Imperial College London

Professor Anthony Gordon

Faculty of MedicineDepartment of Surgery & Cancer

Chair in Anaesthesia and Critical Care
 
 
 
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Contact

 

anthony.gordon

 
 
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Location

 

ICUQueen Elizabeth the Queen Mother Wing (QEQM)St Mary's Campus

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Summary

 

Publications

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223 results found

Axfors C, Schmitt AM, Janiaud P, Van't Hooft J, Abd-Elsalam S, Abdo EF, Abella BS, Akram J, Amaravadi RK, Angus DC, Arabi YM, Azhar S, Baden LR, Baker AW, Belkhir L, Benfield T, Berrevoets MAH, Chen C-P, Chen T-C, Cheng S-H, Cheng C-Y, Chung W-S, Cohen YZ, Cowan LN, Dalgard O, de Almeida E Val FF, de Lacerda MVG, de Melo GC, Derde L, Dubee V, Elfakir A, Gordon AC, Hernandez-Cardenas CM, Hills T, Hoepelman AIM, Huang Y-W, Igau B, Jin R, Jurado-Camacho F, Khan KS, Kremsner PG, Kreuels B, Kuo C-Y, Le T, Lin Y-C, Lin W-P, Lin T-H, Lyngbakken MN, McArthur C, McVerry BJ, Meza-Meneses P, Monteiro WM, Morpeth SC, Mourad A, Mulligan MJ, Murthy S, Naggie S, Narayanasamy S, Nichol A, Novack LA, O'Brien SM, Okeke NL, Perez L, Perez-Padilla R, Perrin L, Remigio-Luna A, Rivera-Martinez NE, Rockhold FW, Rodriguez-Llamazares S, Rolfe R, Rosa R, Røsjø H, Sampaio VS, Seto TB, Shahzad M, Soliman S, Stout JE, Thirion-Romero I, Troxel AB, Tseng T-Y, Turner NA, Ulrich RJ, Walsh SR, Webb SA, Weehuizen JM, Velinova M, Wong H-L, Wrenn R, Zampieri FG, Zhong W, Moher D, Goodman SN, Ioannidis JPA, Hemkens LGet al., 2024, Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials., Nat Commun, Vol: 15

Journal article

Goligher EC, 2024, The Rise of Adaptive Platform Trials in Critical Care, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Journal article

Walsh TS, Aitken LM, McKenzie CA, Boyd J, Macdonald A, Giddings A, Hope D, Norrie J, Weir C, Parker RA, Lone NI, Emerson L, Kydonaki K, Creagh-Brown B, Morris S, McAuley DF, Dark P, Wise MP, Gordon AC, Perkins G, Reade M, Blackwood B, MacLullich A, Glen R, Page VJet al., 2023, Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK, BMJ Open, Vol: 13, ISSN: 2044-6055

INTRODUCTION: Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care. METHODS AND ANALYSIS: Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs. ETHICS AND DISSEMINATION: The Scotland A REC

Journal article

REMAP-CAP Investigators, Hills TE, Lorenzi E, Berry LR, Shyamsundar M, Al-Beidh F, Annane D, Arabi Y, Aryal D, Au C, Beane A, Bhimani Z, Bonten M, Bradbury CA, Brunkhorst FM, Burrell A, Buxton M, Calfee CS, Cecconi M, Cheng AC, Cove ME, Detry MA, Estcourt LJ, Fitzgerald M, Goligher EC, Goossens H, Green C, Haniffa R, Harrison DA, Hashmi M, Higgins AM, Huang DT, Ichihara N, Jayakumar D, Kruger PS, Lamontagne F, Lampro L, Lawler PR, Marshall JC, Mason AJ, McGlothlin A, McGuinness S, McQuilten ZK, McVerry BJ, Mouncey PR, Murthy S, Neal MD, Nichol AD, O'Kane CM, Parke RL, Parker JC, Rabindrarajan E, Reyes LF, Rowan KM, Saito H, Santos M, Saunders CT, Seymour CW, Shankar-Hari M, Sinha P, Thompson BT, Turgeon AF, Turner AM, van de Veerdonk F, Weis S, Young IS, Zarychanski R, Lewis RJ, McArthur CJ, Angus DC, Berry SM, Derde LPG, Webb SA, Gordon AC, McAuley DFet al., 2023, Simvastatin in Critically Ill Patients with Covid-19., The New England journal of medicine, Vol: 389, Pages: 2341-2354, ISSN: 0028-4793

<h4>Background</h4>The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.<h4>Methods</h4>In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2).<h4>Results</h4>Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control.<h4>Conclusions</h4>Al

