, Brett S, 2019, The faculty of intensive care medicine workforce survey – What impacts on our working lives?, Journal of the Intensive Care Society, Vol: 20, Pages: 111-117, ISSN: 1751-1437

The Faculty of Intensive Care Medicine distributes an annual survey to its Consultants, allowing the evaluation of workforce profile, working patterns and the opportunity for analysis of key information on issues affecting these. We undertook an exploratory review of the data provided within the 2016 survey, with the aim of identifying themes within respondents stated career intentions and associated factors. Given the modest (36%) response rate, we are unable to draw conclusions with certainty, but there are indications within the data that the UK Intensive Care Medicine consultant body is facing significant stressors whilst at work, due to working patterns and limited resources. The data within the 2016 survey provide a base from which to develop future Faculty of Intensive Care Medicine workforce surveys that will extract data about the positive aspects of a career in intensive care medicine. The survey data provide a signal that there may be significant potentially modifiable stressors for intensive care doctors, and as such affords support for initiatives to improve job planning and sharing of implemented solutions, as well as a need to focus on workforce wellbeing as an important and necessary contributor to patient safety within intensive care medicine.

Journal article

Antcliffe D, Burnham K, Al-Beidh F, Santhakumaran S, Brett S, Hinds C, Ashby D, Knight J, Gordon ACet al., 2019, Transcriptomic signatures in sepsis and a differential response to steroids: from the VANISH randomized trial, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 980-986, ISSN: 1073-449X

Rationale: There remains uncertainty about the role of corticosteroids in sepsis with clear beneficial effects on shock duration but conflicting survival effects. Two transcriptomic sepsis response signatures (SRS) have been identified. SRS1 is relatively immunosuppressed whilst SRS2 is relatively immunocompetent. Objectives: We aimed to categorized patients based on SRS endotypes to determine if these profiles influenced response to either norepinephrine or vasopressin, or to corticosteroids in septic shock. Methods: A post-hoc analysis was performed of a double-blind randomized clinical trial in septic shock (VANISH). Patients were included within 6 hours of onset of shock and were randomized to receive norepinephrine or vasopressin followed by hydrocortisone or placebo. Genome-wide gene expression profiling was performed and SRS endotype was determined using a previously established model using seven discriminant genes. Measurements and Main Results: Samples were available from 176 patients, 83 SRS1 and 93 SRS2. There was no significant interaction between SRS group and vasopressor assignment (p=0·50). However, there was an interaction between assignment to hydrocortisone or placebo, and SRS endotype (p=0·02). Hydrocortisone use was associated with increased mortality in those with an SRS2 phenotype (OR 7·9, 95%CI 1·6-39·9). Conclusions: Transcriptomic profile at onset of septic shock was associated with response to corticosteroids. Those with the immuno-competent SRS2 endotype had significantly higher mortality when given corticosteroids compared to placebo. Clinical trial registration available at www.isrctn.com, ID ISRCTN20769191.

Journal article

Hutchinson M, Sohal M, Layton M, Sriskandan S, Brett S, Hill P, Youngstein TABet al., 2019, STEROID-FREE MANAGEMENT OF LIFE-THREATENING HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN THE CONTEXT OF SUSPECTED LYMPHOPROLIFERATIVE DISEASE AND INFECTION, Annual Conference of the British-Soceity-for-Rheumatology, Publisher: OXFORD UNIV PRESS, ISSN: 1462-0324

Conference paper

Kemp H, Laycock H, Costello A, Brett Set al., Chronic pain in critical care survivors, BJA: British Journal of Anaesthesia, ISSN: 1471-6771

Chronic pain is an important problem following critical care admission. Estimates of prevalence of chronic pain in the year following discharge range from 14-77% depending on the type of cohort, the tool used to measure pain and the time point when pain was assessed. The majority of data available comefrom studies using health-related quality of life tools,although some have included pain-specific tools. Nociceptive, neuropathic and nociplastic pain can occur in critical caresurvivors butlimited information about aetiology, body site and temporal trajectory of pain is currently available. Older age, pre-existing pain andmedicalco-morbidity have been associated with pain after critical careadmission. No trials were identified of interventions to target chronic pain in survivors specifically. Larger studies, using pain-specific tools, over an extended follow up period are required to confirm prevalence, identify risk factors, explore anyassociation between acute and chronic pain in this setting, determine underlying pathological mechanisms and inform the development of future analgesic interventions.

