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

Publication Type
Year
to

143 results found

McNamee J, Gillies M, Barrett N, Agus A, Beale R, Bentley A, Bodenham A, Brett S, Brodie D, Finney S, Gordon A, Griffiths M, Harrison D, Jackson C, McDowell C, McNally C, Perkins G, Tunnicliffe W, Vuylsteke A, Walsh T, Wise M, Young D, McAuley Det al., 2016, pRotective vEntilation with veno-venouS lung assisT in respiratory failure: A protocol for a multicentre randomised controlled trial of extracorporeal carbon dioxide removal in patients with acute hypoxaemic respiratory failure, Journal of the Intensive Care Society, Vol: 18, Pages: 159-169, ISSN: 1751-1437

One of the few interventions to demonstrate improved outcomes for acute hypoxaemic respiratory failure is reducing tidal volumes when using mechanical ventilation, often termed lung protective ventilation. Veno-venous extracorporeal carbon dioxide removal (vv-ECCO2R) can facilitate reducing tidal volumes. pRotective vEntilation with veno-venouS lung assisT (REST) is a randomised, allocation concealed, controlled, open, multicentre pragmatic trial to determine the clinical and cost-effectiveness of lower tidal volume mechanical ventilation facilitated by vv-ECCO2R in patients with acute hypoxaemic respiratory failure. Patients requiring intubation and mechanical ventilation for acute hypoxaemic respiratory failure will be randomly allocated to receive either vv-ECCO2R and lower tidal volume mechanical ventilation or standard care with stratification by recruitment centre. There is a need for a large randomised controlled trial to establish whether vv-ECCO2R in acute hypoxaemic respiratory failure can allow the use of a more protective lung ventilation strategy and is associated with improved patient outcomes.

Journal article

Gordon AC, Perkins GD, Singer M, McAuley DF, Orme RML, Santhakumaran S, Mason AJ, Cross M, Al-Beidh F, Best-Lane J, Brealey D, Nutt CL, McNamee JJ, Reschreiter H, Breen A, Liu KD, Ashby Det al., 2016, Levosimendan for the prevention of acute organ dysfunction in sepsis, New England Journal of Medicine, Vol: 375, Pages: 1638-1648, ISSN: 0028-4793

BACKGROUNDLevosimendan is a calcium-sensitizing drug with inotropic and other propertiesthat may improve outcomes in patients with sepsis.METHODSWe conducted a double-blind, randomized clinical trial to investigate whether levosimendanreduces the severity of organ dysfunction in adults with sepsis. Patientswere randomly assigned to receive a blinded infusion of levosimendan (at a dose of0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placeboin addition to standard care. The primary outcome was the mean daily SequentialOrgan Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scoresfor each of five systems range from 0 to 4, with higher scores indicating more severedysfunction; maximum score, 20). Secondary outcomes included 28-day mortality,time to weaning from mechanical ventilation, and adverse events.RESULTSThe trial recruited 516 patients; 259 were assigned to receive levosimendan and257 to receive placebo. There was no significant difference in the mean (±SD) SOFAscore between the levosimendan group and the placebo group (6.68±3.96 vs.6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], −0.07 to 1.29;P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9%in the placebo group (absolute difference, 3.6 percentage points; 95% CI, −4.5 to11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendangroup were less likely than those in the placebo group to be successfullyweaned from mechanical ventilation over the period of 28 days (hazard ratio,0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group thanin the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolutedifference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04).CONCLUSIONSThe addition of levosimendan to standard treatment in adults with sepsis was notassociated with less severe organ dysfunction or lower mortality. Levosim

Journal article

Bartz RR, Gantner D, Gordon AC, Leligdowicz A, McNamee JJ, Murthy S, Nichol A, Webb S, for the International Forum for Acute Care Trailistset al., 2016, Who says there’s no “I” in team? Achieving individual success in collaborative clinical research in critical care, American Journal of Respiratory and Critical Care Medicine, Vol: 194, Pages: 911-912, ISSN: 1535-4970

Journal article

Perner A, Gordon AC, De Backer D, Dimopoulos G, Russell JA, Lipman J, Jensen JU, Singer M, Bellomo R, Walsh Tet al., 2016, Sepsis: frontiers in diagnosis, resuscitation and antibiotic therapy, Intensive Care Medicine, Vol: 42, Pages: 1958-1969, ISSN: 1432-1238