Journal article

LOVIT-COVID Investigators, on behalf of the Canadian Critical Care Trials Group, and the REMAP-CAP Investigators, Adhikari NKJ, Hashmi M, Tirupakuzhi Vijayaraghavan BK, Haniffa R, Beane A, Webb SA, Angus DC, Gordon AC, Cook DJ, Guyatt GH, Berry LR, Lorenzi E, Mouncey PR, Au C, Pinto R, Ménard J, Sprague S, Masse M-H, Huang DT, Heyland DK, Nichol AD, McArthur CJ, de Man A, Al-Beidh F, Annane D, Anstey M, Arabi YM, Battista M-C, Berry S, Bhimani Z, Bonten MJM, Bradbury CA, Brant EB, Brunkhorst FM, Burrell A, Buxton M, Cecconi M, Cheng AC, Cohen D, Cove ME, Day AG, Derde LPG, Detry MA, Estcourt LJ, Fagbodun EO, Fitzgerald M, Goossens H, Green C, Higgins AM, Hills TE, Ichihara N, Jayakumar D, Kanji S, Khoso MN, Lawler PR, Lewis RJ, Litton E, Marshall JC, McAuley DF, McGlothlin A, McGuinness SP, McQuilten ZK, McVerry BJ, Murthy S, Parke RL, Parker JC, Reyes LF, Rowan KM, Saito H, Salahuddin N, Santos MS, Saunders CT, Seymour CW, Shankar-Hari M, Tolppa T, Trapani T, Turgeon AF, Turner AM, Udy AA, van de Veerdonk FL, Zarychanski R, Lamontagne Fet al., 2023, Intravenous vitamin C for patients hospitalized with COVID-19: two harmonized randomized clinical trials, JAMA: Journal of the American Medical Association, Vol: 330, Pages: 1745-1759, ISSN: 0098-7484

IMPORTANCE: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain. OBJECTIVE: To determine whether vitamin C improves outcomes for patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents. INTERVENTIONS: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses). MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility. RESULTS: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible i

Journal article

Woodbridge H, Norton C, Jones M, Brett S, Alexander C, Gordon Aet al., 2023, Clinician and patient perspectives on the barriers and facilitators to physical rehabilitation in intensive care: a qualitative interview study, BMJ Open, Vol: 13, ISSN: 2044-6055

Objectives The objective of this study is to explore patient, relative/carer and clinician perceptions of barriers to early physical rehabilitation in intensive care units (ICUs) within an associated group of hospitals in the UK and how they can be overcome.Design Qualitative study using semi-structured interviews and thematic framework analysis.Setting Four ICUs over three hospital sites in London, UK.Participants Former ICU patients or their relatives/carers with personal experience of ICU rehabilitation. ICU clinicians, including doctors, nurses, physiotherapists and occupational therapists, involved in the delivery of physical rehabilitation or decisions over its initiation.Primary and secondary outcomes measures Views and experiences on the barriers and facilitators to ICU physical rehabilitation.Results Interviews were carried out with 11 former patients, 3 family members and 16 clinicians. The themes generated related to: safety and physiological concerns, patient participation and engagement, clinician experience and knowledge, teamwork, equipment and environment and risks and benefits of rehabilitation in intensive care. The overarching theme for overcoming barriers was a change in working model from ICU clinicians having separate responsibilities (a multidisciplinary approach) to one where all parties have a shared aim of providing patient-centred ICU physical rehabilitation (an interdisciplinary approach).Conclusions The results have revealed barriers that can be modified to improve rehabilitation delivery in an ICU. Interdisciplinary working could overcome many of these barriers to optimise recovery from critical illness.

Journal article

Whitehouse T, Hossain A, Perkins GD, Gordon AC, Bion J, Young D, McAuley D, Singer M, Lord J, Gates S, Veenith T, MacCallum NS, Yeung J, Innes R, Welters I, Boota N, Skilton E, Ghuman B, Hill M, Regan SE, Mistry D, Lall R, STRESS-L Collaboratorset al., 2023, Landiolol and organ failure in patients with septic shock: the STRESS-L randomized clinical trial, JAMA: Journal of the American Medical Association, Vol: 330, Pages: 1641-1652, ISSN: 0098-7484

IMPORTANCE: Patients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. β-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality. OBJECTIVES: To assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (>24 hours) vasopressor support. DESIGN, SETTING, AND PARTICIPANTS: An open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 μg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm. INTERVENTION: Sixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion. MAIN OUTCOMES AND MEASURES: The primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group. RESULTS: The trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, -0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, -4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62

Journal article

Nagendran M, Festor P, Komorowski M, Gordon A, Faisal Aet al., 2023, Quantifying the impact of AI recommendations with explanations on prescription decision making, npj Digital Medicine, Vol: 6, ISSN: 2398-6352

The influence of AI recommendations on physician behaviour remains poorly characterised. We assess how clinicians' decisions may be influenced by additional information more broadly, and how this influence can be modified by either the source of the information (human peers or AI) and the presence or absence of an AI explanation (XAI, here using simple feature importance). We used a modified between-subjects design where intensive care doctors (N=86) were presented on a computer for each of 16 trials with a patient case and prompted to prescribe continuous values for two drugs. We used a multi-factorial experimental design with four arms, where each clinician experienced all four arms on different subsets of our 24 patients. The four arms were (i) baseline (control), (ii) peer human clinician scenario showing what doses had been prescribed by other doctors, (iii) AI suggestion and (iv) XAI suggestion. We found that additional information (peer, AI or XAI) had a strong influence on prescriptions (significantly for AI, not so for peers) but simple XAI did not have higher influence than AI alone. There was no correlation between attitudes to AI or clinical experience on the AI-supported decisions and nor was there correlation between what doctors self-reported about how useful they found the XAI and whether the XAI actually influenced their prescriptions. Our findings suggest that the marginal impact of simple XAI was low in this setting and we also cast doubt on the utility of self-reports as a valid metric for assessing XAI in clinical experts.