Journal article

Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, MOSAIC Investigators, Moffatt MF, O'Garra A, Openshaw PJMet al., 2019, Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza., Nature Immunology, Vol: 20, Pages: 373-373, ISSN: 1529-2908

In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article.

Journal article

Corner EJ, Murray EJ, Brett SJ, 2019, A qualitative, grounded theory exploration of patients’ experience of early mobilisation, rehabilitation and recovery after critical illness, BMJ Open, Vol: 9, ISSN: 2044-6055

Rationale Physical rehabilitation (encompassing early mobilisation) of the critically ill patient is recognised best practice; however, further work is needed to explore the patients’ experience of rehabilitation qualitatively; a better understanding may facilitate implementation of early rehabilitation and elucidate the journey of survivorship.Objectives To explore patient experience of physical rehabilitation from critical illness during and after a stay on intensive care unit (ICU).Design Exploratory grounded theory study using semistructured interviews.Setting Adult medical/surgical ICU of a London teaching hospital.Participants A purposive sample of ICU survivors with intensive care unit acquired weakness (ICUAW) and an ICU length of stay of >72 hours.Analysis Data analysis followed a four-stage constant comparison technique: open coding, axial coding, selective coding and model development, with the aim of reaching thematic saturation. Peer debriefing and triangulation through a patient support group were carried out to ensure credibility.Main results Fifteen people were interviewed (with four relatives in attendance). The early rehabilitation period was characterised by episodic memory loss, hallucinations, weakness and fatigue, making early rehabilitation arduous and difficult to recall. Participants craved a paternalised approach to care in the early days of ICU.The central idea that emerged from this study was recalibration of the self. This is driven by a lost sense of self, with loss of autonomy and competence; dehumanised elements of care may contribute to this. Participants described a fractured life narrative due to episodic memory loss, meaning that patients were shocked on awakening from sedation by the discrepancy between their physical form and cognitive representation of themselves.Conclusions Recovery from ICUAW is a complex process that often begins with survivors exploring and adapting to a new body, followed by a period of rec

Journal article

Robinson M, Taylor J, Brett S, Nolan JP, Thomas M, Reeves B, Rogers CA, Voss S, Clout M, Benger JRet al., 2019, Design and implementation of a large and complex trial in emergency medical services, Trials, Vol: 20, ISSN: 1745-6215

BackgroundThe research study titled “Cluster randomised trial of the clinical and cost effectiveness of the i-gel supraglottic airway device versus tracheal intubation in the initial airway management of out-of-hospital cardiac arrest (AIRWAYS-2)” is a large-scale study being run in the English emergency medical (ambulance) services (EMS). It compares two airway management strategies (tracheal intubation and the i-gel) in out-of-hospital cardiac arrest. We describe the methods used to minimise bias and the challenges associated with the set-up, enrolment, and follow-up that were addressed.MethodsAIRWAYS-2 enrols adults without capacity when there is no opportunity to seek prior consent and when the intervention must be delivered immediately. We therefore adopted a cluster randomised design where the unit of randomisation is the individual EMS provider (paramedic). However, because paramedics could not be blinded to the intervention, it was necessary to automatically enrol all eligible patients in the study to avoid bias. Effective implementation required engagement with four large EMS and 95 receiving hospitals. Very high levels of data capture were required to ensure study integrity, and this necessitated collaborative working across multiple organisations. We sought to manage these processes by using a large and comprehensive electronic study database, implementing efficient trial procedures and comprehensive training.ResultsSuccessful implementation of the study design was facilitated by the approaches used. The necessary regulatory and ethical approvals to conduct the study were secured, and benefited from strong patient and public involvement. Early and continued consultation with decision makers within the four participating EMS resulted in a coordinated approach to study set-up. All receiving hospitals gave approval and agreed to collect data. A comprehensive database and programme of training and support were implemented. More than 1500 paramedic

