128 results found
McIntyre WF, Um KJ, Alhazzani W, et 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.
Rawson T, o'hare D, Herrero P, et al., 2018, Delivering precision antimicrobial therapy through closed-loop control systems, Journal of Antimicrobial Chemotherapy, Vol: 73, Pages: 835-843, ISSN: 0305-7453
Sub-optimal exposure to antimicrobial therapy is associated with poor patient outcomes and the development of antimicrobial resistance. Mechanisms for optimizing the concentration of a drug within the individual patient are under development. However, several barriers remain in realizing true individualization of therapy. These include problems with plasma drug sampling, availability of appropriate assays, and current mechanisms for dose adjustment. Biosensor technology offers a means of providing real-time monitoring of antimicrobials in a minimally invasive fashion. We report the potential for using microneedle biosensor technology as part of closed-loop control systems for the optimization of antimicrobial therapy in individual patients.
Annane D, Mira J-P, Ware LB, et al., 2018, Pharmacogenomic biomarkers do not predict response to drotrecogin alfa in patients with severe sepsis, Annals of Intensive Care, Vol: 8, Pages: 1-11, ISSN: 2110-5820
PurposeTo explore potential design for pharmacogenomics trials in sepsis, we investigate the interaction between pharmacogenomic biomarkers and response to drotrecogin alfa (activated) (DrotAA). This trial was designed to validate whether previously identified improved response polymorphisms (IRPs A and B) were associated with an improved response to DrotAA in severe sepsis.MethodsPatients with severe sepsis at high risk of death, who received DrotAA or not, with DNA available were included and matched to controls adjusting for age, APACHE II or SAPS II, organ dysfunction, ventilation, medical/surgical status, infection site, and propensity score (probability that a patient would have received DrotAA given their baseline characteristics). Independent genotyping and two-phase data transfer mitigated bias. The primary analysis compared the effect of DrotAA in IRP+ and IRP− groups on in-hospital 28-day mortality. Secondary endpoints included time to death in hospital; intensive care unit (ICU)-, hospital-, and ventilator-free days; and overall DrotAA treatment effect on mortality.ResultsSix hundred and ninety-two patients treated with DrotAA were successfully matched to 1935 patients not treated with DrotAA. Genotyping was successful for 639 (DrotAA) and 1684 (nonDrotAA) matched patients. The primary hypothesis of a genotype-by-treatment interaction (assessed by conditional logistic regression analysis) was not significant (P = 0.30 IRP A; P = 0.78 IRP B), and there was no significant genotype by treatment interaction for any secondary endpoint.ConclusionsNeither IRP A nor IRP B predicted differential response to DrotAA on in-hospital 28-day mortality.
Tridente A, Bion J, Mills G, et al., 2017, Derivation and validation of a prognostic model for post-operative risk stratification of critically ill patients with faecal peritonitis, Annals of Intensive Care, Vol: 7, ISSN: 2110-5820
BackgroundPrognostic scores and models of illness severity are useful both clinically and for research. The aim of this study was to develop two prognostic models for the prediction of long-term (6 months) and 28-day mortality of postoperative critically ill patients with faecal peritonitis (FP).MethodsPatients admitted to intensive care units with faecal peritonitis and recruited to the European GenOSept study were divided into a derivation and a geographical validation subset; patients subsequently recruited to the UK GAinS study were used for temporal validation. Using all 50 clinical and laboratory variables available on day 1 of critical care admission, Cox proportional hazards regression was fitted to select variables for inclusion in two prognostic models, using stepwise selection and nonparametric bootstrapping sampling techniques. Using Area under the receiver operating characteristic curve (AuROC) analysis, the performance of the models was compared to SOFA and APACHE II.ResultsFive variables (age, SOFA score, lowest temperature, highest heart rate, haematocrit) were entered into the prognostic models. The discriminatory performance of the 6-month prognostic model yielded an AuROC 0.81 (95% CI 0.76–0.86), 0.73 (95% CI 0.69–0.78) and 0.76 (95% CI 0.69–0.83) for the derivation, geographic and temporal external validation cohorts, respectively. The 28-day prognostic tool yielded an AuROC 0.82 (95% CI 0.77–0.88), 0.75 (95% CI 0.69–0.80) and 0.79 (95% CI 0.71–0.87) for the same cohorts. These AuROCs appeared consistently superior to those obtained with the SOFA and APACHE II scores alone.ConclusionsThe two prognostic models developed for 6-month and 28-day mortality prediction in critically ill septic patients with FP, in the postoperative phase, enhanced the day one SOFA score’s predictive utility by adding a few key variables: age, lowest recorded temperature, highest recorded heart rate and haematocrit. External vali