Journal article

Billot L, Cuthbertson B, Gordon A, Al-Beidh F, Correa M, Davis J, Finfer S, Glass P, Goodman F, Hammond N, Iredell J, Miller J, Murthy S, Rose L, Seppelt I, Taylor C, Young P, Myburgh J, The SuDDICU Investigatorset al., 2023, Protocol summary and statistical analysis plan for the Selective Decontamination of the Digestive Tract in Intensive Care Units cross-over, cluster randomised controlled trial. (SuDDICU), Critical Care and Resuscitation, ISSN: 1441-2772

Background:There is uncertainty whether the use of Selective Decontamination of the Digestive Tract (SDD) improves outcomes in ventilated patients in Intensive Care Units (ICUs) and whether SDD is associated with the development of antibiotic resistance. Objectives:To describe the study protocol and statistical analysis plan for the Selective Decontamination of the Digestive Tract in ICUs (SuDDICU) trial.Design, setting and participants:SuDDICU is an international, cross-over, cluster-randomised-controlled trial of mechanically ventilated patients in ICUs using two 12-month trial periods. Participating ICUs will implement either SDD plus standard care or standard care for each period. The SuDDICU drug intervention is an oral paste and gastric suspension of three antibiotics combined with a 4-day course of intravenous antibiotics. An observational ecological assessment will be conducted during the interventional periods and 5 surveillance periods. The trial will be conducted in 19 ICUs in Australia and 10 ICUs in Canada and the UK that will recruit 15000-17000 patients. Recruitment commenced in Australia in 2017. Outcomes:The primary outcome is all-cause hospital mortality. Secondary outcomes include duration of ventilation, ICU and hospital stay, the incidence of new antibiotic resistant organisms during the index ICU admission, changes in antibiotic resistant organism rates, incidence of new Clostridioides difficile infections and total antibiotic usage.Results and conclusions:SuDDICU will determine whether the use of SDD plus standard care is associated with a reduction in hospital mortality in ventilated ICU patients compared to standard care alone and will quantify the impact of the use of SDD on the development of antibiotic resistance. Trial registration:The trial is registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12615000411549) and on ClinicalTrials.gov Registry (NCT02389036).

Journal article

Kanai M, Andrews SJ, Cordioli M, Stevens C, Neale BM, Daly M, Ganna A, Pathak GA, Iwasaki A, Karjalainen J, Mehtonen J, Pirinen M, Chwialkowska K, Trankiem A, Balaconis MK, Veerapen K, Wolford BN, Ahmad HF, Andrews S, von Hohenstaufen Puoti KA, Boer C, Boua PR, Butler-Laporte G, Cadilla CL, Chwiałkowska K, Colombo F, Douillard V, Dueker N, Dutta AK, El-Sherbiny YM, Eltoukhy MM, Esmaeeli S, Faucon A, Fave M-J, Cadenas IF, Francescatto M, Francioli L, Franke L, Fuentes M, Durán RG, Cabrero DG, Harry EN, Jansen P, Szentpéteri JL, Kaja E, Kanai M, Kirk C, Kousathanas A, Krieger JE, Patel SK, Lemaçon A, Limou S, Lió P, Marouli E, Marttila MM, Medina-Gómez C, Michaeli Y, Migeotte I, Mondal S, Moreno-Estrada A, Moya L, Nakanishi T, Nasir J, Pasko D, Pearson NM, Pereira AC, Priest J, Prijatelj V, Prokić I, Teumer A, Várnai R, Romero-Gómez M, Roos C, Rosenfeld J, Ruolin L, Schulte EC, Schurmann C, Sedaghati-khayat B, Shaheen D, Shivanathan I, Sipeky C, Sirui Z, Striano P, Tanigawa Y, Remesal AU, Vadgama N, Vallerga CL, van der Laan S, Verdugo RA, Wang QS, Wei Z, Zainulabid UA, Zárate RN, Auton A, Shelton JF, Shastri AJ, Weldon CH, Filshtein-Sonmez T, Coker D, Symons A, Aslibekyan S, OConnell J, Ye C, Hatoum AS, Agrawal A, Bogdan R, Colbert SMC, Thompson WK, Fan CC, Johnson EC, Niazyan L, Davidyants M, Arakelyan A, Avetyan D, Bekbossynova M, Tauekelova A, Tuleutayev M, Sailybayeva A, Ramankulov Y, Zholdybayeva E, Dzharmukhanov J, Kassymbek K, Tsechoeva T, Turebayeva G, Smagulova Z, Muratov T, Khamitov S, Kwong ASF, Timpson NJ, Niemi MEK, Rahmouni S, Guntz J, Beguin Y, Cordioli M, Pigazzini S, Nkambule L, Georges M, Moutschen M, Misset B, Darcis G, Gofflot S, Bouysran Y, Busson A, Peyrassol X, Wilkin F, Pichon B, Smits G, Vandernoot I, Goffard J-C, Tiembe N, Morrison DR, Afilalo J, Mooser V, Richards JB, Rousseau S, Durand M, Butler-Laporte G, Forgetta V, Laurent L, Afrasiabi Z, Bouab M, Tselios C, Xue X, Afilalo M, Oliveira M, St-Cyr J, Boisclair A, Ragoussis J, Auld D, Kaufet al., 2023, A second update on mapping the human genetic architecture of COVID-19, Nature, Vol: 621, Pages: E7-E26, ISSN: 0028-0836

