Early goal-directed and lactate-guided therapy in adult patients with severe sepsis and septic shock: a meta-analysis of randomized controlled trials.
ABSTRACT: BACKGROUND:The ProCESS, ARISE, and ProMISe trials have failed to show that early goal-directed therapy (EGDT) reduces mortality in patients with severe sepsis and septic shock. Although lactate-guided therapy (LGT) has been shown to result in significantly lower mortality, its use remains controversial. Therefore, we performed a meta-analysis to evaluate EGDT vs. LGT or usual care (UC) in adult patients with severe sepsis and septic shock. METHODS:Relevant randomized controlled trials published from January 1, 2001 to March 30, 2017 were identified in PubMed, EMBASE, Web of Science, and the Cochrane Library. The primary outcome was mortality; secondary outcomes included red cell transfusions, dobutamine use, vasopressor infusion, and mechanical ventilation support within the first 6 h and Acute Physiology and Chronic Health Evaluation II (APACHE II) score. RESULTS:Sixteen studies enrolling 5968 patients with 2956 in EGDT, 2547 in UC, and 465 in LGT were included in this meta-analysis. Compared with UC, EGDT was associated with a lower mortality (10 trials; RR 0.85, 95% CI 0.74-0.97, P?=?0.01), and this difference was more pronounced in the subgroup of UC patients with mortality?>?30%. In addition, EGDT patients received more red cell transfusions, dobutamine, and vasopressor infusions within the first 6 h. Compared with LGT, EGDT was associated with higher mortality (6 trials; RR 1.42, 95% CI 1.19-1.70, P?=?0.0001) with no heterogeneity (P?=?0.727, I2?=?0%). CONCLUSION:EGDT seems to reduce mortality in adult patients with severe sepsis and septic shock, and the benefit may primarily be attributed to red cell transfusions, dobutamine administration, and vasopressor infusions within the first 6 h. However, LGT may result in a greater mortality benefit than EGDT.
Project description:Echocardiography is often used to guide septic shock resuscitation, but without evidence for efficacy. We conducted an intensive care unit (ICU)-based randomized controlled feasibility trial comparing echocardiography-guided septic shock resuscitation (ECHO) with early goal-directed therapy (EGDT).We conducted a single center, randomized controlled feasibility trial at a 468-bed academic tertiary care center in Utah, USA. Adult patients with early septic shock were assessed and treated at defined intervals over 6 h using an echocardiogram-guided resuscitation protocol or a slightly modified EGDT protocol. Feasibility outcomes were fluid balance, dobutamine administration, and time to lactate clearance. The primary clinical outcome was changed in sequential organ failure assessment score at 48 h (delta SOFA). Secondary outcomes included inpatient mortality, ICU-free days, and ventilator-free days at 28 days.Thirty participants, 15 per group, were randomized and completed the study. Baseline characteristics were similar between groups. Patients were randomized within a median of 3.5 h of meeting inclusion criteria but had received a median of 3 L crystalloid by then. Fluid administration during the study protocol was similar in both groups (median ECHO 0 vs EGDT 1 L, p = 0.61). Eleven (73%) subjects in each arm received ≤ 1 L fluid. Dobutamine administration was also similar (20% vs 13%, p > 0.99). Twenty-one patients (70%) had lactate clearance prior to the first study assessment. No difference was observed in delta SOFA (median - 4 for ECHO vs - 6 for EGDT, p = 0.10) nor mortality (33% ECHO vs 20% EGDT, p = 0.68).No experimental separation was observed in this randomized, controlled feasibility trial. Early lactate clearance, coupled with substantial fluid administration before randomization, suggests that patients were already resuscitated before arrival in the ICU. Future trials of echocardiogram-guided sepsis resuscitation will likely need to enroll in the emergency department.This study was retrospectively registered at clinicaltrials.gov (identifier NCT02354742, title Echo vs EGDT in severe sepsis and septic shock) on February 3, 2015. Registration was completed before review or analysis of any data.
