Imperial College London

Professor Anthony Gordon

Faculty of MedicineDepartment of Surgery & Cancer

Chair in Anaesthesia and Critical Care
 
 
 
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Contact

 

+44 (0)20 3312 6328anthony.gordon

 
 
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Location

 

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

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Summary

 

Publications

Publication Type
Year
to

127 results found

Mårtensson J, Gordon AC, 2019, Terlipressin or norepinephrine, or both in septic shock?, Intensive Care Medicine, Vol: 44, Pages: 1964-1966, ISSN: 0342-4642

Journal article

Antcliffe DB, Santhakumaran S, Orme RML, Ward JK, Al-Beidh F, ODea K, Perkins GD, Singer M, McAuley DF, Mason AJ, Cross M, Ashby D, Gordon ACet al., Levosimendan in septic shock in patients with biochemical evidence of cardiac dysfunction: a subgroup analysis of the LeoPARDS randomised trial, Intensive Care Medicine, Pages: 1-9, ISSN: 0342-4642

PurposeMyocardial dysfunction is common in sepsis but optimal treatment strategies are unclear. The inodilator, levosimendan was suggested as a possible therapy; however, the levosimendan to prevent acute organ dysfunction in Sepsis (LeoPARDS) trial found it to have no benefit in reducing organ dysfunction in septic shock. In this study we evaluated the effects of levosimendan in patients with and without biochemical cardiac dysfunction and examined its non-inotropic effects.MethodsTwo cardiac biomarkers, troponin I (cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and five inflammatory mediators were measured in plasma from patients recruited to the LeoPARDS trial at baseline and over the first 6 days. Mean total Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were compared between patients with normal and raised cTnI and NT-proBNP values, and between patients above and below median values.ResultsLevosimendan produced no benefit in SOFA score or 28-day mortality in patients with cardiac dysfunction. There was a statistically significant treatment by subgroup interaction (p = 0.04) in patients with NT-proBNP above or below the median value. Those with NT-proBNP values above the median receiving levosimendan had higher SOFA scores than those receiving placebo (mean daily total SOFA score 7.64 (4.41) vs 6.09 (3.88), mean difference 1.55, 95% CI 0.43–2.68). Levosimendan had no effect on the rate of decline of inflammatory biomarkers.ConclusionAdding levosimendan to standard care in septic shock was not associated with less severe organ dysfunction nor lower mortality in patients with biochemical evidence of cardiac dysfunction.

Journal article

Richards-Belle A, Mouncey P, Grieve R, Harrison D, Sadique Z, Henry D, Whitman C, Camsooksai J, Gordon A, Young D, Rowan K, Lamontagne Fet al., Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Protocol for the 65 randomised clinical trial, Journal of the Intensive Care Society, Pages: 1-11, ISSN: 1751-1437

The 65 trial is a pragmatic, multicentre, parallel-group, open-label, randomised clinical trial of permissive hypotension (targeting a mean arterial pressure target of 60–65 mmHg during vasopressor therapy) versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. The trial will recruit 2600 patients from 65 United Kingdom adult general critical care units. The primary outcome is all-cause mortality at 90 days. An economic evaluation is embedded. This paper describes the proposed statistical and health economic analysis for the 65 trial.

Journal article

Thomas K, Patel A, Sadique MZ, Grieve RD, Mason AJ, Moler S, Gordon AC, Rowan KM, Mouncey PR, Lamontagne F, Harrison DAet al., 2019, Evaluating the clinical and cost-effectiveness of permissive hypotension in critically ill patients aged 65 years or over with vasodilatory hypotension: Statistical and Health Economic Analysis Plan for the 65 trial, Journal of the Intensive Care Society, Pages: 175114371986038-175114371986038, ISSN: 1751-1437

The 65 trial is a pragmatic, multicentre, parallel-group, open-label, randomised clinical trial of permissive hypotension (targeting a mean arterial pressure target of 60–65 mmHg during vasopressor therapy) versus usual care in critically ill patients aged 65 years or over with vasodilatory hypotension. The trial will recruit 2600 patients from 65 United Kingdom adult general critical care units. The primary outcome is all-cause mortality at 90 days. An economic evaluation is embedded. This paper describes the proposed statistical and health economic analysis for the 65 trial.

