Imperial College London


Faculty of MedicineDepartment of Surgery & Cancer

Professor of Critical Care



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




Hammersmith House 570Hammersmith HospitalHammersmith Campus





Publication Type

276 results found

Lound A, Bruton J, Jones K, Shah N, Williams B, Gross J, Post B, Day S, Brett S, Ward Het al., 2023, “I’d rather wait and see what’s around the corner”: a multi-perspective qualitative study of treatment escalation planning in frailty, PLoS One, Vol: 18, Pages: 1-15, ISSN: 1932-6203

IntroductionPeople living with frailty risk adverse outcomes following even minor illnesses. Admission to hospital or the intensive care unit is associated with potentially burdensome interventions and poor outcomes. Decision-making during an emergency is fraught with complexity and potential for conflict between patients, carers and clinicians. Advance care planning is a process of shared decision-making which aims to ensure patients are treated in line with their wishes. However, planning for future care is challenging and those living with frailty are rarely given the opportunity to discuss their preferences. The aim of the ProsPECT (Prospective Planning for Escalation of Care and Treatment) study was to explore perspectives on planning for treatment escalation in the context of frailty. We spoke to people living with frailty, their carers and clinicians across primary and secondary care.MethodsIn-depth online or telephone interviews and online focus groups. The topic guide explored frailty, acute decision-making and planning for the future. Data were thematically analysed using the Framework Method. Preliminary findings were presented to a sample of study participants for feedback in two online workshops.ResultsWe spoke to 44 participants (9 patients, 11 carers and 24 clinicians). Four main themes were identified: frailty is absent from treatment escalation discussions, planning for an uncertain future, escalation in an acute crisis is ‘the path of least resistance’, and approaches to facilitating treatment escalation planning in frailty.ConclusionBarriers to treatment escalation planning include a lack of shared understanding of frailty and uncertainty about the future. Emergency decision-making is focussed on survival or risk aversion and patient preferences are rarely considered. To improve planning discussions, we recommend frailty training for non-specialist clinicians, multi-disciplinary support, collaborative working between patients, carers a

Journal article

Watkins S, Chowdhury FJ, Norman C, Brett S, Couper K, Goodwin L, Gould DW, Harrison DAE, Hossain A, Lall R, Mason J, Nolan JP, Nwankwo H, Perkins GD, Samuel K, Schofield B, Soar J, Starr K, Thomas M, Voss S, Benger JRet al., 2023, Randomised trial of the clinical and cost effectiveness of a supraglottic airway device compared with tracheal intubation for in-hospital cardiac arrest (AIRWAYS-3): protocol, design and implementation, Resuscitation Plus, Vol: 15, Pages: 1-8, ISSN: 2666-5204

Survival from in-hospital cardiac arrest is approximately 18%, but for patients who require advanced airway management survival is lower. Those who do survive are often left with significant disability. Traditionally, resuscitation of cardiac arrest patients has included tracheal intubation, however insertion of a supraglottic airway has gained popularity as an alternative approach to advanced airway management. Evidence from out-of-hospital cardiac arrest suggests no significant differences in mortality or morbidity between these two approaches, but there is no randomised evidence for airway management during in-hospital cardiac arrest.The aim of the AIRWAYS-3 randomised trial, described in this protocol paper, is to determine the clinical and cost effectiveness of a supraglottic airway versus tracheal intubation during in-hospital cardiac arrest. Patients will be allocated randomly to receive either a supraglottic airway or tracheal intubation as the initial advanced airway management. We will also estimate the relative cost-effectiveness of these two approaches. The primary outcome is functional status, measured using the modified Rankin Scale at hospital discharge or 30 days post-randomisation, whichever occurs first.AIRWAYS-3 presents ethical challenges regarding patient consent and data collection. These include the enrolment of unconscious patients without prior consent in a way that avoids methodological bias. Other complexities include the requirement to randomise patients efficiently during a time-critical cardiac arrest. Many of these challenges are encountered in other emergency care research; we discuss our approaches to addressing them.

Journal article

Warner BE, Lound A, Grailey K, Vindrola-Padros C, Wells M, Brett Set al., 2023, Perspectives of healthcare professionals and older patients on shared decision-making for treatment escalation planning in the acute hospital setting: a systematic review and qualitative thematic synthesis, EClinicalMedicine, Vol: 62, Pages: 1-19, ISSN: 2589-5370

Background Shared Decision Making (SDM) between patients and clinicians is increasingly considered important. Treament Escalation Plans (TEP) are individualised documents outlining life-saving interventions to be considered in the event of clinical deterioration. SDM can inform subjective goals of care in TEP but it remains unclear how much it is considered beneficial by patients and clinicians. We aimed to synthesise the existing knowledge of clinician and older patient (generally aged 65 years) perspectives on patient involvement in TEP in the acute setting.Methods Systematic database search was performed in MEDLINE, EMBASE, PSYCinfo and CINAHL databases as well as grey literature from database inception to JUN08, 2023, using the Sample (older patients, clinicians, acute setting; studies relating to patients whose main diagnosis was cancer or single organ failure were excluded as these conditions may have specific TEP considerations), Phenomenon of Interest (Treatment Escalation Planning), Design (any including interview, observational, survey), Evaluation (Shared Decision Making), Research type (qualitative, quantitative, mixed methods) tool. Primary data (published participant quotations, field notes, survey results) and descriptive author comments were extracted and qualitative thematic synthesis was performed to generate analytic themes. Quality assessment was made using the Critical Appraisal Skills Programme and Mixed Methods Appraisal Tools. The GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation - Confidence in the Evidence from Reviews of Qualitative research) approach was used to assess overall confidence in each thematic finding according to methodology, coherence, adequacy and relevance of the contributing studies. The study protocol was registered on PROSPERO, CRD42022361593.Findings Following duplicate exclusion there were 1916 studies screened and ultimately 13 studies were included, all from European and North America