Journal article

Leaf DE, Gordon AC, Lawler PR, 2023, Adverse effects of tocilizumab versus baricitinib in severe COVID-19, Critical Care Medicine, Vol: 51, Pages: e184-e185, ISSN: 0090-3493

Journal article

Torrance HD, Zhang P, Longbottom ER, Mi Y, Whalley JP, Allcock A, Kwok AJ, Cano-Gamez E, Geoghegan CG, Burnham KL, Antcliffe DB, Davenport EE, Pearse RM, ODwyer MJ, Hinds CJ, Knight JC, Gordon ACet al., 2023, A transcriptomic approach to understand patient susceptibility to pneumonia after abdominal surgery, Annals of Surgery, ISSN: 0003-4932

Objective: To describe immune-pathways and gene-networks altered following major-abdominal surgery and identify transcriptomic patterns associated with postoperative pneumonia.Summary Background Data: Nosocomial infections are a major healthcare challenge, developing in over 20% of patients aged 45 or over undergoing major-abdominal surgery, with postoperative pneumonia associated with an almost five-fold increase in 30-day mortality.Methods: From a prospective consecutive cohort (n=150) undergoing major-abdominal surgery whole-blood RNA was collected preoperatively and at three time-points postoperatively (2-6, 24 and 48hrs). Twelve patients diagnosed with postoperative pneumonia and 27 matched patients remaining infection-free were identified for analysis with RNA-sequencing.Results: Compared to preoperative sampling, 3,639 genes were upregulated and 5,043 downregulated at 2-6hrs. Pathway-analysis demonstrated innate-immune activation with neutrophil-degranulation and Toll-like-receptor signalling upregulation alongside adaptive-immune suppression. Cell-type deconvolution of preoperative RNA-sequencing revealed elevated S100A8/9-high neutrophils alongside reduced naïve CD4 T-cells in those later developing pneumonia. Preoperatively, a gene-signature characteristic of neutrophil-degranulation was associated with postoperative pneumonia acquisition (P=0.00092). A previously reported Sepsis Response Signature (SRSq) score, reflecting neutrophil-dysfunction and a more dysregulated host response, at 48hrs postoperatively, differed between patients subsequently developing pneumonia and those remaining infection-free (P=0.045). Analysis of the novel neutrophil gene-signature and SRSq scores in independent major-abdominal surgery and polytrauma cohorts indicated good predictive performance in identifying patients suffering later infection.Conclusions: Major-abdominal surgery acutely upregulates innate-immune pathways while simultaneously suppressing adaptive-immune p

Journal article

Pairo-Castineira E, Rawlik K, Bretherick AD, Qi T, Wu Y, Nassiri I, McConkey GA, Zechner M, Klaric L, Griffiths F, Oosthuyzen W, Kousathanas A, Richmond A, Millar J, Russell CD, Malinauskas T, Thwaites R, Morrice K, Keating S, Maslove D, Nichol A, Semple MG, Knight J, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Begg C, Walsh T, Tenesa A, Flores C, Riancho JA, Rojas-Martinez A, Lapunzina P, Clohisey S, Abellan J, Alex B, Shelton JF, Yang J, Ponting CP, Wilson JF, Vitart V, Abedalthagafi M, Luchessi AD, Parra EJ, Cruz R, Carracedo A, Fawkes A, Murphy L, Rowan K, Pereira AC, Law A, Fairfax B, Hendry SC, Baillie JKet al., 2023, Author Correction: GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19, Nature, Vol: 619, Pages: E61-E61, ISSN: 0028-0836

Journal article

Bradbury CA, Lawler PR, McVerry BJ, Zarychanski R, REMAP CAPIet al., 2023, Continuation of therapeutic dose heparin for critically ill patients with COVID-19, INTENSIVE CARE MEDICINE, Vol: 49, Pages: 873-875, ISSN: 0342-4642

