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Journal of Critical Care Dec 2016Studies and meta-analyses conflict regarding the use of early goal-directed therapy (EGDT) for septic shock. We sought to clarify the conflict by performing a living... (Review)
Review
UNLABELLED
Studies and meta-analyses conflict regarding the use of early goal-directed therapy (EGDT) for septic shock. We sought to clarify the conflict by performing a living systematic review and meta-regression.
METHODS
We performed a meta-analysis and explored heterogeneity with meta-regression. We conformed with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and qualified strength of evidence with a Grading of Recommendations Assessment, Development and Evaluation profile.
RESULTS
Overall, EGDT did not significantly reduce mortality compared with usual care (relative risk, 0.85; 95% confidence interval, 0.67-1.08); however, heterogeneity was substantial (I=64%; 95% confidence interval, 12%-85%). Illness severity did not correlate with mortality reduction; however, there were significant correlations with control rate mortality and the strategy employed by the control group. Benefit was confined to trials with a control mortality greater than 35%. Compared with monitoring of lactate clearance and central venous pressure, EGDT mortality was higher.
CONCLUSION
The benefit of EGDT is evident in populations with high mortality, in line with reported global mortality rates. In settings with low mortality the recent trials challenge the need for 6-hour goals; however, most patients in these trials met 3-hour resuscitation goals as defined by the Surviving Sepsis Campaign. In settings with higher mortality, EGDT or normalization of lactate/central venous pressure may be viable therapeutic options.
Topics: Critical Care; Critical Pathways; Humans; Resuscitation; Sepsis; Shock, Septic
PubMed: 27546746
DOI: 10.1016/j.jcrc.2016.06.017 -
BMC Infectious Diseases Nov 2023The generalizability of the Surviving Sepsis Campaign (SSC) guidelines to various patient populations and hospital settings has been debated. A quantitative assessment...
Patient diversity and author representation in clinical studies supporting the Surviving Sepsis Campaign guidelines for management of sepsis and septic shock 2021: a systematic review of citations.
BACKGROUND
The generalizability of the Surviving Sepsis Campaign (SSC) guidelines to various patient populations and hospital settings has been debated. A quantitative assessment of the diversity and representation in the clinical evidence supporting the guidelines would help evaluate the generalizability of the recommendations and identify strategic research goals and priorities. In this study, we evaluated the diversity of patients in the original studies, in terms of sex, race/ethnicity, and geographical location. We also assessed diversity in sex and geographical representation among study first and last authors.
METHODS
All clinical studies cited in support of the 2021 SSC adult guideline recommendations were identified. Original clinical studies were included, while editorials, reviews, non-clinical studies, and meta-analyses were excluded. For eligible studies, we recorded the proportion of male patients, percentage of each represented racial/ethnic subgroup (when available), and countries in which they were conducted. We also recorded the sex and location of the first and last authors. The World Bank classification was used to categorize countries.
RESULTS
The SSC guidelines included six sections, with 85 recommendations based on 351 clinical studies. The proportion of male patients ranged from 47 to 62%. Most studies did not report the racial/ ethnic distribution of the included patients; when they did so, most were White patients (68-77%). Most studies were conducted in high-income countries (77-99%), which included Europe/Central Asia (33-66%) and North America (36-55%). Moreover, most first/last authors were males (55-93%) and from high-income countries (77-99%).
CONCLUSIONS
To enhance the generalizability of the SCC guidelines, stakeholders should define strategies to enhance the diversity and representation in clinical studies. Though there was reasonable representation in sex among patients included in clinical studies, the evidence did not reflect diversity in the race/ethnicity and geographical locations. There was also lack of diversity among the first and last authors contributing to the evidence.
Topics: Adult; Humans; Male; Female; Shock, Septic; Sepsis; Europe; North America
PubMed: 37915042
DOI: 10.1186/s12879-023-08745-4 -
Critical Care (London, England) Aug 2020The effect of the timing of norepinephrine initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The effect of the timing of norepinephrine initiation on clinical outcomes in patients with septic shock is uncertain. A systematic review and meta-analysis was performed to evaluate the impact of early and late start of norepinephrine support on clinical outcomes in patients with septic shock.
METHODS
We searched the PubMed, Cochrane, and Embase databases for randomized controlled trials (RCTs) and cohort studies from inception to the 1st of March 2020. We included studies involving adult patients (> 18 years) with septic shock. All authors reported our primary outcome of short-term mortality and clearly comparing early versus late norepinephrine initiation with clinically relevant secondary outcomes (ICU length of stay, time to achieved target mean arterial pressure (≥ 65 mmHg), and volume of intravenous fluids within 6 h). Results were expressed as odds ratio (OR) and mean difference (MD) with accompanying 95% confidence interval (CI).
