The incidence of septic shock can be as high as 20% among hospitalized patients.1 Even after the appropriate treatment is administered, mortality from septic shock remains approximately 50%.2,3 Since the first publication of the use of glucocorticoids in severe infection,4 researchers have explored the use of steroids in septic shock. A half-century later, the role of glucocorticoids for decreasing mortality from septic shock remains controversial.5,6 A 1995 meta-analysis found that a short course of high-dose glucocorticoid therapy provided no advantage for the treatment of septic shock and could have negative effects.7 A 2004 meta-analysis found that steroids did not affect mortality from septic shock.8 However, a subgroup analysis of patients treated with low doses of steroids (≤ 300 mg hydrocortisone or equivalent per day) for >5 days found that sustained low-dose steroid therapy reduced 28-day mortality. In 2009, the same group of researchers repeated a meta-analysis on the same issue by integrating recent randomized controlled trials (RCTs).9 The analysis was restricted only to the response to steroid therapy in an adult population with severe sepsis and septic shock. The results demonstrated that long-term, low-dose steroid therapy can increase short-term survival rates.
These studies involved analyses of various corticosteroid therapies10,11 but did not focus on the effect of a single steroid therapy. Glucocorticoids differ in receptor binding, biological half-life, and glucocorticoid–mineralocorticoid hormone actions.12 Glucocorticoids may differ in their efficacy in septic shock. As hydrocortisone is the endogenous glucocorticoid released by the adrenal gland, it might be the best choice of replacement therapy in shock.
An initial literature search found that studies of low-dose corticosteroid therapy for septic shock accounted for most recent studies. Therefore, we investigated the effects of low-dose hydrocortisone on shock reversal and survival in patients with septic shock. We performed a conventional meta-analysis of published trials and a cumulative meta-analysis to evaluate the effects of each study on the final, generalized results.13
We conducted a systematic review and several meta-analyses of the literature according to the methods recommended in the PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions.
Our investigators were divided into 4 groups. CW was primarily responsible for the literature search group (CW and LG). JS and HM were responsible for the 2 literature review groups (JS, FZ, HM, and YZ). JZ was responsible for the data analysis group (JZ and EL). After the 2 separate literature review groups conducted the literature exclusion and inclusion and the data extraction, the data were verified. If there was an inconsistency, the data extraction was repeated until a consensus was reached.
The trials were identified by electronic and manual searches. The electronic searches were performed by 2 authors who independently searched the Medline, Embase, and Cochrane Library databases; the Cochrane Controlled Trials Register; LILACS (http://www.bireme.br; assessed May 2012); and Web of Knowledge (Conference Proceedings Citation Index-Science, Conference Proceedings Citation Index-Social Sciences & Humanities). We did not restrict our search based on language or year of publication. The last search update was May 2012. The Medline database was searched using the PubMed interface. The following search terms (in all fields) were used: sepsis, septic shock, steroids, corticosteroids, adrenal cortex hormones, and glucocorticoids. Embase was searched using the following search terms: sepsis, septic shock, steroids, and corticosteroids. The search terms sepsis and septic shock were searched in the Cochrane infectious diseases group’s trial register. We searched the Cochrane central register using the following search terms: sepsis, septic shock, steroids, and corticosteroids. LILACS was searched using the search terms sepsis, steroids, and corticosteroids, and we searched the proceedings of the annual meetings by using the search terms sepsis, septic shock, steroids, and corticosteroids in the Web of Knowledge (Conference Proceedings Citation Index-Science, Conference Proceedings Citation Index-Social Sciences & Humanities) database. We reviewed the reference lists of published meta-analyses. In addition, we manually searched the Index Medicus of RCTs, meta-analyses, and systematic reviews for studies that were missed in the initial electronic search.
The search strategy identified 1949 studies. Two literature review groups conducted the literature exclusion; 120 studies were included for potential interest. The studies with one or more of the following terms mentioned were considered for inclusion: steroid, any class of glucocorticoid, septic shock, and human study. The selected studies were repeatedly reviewed for exclusion by the literature search groups. The exclusion and inclusion criteria were independently applied to each study by the 2 study review groups (Fig. 1).
The literature search and data extraction strategy were discussed and designed by 2 authors. After all the authors had discussed and reviewed the strategy, the corresponding author approved the final version of the study strategy design.
Definition of Septic Shock
Septic shock was defined according to the standard established by the 1992 American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) Consensus Conference.14 “Shock reversal” was defined as a stable state of systolic blood pressure (> 90 mm Hg) for a period of 24 hours or more without vasopressor support or transfusion.9 Low-dose hydrocortisone was defined as a daily dose of hydrocortisone ≤300 mg.9
Inclusion and Exclusion Criteria
The literature inclusion and exclusion procedures were performed independently by 2 literature review groups. We first excluded retrospective analyses, repeated literature reports, and repeated experiments (the same experiment analyzed and evaluated in different literature reports); purely physiological studies (e.g., the effects of steroids on neutrophils in patients with septic shock);15 imaging studies; pediatric studies; studies with high-dose medications; studies on medications other than hydrocortisone (the initial design was to conduct a separate analysis on a single steroid of other glucocorticoid types; however, the analysis could not be performed separately due to the lack of relevant studies on other medications); nonrandomized controlled studies; and studies without a control group (Table 1). If data were missing, the literature search group contacted the authors for the relevant data.