Sepsis is a major growing global burden and a major challenge to intensive care clinicians, researchers, guideline committee members and policy makers, because of its high and increasing incidence and great pathophysiological, molecular, genetic and clinical complexity. In spite of recent progress, short-term mortality remains high and there is growing evidence of long-term morbidity and increased long-term mortality in survivors of sepsis both in developed and developing countries. Further improvement in the care of patients with sepsis will impact upon global health. In this narrative review, invited experts describe the expected challenges and progress to be made in the near future. We focus on diagnosis, resuscitation (fluids, vasopressors, inotropes, blood transfusion and hemodynamic targets) and infection (antibiotics and infection biomarkers), as these areas are key, if initial management and subsequent outcomes are to be improved in patients with sepsis.

Journal article

Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ, VANISH Investigatorset al., 2016, Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. The VANISH Randomized Clinical Trial, The Journal of the American Medical Association, Vol: 316, Pages: 509-518, ISSN: 0002-9955

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1

Journal article

Farmakis D, Alvarez J, Gal TB, Brito D, Fedele F, Fonseca C, Gordon AC, Gotsman I, Grossini E, Guarracino F, Harjola V-P, Hellman Y, Heunks L, Ivancan V, Karavidas A, Kivikko M, Lomivorotov V, Longrois D, Masip J, Metra M, Morelli A, Nikolaou M, Papp Z, Parkhomenko A, Poelzl G, Pollesello P, Ravn HB, Rex S, Riha H, Ricksten S-E, Schwinger RHG, Vrtovec B, Yilmaz MB, Zielinska M, Parissis Jet al., 2016, Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper, International Journal of Cardiology, Vol: 222, Pages: 303-312, ISSN: 1874-1754

Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps.

Journal article

Patel PB, Brett SJ, O'Callaghan D, Anjum A, Cross M, Warwick J, Gordon ACet al., 2016, Protocol for a randomised control trial of methylnaltrexone for the treatment of opioid-induced constipation and gastrointestinal stasis in intensive care patients (MOTION), BMJ Open, Vol: 6, ISSN: 2044-6055

Introduction: Gastro-intestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to facilitate tolerance of endotracheal tubes and mechanical ventilation, which inhibit gastrointestinal motility and lead to adverse outcomes. Methylnaltrexone is a peripheral opioid antagonist that does not cross the blood-brain barrier and can reverse the peripheral side effects of opioids without affecting the desired central properties. This trial will investigate whether methylnaltrexone can reverse opioid induced constipation and gastro-intestinal dysmotility.Methods: This is a single centre, multi-site, double blind, randomised placebo controlled trial. Eighty-four patients will be recruited from four Intensive Care Units (ICU) within Imperial College Healthcare NHS Trust. Patients will receive intravenous methylnaltrexone or placebo on a daily basis if they are receiving opioid infusion to facilitate mechanical ventilation, and have not opened their bowels for 48 hours. All patients will receive standard laxatives as per the clinical ICU bowel protocol prior to randomisation. The primary outcome of the trial will be time to significant rescue-free laxation following randomisation. Secondary outcomes will include tolerance of enteral feed, gastric residual volumes, incidence of pneumonia, blood stream and Clostridium difficile infection, and any reversal of central opioid effects.Ethics and Dissemination: The trial protocol, the Patient / legal representative Information Sheets and Consent Forms have been reviewed and approved by the Harrow Research Ethics Committee (REC Reference 14/LO/2004). An independent Trial Steering Committee and Data Monitoring Committee are in place, with patient representation. Upon completion, the trial results will be published in peer-reviewed journals and presented at national and international scientific meetings.

Journal article

McIntyre L, Rowe BH, Walsh TS, Gray A, Arabi Y, Perner A, Gordon A, Marshall J, Cook D, Fox-Robichaud A, Bagshaw SM, Green R, Schweitzer I, Turgeon A, Zarychanski R, English S, Chasse M, Stiell I, Fergusson Det al., 2016, Multicountry survey of emergency and critical care medicine physicians’ fluid resuscitation practices for adult patients with early septic shock, BMJ Open, Vol: 6, ISSN: 2044-6055