Project description:Background:EGDT (Early Goal Directed Therapy) or some portion of EGDT has been shown to decrease mortality secondary to sepsis and septic shock. Objective:Our study aims to assess the effect of adopting this approach in the emergency department on in-hospital mortality secondary to sepsis/septic shock in Lebanon. Hypothesis:Implementation of the EGDT protocol of sepsis in ED will decrease in-hospital mortality. Methods:Our retrospective study included 290 adult patients presenting to the ED of a tertiary center in Lebanon with severe sepsis and/or septic shock. 145 patients between years 2013 and 2014 who received protocol care were compared to 145 patients treated by standard care between 2010 and 2012. Data from the EHR were retrieved about patients' demographics, medical comorbidities, and periresuscitation parameters. A multivariate analysis using logistic regression for the outcome in-hospital mortality after adjusting for protocol use and other confounders was done and AOR was obtained for the protocol use. 28-day mortality, ED, and hospital length of stay were compared between the two groups. Results:The most common infection site in the protocol arm was the lower respiratory tract (42.1%), and controls suffered more from UTIs (33.8%). Patients on protocol care had lower in-hospital mortality than that receiving usual care, 31.7% versus 47.6% (p=0.006) with an AOR of 0.429 (p =0.018). Protocol patients received more fluids at 6 and 24 hours (3.8 ± 1.7 L and 6.1 ± 2.1 L) compared to the control group (2.7 ± 2.0 L and 4.9 ± 2.8 L p=<0.001). Time to and duration of vasopressor use, choice of appropriate antibiotics, and length of ED stay were not significantly different between the two groups. Conclusion:EGDT- (Early Goal Directed Therapy-) based sepsis protocol implementation in EDs decreases in-hospital mortality in developing countries. Adopting this approach in facilities with limited resources, ICU capabilities, and prehospital systems may have a pronounced benefit.
Project description:In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary.In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support.We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support.In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. (Funded by the National Institute of General Medical Sciences; ProCESS ClinicalTrials.gov number, NCT00510835.).
Project description:Various trials and meta-analyses have reported conflicting results concerning the application of early goal-directed therapy (EGDT) for sepsis and septic shock. The aim of this study was to update the evidence by performing a systematic review and meta-analysis. Multiple databases were searched from initial through August, 2016 for randomized controlled trials (RCTs) which investigated the associations between the use of EGDT and mortality in patients with sepsis or septic shock. Meta-analysis was performed using random-effects model and heterogeneity was examined through subgroup analyses. The primary outcome of interest was patient all-cause mortality including hospital or ICU mortality. Seventeen RCTs including 6207 participants with 3234 in the EGDT group and 2973 in the control group were eligible for this study. Meta-analysis showed that EGDT did not significantly reduce hospital or intensive care unit (ICU) mortality (relative risk [RR] 0.89, 95% CI 0.78 to 1.02) compared with control group for patients with sepsis or septic shock. The findings of subgroup analyses stratified by study region, number of research center, year of enrollment, clinical setting, sample size, timing of EGDT almost remained constant with that of the primary analysis. Our findings provide evidence that EGDT offers neutral survival effects for patients with sepsis or septic shock. Further meta-analyses based on larger well-designed RCTs or individual patient data meta-analysis are required to explore the survival benefits of EDGT in patients with sepsis or septic shock.
Project description:OBJECTIVE:We aim to synthesise up-to-date randomised trials to investigate the effects of levosimendan on mortality and clinical outcomes in severe sepsis and septic shock. METHODS:A collection of databases including PubMed, EMBASE, Cochrane Central Register and Web of Science were searched updated to August 2017. Randomised trials were included when they pertain to the use of levosimendan in severe sepsis or septic shock compared with any category of inotropes, or as an adjunct to standard therapy with mortality reported. The primary outcome was mortality, and the secondary outcomes were clinical performances including serum lactate, cardiac function, vasopressor requirement and fluid infusion. RESULTS:A total of 10 studies with 1036 patients were included in this meta-analysis. The results revealed that levosimendan could not reduce mortality significantly in severe sepsis and septic shock (OR 0.89, 95%?CI 0.69 to 1.16, P=0.39). Levosimendan use could reduce serum lactate more effectively, and enhance cardiac contractibility with increased cardiac index and left ventricular ejection fraction. However, its use could also increase fluid infusion but not reduce norepinephrine dose. No significant benefit in mortality could be observed of levosimendan versus dobutamine use, or in patients with proven cardiac dysfunction. CONCLUSIONS:Current evidence is not sufficient to support levosimendan as superior to dobutamine or as an optimal adjunct in severe sepsis and septic shock. More large-scale randomised trials are necessary to validate levosimendan use in sepsis.