Journal article

Grailey K, Lound A, Murray E, Brett Set al., 2023, The influence of personality on psychological safety, the presence of stress and chosen professional roles in the healthcare environment, PLoS One, Vol: 18, Pages: 1-20, ISSN: 1932-6203

Healthcare teams are expected to deliver high quality and safe clinical care, a goal facilitated by an environment of psychological safety. We hypothesised that an individual’s personality would influence psychological safety, perceived stressors in the clinical environment and confer a suitability for different professional roles. Staff members were recruited from the Emergency or Critical Care Departments of one National Health Service Trust. Qualitative interviews explored participants’ experiences of personality, incorporating quantitative surveys to evaluate psychological safety and perceived stressors. The 16 Primary Factor Assessment provided a quantitative measure of personality. Participants demonstrated midrange scores for most personality traits, highlighting an ability to adapt to changing environments and requirements. There was a signal that different personality traits predominated between the two professional groups, and that certain traits were significantly associated with higher psychological safety and certain perceived stressors. Personality was described as having a strong influence on teamwork, the working environment and leadership ability. Our analysis highlights that personality can influence team dynamics and the suitability of individuals for certain clinical roles. Understanding the heterogeneity of personalities of team members and their likely responses to challenge may help leaders to support staff in times of challenge and improve team cohesiveness.

Journal article

Warner B, Harry A, Wells M, Brett S, Antcliffe Det al., 2023, Escalation to intensive care for the older patient. An exploratory qualitative study of patients aged over 65 years and their next of kin during the COVID-19 pandemic: the ESCALATE study, Age and Ageing, Vol: 52, Pages: 1-13, ISSN: 0002-0729

Background: Older people comprise the majority of hospital medical inpatients so decision-making regarding admission of this cohort to the intensive care unit (ICU) is important. ICU can be perceived by clinicians as overly burdensome for patients and loved ones, and long-term impact on quality of life considered unacceptable, effecting potential bias against admitting older people to ICU. The COVID-19 pandemic highlighted the challenge of selecting those who could most benefit from ICU. Objective: This qualitative study aimed to explore the views and recollections of escalation to ICU from older patients (aged ≥65 years) and next of kin (NoK)who experienced a COVID-19 ICU admission. Setting: The main site was a large NHS Trust in London, which experienced a high burden of COVID-19 cases. Subjects: 30 participants, comprising 12 patients, 7 NoK of survivor and 11 NoK of deceased. Methods: Semi-structured interviews with thematic analysis using a framework approach. Results: There were five major themes: Inevitability, Disconnect, Acceptance, Implications for future decision making and Unique impact of the COVID-19 pandemic. Life was highly valued and ICU perceived to be the only option. Prior understanding of ICU and admission decision-making explanations were limited. Despite benefit of hindsight, having experienced an ICU admission and its consequences, most could not conceptualise thresholds for future acceptable treatment outcomes.Conclusions: In this study of patients ≥65 years and their NoK experiencing an acute ICU admission, survival was prioritised. Despite the ordeal of an ICU stay and its aftermath, the decision to admit and sequelae were considered acceptable.

Journal article

Woolfall K, Paddock K, Watkins M, Kearney A, Neville K, Frith L, Welters I, Gamble C, Trinder J, Pattison N, White C, Brett S, Dilworth S, Ross M, Mouncey P, Rowan K, Dawson A, Collet C, Walsh T, Young Bet al., 2023, Guidance to inform research recruitment processes for studies involving critically ill patients, Journal of the Intensive Care Society, ISSN: 1751-1437

Clinical research in intensive care units (ICUs) is essential for improving treatments for critically ill patients. However, invitations to participate in clinical research in this situation pose numerous challenges. Studies are frequently initiated within a narrow time window when patients are often unconscious and unable to consent. Consultations or consent discussions must therefore be held with consultees or representatives, usually the patient’s relatives. Conversations about research participation in this setting may be difficult, as relatives are often overwhelmed and may feel uneasy about making decisions on behalf of their relatives. In some circumstances, legislation allows doctors to act as consultees or representatives to enrol patients in research. However, there is little good quality evidence on UK stakeholders’ perspectives to inform how recruitment is carried out in ICU studies. The Perspectives Study collected evidence on the views of over 1400 stakeholders, including patients, relatives and healthcare practitioners, many of whom had first-hand experience of ICU treatment and research. This evidence was used to inform good practice guidance on recruitment of critically ill patients to research. Established social science methods and empirical ethics were employed to reflect the interests of stakeholders and justify recommendations. This guidance aims to bridge the gap between the legal frameworks and the realities of ICU studies and to ensure that research recruitment processes reflect the views of patients and families. Researchers and an expert Advisory Group brought different perspectives to interpreting the evidence to develop the guidance. In this article we present guidance for future ICU studies.

Journal article

Schutzer-Weissmann J, Wojcikiewicz T, Karmali A, Lukosiute A, Sun R, Ahmed A, Purkayastha S, Brett S, Cousins Jet al., 2023, Apnoeic oxygenation in morbid obesity: a randomised controlled trial comparing facemask and high-flow nasal oxygen delivery, British Journal of Anaesthesia, Vol: 130, Pages: 103-110, ISSN: 0007-0912

BackgroundObesity is a risk factor for airway-related incidents during anaesthesia. High flow nasal oxygen has been advocated to improve safety in high-risk groups but its effectiveness in the obese population is uncertain. This study compared the effect of high flow nasal oxygen and low flow facemask oxygen delivery on duration of apnoea in morbidly-obese patients.MethodsPatients undergoing bariatric surgery were randomly allocated to receive either high flow nasal (70 L min-1) or facemask (15 L min-1) oxygen. Following induction of anaesthesia, morbidly-obese patients were apnoeic for 18 minutes or until oxygen saturation dropped to 92%.ResultsEighty patients were studied (41 high flow nasal oxygen, 39 facemask). Median apnoea duration was 18 minutes in both the high flow nasal oxygen (IQR 18-18 minutes) and the facemask (IQR 4.1-18 minutes) groups. Five patients in the high flow nasal oxygen group and 14 patients in the facemask group desaturated to 92% within 18 minutes. The risk of desaturation was lower in the high flow nasal oxygen group (Hazard Ratio 0.27, 95% CI 0.11-0.65, p=0.007). ConclusionsIn experienced hands, apnoeic oxygenation is possible in the morbidly-obese and was tolerated for 18 minutes by the majority of patients, whether oxygen delivery was high flow nasal or low flow facemask. High flow nasal oxygen reduced desaturation risk compared to facemask oxygen. Desaturation risk is a more clinically relevant outcome than duration of apnoea. Individual physiological factors are likely to be the primary determinant of risk rather than method of oxygen delivery.