RESULTS
Five studies including 929 patients were included. The primary outcome of this meta-analysis showed that the short-term mortality of the early group was lower than that of the late group (odds ratio [OR] = 0.45; 95% CI, 0.34 to 0.61; P < 0.00001; χ = 3.74; I = 0%). Secondary outcomes demonstrated that the time to achieved target MAP of the early group was shorter than that of the late group (mean difference = - 1.39; 95% CI, - 1.81 to - 0.96; P < 0.00001; χ = 1.03; I = 0%). The volume of intravenous fluids within 6 h of the early group was less than that of the late group (mean difference = - 0.50; 95% CI, - 0.68 to - 0.32; P < 0.00001; χ = 33.76; I = 94%). There was no statistically significant difference in the ICU length of stay between the two groups (mean difference = - 0.11; 95% CI, - 1.27 to 1.05; P = 0.86; χ = 0.85; I = 0%).
CONCLUSIONS
Early initiation of norepinephrine in patients with septic shock was associated with decreased short-term mortality, shorter time to achieved target MAP, and less volume of intravenous fluids within 6 h. There was no significant difference in ICU length of stay between early and late groups. Further large-scale RCTs are still required to confirm these results.
Topics: Adrenergic alpha-Agonists; Cohort Studies; Humans; Norepinephrine; Randomized Controlled Trials as Topic; Shock, Septic; Time Factors; Treatment Outcome
PubMed: 32762765
DOI: 10.1186/s13054-020-03204-x -
Chest Jun 2021Historically, β-blockers have been considered to be relatively contraindicated for septic shock because they may cause cardiac suppression. On the other hand, there is... (Meta-Analysis)
Meta-Analysis
Effect of Ultrashort-Acting β-Blockers on Mortality in Patients With Sepsis With Persistent Tachycardia Despite Initial Resuscitation: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
BACKGROUND
Historically, β-blockers have been considered to be relatively contraindicated for septic shock because they may cause cardiac suppression. On the other hand, there is an increasing interest in the use of β-blockers for treating patients with sepsis with persistent tachycardia despite initial resuscitation.
RESEARCH QUESTION
Do ultrashort-acting β-blockers such as esmolol and landiolol improve mortality in patients with sepsis with persistent tachycardia despite initial resuscitation?
STUDY DESIGN AND METHODS
This was a systematic review and meta-analysis. We searched MEDLINE, Cochrane Central Register of Controlled Trials, and Embase for randomized controlled trials (RCTs) that compared the mortality of patients with sepsis and septic shock treated with esmolol or landiolol. We updated our search on April 20, 2020. Two independent reviewers assessed whether titles and abstracts met the following eligibility criteria: (1) RCT, (2) patients with sepsis and septic shock ≥ 18 years of age, and (3) treatment with either esmolol/landiolol or placebo/no interventions. Two authors independently extracted selected patient and study characteristics and outcomes. The results of all analyses are presented using random effect models.
RESULTS
Seven RCTs with a pooled sample size of 613 patients were included. Of these, six RCTs with 572 patients reported 28-day mortality. Esmolol or landiolol use in patients with sepsis and septic shock was significantly associated with lower 28-day mortality (risk ratio, 0.68; 95% CI, 0.54-0.85; P < .001). Unimportant heterogeneity was observed (I = 31%). The absolute risk reduction and number of patients to be treated to prevent one death were 18.2% and 5.5, respectively.
INTERPRETATION
The use of ultrashort-acting β-blockers such as esmolol and landiolol in patients with sepsis with persistent tachycardia despite initial resuscitation was associated with significantly lower 28-day mortality.
TRIAL REGISTRY
UMIN Clinical Trials Registry; No.: UMIN000040174; URL: https://www.umin.ac.jp/ctr/index.htm.
Topics: Adrenergic beta-Antagonists; Humans; Randomized Controlled Trials as Topic; Resuscitation; Sepsis; Tachycardia
PubMed: 33434497
DOI: 10.1016/j.chest.2021.01.009 -
JAMA Internal Medicine Feb 2019Although corticosteroids are widely used for adults with sepsis, both the overall benefit and potential risks remain unclear. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Although corticosteroids are widely used for adults with sepsis, both the overall benefit and potential risks remain unclear.
OBJECTIVE
To conduct a systematic review and meta-analysis of the efficacy and safety of corticosteroids in patients with sepsis.