Journal article

Corner E, Puthucheary Z, Cakiroglu A, Brett Set al., 2019, Early Functional Recovery Trajectories of Chronic Critically Ill Patients: An Observational Cohort Study, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Meiring C, Dixit A, Harris S, MacCallum NS, Brealey DA, Watkinson PJ, Jones A, Ashworth S, Beale R, Brett SJ, Singer S, Ercole Aet al., 2018, Optimal intensive care outcome prediction over time using machine learning, PLoS ONE, Vol: 13, ISSN: 1932-6203

BackgroundPrognostication is an essential tool for risk adjustment and decision making in the intensive care unit (ICU). Research into prognostication in ICU has so far been limited to data from admission or the first 24 hours. Most ICU admissions last longer than this, decisions are made throughout an admission, and some admissions are explicitly intended as time-limited prognostic trials. Despite this, temporal changes in prognostic ability during ICU admission has received little attention to date. Current predictive models, in the form of prognostic clinical tools, are typically derived from linear models and do not explicitly handle incremental information from trends. Machine learning (ML) allows predictive models to be developed which use non-linear predictors and complex interactions between variables, thus allowing incorporation of trends in measured variables over time; this has made it possible to investigate prognosis throughout an admission.Methods and findingsThis study uses ML to assess the predictability of ICU mortality as a function of time. Logistic regression against physiological data alone outperformed APACHE-II and demonstrated several important interactions including between lactate & noradrenaline dose, between lactate & MAP, and between age & MAP consistent with the current sepsis definitions. ML models consistently outperformed logistic regression with Deep Learning giving the best results. Predictive power was maximal on the second day and was further improved by incorporating trend data. Using a limited range of physiological and demographic variables, the best machine learning model on the first day showed an area under the receiver-operator characteristic curve (AUC) of 0.883 (σ = 0.008), compared to 0.846 (σ = 0.010) for a logistic regression from the same predictors and 0.836 (σ = 0.007) for a logistic regression based on the APACHE-II score. Adding information gathered on the second day of admission imp

Journal article

Gross J, Williams B, Fade P, Brett SJet al., 2018, Intensive care: balancing risk and benefit to facilitate informed decisions, British Medical Journal, Vol: 363, ISSN: 0959-8138

Journal article

Lipman J, Brett SJ, De Waele J, Osbert Cota M, Davis J, Finfer S, Glass P, Knowles S, McGuiness S, Myburgh J, Paterson D, Peake S, Rajbhandari D, Rhodes A, Roberts J, Shirwadkar C, Starr T, Taylor C, Billott L, Joel Det al., A protocol for a Phase 3 multicentre randomised controlled trial of continuous versus intermittent beta-lactam antibiotic infusion in critically ill patients with sepsis: the BLING III trial, Critical Care and Resuscitation, ISSN: 1441-2772

ackground and rationale:Beta-lactam antibiotics displaya time-dependent mechanism of action with evidence suggesting improved outcomes when administering these drugs via continuous infusion as compared with standard intermittent infusion. However, there is no phase 3randomised controlled trial (RCT) evidence to support one method of administration over another in critically ill patients with sepsis.Design and setting:BLING III is a prospective, multicentre, open, phase 3RCT to compare continuous infusion with standard intermittent infusion of beta-lactam antibiotics in critically ill patients with sepsis.The study will be conducted in approximately 70 Intensive Care Units (ICUs) in Australia, New Zealand, United Kingdom, Belgium and selected other countries from 2018 to 2021.Participants and interventions: BLING IIIwill recruit 7000 critically illpatients with sepsis being treated with one of two beta-lactam antibiotics (piperacillin-tazobactam ormeropenem) to receive the beta-lactam antibiotic by either continuous or intermittentinfusion.Main outcome measures: The primary outcome isall-cause mortality within 90 days after randomisation. Secondary outcomes are clinical cure at Day 14 post randomisation, new acquisition, colonisation or infection with a multi-resistant organism or Clostridium difficilediarrhoea up to 14 days post randomisation, all-cause ICU mortality and all-cause hospital mortality. Tertiary outcomes are ICU length of stay, hospital length of stay and duration of mechanical ventilation andduration of renal replacement therapy up to 90 days after randomisation.Results and conclusions: The BLING IIIstudy will compare the effect on 90-day mortality of beta-lactam antibiotics administered via continuous vs. intermittent infusion in 7000 critically ill patients with sepsis.