Subsequently, the 2 study review groups performed the initial verification. A disagreement occurred only in 1 study, which was eventually excluded after a discussion among all of the authors.
The process yielded 8 published studies, one of which was only published as a meeting abstract. Two groups of researchers independently conducted a second round of data extraction from the literature. Key data were 28-day mortality and shock reversal at 7 and 28 days. If the relevant data were missing or ambiguous, we contacted the authors for clarification.
Quality assessments were performed separately by the 2 literature review groups. Studies that received inconsistent scores were scored again by all of the authors. The quality of the study was assessed using a modified Jadad scale16 in which the generation of random sequences, blinding method, reasons for withdrawal, and dropout at the time of follow-up were evaluated. A 7-point scale was used, with 1 to 3 indicating a low-quality study and 4 to 7 indicating a high-quality study. No studies were excluded from the analysis because of the quality assessment.
The outcomes of interest were 28-day mortality and the shock reversal at 7 and 28 days. The adverse events superinfection, gastrointestinal (GI) bleeding, and hyperglycemia were also evaluated. Statistical analysis was performed using Stata (version 11.1, StataCorp LP, College Station, TX). Because the mortality rate was calculated in most RCTs at different time points, we used the hazard ratio as the parameter for calculating the mortality rate.17 Intratrial variability among the RCTs may have introduced bias in the hazard ratio calculation. Considering that the hazard ratio is very similar to the odds ratio (OR), we calculated the OR value and 95% confidence intervals (CIs) as the approximate parameters for evaluating the effects of hydrocortisone therapy on mortality and shock reversal.18,19
The statistical variable I2 was used to compare heterogeneity among studies (25% indicated low heterogeneity, 50% indicated moderate heterogeneity, and 75% indicated high heterogeneity; I2 > 50% indicated significant heterogeneity).20 The fixed-effects model was applied if there was significant heterogeneity. The DerSimonian–Laird test was applied for the pooled OR value. The fixed-effects model was applied if there was low significant heterogeneity. The Mantel–Haenszel test was applied for the pooled OR value. The Z-test was applied for the significance test for pooled OR values.
To find the source of heterogeneity and ensure the stability of results, we performed a sensitivity analysis for 28-day mortality and 7-day shock reversal. We performed subgroup analyses for sample size (< 100 or > 100) and quality score (6 or 7) for 28-day mortality. To explain the relationship between the log value of the 28-day mortality and the patients’ average age and gender, we performed a secondary analysis by meta-regression method. The variables time and sample size were used in a cumulative meta-analysis to investigate the dynamic changes among 3 indictors: 28-day mortality, 7 day shock reversal, and 28-day shock reversal.
To assess publication bias and test for small sample size bias, we used Egger’s test in continuous data analyses. However, the response variable of this study was a binary variable. Therefore, Harbord test was performed for quantitative assessment, and Begg’s funnel plot was used to qualitatively demonstrate the bias.
Eight publications (Table 2) were incorporated in the meta-analysis, which included 1 meeting abstract.21 All 8 studies were included in the analysis of 28-day mortality. Among these studies, the raw data were provided in 6 studies.20–25 The raw data for the remaining 2 studies21,26 were acquired by writing to the authors. Six studies21,22,24,26–28 were included for shock reversal analysis on day 7. Among these studies, the raw data were originally provided in 4 studies.22,24,27,28 The raw data for the remaining 2 studies21,26 were acquired by writing to the authors. Six studies21–24,26,27 were included in the analysis of shock reversal on day 28. Among these studies, the raw data were provided in 4 studies.22–24,27 The raw data for the remaining 2 studies21,26 were acquired by writing to the authors.
Eight RCTs with a total of 1063 participants were included in the analysis (535 subjects in the patient group and 528 in the control group). The 28-day mortality values were 227 (42.43%) and 237 (44.89%) in the patient and control groups, respectively. The analysis results were OR = 0.891, 95% CI, 0.69–1.15, P = 0.371, and I2 = 29.2%. There were no significant differences in the 28-day mortality analysis (Fig. 2; Table 3).
Sensitivity Analysis of 28-Day Mortality
A sensitivity analysis was performed for the included 8 studies to investigate the source of heterogeneity (Fig. 3). The result for 28-day mortality remained stable after the exclusion of any 1 study. No significant differences were found in the 28-day mortality rates (Table 3).