Objectives: Evidence to guide fluid resuscitationevidence in sepsis continues to evolve. Weconducted a multicountry survey of emergency andcritical care physicians to describe current statedpractice and practice variation related to thequantity, rapidity and type of resuscitation fluidadministered in early septic shock to inform thedesign of future septic shock fluid resuscitationtrials.Methods: Using a web-based survey tool, weinvited critical care and emergency physicians inCanada, the UK, Scandinavia and Saudi Arabia tocomplete a self-administered electronic survey.Results: A total of 1097 physicians’ responseswere included. 1 L was the most frequent quantityof resuscitation fluid physicians indicated theywould administer at a time (46.9%, n=499). Most(63.0%, n=671) stated that they would administerthe fluid challenges as quickly as possible. Overall,normal saline and Ringer’s solutions were thepreferred crystalloid fluids used ‘often’ or ‘always’ in53.1% (n=556) and 60.5% (n=632) of instances,respectively. However, emergency physiciansindicated that they would use normal saline ‘often’or ‘always’ in 83.9% (n=376) of instances, whilecritical care physicians said that they would usesaline ‘often’ or ‘always’ in 27.9% (n=150) ofinstances. Only 1.0% (n=10) of respondentsindicated that they would use hydroxyethyl starch‘often’ or ‘always’; use of 5% (5.6% (n=59)) or 20–25% albumin (1.3% (n=14)) was also infrequent.The majority (88.4%, n=896) of respondentsindicated that a large randomised controlled trialcomparing 5% albumin to a crystalloid fluid in earlyseptic shock was important to conduct.Conclusions: Critical care and emergencyphysicians stated that they rapidly infuse volumes of500–1000 mL of resuscitation fluid in early septicshock. Colloid use, specifically the use of albumin,was infrequently reported. Our survey identifies the need to condu

Journal article

Lambden S, Leiper J, Gordon AC, 2016, Plasma Asymmetric Dimethylarginine (ADMA) Association with Risk of Death in Septic Shock - Subgroup Analysis of Patients from the VANISH Trial, American Thoracic Society International Conference, Publisher: American Thoracic Society, Pages: A2723-A2723

Conference paper

Nagendran M, Maruthappu M, Gordon AC, Gurusamy KSet al., 2016, Comparative safety and efficacy of vasopressors for mortality in septic shock: A network meta-analysis., J Intensive Care Soc, Vol: 17, Pages: 136-145, ISSN: 1751-1437

INTRODUCTION: Septic shock is a life-threatening condition requiring vasopressor agents to support the circulatory system. Several agents exist with choice typically guided by the specific clinical scenario. We used a network meta-analysis approach to rate the comparative efficacy and safety of vasopressors for mortality and arrhythmia incidence in septic shock patients. METHODS: We performed a comprehensive electronic database search including Medline, Embase, Science Citation Index Expanded and the Cochrane database. Randomised trials investigating vasopressor agents in septic shock patients and specifically assessing 28-day mortality or arrhythmia incidence were included. A Bayesian network meta-analysis was performed using Markov chain Monte Carlo methods. RESULTS: Thirteen trials of low to moderate risk of bias in which 3146 patients were randomised were included. There was no pairwise evidence to suggest one agent was superior over another for mortality. In the network meta-analysis, vasopressin was significantly superior to dopamine (OR 0.68 (95% CI 0.5 to 0.94)) for mortality. For arrhythmia incidence, standard pairwise meta-analyses confirmed that dopamine led to a higher incidence of arrhythmias than norepinephrine (OR 2.69 (95% CI 2.08 to 3.47)). In the network meta-analysis, there was no evidence of superiority of one agent over another. CONCLUSIONS: In this network meta-analysis, vasopressin was superior to dopamine for 28-day mortality in septic shock. Existing pairwise information supports the use of norepinephrine over dopamine. Our findings suggest that dopamine should be avoided in patients with septic shock and that other vasopressor agents should continue to be based on existing guidelines and clinical judgement of the specific presentation of the patient.

Journal article

Antcliffe D, Gordon AC, 2016, Metabonomics and Intensive Care, Annual Update in Intensive Care and Emergency Medicine 2016, Editors: Vincent, Publisher: Springer, Pages: 353-364, ISBN: 978-3-319-27348-8

Book chapter

Gordon AC, Antcliffe D, 2016, Metabonomics and intensive care, Critical Care, Vol: 20, ISSN: 1364-8535

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://​www.​biomedcentral.​com/​collections/​annualupdate2016​. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://​www.​springer.​com/​series/​8901.