Journal article

Stacey M, Woods DR, Brett SJ, Britland SE, Fallowfield JL, Allsopp AJ, Delves SKet al., 2018, Heat acclimatisation blunts copeptin responses to hypertonicity from dehydrating exercise in humans, Physiological Reports, Vol: 6, ISSN: 2051-817X

Physiological Reports Volume 6, Issue 18Original Research Open AccessHeat acclimatization blunts copeptin responses to hypertonicity from dehydrating exercise in humansMichael J. Stacey David R. Woods Stephen J. Brett Sophie E. Britland Joanne L. Fallowfield Adrian J. Allsopp Simon K. DelvesFirst published: 17 September 2018https://doi.org/10.14814/phy2.13851Funding InformationThis work was supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London.AboutSections AbstractAcclimatization favors greater extracellular tonicity from lower sweat sodium, yet hyperosmolality may impair thermoregulation during heat stress. Enhanced secretion or action of vasopressin could mitigate this through increased free water retention. Aims were to determine responses of the vasopressin surrogate copeptin to dehydrating exercise and investigate its relationships with tonicity during short and long‐term acclimatization. Twenty‐three participants completed a structured exercise programme following arrival from a temperate to a hot climate. A Heat Tolerance Test (HTT) was conducted on Day‐2, 6, 9 and 23, consisting of 60‐min block‐stepping at 50% VO2peak, with no fluid intake. Resting sweat [Na+] was measured by iontophoresis. Changes in body mass (sweat loss), core temperature, heart rate, osmolality (serum and urine) and copeptin and aldosterone (plasma) were measured with each Test. From Day 2 to Day 23, sweat [Na+] decreased significantly (adjusted P < 0.05) and core temperature and heart rate fell. Over the same interval, HTT‐associated excursions were increased for serum osmolality (5 [−1, 9] vs. 9 [5, 12] mosm·kg−1), did not differ for copeptin (9.6 [6.0, 15.0] vs. 7.9 [4.3, 14.7] pmol·L−1) and were reduced for aldosterone (602 [415, 946] vs. 347 [263, 537] pmol·L−1). Urine osmolality was unchanging and related consi

Journal article

Meyer J, Brett SJ, Waldmann C, 2018, Should ICU clinicians follow patients after ICU discharge? Yes, Intensive Care Medicine, Vol: 44, Pages: 1539-1541, ISSN: 0342-4642

Journal article

Wong JLC, Mason A, Gordon A, Brett Set al., 2018, Are large randomized controlled trials in severe sepsis and septic shock statistically disadvantaged by repeated inadvertent underestimates of required sample size, BMJ Open, Vol: 8, ISSN: 2044-6055

Objectives: We sought to understand why randomized controlled trials in septic shock have failed to demonstrate effectiveness in the face of improving overall outcomes for patients and seemingly promising results of early phase trials of interventions. Design: We performed a retrospective analysis of large critical care trials of severe sepsis and septic shock. Data were collected from the primary trial manuscripts, pre-published statistical plans or by direct communication with corresponding authors. Setting: Critical care randomized control trials in severe sepsis and septic shock. Participants: 14619 patients randomized in 13 trials published between 2005 to 2015, enrolling greater than 500 patients and powered to a primary outcome of mortality. Intervention: Multiple interventions including the evaluation of treatment strategies and novel therapeutics. Primary and secondary outcome measures: Our primary outcome measure was the difference between the anticipated and actual control arm mortality. Secondary analysis examined the actual effect size and the anticipated effect size employed in sample size calculation. Results: In this post-hoc analysis of 13 trials with 14 619 patients randomised, we highlight a global tendency to overestimate control arm mortality in estimating sample size (absolute difference 9.8%, 95% confidence interval, -14.7% to -5%, p<0.001). When we compared anticipated and actual effect size of a treatment there was also a substantial overestimation in proposed values (absolute difference 7.4%, 95% confidence interval -9.0% to -5.8%, p<0.0001). Conclusions: An interpretation of our results is that trials are consistently underpowered in the planning phase by employing erroneous variables to calculate a satisfactory sample size. Our analysis cannot establish if, given a larger sample size, a trial would have had a positive result. It is disappointing so many promising phase II res