Journal article

Antcliffe DB, Burnham KL, Al-Beidh F, Santhakumaran S, Brett SJ, Hinds CJ, Ashby D, Knight JC, Gordon ACet al., 2022, Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial(vol 199, pg 980 year 2019), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 206, Pages: 1572-1573, ISSN: 1073-449X

Journal article

Rubulotta F, Brett S, Boulanger C, Blackwood B, Deschepper M, Labeau SO, Blot SIet al., 2022, Prevalence of skin pressure injury in critical care patients in the UK: results of a single-day point prevalence evaluation in adult critically ill patient, BMJ Open, Vol: 12, ISSN: 2044-6055

Objectives: Hospital-acquired pressure injuries (PIs) are a source of morbidity and mortality, and many are potentially preventable.Design: This study prospectively evaluated the prevalence and the associated factors of PIs in adult critical care patients admitted to intensive care units (ICU) in the UK.Setting: This service evaluation was part of a larger, international, single-day point prevalence study of PIs in adult ICU patients. Training was provided to healthcare givers using an electronic platform to ensure standardised recognition and staging of PIs across all sites.Participants: The characteristics of the ICUs were recorded before the survey; deidentified patient data were collected using a case report form and uploaded onto a secure online platform.Primary and secondary outcome measures: Factors associated with ICU-acquired PIs in the UK were analysed descriptively and using mixed multiple logistic regression analysis.Results: Data from 1312 adult patients admitted to 94 UK ICUs were collected. The proportion of individuals with at least one PI was 16% (211 out of 1312 patients), of whom 8.8% (n=115/1312) acquired one or more PIs in the ICU and 7.3% (n=96/1312) prior to ICU admission. The total number of PIs was 311, of which 148 (47.6%) were acquired in the ICU. The location of majority of these PIs was the sacral area, followed by the heels. Braden score and prior length of ICU stay were associated with PI development.Conclusions: The prevalence and the stage of severity of PIs were generally low in adult critically ill patients admitted to participating UK ICUs during the study period. However, PIs are a problem in an important minority of patients. Lower Braden score and longer length of ICU stay were associated with the development of injuries; most ICUs assess risk using tools which do not account for this.

Journal article

Grailey K, Leon-Villapalos C, Murray E, Brett Set al., 2022, Exploring the working environment of Hospital Managers: a mixed methods study investigating stress, stereotypes, psychological safety and individual resilience, BMC Health Services Research, Vol: 22, ISSN: 1472-6963

Background:Hospital managers are responsible for the delivery of organisational strategy, development of clinical services and maintaining quality standards. There is limited research on hospital managers, in particular how stress manifests and impacts managers and the presence of individual resilience. Managers must work closely with clinical colleagues, however these relationships can be hindered by the perception of stereotyping and differing priorities. This study aimed to explore the working environment of hospital managers, focusing upon the unique stresses faced, psychological safety and the presence of resilience.Methods:This study utilised mixed methodology using an embedded approach. Participants were purposively recruited from all levels of hospital management within one National Health Service Trust in London, United Kingdom. An exploration of managers experiences was undertaken using semi-structured qualitative interviews. Psychological safety and individual resilience were additionally assessed using validated surveys. Qualitative data were analysed iteratively using inductive thematic analysis, and triangulated with quantitative data. Kruskal-Wallis statistical analysis was performed to evaluate differences in resilience and psychological safety according to seniority and background experience.Results:Twenty-two managers were recruited and interviewed, with 20 returning completed surveys. Key findings from the thematic analysis included the importance of good working relationships with clinical colleagues, the persistence of some stereotyping, and feeling unsupported in times of challenge. Stresses described included the bureaucracy involved when delivering change, conflict with colleagues and target driven expectations.Participants described their own psychological safety as lower than desired, supported by quantitative data; but recognised its importance and strived to create it within their own teams. Sixteen participants had ‘normal’ s