Journal article

Cruickshank M, Henderson L, MacLennan G, Fraser C, Campbell M, Blackwood B, Gordon AC, Brazzelli Met al., 2016, Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review, Health Technology Assessment, Vol: 20, Pages: 1-118, ISSN: 1366-5278

BACKGROUND:Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(¯), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(¯), Roche) and lorazepam (Ativan(¯), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(¯), Orion Corporation) and clonidine (Catapres(¯), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents. OBJECTIVES:To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs. DATA SOURCES:We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014. METHODS:Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(¯), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second rev

Journal article

Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, Rautanen A, Gordon AC, Garrard C, Hill AVS, Hinds CJ, Knight JCet al., 2016, Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study, Lancet Respiratory Medicine, Vol: 4, Pages: 259-271, ISSN: 2213-2619

BackgroundEffective targeted therapy for sepsis requires an understanding of the heterogeneity in the individual host response to infection. We investigated this heterogeneity by defining interindividual variation in the transcriptome of patients with sepsis and related this to outcome and genetic diversity.MethodsWe assayed peripheral blood leucocyte global gene expression for a prospective discovery cohort of 265 adult patients admitted to UK intensive care units with sepsis due to community-acquired pneumonia and evidence of organ dysfunction. We then validated our findings in a replication cohort consisting of a further 106 patients. We mapped genomic determinants of variation in gene transcription between patients as expression quantitative trait loci (eQTL).FindingsWe discovered that following admission to intensive care, transcriptomic analysis of peripheral blood leucocytes defines two distinct sepsis response signatures (SRS1 and SRS2). The presence of SRS1 (detected in 108 [41%] patients in discovery cohort) identifies individuals with an immunosuppressed phenotype that included features of endotoxin tolerance, T-cell exhaustion, and downregulation of human leucocyte antigen (HLA) class II. SRS1 was associated with higher 14 day mortality than was SRS2 (discovery cohort hazard ratio (HR) 2·4, 95% CI 1·3–4·5, p=0·005; validation cohort HR 2·8, 95% CI 1·5–5·1, p=0·0007). We found that a predictive set of seven genes enabled the classification of patients as SRS1 or SRS2. We identified cis-acting and trans-acting eQTL for key immune and metabolic response genes and sepsis response networks. Sepsis eQTL were enriched in endotoxin-induced epigenetic marks and modulated the individual host response to sepsis, including effects specific to SRS group. We identified regulatory genetic variants involving key mediators of gene networks implicated in the hypoxic response and the switch to glycolysis t

Journal article

Abdul-Aziz MH, Lipman J, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, Dulhunty J, Kaukonen K-M, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Roberts JA, DALI Study Groupet al., 2015, Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort., Journal of Antimicrobial Chemotherapy, Vol: 71, Pages: 196-207, ISSN: 0305-7453

OBJECTIVES: We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies. METHODS: This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries. RESULTS: Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT>MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving β-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P = 0.012]. Additionally, in patients with a SOFA score of ≥9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P = 0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P = 0.025]. CONCLUSIONS: Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections.

Journal article

Herrmann IK, Bertazzo S, O'Callaghan D, Schlegel AA, Kallepitis C, Antcliffe D, Gordon A, Stevens MMet al., 2015, Differentiating sepsis from non-infectious systemic inflammation based on microvesicle-bacteria aggregation, Nanoscale, Vol: 7, Pages: 13511-13520, ISSN: 2040-3364

Sepsis is a severe medical condition and a leading cause of hospital mortality. Prompt diagnosis and early treatment has a significant, positive impact on patient outcome. However, sepsis is not always easy to diagnose, especially in critically ill patients. Here, we present a conceptionally new approach for the rapid diagnostic differentiation of sepsis from non-septic intensive care unit patients. Using advanced microscopy and spectroscopy techniques, we measure infection-specific changes in the activity of nano-sized cell-derived microvesicles to bind bacteria. We report on the use of a point-of-care-compatible microfluidic chip to measure microvesicle-bacteria aggregation and demonstrate rapid (≤1.5 hour) and reliable diagnostic differentiation of bacterial infection from non-infectious inflammation in a double-blind pilot study. Our study demonstrates the potential of microvesicle activities for sepsis diagnosis and introduces microvesicle-bacteria aggregation as a potentially useful parameter for making early clinical management decisions.