Project description:Despite knowledge that EGDT improves outcomes in septic patients, staff education on EGDT and compliance with the CPOE order set has been variable. Based on results of a resident survey to identify barriers to decrease severe sepsis/septic shock mortality in the medical intensive care unit (MICU), multifaceted interventions such as educational interventions to improve awareness to the importance of early goal-directed therapy (EGDT), and the use of the Computerized Physician Order Entry (CPOE) order set, were implemented in July 2013. CPOE order set was established to improve compliance with the EGDT resuscitation bundle elements. Orders were reviewed and compared for patients admitted to the MICU with severe sepsis/septic shock in July and August 2013 (controls) and 2014 (following the intervention). Similarly, educational slide sets were used as interventions for residents before the start of their ICU rotations in July and August 2013. While CPOE order set compliance did not significantly improve (78% vs. 76%, p = 0.74), overall EGDT adherence improved from 43% to 68% (p = 0.0295). Although there was a trend toward improved mortality, this did not reach statistical significance. This study shows that education interventions can be used to increase awareness of severe sepsis/septic shock and improve overall EGDT adherence.
Project description:OBJECTIVE:To determine whether patients with severe sepsis or septic shock could benefit from a strict and early goal-directed therapy (EGDT) protocol recommended by Surviving Sepsis Campaign (SSC) Guidelines. METHODS:MEDLINE/PubMed, EMBASE/OVID and Cochrane Central Register of Controlled Trials (CENTRAL) were searched between March 1983 and March 2015. Eligible studies evaluated the outcomes of EGDT versus usual care or standard therapy in patients with severe sepsis or septic shock. The primary outcomes were mortality within 28 days, 60 days and 90 days. Included studies must report at least one metric of mortality. RESULTS:5 studies that enrolled 4303 patients with 2144 in the EGDT group and 2159 in the control group were included in this meta-analysis. Overall, there were slight decreases of mortality within 28 days, 60 days and 90 days in the random-effect model in patients with severe sepsis or septic shock receiving EGDT resuscitation. However, none of the differences reached statistical significance (RR=0.86; 95% CI 0.69 to 1.06; p=0.16; p for heterogeneity=0.008, I(2)=71%; RR=0.94; 95% CI 0.81 to 1.10; p=0.46; p for heterogeneity=0.16, I(2)=43%; RR=0.98; 95% CI 0.88 to 1.10; p=0.75; p for heterogeneity=0.87, I(2)=0%, respectively). CONCLUSIONS:The current meta-analysis pooled data from five RCTs and found no survival benefit of EGDT in patients with sepsis. However, the included trials are not sufficiently homogeneous and potential confounding factors in the negative trials (ProCESS, ARISE and ProMISe) might bias the results and diminish the treatment effect of EGDT. Further well-designed studies should eliminate all potential source of bias to determine if EGDT has a mortality benefit.
Project description:BACKGROUND:Criteria for the Sepsis-3 definition of septic shock include vasopressor treatment to maintain a mean arterial pressure?>?65 mmHg and a lactate concentration?>?2 mmol/L. The impact of hyperoxia in patients with septic shock using these criteria is unknown. METHODS:A post hoc analysis was performed of the HYPER2S trial assessing hyperoxia versus normoxia in septic patients requiring vasopressor therapy, in whom a plasma lactate value was available at study inclusion. Mortality was compared between patients fulfilling the Sepsis-3 septic shock criteria and patients requiring vasopressors for hypotension only (i.e., with lactate???2 mmol/L). RESULTS:Of the 434 patients enrolled, 397 had available data for lactate at inclusion. 230 had lactate?>?2 mmol/L and 167???2 mmol/L. Among patients with lactate?>?2 mmol/L, 108 and 122 were "hyperoxia"- and "normoxia"-treated, respectively. Patients with lactate?>?2 mmol/L had significantly less COPD more cirrhosis and required surgery more frequently. They also had higher illness severity (SOFA 10.6?±?2.8 vs. 9.5?±?2.5, p?=?0.0001), required more renal replacement therapy (RRT), and received vasopressor and mechanical ventilation for longer time. Mortality rate at day 28 was higher in the "hyperoxia"-treated patients with lactate?>?2 mmol/L as compared to "normoxia"-treated patients (57.4% vs. 44.3%, p = 0.054), despite similar RRT requirements as well as vasopressor and mechanical ventilation-free days. A multivariate analysis showed an independent association between hyperoxia and mortality at day 28 and 90. In patients with lactate???2 mmol/L, hyperoxia had no effect on mortality nor on other outcomes. CONCLUSIONS:Our results suggest that hyperoxia may be associated with a higher mortality rate in patients with septic shock using the Sepsis-3 criteria, but not in patients with hypotension alone.