Journal article

Cano-Gamez E, Burnham KL, Goh C, Allcock A, Malick ZH, Overend L, Kwok A, Smith DA, Peters-Sengers H, Antcliffe D, GAinS Investigators, McKechnie S, Scicluna BP, van der Poll T, Gordon AC, Hinds CJ, Davenport EE, Knight JC, Webster N, Galley H, Taylor J, Hall S, Addison J, Roughton S, Tennant H, Guleri A, Waddington N, Arawwawala D, Durcan J, Short A, Swan K, Williams S, Smolen S, Mitchell-Inwang C, Gordon T, Errington E, Templeton M, Venatesh P, Ward G, McCauley M, Baudouin S, Higham C, Soar J, Grier S, Hall E, Brett S, Kitson D, Wilson R, Mountford L, Moreno J, Hall P, Hewlett J, McKechnie S, Garrard C, Millo J, Young D, Hutton P, Parsons P, Smiths A, Faras-Arraya R, Soar J, Raymode P, Thompson J, Bowrey S, Kazembe S, Rich N, Andreou P, Hales D, Roberts E, Fletcher S, Rosbergen M, Glister G, Cuesta JM, Bion J, Millar J, Perry EJ, Willis H, Mitchell N, Ruel S, Carrera R, Wilde J, Nilson A, Lees S, Kapila A, Jacques N, Atkinson J, Brown A, Prowse H, Krige A, Bland M, Bullock L, Harrison D, Mills G, Humphreys J, Armitage K, Laha S, Baldwin J, Walsh A, Doherty N, Drage S, Ortiz-Ruiz de Gordoa L, Lowes S, Higham C, Walsh H, Calder V, Swan C, Payne H, Higgins D, Andrews S, Mappleback S, Hind C, Garrard C, Watson D, McLees E, Purdy A, Stotz M, Ochelli-Okpue A, Bonner S, Whitehead I, Hugil K, Goodridge V, Cawthor L, Kuper M, Pahary S, Bellingan G, Marshall R, Montgomery H, Ryu JH, Bercades G, Boluda S, Bentley A, Mccalman K, Jefferies F, Knight J, Davenport E, Burnham K, Maugeri N, Radhakrishnan J, Mi Y, Allcock A, Goh Cet al., 2022, An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression., Science Translational Medicine, Vol: 14, Pages: 1-15, ISSN: 1946-6234

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.

Journal article

Post B, Badea C, Faisal A, Brett Set al., 2022, Breaking bad news in the era of artificial intelligence and algorithmic medicine: an exploration of disclosure and its ethical justification using the hedonic calculus, AI and Ethics, ISSN: 2730-5961

An appropriate ethical framework around the use of Artificial Intelligence (AI) in healthcare has become a key desirable with the increasingly widespread deployment of this technology. Advances in AI hold the promise of improving the precision of outcome prediction at the level of the individual. However, the addition of these technologies to patient–clinician interactions, as with any complex human interaction, has potential pitfalls. While physicians have always had to carefully consider the ethical background and implications of their actions, detailed deliberations around fast-moving technological progress may not have kept up. We use a common but key challenge in healthcare interactions, the disclosure of bad news (likely imminent death), to illustrate how the philosophical framework of the 'Felicific Calculus' developed in the eighteenth century by Jeremy Bentham, may have a timely quasi-quantitative application in the age of AI. We show how this ethical algorithm can be used to assess, across seven mutually exclusive and exhaustive domains, whether an AI-supported action can be morally justified.

Journal article

Wong J, David S, Sanchez Garrido J, Woo J, Low WW, Morecchiato F, Giani T, Rossolini GM, Beis K, Brett S, Clements A, Aaenensen D, Rouskin S, Frankel Get al., 2022, Recurrent emergence of Klebsiella pneumoniae carbapenem resistance mediated by an inhibitory ompK36 mRNA secondary structure, Proceedings of the National Academy of Sciences of USA, Vol: 119, Pages: 1-12, ISSN: 0027-8424

Outer membrane porins in Gram-negative bacteria facilitate antibiotic influx. In Klebsiella pneumoniae (KP), modifications in the porin OmpK36 are implicated in increasing resistance to carbapenems. Analysis of large KP genome collections, encompassing major healthcare-associated clones, revealed the recurrent emergence of a synonymous cytosine to thymine transition at position 25 (25c>t) in ompK36. We show that the 25c>t transition increases carbapenem resistance through depletion of OmpK36 from the outer membrane. The mutation attenuates KP in a murine pneumonia model, which accounts for its limited clonal expansion observed by phylogenetic analysis. However, in the context of carbapenem treatment, the 25c>t transition tips the balance towards treatment failure, thus accounting for its recurrent emergence. Mechanistically, the 25c>t transition mediates an intramolecular mRNA interaction between a uracil encoded by 25t and the first adenine within the Shine-Dalgarno sequence. This specific interaction leads to the formation of an RNA stem structure, which obscures the ribosomal binding site thus disrupting translation. While mutations reducing OmpK36 expression via transcriptional silencing are known, we uniquely demonstrate the repeated selection of a synonymous ompK36 mutation mediating translational suppression in response to antibiotic pressure.

Journal article

Ritchie A, Kadwani O, Saleh D, Baharlo B, Broomhead L, Randell P, Waheed U, Templeton M, Brown E, Stumpfle R, Patel P, Brett S, Soni Set al., 2022, Clinical and Survival differences during separate COVID-19 surges: investigating the impact of the Sars-CoV-2 alpha variant in critical care patients, PLoS One, Vol: 17, ISSN: 1932-6203

A number of studies have highlighted physiological data from the first surge in critically unwell Covid-19 patients but there is a paucity of data describing emerging variants of SARS-CoV-2, such as B.1.1.7. We compared ventilatory parameters, biochemical and physiological data and mortality between the first and second COVID-19 surges in the United Kingdom, where distinct variants of SARS-CoV-2 were the dominant stain. We performed a retrospective cohort study investigating critically unwell patients admitted with COVID-19 across three tertiary regional ICUs in London, UK. Of 1782 adult ICU patients screened, 330 intubated and ventilated patients diagnosed with COVID-19 were included. In the second wave where B.1.1.7 variant was the dominant strain, patients were had increased severity of ARDS whilst compliance was greater (p<0.05) and d-dimer lower. The 28-day mortality was not statistically significant (1st wave: 42.2% vs 2nd wave: 39.8%). However, when adjusted for key covariates, the hazard ratio for 28-day mortality in those patients with B.1.1.7 was 3.79 (CI 1.04–13.8; p=0.043) compared to the original strain. During the second surge in the UK, where theCOVID-19 variant B.1.1.7 was most prevalent, significantly more patients presented to critical care with severe ARDS. Furthermore, mortality risk was significantly greater in our ICU population during the second wave of the pandemic in those patients with B.1.1.7. As ICUs are experiencing further waves (particularly by the delta (B.1.617.2) variant), we highlight the urgent need for prospective studies describing immunological and pathophysiological differences across novel emerging variants.