Journal article

O'Callaghan DJ, O'Dea KP, Scott AJ, Takata M, Gordon ACet al., 2015, Monocyte Tumor Necrosis Factor-α-Converting Enzyme Catalytic Activity and Substrate Shedding in Sepsis and Noninfectious Systemic Inflammation., Critical Care Medicine, Vol: 43, Pages: 1375-1385, ISSN: 1530-0293

OBJECTIVES: To determine the effect of severe sepsis on monocyte tumor necrosis factor-α-converting enzyme baseline and inducible activity profiles. DESIGN: Observational clinical study. SETTING: Mixed surgical/medical teaching hospital ICU. PATIENTS: Sixteen patients with severe sepsis, 15 healthy volunteers, and eight critically ill patients with noninfectious systemic inflammatory response syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Monocyte expression of human leukocyte antigen-D-related peptide, sol-tumor necrosis factor production, tumor necrosis factor-α-converting enzyme expression and catalytic activity, tumor necrosis factor receptor 1 and 2 expression, and shedding at 48-hour intervals from day 0 to day 4, as well as p38-mitogen activated protein kinase expression. Compared with healthy volunteers, both sepsis and systemic inflammatory response syndrome patients' monocytes expressed reduced levels of human leukocyte antigen-D-related peptide and released less sol-tumor necrosis factor on in vitro lipopolysaccharide stimulation, consistent with the term monocyte deactivation. However, patients with sepsis had substantially elevated levels of basal tumor necrosis factor-α-converting enzyme activity that were refractory to lipopolysaccharide stimulation and this was accompanied by similar changes in p38-mitogen activated protein kinase signaling. In patients with systemic inflammatory response syndrome, monocyte basal tumor necrosis factor-α-converting enzyme, and its induction by lipopolysaccharide, appeared similar to healthy controls. Changes in basal tumor necrosis factor-α-converting enzyme activity at day 0 for sepsis patients correlated with Acute Physiology and Chronic Health Evaluation II score and the attenuated tumor necrosis factor-α-converting enzyme response to lipopolysaccharide was associated with increased mortality. Similar changes in monocyte tumor necrosis factor-α-converting enz

Journal article

Mills TC, Chapman S, Hutton P, Gordon AC, Bion J, Chiche JD, Holloway PA, Stüber F, Garrard CS, Hinds CJ, Hill AV, Rautanen A, ESICMECCRN GenOSept Investigatorset al., 2015, Variants in the mannose-binding lectin gene MBL2 do not associate with sepsis susceptibility or survival in a large European cohort, Clinical Infectious Diseases, Vol: 61, Pages: 695-703, ISSN: 1537-6591

BACKGROUND:  Sepsis is an increasingly common condition, which continues to be associated with unacceptably high mortality. A large number of association studies have investigated susceptibility to, or mortality from sepsis for variants in the functionally important immune-related gene MBL2. These studies have largely been underpowered and contradictory. METHODS:  We genotyped and analysed four important MBL2 SNPs (rs5030737, rs1800450, rs1800451 and rs7096206) in 1839 European community-acquired pneumonia (CAP) and peritonitis sepsis cases, and 477 controls from the UK. We analysed the following predefined subgroups and outcomes: 28-day and 6 month mortality from sepsis due to CAP or peritonitis combined, 28-day mortality from CAP sepsis, peritonitis sepsis, pneumococcal sepsis or sepsis in younger patients, and susceptibility to CAP sepsis or pneumococcal sepsis in the UK. RESULTS:  There were no significant associations (all p-values were greater than 0.05 after correction for multiple testing) between MBL2 genotypes and any of our predefined analyses. CONCLUSIONS:  In this large, well-defined cohort of immune competent adult patients, no associations between MBL2 genotype and sepsis susceptibility or outcome were identified.

Journal article

O'Callaghan DJ, Gordon AC, 2015, What's new in vasopressin?, Intensive Care Medicine, Vol: 41, Pages: 2177-2179, ISSN: 1432-1238

Journal article

Tridente A, Clarke GM, Walden A, Gordon AC, Hutton P, Chiche JD, Holloway PA, Mills GH, Bion J, Stuber F, Garrard C, Hinds C, GenOSept Investigatorset al., 2015, Association between trends in clinical variables and outcome in intensive care patients with faecal peritonitis: analysis of the GenOSept cohort., Critical Care, Vol: 19, ISSN: 1364-8535

