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

261 results found

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, 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

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

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

Schutzer-Weissmann J, Wojcikiewicz T, Karmali A, Lukosiute A, Sun R, Ahmed A, Purkayastha S, Brett S, Cousins Jet al., 2022, Apnoeic oxygenation in morbid obesity: a randomised controlled trial comparing facemask and high-flow nasal oxygen delivery, British Journal of Anaesthesia, 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

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

Grailey K, Leon-Villapalos C, Murray E, Brett Set al., 2021, The psychological impact of the workplace environment in critical care a qualitative exploration, Human Factors in Healthcare, Vol: 1, Pages: 1-6, ISSN: 2772-5014

The workplace environment can have a significant impact on an employee’s psychological wellbeing. This has been demonstrated using the Job Demand Control Model, which posits that high job demands and low decision latitude lead to increased job strain.Participants were recruited from three Critical Care Units within one NHS Trust in London. Each participant underwent a qualitative interview exploring attitudes to the workplace environment and its subsequent impact. Data were analysed using a thematic analysis approach. Thirty participants representing the multidisciplinary team and all levels of seniority were recruited according to a purposeful sampling technique. Our analysis demonstrated a measurable incidence of negative psychological consequences resulting from several key areas within the critical care environment, including isolation in single rooms and visibility of senior support. Applying the Job Demand Control model, we were able to identify areas of high job demand and low decision latitude. The critical care environment is highly dynamic and job demands are likely to be unmodifiable. The framework developed in this study highlights areas that can be adapted to improve decision latitude, consequently minimising negative consequences. Leaders wishing to improve the psychological wellbeing of their staff can use our framework to identify areas where individual control can be enhanced. This should lead to increased decision latitude, thereby reducing the psychological strain created by the workplace environment. In addition, a reduction in job strain and improved employee wellbeing may create more commitment to the organisation, improving productivity and enhancing career longevity.

Journal article

Reader T, Dayal R, Brett S, 2021, At the end: a vignette-based investigation of strategies for managing end-of-life decisions in the Intensive Care Unit, Journal of the Intensive Care Society, Vol: 22, Pages: 305-311, ISSN: 1751-1437

Background. Decision-making on End-of-life (EOL) is an inevitable, yet highly complex, aspect of intensive care decision-making. EOL decisions can be challenging both in terms of clinical judgement and social interaction with families, and these two process often become intertwined. This is especially apparent at times when clinicians are required to seek the views of surrogate decision makers (i.e., family members) when considering palliative care. Methods. Using a vignette-based interview methodology, we explored how interactions with family members influence EOL decisions by ICU clinicians (n=24), and identified strategies for reaching consensus with families during this highly emotional phase of ICU care. Results. We found that the enactment of EOL decisions were reported as being affected by a form of loss aversion, whereby concerns over the consequences of not reaching a consensus with families weighed heavily in the minds of clinicians. Fear of conflict with families tended to arise from anticipated unrealistic family expectations of care, family normalization of patient incapacity, and belief systems that prohibit end-of-life decision-making. Conclusions. To support decision makers in reaching consensus, various strategies for effective, coherent, and targeted communication (e.g., patient deterioration and limits of clinical treatment) were suggested as ways to effectively consult with families on EOL decision-making.

Journal article

Shah A, MacCallum N, Harris S, Brealey D, Palmer E, Hetherington J, Shi S, Perez-Suarez D, Ercole A, Watkinson P, Jones A, Ashworth S, Beale R, Brett S, Singer Met al., 2021, Descriptors of sepsis using the Sepsis-3 criteria: a cohort study in critical care units within the UK NIHR Critical Care Health Informatics Collaborative, Critical Care Medicine, Vol: 49, Pages: 1883-1894, ISSN: 0090-3493