DATA SOURCES AND STUDY SELECTION
MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until March 20, 2018, and updated on August 10, 2018. The terms corticosteroids, sepsis, septic shock, hydrocortisone, controlled trials, and randomized controlled trial were searched alone or in combination. Randomized clinical trials (RCTs) were included that compared administration of corticosteroids with placebo or standard supportive care in adults with sepsis.
DATA EXTRACTION AND SYNTHESIS
Meta-analyses were conducted using a random-effects model to calculate risk ratios (RRs) and mean differences (MDs) with corresponding 95% CIs. Two independent reviewers completed citation screening, data abstraction, and risk assessment.
MAIN OUTCOMES AND MEASURES
Twenty-eight-day mortality.
RESULTS
This meta-analysis included 37 RCTs (N = 9564 patients). Eleven trials were rated as low risk of bias. Corticosteroid use was associated with reduced 28-day mortality (RR, 0.90; 95% CI, 0.82-0.98; I2 = 27%) and intensive care unit (ICU) mortality (RR, 0.85; 95% CI, 0.77-0.94; I2 = 0%) and in-hospital mortality (RR, 0.88; 95% CI, 0.79-0.99; I2 = 38%). Corticosteroids were significantly associated with increased shock reversal at day 7 (MD, 1.95; 95% CI, 0.80-3.11) and vasopressor-free days (MD, 1.95; 95% CI, 0.80-3.11) and with ICU length of stay (MD, -1.16; 95% CI, -2.12 to -0.20), the sequential organ failure assessment score at day 7 (MD, -1.38; 95% CI, -1.87 to -0.89), and time to resolution of shock (MD, -1.35; 95% CI, -1.78 to -0.91). However, corticosteroid use was associated with increased risk of hyperglycemia (RR, 1.19; 95% CI, 1.08-1.30) and hypernatremia (RR, 1.57; 95% CI, 1.24-1.99).
CONCLUSIONS AND RELEVANCE
The findings suggest that administration of corticosteroids is associated with reduced 28-day mortality compared with placebo use or standard supportive care. More research is needed to associate personalized medicine with the corticosteroid treatment to select suitable patients who are more likely to show a benefit.
Topics: Adrenal Cortex Hormones; Adult; Glucocorticoids; Humans; Hydrocortisone; Intensive Care Units; Organ Dysfunction Scores; Prednisolone; Sepsis; Shock, Septic; Time Factors
PubMed: 30575845
DOI: 10.1001/jamainternmed.2018.5849 -
Intensive Care Medicine Dec 2016The interpretation of septic shock trial data is profoundly affected by patients, control intervention, co-interventions and selected outcome measures. We evaluated the... (Review)
Review
PURPOSE
The interpretation of septic shock trial data is profoundly affected by patients, control intervention, co-interventions and selected outcome measures. We evaluated the reporting of control groups in recent septic shock trials.
METHODS
We searched for original articles presenting randomized clinical trials (RCTs) in adult septic shock patients from 2006 to 2016. We included RCTs focusing on septic shock patients with at least two parallel groups and at least 50 patients in the control group. We selected and evaluated data items regarding patients, control group characteristics, and mortality outcomes, and calculated a data completeness score to provide an overall view of quality of reporting.
RESULTS
A total of 24 RCTs were included (mean n = 287 patients and 71 % of eligible patients were randomized). Of the 24 studies, 14 (58 %) presented baseline data on vasopressors and 58 % the proportion of patients with elevated lactate values. Five studies (21 %) provided data to estimate the proportion of septic shock patients fulfilling the Sepsis-3 definition. The mean data completeness score was 19 out of 36 (range 8-32). Of 18 predefined control group characteristics, a mean of 8 (range 2-17) were reported. Only 2 (8 %) trials provided adequate data to confirm that their control group treatment represented usual care.
CONCLUSIONS
Recent trials in septic shock provide inadequate data on the control group treatment and hemodynamic values. We propose a standardized trial dataset to be created and validated, comprising characteristics of patient population, interventions administered, hemodynamic values achieved, surrogate organ dysfunction, and mortality outcomes, to allow better analysis and interpretation of future trial results.
Topics: Biomedical Research; Control Groups; Humans; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Shock, Septic
PubMed: 27448676
DOI: 10.1007/s00134-016-4444-y -
Clinical Nutrition (Edinburgh, Scotland) Jun 2024The aim of this network meta-analysis (NMA) was to investigate the effects of different dietary supplements on the mortality and clinical status of adults with sepsis. (Meta-Analysis)
Meta-Analysis
AIM
The aim of this network meta-analysis (NMA) was to investigate the effects of different dietary supplements on the mortality and clinical status of adults with sepsis.