Journal article

Pirracchio R, Annane D, Waschka AK, Lamontagne F, Arabi YM, Bollaert P-E, Billot L, Du B, Briegel J, Cohen J, Finfer S, Gordon A, Hammond N, Hyvernat H, Keh D, Li Y, Liu L, Meduri GU, Mirea L, Myburgh JA, Sprung CL, Tilouche N, Tongyoo S, Venkatesh B, Zheng R, Delaney Aet al., 2023, Patient-level meta-analysis of low-dose hydrocortisone in adults with septic shock, NEJM Evidence, Vol: 2, Pages: 1-12, ISSN: 2766-5526

BACKGROUNDTrials and study-level meta-analyses have failed to resolve the role of corticosteroids in the management of patients with septic shock. Patient-level meta-analyses may provide more precise estimates of treatment effects, particularly subgroup effects.METHODSWe pooled individual patient data from septic shock trials investigating the adjunctive use of intravenous hydrocortisone. The primary outcome was 90-day all-cause mortality, and it was also analyzed across predefined subgroups. Secondary outcomes included mortality at intensive care unit and hospital discharge, at 28 and 180 days, and vasopressor-, ventilator-, and organ failure–free days. Adverse events included superinfection, muscle weakness, hyperglycemia, hypernatremia, and gastroduodenal bleeding.RESULTSOf 24 eligible trials (n=8528), 17 (n=7882) provided individual patient data, and 7 (n=5929) provided 90-day mortality. The marginal relative risk (RR) for 90-day mortality of hydrocortisone versus placebo was 0.93 (95% confidence interval [CI], 0.82 to 1.04; P=0.22; moderate certainty). It was 0.86 (9% CI, 0.79 to 0.92) for hydrocortisone with fludrocortisone and 0.96 (95% CI, 0.82 to 1.12) without fludrocortisone. There was no significant differential treatment effect across subgroups. Hydrocortisone was associated with little to no difference in any of the secondary outcomes except vasopressor-free days (mean difference, 1.24 days; 95% CI, 0.74 to 1.73; high certainty). Hydrocortisone may not be associated with an increase in the risk of superinfection (RR, 1.04; 95% CI, 0.95 to 1.15; low certainty), hyperglycemia (RR, 1.05; 95% CI, 0.98 to 1.12; low certainty), or gastroduodenal bleeding (RR, 1.11; 95% CI, 0.83 to 1.48; low certainty). Hydrocortisone may be associated with an increase in the risk of hypernatremia (RR, 2.01; 95% CI, 1.56 to 2.60; low certainty) and muscle weakness (n=2647; RR, 1.73; 95% CI, 1.49 to 1.99; low certainty).CONCLUSIONSIn this patient-level meta-analysis, hydr

Journal article

Pairo-Castineira E, Rawlik K, Bretherick AD, Qi T, Wu Y, Nassiri I, McConkey GA, Zechner M, Klaric L, Griffiths F, Oosthuyzen W, Kousathanas A, Richmond A, Millar J, Russell CD, Malinauskas T, Thwaites R, Morrice K, Keating S, Maslove D, Nichol A, Semple MG, Knight J, Shankar-Hari M, Summers C, Hinds C, Horby P, Ling L, McAuley D, Montgomery H, Openshaw PJM, Begg C, Walsh T, Tenesa A, Flores C, Riancho JA, Rojas-Martinez A, Lapunzina P, GenOMICC Investigators, SCOURGE Consortium, ISARICC Investigators, 23andMe COVID-19 Team, Yang J, Ponting CP, Wilson JF, Vitart V, Abedalthagafi M, Luchessi AD, Parra EJ, Cruz R, Carracedo A, Fawkes A, Murphy L, Rowan K, Pereira AC, Law A, Fairfax B, Hendry SC, Baillie JKet al., 2023, GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19, Nature, Vol: 617, Pages: 764-768, ISSN: 0028-0836

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Journal article

Saito H, 2023, International platform trials: as diseases cross borders, so should trials, Lancet Infectious Diseases, Vol: 23, Pages: 530-531, ISSN: 1473-3099

Journal article

Dark P, Perkins GD, McMullan R, McAuley D, Gordon AC, Clayton J, Mistry D, Young K, Regan S, McGowan N, Stevenson M, Gates S, Carlson GL, Walsh T, Lone N, Mouncey PR, Singer M, Wilson P, Felton T, Marshall K, Hossain AM, Lall Ret al., 2023, biomArker-guided Duration of Antibiotic treatment in hospitalised Patients with suspecTed Sepsis (ADAPT-Sepsis): A protocol for a multicentre randomised controlled trial, JOURNAL OF THE INTENSIVE CARE SOCIETY, ISSN: 1751-1437