Journal article

Antcliffe DB, Gordon AC, 2019, Why understanding sepsis endotypes is important for steroid trials in septic shock?, Critical Care Medicine, ISSN: 0090-3493

Journal article

Peden CJ, Stephens T, Martin G, Kahan BC, Thomson A, Rivett K, Wells D, Richardson G, Kerry S, Bion J, Pearse RM, Enhanced Peri-Operative Care for High-risk patients EPOCH trial groupet al., 2019, Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial, Lancet, Vol: 393, Pages: 2213-2221, ISSN: 0140-6736

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both t

Journal article

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

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

Journal article

Tridente A, Holloway PAH, Hutton P, Gordon AC, Mills GH, Clarke GM, Chiche J-D, Stuber F, Garrard C, Hinds C, Bion Jet al., 2019, Methodological challenges in European ethics approvals for a genetic epidemiology study in critically ill patients: The GenOSept experience, BMC Medical Ethics, Vol: 20, ISSN: 1472-6939

BackgroundDuring the set-up phase of an international study of genetic influences on outcomes from sepsis, we aimed to characterise potential differences in ethics approval processes and outcomes in participating European countries.MethodsBetween 2005 and 2007 of the FP6-funded international Genetics Of Sepsis and Septic Shock (GenOSept) project, we asked national coordinators to complete a structured survey of research ethic committee (REC) approval structures and processes in their countries, and linked these data to outcomes. Survey findings were reconfirmed or modified in 2017.ResultsEighteen countries participated in the study, recruiting 2257 patients from 160 ICUs. National practices differed widely in terms of composition of RECs, procedures and duration of the ethics approval process. Eight (44.4%) countries used a single centralised process for approval, seven (38.9%) required approval by an ethics committee in each participating hospital, and three (16.7%) required both. Outcomes of the application process differed widely between countries because of differences in national legislation, and differed within countries because of interpretation of the ethics of conducting research in patients lacking capacity. The RECs in four countries had no lay representation. The median time from submission to final decision was 1.5 (interquartile range 1–7) months; in nine (50%) approval was received within 1 month; six took over 6 months, and in one 24 months; had all countries been able to match the most efficient approvals processes, an additional 74 months of country or institution-level recruitment would have been available. In three countries, rejection of the application by some local RECs resulted in loss of centres; and one country rejected the application outright.ConclusionsThe potential benefits of the single application portal offered by the European Clinical Trials Regulation will not be realised without harmonisation of research

Journal article

Santhakumaran S, Gordon AC, Prevost A, O'Kane C, McAuley DF, Shankar-Hari Met al., 2019, Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials, Critical Care, Vol: 23, ISSN: 1364-8535

BackgroundRandomised controlled trials (RCTs) enrolling patients with sepsis or acute respiratory distress syndrome (ARDS) generate heterogeneous trial populations. Non-random variation in the treatment effect of an intervention due to differences in the baseline risk of death between patients in a population represents one form of heterogeneity of treatment effect (HTE). We assessed whether HTE in two sepsis and one ARDS RCTs could explain indeterminate trial results and inform future trial design.MethodsWe assessed HTE for vasopressin, hydrocortisone and levosimendan in sepsis and simvastatin in ARDS patients, on 28-day mortality, using the total Acute Physiology And Chronic Health Evaluation II (APACHE II) score as the baseline risk measurement, comparing above (high) and below (low) the median score. Secondary risk measures were the acute physiology component of APACHE II and predicted risk of mortality using the APACHE II score. HTE was quantified both in additive (difference in risk difference (RD)) and multiplicative (ratio of relative risks (RR)) scales using estimated treatment differences from a logistic regression model with treatment risk as the interaction term.ResultsThe ratio of the odds of death in the highest APACHE II quartile was 4.9 to 7.4 times compared to the lowest quartile, across the three trials. We did not observe HTE for vasopressin, hydrocortisone and levosimendan in the two sepsis trials. In the HARP-2 trial, simvastatin reduced mortality in the low APACHE II group and increased mortality in the high APACHE II group (difference in RD = 0.34 (0.12, 0.55) (p = 0.02); ratio of RR 3.57 (1.77, 7.17) (p < 0.001). The HTE patterns were inconsistent across the secondary risk measures. The sensitivity analyses of HTE effects for vasopressin, hydrocortisone and levosimendan were consistent with the main analyses and attenuated for simvastatin.ConclusionsWe assessed HTE in three recent ICU RCTs, using m