Journal article

David S, Wong JLC, Sanchez-Garrido J, Kwong H-S, Low WW, Morecchiato F, Giani T, Rossolini GM, Brett SJ, Clements A, Beis K, Aanensen DM, Frankel Get al., 2022, Widespread emergence of OmpK36 loop 3 insertions among multidrug-resistant clones of Klebsiella pneumoniae., PLoS Pathogens, Vol: 18, Pages: 1-23, ISSN: 1553-7366

Mutations in outer membrane porins act in synergy with carbapenemase enzymes to increase carbapenem resistance in the important nosocomial pathogen, Klebsiella pneumoniae (KP). A key example is a di-amino acid insertion, Glycine-Aspartate (GD), in the extracellular loop 3 (L3) region of OmpK36 which constricts the pore and restricts entry of carbapenems into the bacterial cell. Here we combined genomic and experimental approaches to characterise the diversity, spread and impact of different L3 insertion types in OmpK36. We identified L3 insertions in 3588 (24.1%) of 14,888 KP genomes with an intact ompK36 gene from a global collection. GD insertions were most common, with a high concentration in the ST258/512 clone that has spread widely in Europe and the Americas. Aspartate (D) and Threonine-Aspartate (TD) insertions were prevalent in genomes from Asia, due in part to acquisitions by KP sequence types ST16 and ST231 and subsequent clonal expansions. By solving the crystal structures of novel OmpK36 variants, we found that the TD insertion causes a pore constriction of 41%, significantly greater than that achieved by GD (10%) or D (8%), resulting in the highest levels of resistance to selected antibiotics. We show that in the absence of antibiotics KP mutants harbouring these L3 insertions exhibit both an in vitro and in vivo competitive disadvantage relative to the isogenic parental strain expressing wild type OmpK36. We propose that this explains the reversion of GD and TD insertions observed at low frequency among KP genomes. Finally, we demonstrate that strains expressing L3 insertions remain susceptible to drugs targeting carbapenemase-producing KP, including novel beta lactam-beta lactamase inhibitor combinations. This study provides a contemporary global view of OmpK36-mediated resistance mechanisms in KP, integrating surveillance and experimental data to guide treatment and drug development strategies.

Journal article

Bottle R, Faitna P, Brett S, Aylin Pet al., 2022, Factors associated with, and variations in, COVID-19 hospital death rates in England’s first two waves: observational study, BMJ Open, Vol: 12, Pages: 1-11, ISSN: 2044-6055

Objectives:To assess patient- and hospital-level predictors of death and variation in death rates following admission for COVID-19 in England’s first two waves after accounting for random variation. To quantify the correlation between hospitals’ first and second wave death rates.Design:Observational study using administrative data.Setting:Acute non-specialist hospitals in England.Participants:All patients admitted with a primary diagnosis of COVID-19.Primary and secondary outcomes:In-hospital death.Results:Hospital Episode Statistics (HES) data were extracted for all acute hospitals in England for COVID-19 admissions for March 2020 to March 2021. In wave one (March-July 2020) there were 74,484 admissions and 21,883 deaths (crude rate 29.4%); in wave two (August 2020 to March 2021) there were 165,642 admissions and 36,040 deaths (21.8%). Wave two patients were younger, with more hypertension and obesity but lower rates of other comorbidities. Mortality improved for all ages; in wave two it peaked in December 2020 at 24.2% (lower than wave one’s peak) but halved by March 2021. In multiple multilevel modelling combining HES with hospital-level data from Situational Reports, wave two and wave one variables significantly associated with death were mostly the same. The median odds ratio for wave one was just 1.05 and for wave two was 1.07. At 99.8% control limits, 3% of hospitals were high and 7% were low funnel plot outliers in wave one; these figures were 9% and 12% for wave two. Four hospitals were (low) outliers in both waves. The correlation between hospitals’ adjusted mortality rates between waves was 0.45 (p<0.0001). Length of stay was similar in each wave.Conclusions:England’s first two COVID-19 waves were similar regarding predictors and moderate inter-hospital variation. Despite the challenges, variation in death rates and length of stay between hospitals was modest and might be accounted for by unobserved patient factors.

Journal article

Post B, Badea C, Faisal A, Brett Set al., 2022, Breaking Bad News in the Era of Artificial Intelligence and Algorithmic Medicine: An Exploration of Disclosure and its Ethical Justification using the Hedonic Calculus

An appropriate ethical framework around the use of Artificial Intelligence (AI) in healthcare has becomea key desirable with the increasingly widespread deployment of this technology. Advances in AI hold thepromise of improving the precision of outcome prediction at the level of the individual. However, theaddition of these technologies to patient-clinician interactions, as with any complex human interaction,has potential pitfalls. While physicians have always had to carefully consider the ethical background andimplications of their actions, detailed deliberations around fast-moving technological progress may nothave kept up. We use a common but key challenge in healthcare interactions, the disclosure of bad news(likely imminent death), to illustrate how the philosophical framework of the 'Felicific Calculus' developedin the 18th century by Jeremy Bentham, may have a timely quasi-quantitative application in the age of AI.We show how this ethical algorithm can be used to assess, across seven mutually exclusive and exhaustivedomains, whether an AI-supported action can be morally justified.