METHODS
We searched PubMed, EMBASE, and the Cochrane Library Central Register of Controlled Trials until February 2023. The inclusion criteria were: 1) randomized controlled trials (RCT)s; 2) adults suffering sepsis or septic shock; 3) evaluation of short- or long-mortality; and 4) publications between 1994 and 2023. The general information of studies and details of interventions were extracted. The primary outcome was short-term mortality (<90 days), and the secondary outcomes were long-term mortality (≥90 days), length of ICU and hospital stays, and duration of mechanical ventilation (MV). The risk of bias of RCTs was assessed using the Cochrane risk of bias tool 2 (ROB2). A random effect NMA was performed to rank the effect of each intervention using a frequentist approach.
RESULTS
Finally, 56 RCTs with 5957 participants met the criteria. Approximately, one-third of RCTs were low risk of bias. NMA analysis revealed that there was no treatment more effective in short- or long-term mortality than control or other interventions, except for magnesium (RR: 0.33, 95% CI: 0.14, 0.79; GRADE = low) and vitamin C (RR: 0.81, 95% CI: 0.67, 0.99; low certainty evidence), which had beneficial effects on short-term mortality. Moreover, eicosapentaenoic acid, gamma-linolenic acid, and antioxidants (EPA + GLA + AOs) combination was the most effective, and magnesium, vitamin D and vitamin C were the other effective approaches in terms of duration of MV, and ICU length of stay. There was no beneficial dietary supplement for hospital stay in these patients.
CONCLUSIONS
In septic patients, none of the dietary supplements had a substantial effect on mortality except for magnesium and vitamin C, which were linked to lower short-term mortality with low certainty of evidence. Further investigation into high-quality studies with the use of dietary supplements for sepsis should be highly discouraged.
Topics: Humans; Dietary Supplements; Sepsis; Network Meta-Analysis; Shock, Septic; Randomized Controlled Trials as Topic; Treatment Outcome; Length of Stay; Adult; Respiration, Artificial
PubMed: 38663051
DOI: 10.1016/j.clnu.2024.03.030 -
Frontiers in Medicine 2024Methylene blue is an interesting approach in reducing fluid overload and vasoactive drug administration in vasodilatory shock. The inhibition of guanylate cyclase...
BACKGROUND
Methylene blue is an interesting approach in reducing fluid overload and vasoactive drug administration in vasodilatory shock. The inhibition of guanylate cyclase induced by methylene blue infusion reduces nitric oxide production and improves vasoconstriction. This systematic review and meta-analysis aimed to assess the effects of methylene blue administration compared to placebo on the hemodynamic status and clinical outcomes in patients with sepsis and septic shock.
METHODS
The authors specifically included randomized controlled trials that compared the use of methylene blue with placebo in adult patients with sepsis and septic shock. The outcomes were length of intensive care unit stay, hemodynamic parameters [vasopressor use], and days on mechanical ventilation. We also evaluated the abnormal levels of methemoglobinemia. This systematic review and meta-analysis were recorded in PROSPERO with the ID CRD42023423470.
RESULTS
During the initial search, a total of 1,014 records were identified, out of which 393 were duplicates. Fourteen citations were selected for detailed reading, and three were selected for inclusion. The studies enrolled 141 patients, with 70 of them in the methylene blue group and 71 of them in the control group. Methylene blue treatment was associated with a lower length of intensive care unit stay (MD -1.58; 95%CI -2.97, -0.20; = 25%; = 0.03), decreased days on mechanical ventilation (MD -0.72; 95%CI -1.26, -0.17; = 0%; = 0.010), and a shorter time to vasopressor discontinuation (MD -31.49; 95%CI -46.02, -16.96; = 0%; < 0.0001). No association was found with methemoglobinemia.
CONCLUSION
Administering methylene blue to patients with sepsis and septic shock leads to reduced time to vasopressor discontinuation, length of intensive care unit stay, and days on mechanical ventilation.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023423470, CRD42023423470.
PubMed: 38698779
DOI: 10.3389/fmed.2024.1366062 -
JAMA Jun 2009The benefit of corticosteroids in severe sepsis and septic shock remains controversial. (Meta-Analysis)
Meta-Analysis Review
CONTEXT
The benefit of corticosteroids in severe sepsis and septic shock remains controversial.
OBJECTIVE
We examined the benefits and risks of corticosteroid treatment in severe sepsis and septic shock and the influence of dose and duration.
DATA SOURCES
We searched the CENTRAL, MEDLINE, EMBASE, and LILACS (through March 2009) databases as well as reference lists of articles and proceedings of major meetings, and we contacted trial authors.