Journal article

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

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

Journal article

Rawson TM, Hernandez B, Moore L, Blandy O, Herrero P, Gilchrist M, Gordon A, Toumazou C, Sriskandan S, Georgiou P, Holmes Aet al., 2019, Supervised machine learning for the prediction of infection on admission to hospital: a prospective observational cohort study, Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 1108-1115, ISSN: 0305-7453

BackgroundInfection diagnosis can be challenging, relying on clinical judgement and non-specific markers of infection. We evaluated a supervised machine learning (SML) algorithm for diagnosing bacterial infection using routinely available blood parameters on presentation to hospital.MethodsAn SML algorithm was developed to classify cases into infection versus no infection using microbiology records and six available blood parameters (C-reactive protein, white cell count, bilirubin, creatinine, ALT and alkaline phosphatase) from 160 203 individuals. A cohort of patients admitted to hospital over a 6 month period had their admission blood parameters prospectively inputted into the SML algorithm. They were prospectively followed up from admission to classify those who fulfilled clinical case criteria for a community-acquired bacterial infection within 72 h of admission using a pre-determined definition. Predictive ability was assessed using receiver operating characteristics (ROC) with cut-off values for optimal sensitivity and specificity explored.ResultsOne hundred and four individuals were included prospectively. The median (range) cohort age was 65 (21–98)  years. The majority were female (56/104; 54%). Thirty-six (35%) were diagnosed with infection in the first 72 h of admission. Overall, 44/104 (42%) individuals had microbiological investigations performed. Treatment was prescribed for 33/36 (92%) of infected individuals and 4/68 (6%) of those with no identifiable bacterial infection. Mean (SD) likelihood estimates for those with and without infection were significantly different. The infection group had a likelihood of 0.80 (0.09) and the non-infection group 0.50 (0.29) (P < 0.01; 95% CI: 0.20–0.40). ROC AUC was 0.84 (95% CI: 0.76–0.91).ConclusionsAn SML algorithm was able to diagnose infection in individuals presenting to hospital using routinely available blood parameters.

Journal article

Komorowski M, Celi LA, Badawi O, Gordon AC, Faisal AAet al., 2019, Understanding the artificial intelligence clinician and optimal treatment strategies for sepsis in intensive care

In this document, we explore in more detail our published work (Komorowski,Celi, Badawi, Gordon, & Faisal, 2018) for the benefit of the AI in Healthcareresearch community. In the above paper, we developed the AI Clinician system,which demonstrated how reinforcement learning could be used to make usefulrecommendations towards optimal treatment decisions from intensive care data.Since publication a number of authors have reviewed our work (e.g. Abbasi,2018; Bos, Azoulay, & Martin-Loeches, 2019; Saria, 2018). Given the differenceof our framework to previous work, the fact that we are bridging two verydifferent academic communities (intensive care and machine learning) and thatour work has impact on a number of other areas with more traditionalcomputer-based approaches (biosignal processing and control, biomedicalengineering), we are providing here additional details on our recentpublication.