Working paper

Mathiszig-Lee JF, Catling FJR, Moonesinghe SR, Brett SJet al., 2022, Highlighting uncertainty in clinical risk prediction using a model of emergency laparotomy mortality risk, npj Digital Medicine, Vol: 5, ISSN: 2398-6352

Clinical prediction models typically make point estimates of risk. However, values of key variables are often missing during model development or at prediction time, meaning that the point estimates mask significant uncertainty and can lead to over-confident decision making. We present a model of mortality risk in emergency laparotomy which instead presents a distribution of predicted risks, highlighting the uncertainty over the risk of death with an intuitive visualisation. We developed and validated our model using data from 127134 emergency laparotomies from patients in England and Wales during 2013–2019. We captured the uncertainty arising from missing data using multiple imputation, allowing prospective, patient-specific imputation for variables that were frequently missing. Prospective imputation allows early prognostication in patients where these variables are not yet measured, accounting for the additional uncertainty this induces. Our model showed good discrimination and calibration (95% confidence intervals: Brier score 0.071–0.078, C statistic 0.859–0.873, calibration error 0.031–0.059) on unseen data from 37 hospitals, consistently improving upon the current gold-standard model. The dispersion of the predicted risks varied significantly between patients and increased where prospective imputation occurred. We present a case study that illustrates the potential impact of uncertainty quantification on clinical decision making. Our model improves mortality risk prediction in emergency laparotomy and has the potential to inform decision-makers and assist discussions with patients and their families. Our analysis code was robustly developed and is publicly available for easy replication of our study and adaptation to predicting other outcomes.

Journal article

Thompson JY, Menzies JC, Manning JC, McAnuff J, Brush EC, Ryde F, Rapley T, Pathan N, Brett S, Moore DJ, Geary M, Colville GA, Morris KP, Parslow RC, Feltbower RG, Lockley S, Kirkham FJ, Forsyth RJ, Scholefield BRet al., 2022, Early mobilisation and rehabilitation in the PICU: a UK survey, BMJ Paediatrics Open, Vol: 6, ISSN: 2399-9772

Objective To understand the context and professional perspectives of delivering early rehabilitation and mobilisation (ERM) within UK paediatric intensive care units (PICUs).Design A web-based survey administered from May 2019 to August 2019.Setting UK PICUs.Participants A total of 124 staff from 26 PICUs participated, including 22 (18%) doctors, 34 (27%) nurses, 28 (23%) physiotherapists, 19 (15%) occupational therapists and 21 (17%) were other professionals.Results Key components of participants’ definitions of ERM included tailored, multidisciplinary rehabilitation packages focused on promoting recovery. Multidisciplinary involvement in initiating ERM was commonly reported. Over half of respondents favoured delivering ERM after achieving physiological stability (n=69, 56%). All age groups were considered for ERM by relevant health professionals. However, responses differed concerning the timing of initiation. Interventions considered for ERM were more likely to be delivered to patients when PICU length of stay exceeded 28 days and among patients with acquired brain injury or severe developmental delay. The most commonly identified barriers were physiological instability (81%), limited staffing (79%), sedation requirement (73%), insufficient resources and equipment (69%), lack of recognition of patient readiness (67%), patient suitability (63%), inadequate training (61%) and inadequate funding (60%). Respondents ranked reduction in PICU length of stay (74%) and improvement in psychological outcomes (73%) as the most important benefits of ERM.Conclusion ERM is gaining familiarity and endorsement in UK PICUs, but significant barriers to implementation due to limited resources and variation in content and delivery of ERM persist. A standardised protocol that sets out defined ERM interventions, along with implementation support to tackle modifiable barriers, is required to ensure the delivery of high-quality ERM.

Journal article

Berry M, Gosling J, Bartlett R, Brett Set al., 2022, Exploring red cell distribution width as a potential risk factor in emergency bowel surgery – a retrospective cohort study, PLoS One, Vol: 17, Pages: 1-14, ISSN: 1932-6203

Increased preoperative red cell distribution width (RDW) is associated with higher mortality following non-cardiac surgery in patients older than 65 years. Little is known if this association holds for all adult emergency laparotomy patients and whether it affects 30-day or long-term mortality. Thus, we examined the relationship between increased RDW and postoperative mortality. Furthermore, we investigated the prognostic worth of anisocytosis and explored a possible association between increased RDW and frailty in this cohort. We conducted a retrospective, single centre National Emergency Laparotomy Audit (NELA) database study at St Mary’s Hospital Imperial NHS Trust between January 2014 and April 2018. A total of 356 patients were included. Survival models were developed using Cox regression analysis, whereas RDW and frailty were analysed using multivariable logistic regression. Underlying model assumptions were checked, including discrimination and calibration. We internally validated our models using bootstrap resampling. There were 33 (9.3%) deaths within 30-days and 72 (20.2%) overall. Median RDW values for 30-day mortality were 13.8% (IQR 13.1%-15%) in survivors and 14.9% (IQR 13.7%-16.1%) in non-survivors, p = 0.007. Similarly, median RDW values were lower in overall survivors (13.7% (IQR 13%-14.7%) versus 14.9% (IQR 13.9%-15.9%) (p<0.001)). Mortality increased across quartiles of RDW, as did the proportion of frail patients. Anisocytosis was not associated with 30-day mortality but demonstrated a link with overall death rates. Increasing RDW was associated with a higher probability of frailty for 30-day (Odds ratio (OR) 4.3, 95% CI 1.22–14.43, (p = 0.01)) and overall mortality (OR 4.9, 95% CI 1.68–14.09, (p = 0.001)). We were able to show that preoperative anisocytosis is associated with greater long-term mortality after emergency laparotomy. Increasing RDW demonstrates a relationship with frailty. Given that RDW is readily available at

Journal article

Lound A, Bruton P, Jones K, Brett S, Gross J, Williams B, Shah N, Ward Het al., 2022, Exploring decision making regarding future care planning with older people living with frailty: Prospective Planning for Escalation of Care and Treatment (ProsPECT), RCN International Nursing Research Conference 2022

Conference paper

Huq F, manners E, O'Callaghan D, Thakuria L, Weaver C, Waheed U, Stümpfle R, Brett SJ, Patel P, Soni Set al., 2022, Patient outcomes following transfer between intensive care units during the COVID-19 pandemic, Anaesthesia, Vol: 77, Pages: 398-404, ISSN: 0003-2409

