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      Vasopressors for the Treatment of Septic Shock: Systematic Review and Meta-Analysis

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          Abstract

          Objective

          International guidelines recommend dopamine or norepinephrine as first-line vasopressor agents in septic shock. Phenylephrine, epinephrine, vasopressin and terlipressin are considered second-line agents. Our objective was to assess the evidence for the efficiency and safety of all vasopressors in septic shock.

          Methods

          Systematic review and meta-analysis. We searched electronic database of MEDLINE, CENTRAL, LILACS and conference proceedings up to June 2014. We included randomized controlled trials comparing different vasopressors for the treatment of adult patients with septic shock. Primary outcome was all-cause mortality. Other clinical and hemodynamic measurements were extracted as secondary outcomes. Risk ratios (RR) and mean differences with 95% confidence intervals (CI) were pooled.

          Results

          Thirty-two trials (3,544 patients) were included. Compared to dopamine (866 patients, 450 events), norepinephrine (832 patients, 376 events) was associated with decreased all-cause mortality, RR 0.89 (95% CI 0.81-0.98), corresponding to an absolute risk reduction of 11% and number needed to treat of 9. Norepinephrine was associated with lower risk for major adverse events and cardiac arrhythmias compared to dopamine. No other mortality benefit was demonstrated for the comparisons of norepinephrine to epinephrine, phenylephrine and vasopressin / terlipressin. Hemodynamic data were similar between the different vasopressors, with some advantage for norepinephrine in central venous pressure, urinary output and blood lactate levels.

          Conclusions

          Evidence suggests a survival benefit, better hemodynamic profile and reduced adverse events rate for norepinephrine over dopamine. Norepinephrine should be regarded as the first line vasopressor in the treatment of septic shock.

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          Most cited references30

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          American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.

          (1992)
          To define the terms "sepsis" and "organ failure" in a precise manner. Review of the medical literature and the use of expert testimony at a consensus conference. American College of Chest Physicians (ACCP) headquarters in Northbrook, IL. Leadership members of ACCP/Society of Critical Care Medicine (SCCM). An ACCP/SCCM Consensus Conference was held in August of 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic variables by which a patient could be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods were recommended when dealing with septic patients as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
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            Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial.

            International guidelines for management of septic shock recommend that dopamine or norepinephrine are preferable to epinephrine. However, no large comparative trial has yet been done. We aimed to compare the efficacy and safety of norepinephrine plus dobutamine (whenever needed) with those of epinephrine alone in septic shock. This prospective, multicentre, randomised, double-blind study was done in 330 patients with septic shock admitted to one of 19 participating intensive care units in France. Participants were assigned to receive epinephrine (n=161) or norepinephrine plus dobutamine (n=169), which were titrated to maintain mean blood pressure at 70 mm Hg or more. The primary outcome was 28-day all-cause mortality. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148278. There were no patients lost to follow-up; one patient withdrew consent after 3 days. At day 28, there were 64 (40%) deaths in the epinephrine group and 58 (34%) deaths in the norepinephrine plus dobutamine group (p=0.31; relative risk 0.86, 95% CI 0.65-1.14). There was no significant difference between the two groups in mortality rates at discharge from intensive care (75 [47%] deaths vs 75 [44%] deaths, p=0.69), at hospital discharge (84 [52%] vs 82 [49%], p=0.51), and by day 90 (84 [52%] vs 85 [50%], p=0.73), time to haemodynamic success (log-rank p=0.67), time to vasopressor withdrawal (log-rank p=0.09), and time course of SOFA score. Rates of serious adverse events were also similar. There is no evidence for a difference in efficacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock.
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              Has the mortality of septic shock changed with time.

              To determine whether a systematic review of the literature could identify changes in the mortality of septic shock over time. A review of all relevant papers from 1958 to August 1997, identified through a MEDLINE search and from the bibliographies of articles identified. The search identified 131 studies (99 prospective and 32 retrospective) involving a total of 10,694 patients. The patients' mean age was 57 yrs with no change over time. The overall mortality rate in the 131 studies was 49.7%. There was an overall significant trend of decreased mortality over the period studied (r=.49, p < .05). The mortality rate in those patients with bacteremia as an entry criterion was greater than that rate in patients whose entry criterion was sepsis without definite bacteremia (52.1% vs. 49.1%; chi2=6.1 and p< .05). The site of infection altered noticeably over the years. Chest-related infections increased over time, with Gram-negative infections becoming proportionately less common. If all other organisms and mixed infections are included with the Gram-positives, the result is more dramatic, with these organisms being causative in just 10% of infections between 1958 and 1979 but in 31% of infections between 1980 and 1997. The present review showed a slight reduction in mortality from septic shock over the years, although this result should be approached with caution. The heterogeneity of the articles and absence of a severity score for most of the studies limited our analysis. Furthermore, there was an increasing prevalence of Gram-positive causative organisms, and a change of the predominant origin of sepsis from the abdomen to the chest.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                3 August 2015
                2015
                : 10
                : 8
                : e0129305
                Affiliations
                [1 ]Medicine E, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
                [2 ]Intensive Care Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
                [3 ]Infectious diseases Unit, Rambam Medical Center and Rappaport Faculty of Medicine, Tehnion—Israel Institute of Technology, Haifa, Israel
                San Raffaele Scientific Institute, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TA. Performed the experiments: TA AL SL LL MP AG. Analyzed the data: TA AL. Contributed reagents/materials/analysis tools: TA. Wrote the paper: TA.

                Article
                PONE-D-14-45367
                10.1371/journal.pone.0129305
                4523170
                26237037
                f7432cfd-0971-48bd-9827-2d5bbfdd306f
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 22 November 2014
                : 8 May 2015
                Page count
                Figures: 4, Tables: 2, Pages: 17
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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