Working paper

Mich V, Pho Y, Bory S, Vann M, Teav B, Som L, Jarrvisalo MJ, Pulkkinen A, Kuitunen A, Ala-kokko T, Melto S, Daix T, Philippart F, Antoine M, Tiercelet K, Bruel C, Nicholas S, Siami S, Fabienne T, Bruyere R, Forceville X, Erickson S, Campbell L, Sonawane R, Santamaria J, Kol M, Awasthi S, Powis J, Hall R, McCarthy AE, Jouvet P, Opaysky MA, Gilfoyle E, Farshait N, Martin D-A, Griesdale D, Katz K, Ruberto AJ, Carrier FM, Lamontagne F, Muscedere J, Rishu A, Sin WC, Ngai WCW, Young P, Forrest A, Kazemi A, Henderson S, Browne T, Ganeshalingham A, McConnochie R, Cho JH, Park TS, Sim YS, Chang Y, Lee HB, Park SY, Chan WM, Lee W-Y, Wallace DJ, Angus DC, Charles AG, van Doom HR, Nguyen VK, Nguyen VT, Prin M, Twagirumugabe T, Umuhire OF, Sylvain H, Al Qasim E, Heraud J-M, Raberahona M, Rabarison JH, Patrigeon SP, Ramirez-Venegas A, Melendez JA, Guerrero ML, Mambule I, Ochieng OG, Nadjm B, Li IWS, Choi W-I, Florence K-P, Arabi YM, West TE, Riviello ED, Parke R, Djillali AE, Fowler R, Murthy S, Nichol A, Cheng AC, Semple C, George M, Valkonen M, McArthur C, Carson G, O'Neill G, Cobb JP, Dunning J, Chiche J-D, Huh J-W, Marshall J, Rello J, Guillebaud J, Razanazatovo N, Otieno JW, Green K, Rowan K, Baillie JK, Merson L, Hsu LY, Christian MD, Egi M, Shindo N, Horby P, Pardinaz-Solis R, Ubiergo SU, Webb SAR, Uyeki TM, Gordon AC, Paterson DL, Everett D, Giamarellos-Bourboulis EJ, Longuere K-S, Maslove D, Ohuma E, Growl G, PedutemHumber T, EllazarHumber E, Bahinskaya I, Osbourne-Townsend J, Bentley A, Goodson J, Welters I, Malik N, Browne TS, Mahesh Vet al., 2019, Using research to prepare for outbreaks of severe acute respiratory infection, BMJ Global Health, Vol: 4, ISSN: 2059-7908

Severe acute respiratory infections (SARI) remain one of the leading causes of mortality around the world in all age groups. There is large global variation in epidemiology, clinical management and outcomes, including mortality. We performed a short period observational data collection in critical care units distributed globally during regional peak SARI seasons from 1 January 2016 until 31 August 2017, using standardised data collection tools. Data were collected for 1 week on all admitted patients who met the inclusion criteria for SARI, with follow-up to hospital discharge. Proportions of patients across regions were compared for microbiology, management strategies and outcomes. Regions were divided geographically and economically according to World Bank definitions. Data were collected for 682 patients from 95 hospitals and 23 countries. The overall mortality was 9.5%. Of the patients, 21.7% were children, with case fatality proportions of 1% for those less than 5 years. The highest mortality was in those above 60 years, at 18.6%. Case fatality varied by region: East Asia and Pacific 10.2% (21 of 206), Sub-Saharan Africa 4.3% (8 of 188), South Asia 0% (0 of 35), North America 13.6% (25 of 184), and Europe and Central Asia 14.3% (9 of 63). Mortality in low-income and low-middle-income countries combined was 4% as compared with 14% in high-income countries. Organ dysfunction scores calculated on presentation in 560 patients where full data were available revealed Sequential Organ Failure Assessment (SOFA) scores on presentation were significantly associated with mortality and hospital length of stay. Patients in East Asia and Pacific (48%) and North America (24%) had the highest SOFA scores of >12. Multivariable analysis demonstrated that initial SOFA score and age were independent predictors of hospital survival. There was variability across regions and income groupings for the critical care management and outcomes of SARI. Intensive care unit-sp

Journal article

Russell JA, Gordon AC, Walley KR, Early may be better – early low dose norepinephrine in septic shock, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Journal article

Scheeren TWL, Bakker J, De Backer D, Annane D, Asfar P, Boerma EC, Cecconi M, Dubin A, Dünser MW, Duranteau J, Gordon AC, Hamzaoui O, Hernández G, Leone M, Levy B, Martin C, Mebazaa A, Monnet X, Morelli A, Payen D, Pearse R, Pinsky MR, Radermacher P, Reuter D, Saugel B, Sakr Y, Singer M, Squara P, Vieillard-Baron A, Vignon P, Vistisen ST, van der Horst ICC, Vincent J-L, Teboul J-Let al., 2019, Current use of vasopressors in septic shock, Annals of Intensive Care, Vol: 9, ISSN: 2110-5820