Journal article

Benger JR, Kirby K, Black S, Brett SJ, Clout M, Lazaroo MJ, Nolan JP, Reeves BC, Robinson M, Scott LJ, Smartt H, South A, Stokes EA, Taylor J, Thomas M, Voss S, Wordsworth S, Rogers CAet al., 2018, Effect of a strategy of supraglottic airway device versus tracheal intubation 4 during out-of-hospital cardiac arrest on functional outcome: the AIRWAYS-2 5 randomized clinical trial, Journal of the American Medical Association, Vol: 320, Pages: 779-791, ISSN: 0098-7484

Importance The optimal approach to airway management during out-of-hospital cardiac arrest is unknown.Objective To determine whether a supraglottic airway device (SGA) is superior to tracheal intubation (TI) as the initial advanced airway management strategy in adults with nontraumatic out-of-hospital cardiac arrest.Design, Setting, and Participants Multicenter, cluster randomized clinical trial of paramedics from 4 ambulance services in England responding to emergencies for approximately 21 million people. Patients aged 18 years or older who had a nontraumatic out-of-hospital cardiac arrest and were treated by a participating paramedic were enrolled automatically under a waiver of consent between June 2015 and August 2017; follow-up ended in February 2018.Interventions Paramedics were randomized 1:1 to use TI (764 paramedics) or SGA (759 paramedics) as their initial advanced airway management strategy.Main Outcomes and Measures The primary outcome was modified Rankin Scale score at hospital discharge or 30 days after out-of-hospital cardiac arrest, whichever occurred sooner. Modified Rankin Scale score was divided into 2 ranges: 0-3 (good outcome) or 4-6 (poor outcome; 6 = death). Secondary outcomes included ventilation success, regurgitation, and aspiration.Results A total of 9296 patients (4886 in the SGA group and 4410 in the TI group) were enrolled (median age, 73 years; 3373 were women [36.3%]), and the modified Rankin Scale score was known for 9289 patients. In the SGA group, 311 of 4882 patients (6.4%) had a good outcome (modified Rankin Scale score range, 0-3) vs 300 of 4407 patients (6.8%) in the TI group (adjusted risk difference [RD], −0.6% [95% CI, −1.6% to 0.4%]). Initial ventilation was successful in 4255 of 4868 patients (87.4%) in the SGA group compared with 3473 of 4397 patients (79.0%) in the TI group (adjusted RD, 8.3% [95% CI, 6.3% to 10.2%]). However, patients randomized to receive TI were less likely to receive

Journal article

Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, Moffatt MF, OGarra A, Openshaw PJMet al., 2018, Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza, Nature Immunology, ISSN: 1529-2916

Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.

Journal article

Vincent J-L, Lefrant J-Y, Kotfis K, Nanchal R, Martin-Loeches I, Wittebole X, Sakka SG, Pickkers P, Moreno R, Sakr Y, ICON and SOAP investigators, SOAP investigatorset al., 2018, Comparison of European ICU patients in 2012 (ICON) versus 2002 (SOAP)., Intensive Care Med, Vol: 44, Pages: 337-344

PURPOSE: To evaluate differences in the characteristics and outcomes of intensive care unit (ICU) patients over time. METHODS: We reviewed all epidemiological data, including comorbidities, types and severity of organ failure, interventions, lengths of stay and outcome, for patients from the Sepsis Occurrence in Acutely ill Patients (SOAP) study, an observational study conducted in European intensive care units in 2002, and the Intensive Care Over Nations (ICON) audit, a survey of intensive care unit patients conducted in 2012. RESULTS: We compared the 3147 patients from the SOAP study with the 4852 patients from the ICON audit admitted to intensive care units in the same countries as those in the SOAP study. The ICON patients were older (62.5 ± 17.0 vs. 60.6 ± 17.4 years) and had higher severity scores than the SOAP patients. The proportion of patients with sepsis at any time during the intensive care unit stay was slightly higher in the ICON study (31.9 vs. 29.6%, p = 0.03). In multilevel analysis, the adjusted odds of ICU mortality were significantly lower for ICON patients than for SOAP patients, particularly in patients with sepsis [OR 0.45 (0.35-0.59), p < 0.001]. CONCLUSIONS: Over the 10-year period between 2002 and 2012, the proportion of patients with sepsis admitted to European ICUs remained relatively stable, but the severity of disease increased. In multilevel analysis, the odds of ICU mortality were lower in our 2012 cohort compared to our 2002 cohort, particularly in patients with sepsis.