Journal article

Writing Committee for the REMAP-CAP Investigators, Lawler PR, Derde LPG, van de Veerdonk FL, McVerry BJ, Huang DT, Berry LR, Lorenzi E, van Kimmenade R, Gommans F, Vaduganathan M, Leaf DE, Baron RM, Kim EY, Frankfurter C, Epelman S, Kwan Y, Grieve R, O'Neill S, Sadique Z, Puskarich M, Marshall JC, Higgins AM, Mouncey PR, Rowan KM, Al-Beidh F, Annane D, Arabi YM, Au C, Beane A, van Bentum-Puijk W, Bonten MJM, Bradbury CA, Brunkhorst FM, Burrell A, Buzgau A, Buxton M, Cecconi M, Cheng AC, Cove M, Detry MA, Estcourt LJ, Ezekowitz J, Fitzgerald M, Gattas D, Godoy LC, Goossens H, Haniffa R, Harrison DA, Hills T, Horvat CM, Ichihara N, Lamontagne F, Linstrum KM, McAuley DF, McGlothlin A, McGuinness SP, McQuilten Z, Murthy S, Nichol AD, Owen DRJ, Parke RL, Parker JC, Pollock KM, Reyes LF, Saito H, Santos MS, Saunders CT, Seymour CW, Shankar-Hari M, Singh V, Turgeon AF, Turner AM, Zarychanski R, Green C, Lewis RJ, Angus DC, Berry S, Gordon AC, McArthur CJ, Webb SAet al., 2023, Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support–free days in patients hospitalized with COVID-19, JAMA: Journal of the American Medical Association, Vol: 329, Pages: 1183-1196, ISSN: 0098-7484

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. OBJECTIVE: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsen

Journal article

Goligher EC, Lawler PR, Jensen TP, Talisa V, Berry LR, Lorenzi E, McVerry BJ, Chang C-CH, Leifer E, Bradbury C, Berger J, Hunt BJ, Castellucci LA, Kornblith LZ, Gordon AC, McArthur C, Webb S, Hochman J, Neal MD, Zarychanski R, Berry S, Angus DC, Aday A, Ahuja T, Al-Beidh F, Angus DC, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Berger JS, Berry SM, Berry LR, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Bradbury CA, Brooks MM, Brunkhorst F, Buxton M, Buzgau A, Carrier M, Castelucci LA, Chekuri S, Chen J-T, Cheng AC, Chkhikvadze T, Coiffard B, Contreras A, Costantini TW, Cushman M, de Brouwer S, Derde LPG, Detry MA, Duggal A, Džavík V, Effron MB, Eng HF, Escobedo J, Estcourt LJ, Everett BM, Farkough ME, Fergusson DA, Fitzgerald M, Fowler RA, Froess JD, Fu Z, Galanaud J-P, Galen BT, Gandotra S, Girard TD, Godoy LD, Goligher EC, Gong MN, Goodman AL, Goossens H, Gordon AC, Green C, Greenstein YY, Gross PL, Guerrero RM, Hamburg N, Haniffa R, Hanna G, Hanna N, Hedge SM, Hendrickson CM, Higgins AM, Hindenburg AA, Hite RD, Hochman JS, Hope AA, Horowitz JM, Horvat CM, Houston BL, Huang DT, Hudock K, Hunt BJ, Husain M, Hyzy RC, Iyer V, Jacobson JR, Jayakumar D, Kahn SR, Keller NM, Khan A, Kim Y, Kim KS, Kindzelski A, King AJ, Kirwan B-A, Knudson MM, Kornblith LZ, Kornblith AE, Krishnan V, Kumar A, Kutcher ME, Laffan MA, Lamontagne F, Lawler PR, Le Gal G, Leeper CM, Leifer ES, Lewis RJ, Lim G, Lima FG, Linstrum K, Litton E, Lopez-Sendon J, Lopez-Sendon Moreno JL, Lorenzi E, Lother SA, Madrona SG, Malhotra S, Marcos Martin M, Marshall JC, Marten N, Martinez AS, Martinez M, Mateos Garcia E, Matthay MA, Mavromichalis S, McArthur CJ, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, McQuilten ZK, McVerry BJ, Middeldorp S, Montgomery SK, Moore SC, Mouncey PR, Murthy S, Nair GB, Nair R, Neal MD, Nichol AD, Nicolau JC, Nunez-Garcia B, Pandey A, Park JJ, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Pompilio M, Prekker M, Quigley JG, Reynolds HR, Rosenson RSet al., 2023, Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19, JAMA: Journal of the American Medical Association, Vol: 329, Pages: 1-12, ISSN: 0098-7484

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making.Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE.Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial.Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis.Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival.Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose hep

Journal article

Verghis R, Blackwood B, McDowell C, Toner P, Hadfield D, Gordon AC, Clarke M, McAuley Det al., 2023, Heterogeneity of surrogate outcome measures used in critical care studies: A systematic review., Clinical Trials, Vol: 20, Pages: 307-318, ISSN: 1740-7745