BackgroundVasopressors are commonly applied to restore and maintain blood pressure in patients with sepsis. We aimed to evaluate the current practice and therapeutic goals regarding vasopressor use in septic shock as a basis for future studies and to provide some recommendations on their use.MethodsFrom November 2016 to April 2017, an anonymous web-based survey on the use of vasoactive drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 17 questions focused on the profile of respondents, triggering factors, first choice agent, dosing, timing, targets, additional treatments, and effects of vasopressors. We investigated whether the answers complied with current guidelines. In addition, a group of 34 international ESICM experts was asked to formulate recommendations for the use of vasopressors based on 6 questions with sub-questions (total 14).ResultsA total of 839 physicians from 82 countries (65% main specialty/activity intensive care) responded. The main trigger for vasopressor use was an insufficient mean arterial pressure (MAP) response to initial fluid resuscitation (83%). The first-line vasopressor was norepinephrine (97%), targeting predominantly a MAP > 60–65 mmHg (70%), with higher targets in patients with chronic arterial hypertension (79%). The experts agreed on 10 recommendations, 9 of which were based on unanimous or strong (≥ 80%) agreement. They recommended not to delay vasopressor treatment until fluid resuscitation is completed but rather to start with norepinephrine early to achieve a target MAP of ≥ 65 mmHg.ConclusionReported vasopressor use in septic shock is compliant with contemporary guidelines. Future studies should focus on individualized treatment targets including earlier use of vasopressors.

Journal article

Lambden S, Tomlinson J, Piper S, Gordon AC, Leiper Jet al., 2018, Evidence for a protective role for the rs805305 single nucleotide polymorphism of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in septic shock through the regulation of DDAH activity, Critical Care, Vol: 22, ISSN: 1364-8535

BackgroundDimethylarginine dimethylaminohydrolase 2 (DDAH2) regulates the synthesis of nitric oxide (NO) through the metabolism of the endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA). Pilot studies have associated the rs805305 SNP of DDAH2 with ADMA concentrations in sepsis. This study explored the impact of the rs805305 polymorphism on DDAH activity and outcome in septic shock.MethodsWe undertook a secondary analysis of data and samples collected during the Vasopressin versus noradrenaline as initial therapy in septic shock (VANISH) trial. Plasma and DNA samples isolated from 286 patients recruited into the VANISH trial were analysed. Concentrations of L-Arginine and the methylarginines ADMA and symmetric dimethylarginine (SDMA) were determined from plasma samples. Whole blood and buffy-coat samples were genotyped for polymorphisms of DDAH2. Clinical data collected during the study were used to explore the relationship between circulating methylarginines, genotype and outcome.ResultsPeak ADMA concentration over the study period was associated with a hazard ratio for death at 28 days of 3.3 (95% CI 2.0–5.4), p < 0.001. Reduced DDAH activity measured by an elevated ADMA:SDMA ratio was associated with a reduced risk of death in septic shock (p = 0.03). The rs805305 polymorphism of DDAH2 was associated with reduced DDAH activity (p = 0.004) and 28-day mortality (p = 0.02). Mean SOFA score and shock duration were also reduced in the less common G:G genotype compared to heterozygotes and C:C genotype patients (p = 0.04 and p = 0.02, respectively).ConclusionsPlasma ADMA is a biomarker of outcome in septic shock, and reduced DDAH activity is associated with a protective effect. The polymorphism rs805305 SNP is associated with reduced mortality, which is potentially mediated by reduced DDAH2 activity.

Journal article

Gordon AC, Russell JA, 2018, Innovation and safety in critical care: should we collaborate with the industry? Yes, Intensive Care Medicine, Vol: 44, Pages: 2276-2278, ISSN: 0342-4642

As clinicians we all want to improve care for our patients. We can do that in two ways. We can do what we currently do better, or we can do new things (better). The development of large clinical academic trials groups and networks has enabled clinicians to understand what particular clinical care leads to better patient-centred outcomes. Ironically, we have learnt that many of our “usual” interventions either provided no benefit or were even harmful. Thus, clinicians, can improve the safety and effectiveness of critical care practice. But when it comes to innovation - new therapeutics and novel diagnostics - then it is hard to imagine that we could achieve this without input from or partnership with industry. Furthermore, a brief walk around an ICU illustrates cogently the vast number of devices used and drugs being infused, all of which originated in industry, some with much and some with little clinician scientist input. We argue herein that such collaboration is not only acceptable, it is necessary and can be done ethically, using established guidelines and conflict of interest disclosure.