Transferring critically ill patients between intensive care units is often required in the UK, particularly during the COVID-19 pandemic. However, there is a paucity of data examining clinical outcomes following transfer of patients with COVID-19 and whether this strategy affects their acute physiology or outcome. We investigated all transfers critically ill patients with COVID-19 between three different hospital intensive care units, between March 2020 and March 2021. We focused on inter-hospital intensive care unit transfers, i.e. those patients transferred between intensive care units from different hospitals and compared this cohort with intra-hospital intensive care unit transfers, i.e. patients moved between different intensive care units within the same hospital. A total of 507 transfers were assessed, of which 137 met the inclusion criteria. Forty-five patients underwent inter-hospital transfers compared with 92 intra-hospital transfers. There was no significant change in median compliance 6 hours pre-transfer, immediately post-transfer and 24 hours post-transfer in patients who underwent either intra-hospital or inter-hospital transfers. For inter-hospital transfers, there was an initial drop in median PaO2/FiO2 ratio: from median (IQR [range]) 25.1 (17.8–33.7 [12.1–78.0]) kPa 6 hours pre-transfer to 19.5 (14.6–28.9 [9.8–52.0]) kPa immediately post-transfer (p<0.05). However, this had resolved at 24 hours post-transfer: 25.4 (16.2–32.9 [9.4–51.9]) kPa. For intra-hospital transfers, there was no significant change in PaO2/FiO2 ratio. We also found no meaningful difference in pH; PaCO2;, base excess; bicarbonate; or norepinephrine requirements. Our data demonstrate that patients with COVID-19 undergoing mechanical ventilation of the lungs may have short-term physiological deterioration when transferred between nearby hospitals but this resolves within 24 hours. This finding is relevant to the UK critical care strategy in

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., 2022, Supraglottic airway device versus tracheal intubation in the initial airway management of out-of-hospital cardiac arrest: the AIRWAYS-2 cluster RCT, HEALTH TECHNOLOGY ASSESSMENT, Vol: 26, Pages: 1-158, ISSN: 1366-5278

Journal article

Kousathanas A, Pairo-Castineira E, Rawlik K, Stuckey A, Odhams CA, Walker S, Russell CD, Malinauskas T, Wu Y, Millar J, Shen X, Elliott KS, Griffiths F, Oosthuyzen W, Morrice K, Keating S, Wang B, Rhodes D, Klaric L, Zechner M, Parkinson N, Siddiq A, Goddard P, Donovan S, Maslove D, Nichol A, Semple MG, Zainy T, Maleady-Crowe F, Todd L, Salehi S, Knight J, Elgar G, Chan G, Arumugam P, Patch C, Rendon A, Bentley D, Kingsley C, Kosmicki JA, Horowitz JE, Baras A, Abecasis GR, Ferreira MAR, Justice A, Mirshahi T, Oetjens M, Rader DJ, Ritchie MD, Verma A, Fowler TA, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Elliott P, Walsh T, Tenesa A, GenOMICC Investigators, 23andMe, Covid-19 Human Genetics Initiative, Fawkes A, Murphy L, Rowan K, Ponting CP, Vitart V, Wilson JF, Yang J, Bretherick AD, Scott RH, Hendry SC, Moutsianas L, Law A, Caulfield MJ, Baillie JKet al., 2022, Whole genome sequencing reveals host factors underlying critical Covid-19, Nature, Vol: 607, Pages: 97-103, ISSN: 0028-0836

Critical Covid-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalisation2-4 following SARS-CoV-2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing in 7,491 critically-ill cases compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical Covid-19. We identify 16 new independent associations, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. Mendelian randomisation provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5, CD209) and coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of Covid-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication, or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between critically-ill cases and population controls is highly efficient for detection of therapeutically-relevant mechanisms of disease.

Journal article

Pandolfo A, Horne R, Yogini J, Reader T, Bidad N, Brealey D, Enne V, Livermore D, Gant V, Brett Set al., 2022, Understanding decisions about antibiotic prescribing in ICU: an application of the Necessity Concerns Framework, BMJ Quality and Safety, Vol: 31, Pages: 199-210, ISSN: 2044-5415

Background: Antibiotics are extensively prescribed in intensive care units (ICUs), yet little is known about how antibiotic-related decisions are made in this setting. We explored how beliefs, perceptions and contextual factors influenced ICU clinicians’ antibiotic prescribing.Methods: We conducted 4 focus groups and 34 semistructured interviews with clinicians involved in antibiotic prescribing in four English ICUs. Focus groups explored factors influencing prescribing, whereas interviews examined decision-making processes using two clinical vignettes. Data were analysed using thematic analysis, applying the Necessity Concerns Framework.Results: Clinicians’ antibiotic decisions were influenced by their judgement of the necessity for prescribing/not prescribing, relative to their concerns about potential adverse consequences. Antibiotic necessity perceptions were strongly influenced by beliefs that antibiotics would protect patients from deterioration and themselves from the ethical and legal consequences of undertreatment. Clinicians also reported concerns about prescribing antibiotics. These generally centred on antimicrobial resistance; however, protecting the individual patient was prioritised over these societal concerns. Few participants identified antibiotic toxicity concerns as a key influencer. Clinical uncertainty often complicated balancing antibiotic necessity against concerns. Decisions to start or continue antibiotics often represented ‘erring on the side of caution’ as a protective response in uncertainty. This approach was reinforced by previous experiences of negative consequences (‘being burnt’) which motivated prescribing ‘just in case’ of an infection. Prescribing decisions were also context-dependent, exemplified by a lower perceived threshold to prescribe antibiotics out-of-hours, input from external team members and local prescribing norms.Conclusion: Efforts to improve antibiotic stewardship sho

Journal article

Warner B, Harry A, Brett S, Wells M, Antcliffe Det al., 2022, The end is just the beginning: involvement of bereaved next of kin in qualitative research, BMJ Supportive & Palliative Care, Vol: 12, ISSN: 2045-4368