Chean CS, McAuley DF, Gordon AC, et al., 2017, Current practice in the management of new-onset atrial fibrillation in critically ill patients: A UK-wide survey, PeerJ, Vol: 5, ISSN: 2167-8359
BackgroundNew-onset atrial fibrillation (AF) is the most common arrhythmia in critically ill patients. Although evidence base and expert consensus opinion for management have been summarised in several international guidelines, no specific considerations for critically ill patients have been included. We aimed to establish current practice of management of critically ill patients with new-onset AF.MethodsWe designed a short user-friendly online questionnaire. All members of the Intensive Care Society were invited via email containing a link to the questionnaire, which comprised 21 questions. The online survey was conducted between November 2016 and December 2016.ResultsThe response rate was 397/3152 (12.6%). The majority of respondents (81.1%) worked in mixed Intensive Care Units and were consultants (71.8%). Most respondents (39.5%) would start intervention on patients with fast new-onset AF and stable blood pressure at a heart rate between 120 and 139 beats/min. However, 34.8% of participants would treat all patients who developed new-onset fast AF. Amiodarone and beta-blockers (80.9% and 11.6% of answers) were the most commonly used anti-arrhythmics. A total of 63.8% of respondents do not regularly anti-coagulate critically ill patients with new-onset fast AF, while 30.8% anti-coagulate within 72 hours. A total of 68.0% of survey respondents do not routinely use stroke risk scores in critically ill patients with new-onset AF. A total of 85.4% of participants would consider taking part in a clinical trial investigating treatment of new-onset fast AF in the critically ill.DiscussionOur results suggest a considerable disparity between contemporary practice of management of new-onset AF in critical illness and treatment recommendations for the general patient population suffering from AF, particularly with regard to anti-arrhythmics and anti-coagulation used. Amongst intensivists, there is a substantial interest in research for management of new-onset AF in criticall
Perner A, Gordon AC, Angus DC, et al., 2017, The intensive care medicine research agenda on septic shock, Intensive Care Medicine, Vol: 43, Pages: 1294-1305, ISSN: 1432-1238
Septic shock remains a global health challenge with millions of cases every year, high rates of mortality and morbidity, impaired quality of life among survivors and relatives, and high resource use both in developed and developing nations. Care and outcomes are improving through organisational initiatives and updated clinical practice guidelines based on clinical research mainly carried out by large collaborative networks. This progress is likely to continue through the collaborative work of the established and merging trials groups in many parts of the world and through refined trial methodology and translational work. In this review, international experts summarize the current position of clinical research in septic shock and propose a research agenda to advance this field.
Mason A, Grieve R, Gordon AC, et al., 2017, A bayesian framework to address missing not at random data in longitudinal studies with multiple types of missingness, Publisher: BIOMED CENTRAL LTD, ISSN: 1745-6215
Santhakumaran S, Mason AJ, Gordon AC, et al., 2017, Bayesian methods for informative missingness in longitudinal intensive care data, 3rd International Clinical Trials Methodology Conference, Publisher: BIOMED CENTRAL LTD, ISSN: 1745-6215
Mehta S, Granton J, Gordon AC, et al., 2017, Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine (vol 17, R117, 2013), Critical Care, Vol: 21, ISSN: 1364-8535
Antcliffe D, Jimenez B, Veselkov K, et al., 2017, Metabolic profiling in patients with pneumonia on intensive care, EBioMedicine, Vol: 18, Pages: 244-253, ISSN: 2352-3964
Clinical features and investigations lack predictive value when diagnosing pneumonia, especially when patients are ventilated and when patients develop ventilator associated pneumonia (VAP). New tools to aid diagnosis are important to improve outcomes. This pilot study examines the potential for metabolic profiling to aid the diagnosis in critical care.In this prospective observational study ventilated patients with brain injuries or pneumonia were recruited in the intensive care unit and serum samples were collected soon after the start of ventilation. Metabolic profiles were produced using 1D 1H NMR spectra. Metabolic data were compared using multivariate statistical techniques including Principal Component Analysis (PCA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA).We recruited 15 patients with pneumonia and 26 with brain injuries, seven of whom went on to develop VAP. Comparison of metabolic profiles using OPLS-DA differentiated those with pneumonia from those with brain injuries (R2Y = 0.91, Q2Y = 0.28, p = 0.02) and those with VAP from those without (R2Y = 0.94, Q2Y = 0.27, p = 0.05). Metabolites that differentiated patients with pneumonia included lipid species, amino acids and glycoproteins.Metabolic profiling shows promise to aid in the diagnosis of pneumonia in ventilated patients and may allow a more timely diagnosis and better use of antibiotics.