Journal article

Davies R, ODea K, Gordon A, 2018, Immune therapy in sepsis; are we ready to try again?, Journal of the Intensive Care Society, Vol: 19, Pages: 326-344, ISSN: 1751-1437

Immune-therapy to ease the burden of sepsis has thus far failed to consistently improve patient outcomes. Advances in cancer immune-therapy and awareness that prolonged immune suppression in sepsis can leave patients vulnerable to secondary infection and death, have driven resurgence in the field of sepsis immune-therapy investigation. As we develop and evaluate these novel therapies, we must learn from past experiences where single-mediator targeted immune-therapies were blindly delivered to heterogeneous patient cohorts with complex and evolving immune responses. Advances in genomics, proteomics, metabolomics, and point-of-care technology, coupled with a better understanding of sepsis pathogenesis have meant that personalised immune-therapy is on the horizon. Here we review the complex immune pathogenesis in sepsis and the contemporary immune therapies that are being investigated to manipulate this response. An outline of the immune biomarkers that may be used to support this approach is also provided.

Journal article

Gordon AC, Santhakumaran S, Al-Beidh F, Orme RML, Perkins GD, Singer M, McAuley DF, Mason AJ, Ward JK, ODea KP, Felton T, Cross M, Best-Lane J, Lexow J, Campbell A, Ashby Det al., Levosimendan to prevent acute organ dysfunction in sepsis: the LeoPARDS RCT, Efficacy and Mechanism Evaluation, Vol: 5, Pages: 1-94, ISSN: 2050-4365

<jats:sec id="abs1-1"> <jats:title>Background</jats:title> <jats:p>In septic shock, cardiovascular resuscitation using catecholamine vasopressors and inotropes is standard therapy, but catecholamines have important side effects. Levosimendan (Simdax<jats:sup>®</jats:sup>; Orion Pharma, Newbury, UK) is a calcium-sensitising drug with inotropic and other properties that may have a role in sepsis.</jats:p> </jats:sec> <jats:sec id="abs1-2"> <jats:title>Objectives</jats:title> <jats:p>To determine, in adult septic shock, whether or not levosimendan reduces the incidence and severity of acute organ dysfunction, the effect of levosimendan on individual organ function and the safety profile of levosimendan.</jats:p> </jats:sec> <jats:sec id="abs1-3"> <jats:title>Design</jats:title> <jats:p>Multicentre, randomised, double-blind, parallel-group, placebo-controlled study.</jats:p> </jats:sec> <jats:sec id="abs1-4"> <jats:title>Setting</jats:title> <jats:p>UK intensive care units.</jats:p> </jats:sec> <jats:sec id="abs1-5"> <jats:title>Participants</jats:title> <jats:p>Adult patients with sepsis and cardiovascular failure requiring vasopressors to maintain blood pressure despite adequate fluid resuscitation.</jats:p> </jats:sec> <jats:sec id="abs1-6"> <jats:title>Intervention</jats:title> <jats:p>Levosimendan, at a dosage of 0.05–0.2 µg/kg/minute

Journal article

Komorowski M, Celi LA, Badawi O, Gordon AC, Faisal Aet al., 2018, The Artificial Intelligence Clinician learns optimal treatment strategies for sepsis in intensive care, Nature Medicine, Vol: 24, Pages: 1716-1720, ISSN: 1078-8956

Sepsis is the third leading cause of death worldwide and the main cause of mortality in hospitals1–3, but the best treatment strategy remains uncertain. In particular, evidence suggests that current practices in the administration of intravenous fluids and vasopressors are suboptimal and likely induce harm in a proportion of patients1,4–6. To tackle this sequential decision-making problem, we developed a reinforcement learning agent, the artificial intelligence (AI) Clinician, which learns from data to predict patient dynamics given specific treatment decisions. Our agent extracted implicit knowledge from an amount of patient data that exceeds many-fold the life-time experience of human clinicians and learned optimal treatment by having analysed myriads of (mostly sub-optimal) treatment decisions. We demonstrate that the value of the AI Clinician’s selected treatment is on average reliably higher than the human clinicians. In a large validation cohort independent from the training data, mortality was lowest in patients where clinicians’ actual doses matched the AI policy. Our model provides individualized and clinically interpretable treatment decisions for sepsis that could improve patient outcomes.