Journal article

Stacey MJ, Hill N, Parsons I, Wallace J, Taylor N, Grimaldi R, Shah N, Marshall A, House C, O'Hara J, Brett S, Woods DRet al., 2022, Relative changes in brain and kidney biomarkers with Exertional Heat Illness during a cool weather marathon, PLoS One, Vol: 17, ISSN: 1932-6203

Background:Medical personnel may find it challenging to distinguish severe Exertional Heat Illness (EHI), with attendant risks of organ-injury and longer-term sequalae, from lesser forms of incapacity associated with strenuous physical exertion. Early evidence for injury at point-of-incapacity could aid the development and application of targeted interventions to improve outcomes. We aimed to investigate whether biomarker surrogates for end-organ damage sampled at point-of-care (POC) could discriminate EHI versus successful marathon performance.Methods:Eight runners diagnosed as EHI cases upon reception to medical treatment facilities and 30 successful finishers of the same cool weather marathon (ambient temperature 8 rising to 12 ºC) were recruited. Emerging clinical markers associated with injury affecting the brain (neuron specific enolase, NSE; S100 calcium-binding protein B, S100β) and renal system (cystatin C, cysC; kidney-injury molecule-1, KIM-1; neutrophil gelatinase-associated lipocalin, NGAL), plus copeptin as a surrogate for fluid-regulatory stress, were sampled in blood upon marathon collapse/completion, as well as beforehand at rest (successful finishers only).Results:Versus successful finishers, EHI showed significantly higher NSE (10.33 [6.37, 20.00] vs. 3.17 [2.71, 3.92] ug.L-1, P<0.0001), cysC (1.48 [1.10, 1.67] vs. 1.10 [0.95, 1.21] mg.L-1, P = 0.0092) and copeptin (339.4 [77.0, 943] vs. 18.7 [7.1, 67.9] pmol.L-1, P = 0.0050). Discrimination of EHI by ROC (Area-Under-the-Curve) showed performance that was outstanding for NSE (0.97, P<0.0001) and excellent for copeptin (AUC = 0.83, P = 0.0066).Conclusions:As novel biomarker candidates for EHI outcomes in cool-weather endurance exercise, early elevations in NSE and copeptin provided sufficient discrimination to suggest utility at point-of-incapacity. Further investigation is warranted in patients exposed to greater thermal insult, followed up over a more extended period.

Journal article

Look N, Voss S, Blennow Nordström E, Brett S, Jenkinson E, Shaw P, White P, Benger Jet al., 2022, Neurocognitive function following out-of-hospital cardiac arrest: a systematic review, Resuscitation, Vol: 170, Pages: 238-246, ISSN: 0300-9572

ObjectivesThe primary aim of this review was to investigate neurocognitive outcomes following out-of-hospital cardiac arrest (OHCA). Specifically, the focus was on identifying the different neurocognitive domains that are assessed, the measures used, and the level of, and criteria for, impairment.Design and review methodsA systematic review of the literature from 2006 to 2021 was completed using Medline, Cinahl and Psychinfo. Criteria for inclusion were studies with participants over the age of 18, OHCA and at least one neurocognitive function measure. Qualitative and case studies were excluded. Reviewers assessed criteria and risk of bias using a modified version of Downs and Black.ResultsForty-three studies were identified. Most studies had a low risk of bias (n = 31) or moderate risk of bias (n = 11) and one had a high risk; however, only six reported effect sizes or power analyses. Multiple measures of neurocognitive outcomes were used (>50) and level of impairment criteria varied considerably. Memory impairments were frequently found and were also more likely to be impaired followed by executive function and processing speed.DiscussionThis review highlights the heterogeneity of measures and approaches used to assess neurocognitive outcomes following OHCA as well as the need to improve risk of bias concerning generalizability. Improved understanding of the approaches used for assessment and the subsequent findings will facilitate a standardized evaluation of neurocognitive outcomes following OHCA.

Journal article

Grailey K, Lound A, Brett S, 2021, Lived experiences of healthcare workers on the frontline during the COVID-19 pandemic – a qualitative interview study., BMJ Open, Vol: 11, Pages: 1-13, ISSN: 2044-6055

Objectives: This study aimed to investigate the presence of perceived stressors, psychological safety and teamwork in healthcare professionals. As the timeframe for this study spanned the first wave of the COVID-19 pandemic, data were captured demonstrating the impact of the pandemic on these factors. Design: Qualitative Interview Study Setting: All staff working within the Emergency and Critical Care Departments of one National Health Service Trust in London, United Kingdom. Participants: Forty-nine participants were recruited using a purposive sampling technique and interviewed when the first wave of the COVID-19 pandemic had subsided. Main Outcome Measures: Evaluation of changes in perceived stressors, psychological safety and teamwork in individuals working during the COVID-19 pandemic. Results: The thematic analysis relating to a participant’s lived experiences whilst working during COVID-19 led to the construction of 5 key themes, including ‘Psychological effects’ and ‘Changes in team dynamics’. Several psychological effects were described, including the presence of psychological distress and insights into the aetiology of moral injury. There was marked heterogeneity in participants response to COVID-19, particularly with respect to changes in team dynamics and the perception of a psychologically safe environment. Descriptions of improved team cohesiveness and camaraderie contrasted with stories of new barriers, notably due to the high workload and the impact of personal protective equipment. Building on these themes, a map of key changes arising due to the pandemic was developed, highlighting potential opportunities to provide targeted support. Conclusions: Working on the frontline of a pandemic can have significant implications for healthcare workers, putting them at risk of psychological distress and moral injury, as well as affecting team dynamics. There is striking heterogeneity in the manifestation of these challenges.

Journal article

ISARIC Clinical Characterisation Group, 2021, The value of open-source clinical science in pandemic response: lessons from ISARIC., Lancet Infectious Diseases, Vol: 21, Pages: 1623-1624, ISSN: 1473-3099

Journal article

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