BACKGROUND: The choice of outcome measure is a critical decision in the design of any clinical trial, but many Phase III clinical trials in critical care fail to detect a difference between the interventions being compared. This may be because the surrogate outcomes used to show beneficial effects in early phase trials (which informed the design of the subsequent Phase III trials) are not valid guides to the differences between the interventions for the main outcomes of the Phase III trials. We undertook a systematic review (1) to generate a list of outcome measures used in critical care trials, (2) to determine the variability in the outcome reporting in the respiratory subgroup and (3) to create a smaller list of potential early phase endpoints in the respiratory subgroup. METHODS: Data related to outcomes were extracted from studies published in the six top-ranked critical care journals between 2010 and 2020. Outcomes were classified into subcategories and categories. A subset of early phase endpoints relevant to the respiratory subgroup was selected for further investigation. The variability of the outcomes and the variability in reporting was investigated. RESULTS: A total of 6905 references were retrieved and a total of 294 separate outcomes were identified from 58 studies. The outcomes were then classified into 11 categories and 66 subcategories. A subset of 22 outcomes relevant for the respiratory group were identified as potential early phase outcomes. The summary statistics, time points and definitions show the outcomes are analysed and reported in different ways. CONCLUSION: The outcome measures were defined, analysed and reported in a variety of ways. This creates difficulties for synthesising data in systematic reviews and planning definitive trials. This review once again highlights an urgent need for standardisation and validation of surrogate outcomes reported in critical care trials. Future work should aim to validate and develop a core outcome set

Journal article

Cleasby C, Marshall T, Gordon AC, Antcliffe Det al., 2023, The effect of vasopressin and hydrocortisone on cytokine trajectories: exploratory analysis from the VANISH trial, Intensive Care Medicine, Vol: 49, Pages: 241-243, ISSN: 0342-4642

Journal article

Florescu S, Stanciu D, Zaharia M, Kosa A, Codreanu D, Kidwai A, Masood S, Kaye C, Coutts A, MacKay L, Summers C, Polgarova P, Farahi N, Fox E, McWilliam S, Hawcutt D, Rad L, OMalley L, Whitbread J, Jones D, Dore R, Saunderson P, Kelsall O, Cowley N, Wild L, Thrush J, Wood H, Austin K, Bélteczki J, Magyar I, Fazekas Á, Kovács S, Szőke V, Donnelly A, Kelly M, Smyth N, OKane S, McClintock D, Warnock M, Campbell R, McCallion E, Azaiz A, Charron C, Godement M, Geri G, Vieillard-Baron A, Johnson P, McKenna S, Hanley J, Currie A, Allen B, McGoldrick C, McMaster M, Mani A, Mathew M, Kandeepan R, Vignesh C, TV B, Ramakrishnan N, James A, Elvira E, Jayakumar D, Pratheema R, Babu S, Ebenezer R, Krishnaoorthy S, Ranganathan L, Ganesan M, Shree M, Guilder E, Butler M, Cowdrey K-A, Robertson M, Ali F, McMahon E, Duffy E, Chen Y, Simmonds C, McConnochie R, OConnor C, El-Khawas K, Richardson A, Hill D, Commons R, Abdelkharim H, Saxena M, Muteithia M, Dobell-Brown K, Jha R, Kalogirou M, Ellis C, Krishnamurthy V, OConnor A, Thurairatnam S, Mukherjee D, Kaliappan A, Vertue M, Nicholson A, Riches J, Maloney G, Kittridge L, Solesbury A, Ramos A, Collins D, Brickell K, Reid L, Smyth M, Breen P, Spain S, Curley G, McEvoy N, Geoghegan P, Clarke J, Silversides J, McGuigan P, Ward K, ONeill A, Finn S, Wright C, Green J, Collins É, Knott C, Smith J, Boschert C, Slieker K, Ewalds E, Sanders A, Wittenberg W, Geurts H, Poojara L, Sara T, Nand K, Reeve B, Dechert W, Phillips B, Oritz-Ruiz deGordoa L, Affleck J, Shaikh A, Murray A, Ramanan M, Frakking T, Pinnell J, Robinson M, Gledhill L, Wood T, Sanghavi R, Bhonagiri D, Ford M, Parikh HG, Avard B, Nourse M, McDonald B, Edmunds N, Hoiting O, Peters M, Rengers E, Evers M, Prinssen A, Morgan M, Cole J, Hill H, Davies M, Williams A, Thomas E, Davies R, Wise M, Grimm P, Soukup J, Wetzold R, Löbel M, Starke L, Lellouche F, Lizotte P, Declerq P, Antoine M, Stephanie G, Jean-Pierre E, François B, Marion B, Philippe R, Pourcine F, Monchi M, Luis Det al., 2023, Long-term (180-Day) outcomes in critically Ill patients with COVID-19 in the REMAP-CAP randomized clinical trial, JAMA: Journal of the American Medical Association, Vol: 329, Pages: 39-51, ISSN: 0098-7484

Importance The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.Objective To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.Design, Setting, and Participants Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.Interventions Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).Main Outcomes and Measures The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.Results Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasm

Journal article

Gordon A, 2022, Erratum: transcriptomic signatures in sepsis and a differential response to steroids. from the VANISH randomized trial., American Journal of Respiratory and Critical Care Medicine, Vol: 206, Pages: 1572-1573, ISSN: 1073-449X