Journal article

Antcliffe D, Al-Beidh F, Gordon A, 2018, Metabolic profiles in sepsis evolve over time, European Society of Intensive Care Medicine Congress, Publisher: SpringerOpen, ISSN: 2197-425X

Conference paper

Antcliffe D, Ward J, Marshall T, Al-Beidh F, O'Dea K, Gordon Aet al., 2018, Multivariate analysis of cytokines in septic shock predicts outcome, European Society of Intensive Care Medicine Congress, Publisher: SpringerOpen, ISSN: 2197-425X

Conference paper

Fiorini F, Antcliffe D, Al-Beidh F, Gordon Aet al., 2018, Analysis of lipoproteins in septic shock, European Society of Intensive Care Medicine Congress, Publisher: SpringerOpen, ISSN: 2197-425X

Conference paper

Antcliffe D, Wolfer A, O'Dea K, Takata M, Holmes E, Gordon ACet al., 2018, Profiling inflammatory markers in patients with pneumonia on intensive care, Scientific Reports, Vol: 8, ISSN: 2045-2322

Clinical investigations lack predictive value when diagnosing pneumonia, especially when patients are ventilated and develop ventilator associated pneumonia (VAP). New tools to aid diagnosis are important to improve outcomes. This pilot study examines the potential for a panel of inflammatory mediators to aid in the diagnosis. Forty-four ventilated patients, 17 with pneumonia and 27 with brain injuries, eight of whom developed VAP, were recruited. 51 inflammatory mediators, including cytokines and oxylipins, were measured in patients’ serum using flow cytometry and mass spectrometry. The mediators could separate patients admitted to ICU with pneumonia compared to brain injury with an area under the receiver operating characteristic curve (AUROC) 0.75 (0.61–0.90). Changes in inflammatory mediators were similar in both groups over the course of ICU stay with 5,6-dihydroxyeicosatrienoic and 8,9-dihydroxyeicosatrienoic acids increasing over time and interleukin-6 decreasing. However, brain injured patients who developed VAP maintained inflammatory profiles similar to those at admission. A multivariate model containing 5,6-dihydroxyeicosatrienoic acid, 8,9-dihydroxyeicosatrienoic acid, intercellular adhesion molecule-1, interleukin-6, and interleukin-8, could differentiate patients with VAP from brain injured patients without infection (AUROC 0.94 (0.80–1.00)). The use of a selected group of markers showed promise to aid the diagnosis of VAP especially when combined with clinical data.

Journal article

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

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

Journal article

Textoris J, Gordon AC, 2018, Sepsis: who will shoot first? Pharma or diagnostics?, Intensive Care Medicine, Vol: 44, Pages: 1331-1333, ISSN: 0342-4642

Journal article

Antcliffe D, Fiorini F, Gordon A, 2018, Lessons from the ICU: Choosing the Right Vasopressor, Hemodynamic Monitoring, Editors: Pinsky, Teboul, Vincent, Publisher: Springer, ISBN: 9783319692692

This book, part of the European Society of Intensive Care Medicine textbook series, teaches readers how to use hemodynamic monitoring, an essential skill for today’s intensivists.

Book chapter

Gordon AC, Santhakumaran S, Al-Beidh F, Orme RML, Perkins GD, Singer M, McAuley DF, Mason AJ, Ward J, O'Dea K, Felton T, Cross M, Best-Lane J, Lexow J, Campbell A, Ashby Det al., 2018, Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis: the LeoPARDS Randomised Controlled Trial, Efficacy and Mechanism Evaluation, ISSN: 2050-4365

Background:In septic shock, cardiovascular resuscitation using catecholamine vasopressors and inotropes is standard therapy but catecholamines have important side-effects. Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may have a role in sepsis.Objectives: In adult septic shock1. Does levosimendan reduce the incidence and severity of acute organ dysfunction ?2. What is the effect of levosimendan on individual organ function ?3. What is the safety profile of levosimendan?Design: Multi-centre, randomised, double-blind, parallel-group, placebo-controlled study.Setting: UK Intensive Care UnitsParticipants: Adult patients who have sepsis and cardiovascular failure requiring vasopressors to maintain blood pressure despite adequate fluid resuscitation.Interventions: Levosimendan 0.05 to 0.2 µg/kg/min vs. placebo for 24 hour, in addition to standard care, within 24 hours of meeting inclusion criteria.Primary outcome measure: Mean SOFA score on ICU after randomisation to a maximum of 28 days.Secondary outcome measures: Time to extubationSurvival upto 6 monthsSerious Adverse EventsResults: 2382 patients were screened at 34 centres, of whom 516 were randomised to treatment, 259 allocated to levosimendan and 257 to placebo. Baseline characteristics were well balanced across treatment arms.There was no significant difference in mean (±SD) SOFA score in the levosimendan group (6.7 ± 4.0) compared with placebo (6.1 ± 3.9); (mean difference 0.61, 95%CI -0.07 to 1.29). 28-day mortality was 34.5% versus 30.9% in the levosimendan and placebo groups respectively (absolute difference 3.6%, 95%CI -4.5 to 11.7). Patients in the levosimendan group were less likely to be successfully extubated over 28 days than the placebo group (hazard ratio 0.77, 95%CI 0.60 to 0.97). More patients in the levosimendan group had supraventricular tachyarrhythmias, (3.1% versus 0.4% absolute difference 2.7%, 95%CI 0.1 to 5.3), but there was no