Project description:<h4>Background</h4>Mottling score, a tissue perfusion parameter, is correlated with outcome in septic shock patients. However, its predictive value on mortality according to prognostic covariates such as vasopressor dose and other tissue perfusion parameters remains unknown.<h4>Methods</h4>Mottling score and tissue perfusion parameters were recorded at ICU admission (H0), H-6, H 12, and H-24 and used to assess the predictive value of mottling score on 14-day mortality in a development cohort. Results were then validated in an independent cohort of septic shock patients in Brazil.<h4>Results</h4>Overall, 259 patients with sepsis or septic shock were included, 14-day mortality was 37%. Factors associated with death were mottling score (OR 2.26 [95% CI, 1.72-2.97]), arterial lactate level (OR 1.29 [1.11-1.5]), and urine output <?0.5?ml/Kg/h (OR 3.03 [1.37-6.69]). The C statistic for the model was 0.90 in the development cohort and 0.76 in the validation cohort. The predictive value of mottling score was not affected by vasopressor doses (p for interaction?=?0.33): OR for mottling score ranged from 2.34 [1.10-3.15] in patients without vasopressor to 3.84 [1.98-7.43] in patients infused with high doses of vasopressor (>?0.8??g/kg/min). There was no difference in the effect of mottling score on mortality according to mean arterial pressure, heart rate, cardiac index, and urine output, but we found a significant interaction between arterial lactate level and mottling score (p?=?0.04). The predictive value of the mottling score remains significant when using the recent SEPSIS-3 definition of septic shock. Finally, a decrease of mottling score during resuscitation was significantly associated with better outcome after adjustment on SOFA score (p?=?0.001).<h4>Conclusions</h4>Our results support the high prognostic value of mottling score for 14-day mortality in septic patients, whatever vasopressor dosage and other perfusion parameters. Mottling score variations during resuscitation are also predictive of mortality.
Project description:Even though there are continually upgraded recommendations for managing sepsis, such as "Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock", mortality is still high. Si-ni-tang, a remedy documented in Shanghan Lun, a medical collection from ancient China, is used for treating patients with sepsis and septic shock. Using a well-designed clinical trial, we are eager to survey the effectiveness of the concurrent use of this remedy in restoring these patients' hemodynamic status, or "Yang Qi".Patients admitted to our medical intensive care units with the diagnosis of septic shock, defined as persistent hypotension induced by sepsis despite adequate fluid resuscitation, are eligible for participation. The inclusion criteria include: age from 20 to 85 years, conditions meeting the definition of septic shock, use of vasopressors within 24 hours of entering the study, and use of a nasogastric tube for feeding. The enrolled patients are randomly allocated either to the si-ni-tang group or the placebo group. The prescription of the trial drugs (si-ni-tang/placebo) is 2.25 grams 4 times a day for 7 days or till shock reversal (if shock reversal occurs in less than 7 days). Data, including duration of vasopressor infusion, gender, age, co-morbidities, APACHE II score, predicted mortality, ICU mortality, ICU length of stay, hospital mortality, hospital length of stay, source of sepsis, and culture results, are collected for the following analysis.Si-ni-tang is composed of processed Zingiber officinale, Glycyrrhiza uralensis, and Aconitum carmichaeli. Zingiber officinale and Glycyrrhiza uralensis are found to have the ability to reduce pro-inflammatory cytokine production, to inhibit lipopolisaccharide-induced macrophage activation and function, and to lessen the bacterial load and suppress acute and chronic inflammation. Aconitum carmichaeli is known to have vasopressor activity, and positive chronotropic and inotropic effects. As this remedy has a potential benefit in treating septic shock patients, we designed a double-blind, prospective, randomized controlled trial and would like to publish the results and conclusions later.ClinicalTrials.gov: NCT01223430.