STUDY SELECTION
Randomized and quasi-randomized trials of corticosteroids vs placebo or supportive treatment in adult patients with severe sepsis/septic shock per the American College of Chest Physicians/Society of Critical Care Medicine consensus definition were included.
DATA EXTRACTION
All reviewers agreed on trial eligibility. One reviewer extracted data, which were checked by the other reviewers and by the trials' authors whenever possible. Some unpublished data were obtained from the trials' authors. The primary outcome for this review was 28-day mortality.
RESULTS
We identified 17 randomized trials (n = 2138) and 3 quasi-randomized trials (n = 246) that had acceptable methodological quality to pool in a meta-analysis. Twenty-eight-day mortality for treated vs control patients was 388/1099 (35.3%) vs 400/1039 (38.5%) in randomized trials (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.71-1.00; P = .05; I(2) = 53% by random-effects model) and 28/121 (23.1%) vs 24/125 (19.2%) in quasi-randomized trials (RR, 1.05, 95% CI, 0.69-1.58; P = .83). In 12 trials investigating prolonged low-dose corticosteroid treatment, 28-day mortality for treated vs control patients was 236/629 (37.5%) vs 264/599 (44%) (RR, 0.84; 95% CI, 0.72-0.97; P = .02). This treatment increased 28-day shock reversal (6 trials; 322/481 [66.9%] vs 276/471 [58.6%]; RR, 1.12; 95% CI, 1.02-1.23; P = .02; I(2) = 4%) and reduced intensive care unit length of stay by 4.49 days (8 trials; 95% CI, -7.04 to -1.94; P < .001; I(2) = 0%) without increasing the risk of gastroduodenal bleeding (13 trials; 65/800 [8.1%] vs 56/764 [7.3%]; P = .50; I(2) = 0%), superinfection (14 trials; 184/998 [18.4%] vs 170/950 [17.9%]; P = .92; I(2) = 8%), or neuromuscular weakness (3 trials; 4/407 [1%] vs 7/404 [1.7%]; P = .58; I(2) = 30%). Corticosteroids increased the risk of hyperglycemia (9 trials; 363/703 [51.6%] vs 308/670 [46%]; P < .001; I(2) = 0%) and hypernatremia (3 trials; 127/404 [31.4%] vs 77/401 [19.2%]; P < .001; I(2) = 0%).
CONCLUSIONS
Corticosteroid therapy has been used in varied doses for sepsis and related syndromes for more than 50 years, with no clear benefit on mortality. Since 1998, studies have consistently used prolonged low-dose corticosteroid therapy, and analysis of this subgroup suggests a beneficial drug effect on short-term mortality.
Topics: Adrenal Cortex Hormones; Adult; Glucocorticoids; Humans; Randomized Controlled Trials as Topic; Risk Assessment; Sepsis; Shock, Septic; Survival Analysis
PubMed: 19509383
DOI: 10.1001/jama.2009.815 -
Journal of Pharmacy Practice Aug 2023Sepsis and septic shock are associated with enormous mortality and health care burden. Since the study of Marik et al suggested mortality benefit, there has been great... (Review)
Review
Sepsis and septic shock are associated with enormous mortality and health care burden. Since the study of Marik et al suggested mortality benefit, there has been great interest in evaluating the role of hydrocortisone, ascorbic acid and thiamine (HAT therapy) in sepsis and septic shock. The objective of this article is to review current literature of using HAT therapy in sepsis and septic shock, and discuss the findings in hospital mortality, change in 72 hr SOFA score, other outcomes, and the study limitations. Three databases (PubMed, Embase, and Cochrane) were screened using predefined search terms ascorbic acid, vitamin C, thiamine, vitamin B1, hydrocortisone, sepsis, septic shock. Data extracted from eligible studies include authors, publication year, sample size, study design, intervention, outcome measures and study results. Each study was reviewed critically. Among 11 studies included in this literature review, 3 studies reported HAT therapy was associated with mortality benefit, 1 reported hospital mortality was significantly higher in HAT group and the rest of studies didn't reach statistical significance in mortality analysis. Significant improvement of secondary outcomes, although not consistently, were reported. In conclusion, HAT therapy has demonstrated a good safety profile and potential benefits in management of sepsis and septic shock. Further research is required to confirm these findings.
Topics: Humans; Thiamine; Ascorbic Acid; Hydrocortisone; Shock, Septic; Drug Therapy, Combination; Sepsis
PubMed: 35465689
DOI: 10.1177/08971900221097193