Davies R, O'Dea KP, Soni S, et al., 2017, P362: Vasopressin alone and with noradrenaline attenuates TNF-α production in an in-vitro model of monocyte priming and deactivation, 37th International Symposium on Intensive Care and Emergency Medicine, Publisher: BioMed Central, ISSN: 1364-8535
Gordon AC, Orme RML, Singer M, 2017, Levosimendan in Sepsis REPLY, New England Journal of Medicine, Vol: 376, Pages: 800-800, ISSN: 0028-4793
Gordon AC, Orme RML, Singer M, 2017, Levosimendan in Sepsis., New England Journal of Medicine, Vol: 376, Pages: 798-800, ISSN: 0028-4793
Burnham KL, Davenport EE, Radhakrishnan J, et al., 2016, Shared and distinct aspects of the sepsis transcriptomic response to fecal peritonitis and pneumonia., American Journal of Respiratory and Critical Care Medicine, Vol: 196, Pages: 328-339, ISSN: 1535-4970
RATIONALE: Heterogeneity in the septic response has hindered efforts to understand pathophysiology and develop targeted therapies. Source of infection, with different causative organisms and temporal changes, might influence this heterogeneity. OBJECTIVES: To investigate individual and temporal variation in the transcriptomic response to sepsis due to fecal peritonitis, and to compare with community acquired pneumonia. METHODS: We performed genome-wide gene expression profiling in peripheral blood leukocytes for adult patients admitted to intensive care with sepsis due to fecal peritonitis (n=117) or community acquired pneumonia (n=126), and non-septic controls (n=10). MEASUREMENTS AND MAIN RESULTS: A substantial portion of the transcribed genome (18%) was differentially expressed compared to controls, independent of source of infection, with EIF2 signaling the most enriched canonical pathway. We identify two sepsis response signature subgroups in fecal peritonitis associated with early mortality (p-value=0.01, hazard ratio=4.78). We define gene sets predictive of SRS group, and serial sampling demonstrates subgroup membership is dynamic during ICU admission. We find SRS is the major predictor of transcriptomic variation; a small number of genes (n=263) were differentially regulated according to the source of infection, enriched for interferon signaling and antigen presentation. We define temporal changes in gene expression from disease onset involving phagosome formation, NK cell and IL-3 signaling. CONCLUSIONS: The majority of the sepsis transcriptomic response is independent of source of infection and includes signatures reflecting immune response state and prognosis. A modest number of genes show evidence of specificity. Our findings highlight opportunities for patient stratification and precision medicine in sepsis.
Nagendran M, McAuley DF, Kruger PS, et al., 2016, Statin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trials, Intensive Care Medicine, Vol: 43, Pages: 663-671, ISSN: 1432-1238
PurposeWe performed an individual patient data meta-analysis to assess the possible benefits and harms of statin therapy in adults with acute respiratory distress syndrome (ARDS) as well as investigate effects in specific ARDS subgroups.MethodsWe identified randomised clinical trials up to 31st October 2016 investigating statin therapy versus placebo in patients with ARDS. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed for primary and secondary outcomes and one-stage regression models with single treatment covariate interactions for subgroup analyses. Risk of bias was assessed using the Cochrane Risk of Bias tool.ResultsSix trials were included with a total of 1,755 patients. For the primary outcomes, there was no significant effect of statin therapy on 28-day mortality (relative risk (RR) 1.03, 95% CI 0.86 to 1.23), ventilator free days (mean difference 0.34 days, 95% CI -0.68 to 1.36) or serious adverse events (RR 1.14, 95% CI 0.84 to 1.53). There was a significantly increased incidence of raised serum creatine kinase or transaminase levels with statin therapy (106/879; 12.1%) versus control (78/876; 8.9%) (RR 1.40, 95% CI 1.07 to 1.83, p=0.015). There were no significant treatment covariate interactions in the pre-defined subgroups investigated.ConclusionsWe found no clinical benefit from initiation of statin therapy in adult patients with ARDS, either overall or in pre-defined subgroups. While there was an increased incidence of raised serum creatine kinase and transaminase levels, there was no difference in serious adverse events between groups. Therefore, we do not recommend initiation of statin therapy for the treatment of ARDS.
McNamee J, Gillies M, Barrett N, et 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.
Gordon AC, Perkins GD, Singer M, et 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
Perner A, Gordon AC, De Backer D, et 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.
Bartz RR, Gantner D, Gordon AC, et 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
Gordon AC, Mason AJ, Thirunavukkarasu N, et 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
Farmakis D, Alvarez J, Gal TB, et 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.
Patel PB, Brett SJ, O'Callaghan D, et 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.
McIntyre L, Rowe BH, Walsh TS, et 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
Lambden S, Leiper J, Gordon AC, 2016, The rs805305 SNP of Dimethylarginine Dimethylaminohydrolase 2(DDAH2) Is Associated with Reduced Duration of Shock, Improved Mortality and an Elevated Plasma ADMA:SDMA Ratio in Septic Shock - Subgroup Analysis of Patients from the VANISH Trial, American Thoracic Society International Conference, Publisher: American Thoracic Society, Pages: A7800-A7800
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
Nagendran M, Maruthappu M, Gordon AC, et 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.
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.
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
Cruickshank M, Henderson L, MacLennan G, et 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
Davenport EE, Burnham KL, Radhakrishnan J, et 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
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