Journal article

Annane D, Ouanes-Besbes L, De Backer D, Du B, Gordon AC, Hernandez G, Olsen K, Osborn T, Peake S, Russell JA, Zanotti Cavazzoni Set al., 2018, A global perspective on vasoactive agents in shock, Intensive Care Medicine, Vol: 44, Pages: 833-846, ISSN: 0342-4642

Purpose:We set out to summarize the current knowledge on vasoactive drugs and their use in the management of shock to inform physicians’ practices.Methods:This is a narrative review by a multidisciplinary, multinational—from six continents—panel of experts including physicians, a pharmacist, trialists, and scientists.Results and conclusions:Vasoactive drugs are an essential part of shock management. Catecholamines are the most commonly used vasoactive agents in the intensive care unit, and among them norepinephrine is the first-line therapy in most clinical conditions. Inotropes are indicated when myocardial function is depressed and dobutamine remains the first-line therapy. Vasoactive drugs have a narrow therapeutic spectrum and expose the patients to potentially lethal complications. Thus, these agents require precise therapeutic targets, close monitoring with titration to the minimal efficacious dose and should be weaned as promptly as possible. Moreover, the use of vasoactive drugs in shock requires an individualized approach. Vasopressin and possibly angiotensin II may be useful owing to their norepinephrine-sparing effects.

Journal article

McIntyre WF, Um KJ, Alhazzani W, Lengyel AP, Hajjar L, Gordon AC, Lamontagne F, Healey JS, Whitlock RP, Belley-Cote EPet al., 2018, Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock, Journal of the American Medical Association, Vol: 319, Pages: 1889-1900, ISSN: 0098-7484

Importance Vasopressin is an alternative to catecholamine vasopressors for patients with distributive shock—a condition due to excessive vasodilation, most frequently from severe infection. Blood pressure support with a noncatecholamine vasopressor may reduce stimulation of adrenergic receptors and decrease myocardial oxygen demand. Atrial fibrillation is common with catecholamines and is associated with adverse events, including mortality and increased length of stay (LOS).Objectives To determine whether treatment with vasopressin + catecholamine vasopressors compared with catecholamine vasopressors alone was associated with reductions in the risk of adverse events.Data Sources MEDLINE, EMBASE, and CENTRAL were searched from inception to February 2018. Experts were asked and meta-registries searched to identify ongoing trials.Study Selection Pairs of reviewers identified randomized clinical trials comparing vasopressin in combination with catecholamine vasopressors to catecholamines alone for patients with distributive shock.Data Extraction and Synthesis Two reviewers abstracted data independently. A random-effects model was used to combine data.Main Outcomes and Measures The primary outcome was atrial fibrillation. Other outcomes included mortality, requirement for renal replacement therapy (RRT), myocardial injury, ventricular arrhythmia, stroke, and LOS in the intensive care unit and hospital. Measures of association are reported as risk ratios (RRs) for clinical outcomes and mean differences for LOS.Results Twenty-three randomized clinical trials were identified (3088 patients; mean age, 61.1 years [14.2]; women, 45.3%). High-quality evidence supported a lower risk of atrial fibrillation associated with vasopressin treatment (RR, 0.77 [95% CI, 0.67 to 0.88]; risk difference [RD], −0.06 [95% CI, −0.13 to 0.01]). For mortality, the overall RR estimate was 0.89 (95% CI, 0.82 to 0.97; RD, −0.04 [95% CI, −0.07 to 0.

Journal article

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