INTRODUCTION: Patients admitted to intensive care following surgery for faecal peritonitis present particular challenges in terms of clinical management and risk assessment. Collaborating surgical and intensive care teams need shared perspectives on prognosis. We aimed to determine the relationship between dynamic assessment of trends in selected variables and outcomes. METHODS: We analysed trends in physiological and laboratory variables during the first week of ICU stay in 977 patients from 102 centres across 16 European countries. The primary outcome was 6-month mortality. Secondary end-points were ICU, hospital and 28 day mortality. For each trend, Cox proportional hazards (PH) regression analyses, adjusted for age and gender, were performed for each endpoint. Trends remaining significant after Bonferroni correction for multiple testing were entered into a multivariate Cox PH model to determine independent associations with mortality. RESULTS: Trends over the first 7 days ICU stay independently associated with 6 month mortality were worsening thrombocytopaenia (mortality HR = 1.02, 95% CI 1.01-1.03, p < 0.001) and renal function (total daily urine output HR = 1.02, 95%CI 1.01-1.03, p < 0.001; renal SOFA sub-score HR = 0.87, 95%CI 0.75-0.99, p = 0.047), maximum bilirubin level (HR = 0.99, 95%CI 0.99-0.99, p = 0.02) and GCS SOFA sub-score (HR = 0.81, 95%CI 0.68-0.98, p = 0.028). Changes in renal function (total daily urine output and renal component of the SOFA score), GCS component of the SOFA score, total SOFA and worsening thrombocytopaenia were also independently associated with secondary outcomes (ICU, hospital and 28 day mortality). We detected the same pattern when analysing trends on days 2, 3 and 5. Dynamic trends in all other measured laboratory and physiological variables and in radiologica

Journal article

Gordon A, 2015, Disease Management - Sepsis, Guidelines for the Provision of Intensive Care Services, Pages: 67-70

Book chapter

Gordon AC, 2015, Evidence about inotropes: when is enough, enough?, Intensive Care Medicine, Vol: 41, Pages: 695-697, ISSN: 1432-1238

Journal article

Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, Chiche J-D, Parks T, Chapman SJ, Davenport EE, Elliott KS, Bion J, Lichtner P, Meitinger T, Wienker TF, Caulfield MJ, Mein C, Bloos F, Bobek I, Cotogni P, Sramek V, Sarapuu S, Kobilay M, Ranieri VM, Rello J, Sirgo G, Weiss YG, Russwurm S, Schneider EM, Reinhart K, Holloway PAH, Knight JC, Garrard CS, Russell JA, Walley KR, Stueber F, Hill AVS, Hinds CJet al., 2015, Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study, LANCET RESPIRATORY MEDICINE, Vol: 3, Pages: 53-60, ISSN: 2213-2600

Journal article

Antcliffe D, Wolfer A, O'Dea KP, Hanna G, Takata M, Holmes E, Gordon ACet al., 2015, Profiling Of Eicosanoids And Cytokines As An Aid To Diagnosing Pneumonia On Intensive Care, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Wilkinson KM, Krige A, Brearley SG, Lane S, Scott M, Gordon AC, Carlson GLet al., 2014, Thoracic Epidural analgesia versus Rectus Sheath Catheters for open midline incisions in major abdominal surgery within an enhanced recovery programme (TERSC): study protocol for a randomised controlled trial., Trials, Vol: 15, Pages: 400-400

Journal article

Antcliffe D, Jimenez B, Veselkov K, Holmes E, Hanna G, Takata M, Gordon ACet al., 2014, DIAGNOSING PNEUMONIA ON THE INTENSIVE CARE UNIT WITH SERUM H-1 NMR SPECTROSCOPY, 27th Annual Congress of the European-Society-of-Intensive-Care-Medicine (ESICM), Publisher: SPRINGER, Pages: S237-S238, ISSN: 0342-4642

Conference paper

Hatcher J, Myers A, Donaldson H, Gordon AC, Meacher R, Baruah Jet al., 2014, Comment on: Effects of selective digestive decontamination (SDD) on the gut resistome., Journal of Antimicrobial Chemotherapy, Pages: dku288-dku288

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Orme RMLE, Perkins GD, McAuley DF, Liu KD, Mason AJ, Morelli A, Singer M, Ashby D, Gordon ACet al., 2014, An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial, Trials, Vol: 15, Pages: 1-10

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Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, Kaukonen K-M, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Lipman Jet al., 2014, DALI: Defining Antibiotic Levels in Intensive Care Unit Patients: Are Current beta-Lactam Antibiotic Doses Sufficient for Critically Ill Patients?, CLINICAL INFECTIOUS DISEASES, Vol: 58, Pages: 1072-1083, ISSN: 1058-4838

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