Objective: To describe the epidemiology of sepsis in critical care by applying the Sepsis-3 criteria to electronic health records. Design: Retrospective cohort study using electronic health records. Setting: Ten intensive care units (ICU) from four United Kingdom National Health Service hospital trusts contributing to the National Institute for Health Research Critical Care Health Informatics Collaborative (CC-HIC).Patients: 28,456 critical care admissions (14,332 emergency medical, 4,585 emergency surgical, and 9,539 elective surgical)Measurements and Main Results: 29,343 episodes of clinical deterioration were identified with a rise in Sequential Organ Failure Assessment (SOFA) score of at least 2 points, of which 14,869 (50.7%) were associated with antibiotic escalation and thereby met the Sepsis-3 criteria for sepsis. 4,100 episodes of sepsis (27.6%) were associated with vasopressor use and lactate > 2.0 mmol/l, and therefore met the Sepsis-3 criteria for septic shock. ICU mortality by source of sepsis was highest for ICU-acquired sepsis (23.7%, 95% CI 21.9%, 25.6%), followed by hospital-acquired sepsis (18.6%, 95% CI 17.5%, 19.9%), and community-acquired sepsis (12.9%, 95% CI 12.1%, 13.6%) (p for comparison <0.0001).Conclusions: We successfully operationalized the Sepsis-3 criteria to an electronic health record dataset to describe the characteristics of critical care patients with sepsis. This may facilitate sepsis research using electronic health record data at scale without relying on human coding.

Journal article

Stacey M, Hill N, Brett S, Fitchett G, Woods Det al., 2021, What do environment-related illnesses tell us about the character of military medicine and future clinical requirements?, BMJ Military Health, ISSN: 2633-3767

Extreme environments present medical and occupational challenges that extend beyond generic resuscitation, to formulating bespoke diagnoses and prognoses and embarking on management pathways rarely encountered in civilian practice. Pathophysiological complexity and clinical uncertainty call for military physicians of all kinds to balance intuition with pragmatism, adapting according to the predominant patterns of care required. In an era of smaller operational footprints and less concentrated clinical experience, proposals aimed at improving the systematic care of Service Personnel incapacitated at environmental extremes must not be lost to corporate memory. These general issues are explored in the particular context of thermal stress and metabolic disruption. Specific focus is given to the accounts of military physicians who served on large-scale deployments into the heat of Iraq and Kuwait (Operation TELIC) and Oman (Exercise SAIF SAREEA). Generalisable insights into the enduring character of military medicine and future clinical requirements result.

Journal article

Stokes E, Lazaroo M, Clout M, Brett S, Black S, Kirby K, Nolan J, Reeves B, Robinson M, Rogers C, Scott L, Smartt H, South A, Taylor J, Thomas M, Voss S, Benger J, Wordsworth Set al., 2021, Cost-effectiveness of the i-gel supraglottic airway device compared to tracheal intubation during out-of-hospital cardiac arrest: findings from the AIRWAYS-2 randomised controlled trial, Resuscitation, Vol: 167, Pages: 1-9, ISSN: 0300-9572

Aim:Optimal airway management during out-of-hospital cardiac arrest (OHCA) is uncertain. Complications from tracheal intubation (TI) may be avoided with supraglottic airway (SGA) devices. The AIRWAYS-2 cluster randomised controlled trial (ISRCTN08256118) compared the i-gel SGA with TI as the initial advanced airway management (AAM) strategy by paramedics treating adults with non-traumatic OHCA. This paper reports the trial cost-effectiveness analysis.Methods:A within-trial cost-effectiveness analysis of the i-gel compared with TI was conducted, with a 6-month time horizon, from the perspective of the UK National Health Service (NHS) and personal social services. The primary outcome measure was quality-adjusted life years (QALYs), estimated using the EQ-5D-5L questionnaire. Multilevel linear regression modelling was used to account for clustering by paramedic when combining costs and outcomes.Results:9,296 eligible patients were attended by 1,382 trial paramedics and enrolled in the AIRWAYS-2 trial (4410 TI, 4886 i-gel). Mean QALYs to 6 months were 0.03 in both groups (i-gel minus TI difference -0.0015, 95% CI –0.0059 to 0.0028). Total costs per participant up to 6 months post-OHCA were £3,570 and £3,413 in the i-gel and TI groups respectively (mean difference £157, 95% CI –£270 to £583). Based on mean difference point estimates, TI was more effective and less costly than i-gel; however differences were small and there was great uncertainty around these results.Conclusion:The small differences between groups in QALYs and costs shows no difference in the cost-effectiveness of the i-gel and TI when used as the initial AAM strategy in adults with non-traumatic OHCA.