Journal article

Baharlo B, Bryden D, Brett SJ, 2018, Deprivation of liberty and intensive care: an update post Ferreira., J Intensive Care Soc, Vol: 19, Pages: 35-42, ISSN: 1751-1437

The right to liberty and security of the person is protected by Article 5 of the European Convention on Human Rights which has been incorporated into the Human Rights Act 1998. The 2014 Supreme Court judgment in the case commonly known as Cheshire West provided for an 'acid test' to be employed in establishing a deprivation of liberty. This 'acid test' of 'continuous supervision and not free to leave' led to concerns that patients lacking capacity being treated on an Intensive Care Unit could be at risk of a 'deprivation of liberty', if this authority was applicable to this setting. This article revisits the aftermath of Cheshire West before describing the recent legal developments around deprivation of liberty pertaining to intensive care by summarising the recent Ferreira judgments which appear for now to answer the question as to the applicability of Cheshire West in life-saving treatment.

Journal article

Harris S, Shi S, Brealey D, MacCallum NS, Denaxas S, Perez-Suarez D, Ercole A, Watkinson P, Jones A, Ashworth S, Beale R, Young D, Brett S, Singer Met al., 2018, Critical Care Health Informatics Collaborative (CCHIC): data, tools and methods for reproducible research: a multi-centre UK intensive care database, International Journal of Medical Informatics, Vol: 112, Pages: 82-89, ISSN: 1386-5056

To build and curate a linkable multi-centre database of high resolution longitudinal electronic health records (EHR) from adult Intensive Care Units (ICU). To develop a set of open-source tools to make these data ‘research ready’ while protecting patient's privacy with a particular focus on anonymisation. Materials and methods: We developed a scalable EHR processing pipeline for extracting, linking, normalising and curating and anonymising EHR data. Patient and public involvement was sought from the outset, and approval to hold these data was granted by the NHS Health Research Authority's Confidentiality Advisory Group (CAG). The data are held in a certified Data Safe Haven. We followed sustainable software development principles throughout, and defined and populated a common data model that links to other clinical areas. Results: Longitudinal EHR data were loaded into the CCHIC database from eleven adult ICUs at 5 UK teaching hospitals. From January 2014 to January 2017, this amounted to 21,930 and admissions (18,074 unique patients). Typical admissions have 70 data-items pertaining to admission and discharge, and a median of 1030 (IQR 481–2335) time-varying measures. Training datasets were made available through virtual machine images emulating the data processing environment. An open source R package, cleanEHR, was developed and released that transforms the data into a square table readily analysable by most statistical packages. A simple language agnostic configuration file will allow the user to select and clean variables, and impute missing data. An audit trail makes clear the provenance of the data at all times. Discussion: Making health care data available for research is problematic. CCHIC is a unique multi-centre longitudinal and linkable resource that prioritises patient privacy through the highest standards of data security, but also provides tools to clean, organise, and anonymise the data. We believe the development of such tools are

Journal article

Galloway M, Hegarty A, McGill S, Arulkumaran N, Brett SJ, Harrison DAet al., 2018, The effect of intensive care unit out-of-hours admission on mortalityA systematic review and meta-analysis, Critical Care Medicine, Vol: 46, Pages: 290-299, ISSN: 0090-3493

