137 results found
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
Antcliffe D, Ward J, Marshall T, et al., 2018, Multivariate analysis of cytokines in septic shock predicts outcome, European Society of Intensive Care Medicine Congress, Publisher: SpringerOpen, ISSN: 2197-425X
Antcliffe D, Wolfer A, O'Dea K, et 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.
Wong JLC, Mason A, Gordon A, et 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
Textoris J, Gordon AC, 2018, Sepsis: who will shoot first? Pharma or diagnostics?, Intensive Care Medicine, Vol: 44, Pages: 1331-1333, ISSN: 0342-4642
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.
Gordon AC, Santhakumaran S, Al-Beidh F, et 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
Annane D, Ouanes-Besbes L, De Backer D, et 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.
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.
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
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
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.
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