Journal article

Glampson B, Brittain J, Kaura A, Mulla A, Mercuri L, Brett S, Aylin P, tessa S, goodman I, Redhead J, kavitha S, Mayer Eet al., 2021, North West London Covid-19 Vaccination Programme: Real-world evidence for Vaccine uptake and effectiveness: Retrospective Cohort Study, JMIR Public Health and Surveillance, Vol: 7, Pages: 1-17, ISSN: 2369-2960

Background:On March 11, 2020 the World Health Organisation declared the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus Disease 2019 (COVID-19) syndrome, as a pandemic. The UK mass vaccination programme commenced on December 08, 2020 vaccinating groups of the population deemed to be most vulnerable to severe COVID-19 infection.Objective:To assess the early vaccine administration coverage and outcome data across an integrated care system in North West London (NWL), leveraging a unique population-level care dataset. Vaccine effectiveness of a single dose of the Oxford/Astrazeneca and Pfizer/BioNtech vaccines were compared.Methods:A retrospective cohort study identified 2,183,939 individuals eligible for COVID-19 vaccination between December 08, 2020 and February 24, 2021 within a primary, secondary and community care integrated care dataset. These data were used to assess vaccination hesitancy across ethnicity, gender and socio-economic deprivation measures (Pearson Product-Moment Correlations); investigated COVID-19 transmission related to vaccination hubs; and assessed the early effectiveness of COVID-19 vaccination (after a single dose) using time to event analyses with multivariable Cox regression analysis to investigate if vaccination independently predicted positive SARS-CoV-2 in those vaccinated compared to those unvaccinated.Results: In the study 5.88% (24,332/413,919) of individuals declined and did not receive a vaccination. Black or Black British individuals had the highest rate of declining a vaccine at 16.14% (4,337/26,870). There was a strong negative association between socio-economic deprivation and rate of declining vaccination (r=-0.94, P=.002) with 13.5% (1980/14571) of individuals declining vaccination in the most deprived areas compared to 0.98% (869/9609) in the least. In the first six days after vaccination 344 of 389587 individuals tested positive for SARS-CoV-2 (0.09%). The rate increased to 0.13% (525/389,243)

Journal article

Billot L, Lipman J, Brett SJ, De Waele JJ, Cotta MO, Davis JS, Finfer S, Hammond N, Knowles S, McGuinness S, Myburgh J, Paterson DL, Peake S, Rajbhandari D, Rhodes A, Roberts JA, Roger C, Shirwadkar C, Starr T, Taylor C, Dulhunty JMet al., 2021, Statistical analysis plan for the BLING III study: a phase 3 multicentre randomised controlled trial of continuous versus intermittent beta-lactam antibiotic infusion in critically ill patients with sepsis, Critical Care and Resuscitation, Vol: 23, Pages: 273-284, ISSN: 1441-2772

BACKGROUND: The β-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 randomised controlled trial comparing continuous infusion with intermittent infusion of β-lactam antibiotics in 7000 critically ill patients with sepsis.OBJECTIVE: To describe a statistical analysis plan for the BLING III study.METHODS: The statistical analysis plan was designed by the trial statistician and chief investigators and approved by the BLING III management committee before the completion of data collection. Statistical analyses for primary, secondary and tertiary outcomes and planned subgroup analyses are described in detail. Interim analysis by the Data Safety and Monitoring Committee (DSMC) has been conducted in accordance with a pre-specified DSMC charter.RESULTS AND CONCLUSIONS: The statistical analysis plan for the BLING III study is published before completion of data collection and unblinding to minimise analysis bias and facilitate public access and transparent analysis and reporting of study findings.TRIAL REGISTRATION: ClinicalTrials.gov Registry NCT03212990.

Journal article

Grailey K, Murray E, Reader T, Brett Set al., 2021, The presence and potential impact of psychological safety in the healthcare setting: An evidence synthesis, BMC Health Services Research, Vol: 21, Pages: 1-15, ISSN: 1472-6963

IntroductionPsychological safety is the shared belief that the team is safe for interpersonal risk taking. Its presence improves innovation and error prevention. This evidence synthesis had 3 objectives: explore the current literature regarding psychological safety, identify methods used in its assessment and investigate for evidence of consequences of a psychologically safe environmentMethodsWe searched multiple trial registries through December 2018. All studies addressing psychological safety within healthcare workers were included and reviewed for methodological limitations. A thematic analysis approach explored the presence of psychological safety. Content analysis was utilised to evaluate potential consequences.ResultsWe included 62 papers from 19 countries. The thematic analysis demonstrated high and low levels of psychological safety both at the individual level in study participants and across the studies themselves. There was heterogeneity in responses across all studies, limiting generalisable conclusions about the overall presence of psychological safety. A wide range of methods were used. Twenty-five used qualitative methodology, predominantly semi-structured interviews. Thirty quantitative or mixed method studies used surveys. Ten studies inferred that low psychological safety negatively impacted patient safety. Nine demonstrated a significant relationship between psychological safety and team outcomes. The thematic analysis allowed the development of concepts beyond the content of the original studies. This analytical process provided a wealth of information regarding facilitators and barriers to psychological safety and the development of a model demonstrating the influence of situational context.Discussion This evidence synthesis highlights that whilst there is a positive and demonstrable presence of psychological safety within healthcare workers worldwide, there is room for improvement. The variability in methods used demonstrates scope to harmonis