Objectives: Organizational factors are associated with outcome ofcritically ill patients and may vary by time of day and day of week.We aimed to identify the association between out-of-hours admissionto critical care and mortality.Data Sources: MEDLINE (via Ovid) and EMBASE (via Ovid).Study Selection: We performed a systematic search of the literaturefor studies on out-of-hours adult general ICU admission onpatient mortality.Data Extraction: Meta-analyses were performed and Forest plotsdrawn using RevMan software. Data are presented as odds ratios([95% CIs], p values).Data Synthesis: A total of 16 studies with 902,551 patients wereincluded in the analysis with a crude mortality of 18.2%. Fourteenstudies with 717,331 patients reported mortality rates bytime of admission and 11 studies with 835,032 patients by dayof admission. Admission to ICU at night was not associated withan increased odds of mortality compared with admissions duringthe day (odds ratio, 1.04 [0.98–1.11]; p = 0.18). However, admissionsduring the weekend were associated with an increased oddsof death compared with ICU admissions during weekdays (1.05[1.01–1.09]; p = 0.006). Increased mortality associated withweekend ICU admissions compared with weekday ICU admissionswas limited to North American countries (1.08 [1.03–1.12];p = 0.0004). The absence of a routine overnight on-site intensivistwas associated with increased mortality among weekendICU admissions compared with weekday ICU admissions (1.11[1.00–1.22]; p = 0.04) and nighttime admissions compared withdaytime ICU admissions (1.11 [1.00–1.23]; p = 0.05).Conclusions: Adjusted risk of death for ICU admission was greaterover the weekends compared with weekdays. The absence of adedicated intensivist on-site overnight may be associated withincreased mortality for acute admissions. These results need tobe interpreted in context of the organization of local healthcareresources before changes to healthcare policy are impleme

Journal article

D'Lima DM, Murray EJ, Brett SJ, 2018, Perceptions of risk and safety in the ICU: a qualitative study of cognitive processes relating to staffing, Critical Care Medicine, Vol: 46, Pages: 60-70, ISSN: 0090-3493

Objectives: The aims of this study were to 1) examine individual professionals’ perceptions of staffing risks and safe staffing in intensive care and 2) identify and examine the cognitive processes that underlie these perceptions.Design: Qualitative case study methodology with nurses, doctors, and physiotherapists.Setting: Three mixed medical and surgical adult ICUs, each on a separate hospital site within a 1,200-bed academic, tertiary London hospital group.Subjects: Forty-four ICU team members of diverse professional backgrounds and seniority.Interventions: None.Main Results: Four themes (individual, team, unit, and organizational) were identified. Individual care provision was influenced by the pragmatist versus perfectionist stance of individuals and team dynamics by the concept of an “A” team and interdisciplinary tensions. Perceptions of safety hinged around the importance of achieving a “dynamic balance” influenced by the burden of prevailing circumstances and the clinical status of patients. Organizationally, professionals’ risk perceptions affected their willingness to take personal responsibility for interactions beyond the unit.Conclusions: This study drew on cognitive research, specifically theories of cognitive dissonance, psychological safety, and situational awareness to explain how professionals’ cognitive processes impacted on ICU behaviors. Our results may have implications for relationships, management, and leadership in ICU. First, patient care delivery may be affected by professionals’ perfectionist or pragmatic approach. Perfectionists’ team role may be compromised and they may experience cognitive dissonance and subsequent isolation/stress. Second, psychological safety in a team may be improved within the confines of a perceived “A” team but diminished by interdisciplinary tensions. Third, counter intuitively, higher “situational” awareness for some individuals incre

Journal article

Sakr Y, Ferrer R, Reinhart K, Beale R, Rhodes A, Moreno R, Timsit JF, Brochard L, Thompson BT, Rezende E, Chiche JD, IC-GLOSSARI Investigators and ESICM Trials Groupet al., 2018, Correction to: The Intensive Care Global Study on Severe Acute Respiratory Infection (IC-GLOSSARI): a multicenter, multinational, 14-day inception cohort study., Intensive Care Med, Vol: 44, Pages: 144-152

In both the original publication (DOI 10.1007/s00134-015-4206-2) and the first erratum (DOI 10.1007/s00134-016-4317-4), the members of the IC-GLOSSARI Investigators and the ESICM Trials Group were provided in such a way that they could not be indexed as collaborators on PubMed. The publisher apologizes for these errors and is pleased to list the members of the groups here.

Journal article

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