Journal article

Ahmad R, Gordon AC, Aylin P, Redhead J, Holmes A, Evans DPet al., 2022, Effective knowledge mobilisation: creating environments for quick generation, dissemination, and use of evidence., The BMJ, Vol: 379, Pages: 1-5, ISSN: 1759-2151

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

Myburgh JA, Seppelt IM, Goodman F, Billot L, Correa M, Davis JS, Gordon AC, Hammond NE, Iredell J, Li Q, Micallef S, Miller J, Mysore J, Taylor C, Young PJ, Cuthbertson BH, Finfer SRet al., 2022, Effect of selective decontamination of the digestive tract on hospital mortality in critically Ill patients receiving mechanical ventilation a randomized clinical trial, JAMA: Journal of the American Medical Association, Vol: 328, Pages: 1911-1921, ISSN: 0098-7484

Importance Whether selective decontamination of the digestive tract (SDD) reduces mortality in critically ill patients remains uncertain.Objective To determine whether SDD reduces in-hospital mortality in critically ill adults.Design, Setting, and Participants A cluster, crossover, randomized clinical trial that recruited 5982 mechanically ventilated adults from 19 intensive care units (ICUs) in Australia between April 2018 and May 2021 (final follow-up, August 2021). A contemporaneous ecological assessment recruited 8599 patients from participating ICUs between May 2017 and August 2021.Interventions ICUs were randomly assigned to adopt or not adopt a SDD strategy for 2 alternating 12-month periods, separated by a 3-month interperiod gap. Patients in the SDD group (n = 2791) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191) received standard care.Main Outcomes and Measures The primary outcome was in-hospital mortality within 90 days. There were 8 secondary outcomes, including the proportion of patients with new positive blood cultures, antibiotic-resistant organisms (AROs), and Clostridioides difficile infections. For the ecological assessment, a noninferiority margin of 2% was prespecified for 3 outcomes including new cultures of AROs.Results Of 5982 patients (mean age, 58.3 years; 36.8% women) enrolled from 19 ICUs, all patients completed the trial. There were 753/2791 (27.0%) and 928/3191 (29.1%) in-hospital deaths in the SDD and standard care groups, respectively (mean difference, −1.7% [95% CI, −4.8% to 1.3%]; odds ratio, 0.91 [95% CI, 0.82-1.02]; P = .12). Of 8 prespecified secondary outcomes, 6 showed no significant differences. In the SDD vs

Journal article

Fish M, Rynne J, Jennings A, Lam C, Lamikanra AA, Ratcliff J, Cellone-Trevelin S, Timms E, Jiriha J, Tosi I, Pramanik R, Simmonds P, Seth S, Williams J, Gordon AC, Knight J, Smith DJ, Whalley J, Harrison D, Rowan K, Harvala H, Klenerman P, Estcourt L, Menon DK, Roberts D, Shankar-Hari Met al., 2022, Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial, Intensive Care Medicine, Vol: 48, Pages: 1525-1538, ISSN: 0342-4642

PurposeBenefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs .MethodsWe tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) .ResultsUnsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (− 1, 21) vs 10 (− 1, to 21) in subphenotype-2; 1.5 (− 1, 21) vs 12 (− 1, to 21) in suphenotype-3, and 0 (− 1, 21) vs 0 (− 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008).ConclusionsWe reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results

Journal article

Mi Y, Burnham KL, Charles PD, Heilig R, Vendrell I, Whalley J, Torrance HD, Antcliffe DB, May SM, Neville MJ, Berridge G, Hutton P, Goh C, Radhakrishnan J, Nesvizhskii A, Yu F, Davenport EE, McKechnie S, Davies R, OCallaghan DJP, Patel P, Karpe F, Gordon AC, Ackland GL, Hinds CJ, Fischer R, Knight JCet al., 2022, High-throughput mass spectrometry maps the sepsis plasma proteome and differences in response

<jats:title>Summary</jats:title><jats:p>Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is an unmet global health challenge. Here we apply high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (non-infected critical illness, post-operative inflammation and healthy volunteers) involving 2622 samples and 4553 liquid chromatography-mass spectrometry analyses in a single batch, at 100 samples/day. We show how this scale of data can establish shared and specific proteins, pathways and co-expression modules in sepsis, and be integrated with paired leukocyte transcriptomic data (n=837 samples) using matrix decomposition. We map the landscape of the host response in sepsis including changes over time, and identify features relating to etiology, clinical phenotypes and severity. This work reveals novel subphenotypes informative for sepsis response state, disease processes and outcome, highlights potential biomarkers, pathways and processes for drug targets, and advances a systems-based precision medicine approach to sepsis.</jats:p>

Journal article

Woodbridge H, Alexander C, Jones M, Gordon Aet al., 2022, Exploring the barriers to early physical rehabilitation and investigating its safety in critically ill patients receiving vasoactive drugs. Rising Star - ICS Gold Medal., Intensive Care Society State of the Art 2021 Congress, Publisher: SAGE Publications

Conference paper

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