Journal article

Grailey K, Leon-Villapolos C, Murray E, Brett Set al., 2021, Exploring the factors which promote or diminish a psychologically safe environment: a qualitative interview study with critical care staff., BMJ Open, Vol: 11, Pages: 1-8, ISSN: 2044-6055

ObjectivesThis study aimed to quantify the presence of psychological safety (defined as an environment “safe for interpersonal risk taking”) in critical care staff, exploring the ways in which this manifestedDesignQualitative interview study incorporating a short quantitative survey. SettingThree Intensive Care Units within one NHS Trust in London ParticipantsThirty participants were recruited from all levels of seniority and roles within the multidisciplinary team. A purposive sampling technique was used, with recruitment ceasing at the point of thematic saturation. InterventionsSemi-structured interviews explored attitudes towards psychological safety and contained a quantitative assessment measuring the climate of psychological safety present. ResultsTwenty-eight participants agreed that it was easy to ask for help, with 20 agreeing it is safe to take a risk on the team, demonstrating a strong perception of psychological safety in this group. Our thematic analysis highlighted areas where the context influenced an individual’s psychological safety including personality, culture & leadership. Possible negative consequences of psychological safety included distraction and fatigue for the team leader. We demonstrated that speaking up can be influenced by motivations other than patient safety – such as undermining or self-promotion. ConclusionsOur data demonstrate reassuring levels of psychological safety within the participants studied. This allowed us to explore in depth the participant experience of working within a psychologically safe environment. We add to the current literature by uniquely demonstrating there can be negative consequences to a psychologically safe environment in the healthcare setting. We expand on the influence of context on psychological safety by developing a model – allowing leaders to identify which elements of context can be modified in order to promote speaking up. Team leaders can use this data to help f

Journal article

Goodwin L, Samuel K, Schofield B, Voss S, Brett S, Couper K, Gould D, Harrison D, Lall R, Nolan J, Perkins G, Soar J, Thomas M, Benger Jet al., 2021, Airway management during in-hospital cardiac arrest (IHCA) in adults: UK national survey and interview study with anaesthetic and intensive care trainees, Journal of the Intensive Care Society, Vol: 22, Pages: 192-197, ISSN: 1751-1437

Background: The optimal airway management strategy for in-hospital cardiac arrest (IHCA) is unknown.Methods: An online survey and telephone interviews with anaesthetic and intensive care trainee doctors identified by the United Kingdom (UK) Research and Audit Federation of Trainees. Questions explored IHCA frequency, grade and specialty of those attending, proportion of patients receiving advanced airway management, airway strategies immediately available, and views on a randomised trial of airway management strategies during IHCA.Results: Completed surveys were received from 128 hospital sites (76% response rate). Adult IHCAs were attended by anaesthesia staff at 40 sites (31%), intensive care staff at 37 sites (29%), and a combination of specialties at 51 sites (40%). The majority (123/128, 96%) of respondents reported immediate access to both tracheal intubation (TI) and supraglottic airways (SGAs). A bag-mask technique was used ‘very frequently’ or ‘frequently’ during IHCA by 111/128 (87%) of respondents, followed by SGAs (101/128, 79%) and TI (69/128, 54%). The majority (60/100, 60%) of respondents estimated that ≤30% of IHCA patients undergo TI, while 34 (34%) estimated this to be between 31-70%. Most respondents (102/128, 80%) would be ‘likely’ or ‘very likely’ to recruit future patients to a trial of alternative airway management strategies during IHCA. Interview data identified several barriers and facilitators to conducting research on airway management in IHCA.Conclusions: There is variation in airway management strategies for adult IHCA across the UK. Most respondents would be willing to take part in a randomised trial of airway management during IHCA.

Journal article

COVID-19 Host Genetics Initiative, 2021, Mapping the human genetic architecture of COVID-19, Nature, Vol: 600, Pages: 472-477, ISSN: 0028-0836

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Journal article

Glampson B, Brittain J, Kaura A, Mulla A, Mercuri L, Brett SJ, Aylin P, Sandall T, Goodman I, Redhead J, Saravanakumar K, Mayer EKet al., 2021, Assessing COVID-19 vaccine uptake and effectiveness through the north west London vaccination program: retrospective cohort study, Publisher: JMIR Publications

Background:Real world data supporting the effectiveness of the COVID-19 vaccination strategy in the UK population is needed to guide health policy. This real-word data-driven evidence study of the UK COVID-19 Vaccination Programme in the Northwest London (NWL) population used a unique dataset established as part of the Gold Command Covid-19 response in NWL (iCARE https://imperialbrc.nihr.ac.uk/facilities/icare/), which included the pre-established Whole System Integrated Care (WSIC) data collated for the purposes of population health in the sector.Objective:To assess the early vaccine administration coverage and vaccine effectiveness and outcome data across an integrated care system of eight CCGs leveraging a unique population-level care datasetMethods:Design - Retrospective cohort study. Setting - Individuals eligible for COVID 19 vaccination in North West London based on linked primary and secondary care data. Participants - 2,183,939 individuals eligible for COVID 19 vaccinationResults:During the NWL vaccine programme study time period 5.88% of individuals declined and did not receive a vaccination. Black or black British individuals had the highest rate of declining a vaccine at 16.14% (4,337). There was a strong negative association between deprivation and rate of declining vaccination (r=-0.94, p<0.01) with 13.5% of individuals declining vaccination in the most deprived postcodes compared to 0.98% in the least deprived postcodes. In the first six days after vaccination 344 of 389587 individuals tested positive for COVID-19 (0.09%). The rate increased to 0.13% (525/389,243) between days 7 and 13, before then gradually falling week on week. At 28 days post vaccination there was a 74% (HR 0.26 (0.19-0.35)) and 78% (HR 0.22 (0.18-0.27)) reduction in risk of testing positive for COVID -19 for individuals that received the Oxford/Astrazeneca and Pfizer/BioNTech vaccines respectively, when compared with unvaccinated individuals. After vaccination very low rates of

Working paper

Pandolfo A, Horne R, Jani Y, Reader T, Bidad N, Brealey D, Enne V, Livermore D, Gant V, Brett Set al., 2021, Intensivists’ beliefs about rapid multiplex molecular diagnostic testing and its potential role in improving prescribing decisions and antimicrobial stewardship: a qualitative study, Antimicrobial Resistance and Infection Control, Vol: 10, Pages: 1-8, ISSN: 2047-2994

Background: Rapid molecular diagnostic tests to investigate the microbial aetiology of pneumonias may improve treatment and antimicrobial stewardship in intensive care units (ICUs). Clinicians’ endorsement and uptake of these tests is crucial to maximise engagement; however, adoption may be impeded if users harbour unaddressed concerns or if device usage is incompatible with local practice. Accordingly, we strove to identify ICU clinicians’ beliefs about molecular diagnostic tests for pneumonias before implementation at the point-of-care.Methods: We conducted semi-structured interviews with 35 critical care doctors working in four ICUs in the United Kingdom. A clinical vignette depicting a fictitious patient with signs of pneumonia was used to explore clinicians’ beliefs about the importance of molecular diagnostics and their concerns. Data were analysed thematically.Results: Clinicians’ beliefs about molecular tests could be grouped into two categories: perceived potential of molecular diagnostics to improve antibiotic prescribing (Molecular Diagnostic Necessity) and concerns about how the test results could be implemented into practice (Molecular Diagnostic Concerns). Molecular Diagnostic Necessity stemmed from beliefs that positive results would facilitate targeted antimicrobial therapy; that negative results would signal the absence of a pathogen, and consequently that having the molecular diagnostic results would bolster clinicians’ prescribing confidence. Molecular Diagnostic Concerns included unfamiliarity with the device’s capabilities, worry that it would detect non-pathogenic bacteria, uncertainty whether it would fail to detect pathogens, and discomfort with withholding antibiotics until receiving molecular test results.Conclusions: Clinicians believed rapid molecular diagnostics for pneumonias were potentially important and were open to using them; however, they harboured concerns about the tests’ capabilities an

Journal article

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