Subgroup Analysis of 28-Day Mortality
We performed subgroup analyses of the 8 studies to investigate the effects of sample size (categorized to >100 and <100) and quality score (divided into a 6-score group and a 7-score group) on heterogeneity (Table 3). Two studies with sample sizes of >100 were included in this subgroup with OR = 0.972, 95% CI, 0.73–1.30, P = 0.850, and I2 = 40.0%. Six studies were included in the subgroup with sample sizes of <100, with OR = 0.665, 95% CI, 0.39–1.13, P = 0.131, and I2 = 25.2%. The subgroup with quality assessment scores of 6 included 3 studies, with OR = 1.052, 95% CI, 0.74–1.49, P = 0.775, and I2 = 0.0%. Four studies were included in the subgroup with quality assessment scores of 7, with OR = 0.786, 95% CI, 0.53–1.16, P = 0.224, and I2 = 45.7%. One study was only published as a meeting abstract and therefore could not be included for quality analysis.
The results of the subgroup analysis showed no significant differences in the 28-day mortality rates among subgroups. Heterogeneity decreased in some subgroups (such as the subgroup with sample sizes of <100 and the subgroup with quality assessment scores of 6), whereas heterogeneity increased in the subgroup with sample sizes of >100 and the subgroup with quality assessment scores of 7, compared with overall heterogeneity. These results suggest that sample size and quality assessment were not sources of heterogeneity.
Secondary Analysis of 28-Day Mortality
For exploratory purposes, a secondary analysis was performed by meta-regression method between the log value of the 28-day mortality and the patients’ average age and gender (Table 3). Among the 8 studies, 7 studies provided gender information and 7 studies provided age information (P = 0.471). Therefore, gender and age were not associated with the heterogeneity of 28-day mortality.
The 7-day shock reversal analysis included 6 RCTs with a total of 964 participants (484 subjects in the patient group and 480 in the control group). The number of patients with 7-day shock reversal was 307 (63.43%) in the patient group and 228 (47.50%) in the control group. The increase in shock reversal at 7 days with hydrocortisone was statistically significant: OR = 2.078, 95% CI, 1.58–2.73, P < 0.0001, and I2 = 26.9% (Fig. 4, Table 3). The source of heterogeneity was not found by a subgroup analysis of sample size or quality assessment score (Table 3).
The 28-day shock reversal analysis included 6 RCTs with a total of 947 participants (478 subjects in the hydrocortisone group and 469 in the placebo group). The number of patients with 28-day shock reversal was 328 (68.62%) in the patient group and 283 (60.34%) in the control group. The increase in shock reversal at 28 days with hydrocortisone was statistically significant: OR = 1.495, 95% CI, 1.12–1.99, P = 0.006, and I2 = 0.0% (Fig. 4; Table 3).
A sensitivity analysis was performed to investigate the source of heterogeneity of 7-day shock reversal (Fig. 5). The results remained stable after the exclusion of any 1 study. Because no heterogeneity (I2 = 0.0%) was observed in the 28-day shock reversals, a sensitivity analysis was not performed for this variable.
Publication Bias Analysis
We analyzed publication bias for the studies included in the analyses of 28-day mortality and 7-day/28-day shock reversal. Because the dependent variable was a binary variable, we conducted the Harbord test for quantitative assessment of 3 indicators to determine the possibility of publication bias. Begg’s funnel plot was performed for qualitative analysis. The P value was 0.225 for 28-day mortality, 0.553 for 7-day shock reversal, and 0.019 for 28-day shock reversal. Begg’s funnel plot for 28-day mortality is shown in Figure 6.
Using the variables publication year and sample size, a cumulative meta-analysis was performed for 28-day mortality and 7-day/28-day shock reversal. The cumulative analysis of 28-day mortality showed that the OR value gradually increased from 0.27 to 0.89 and that the 95% CI increased from (0.07–0.99) to (0.69–1.15) as a function of publication date. The tendency of the OR value to approach 1 was significant (Fig. 7).
The cumulative analysis of 7-day shock reversal showed that the OR value gradually decreased from 8.04 to 2.08 and the 95% CI decreased from (1.94–33.30) to (1.58–2.73) as a function of publication date. However, the OR value and 95% CI were still significantly >1 (Fig. 7).
The cumulative analysis of 28-day shock reversal showed that the OR value gradually decreased from 3.67 to 1.49 and the 95% CI decreased from (1.01–13.40) to (1.12–1.99) as a function of publication date. However, the OR value and 95% CI were still significantly >1 (Fig. 7).
The 3 indicators did not show any trend with increases in sample size.
Meta-analysis of superinfection showed an OR = 1.103, 95% CI, 0.83–1.18, P = 0.507, and I2 = 3.1%. The results were not significant, indicating that low-dose hydrocortisone therapy did not increase the likelihood of superinfection in patients with septic shock. No significant trend was found in the cumulative analysis (Table 4).
Meta-analysis of GI bleeding showed an OR = 1.601, 95% CI, 0.99–2.60, P = 0.057, and I2 = 26.9%. Although the result did not reach statistical significance, the OR (1.6) and the nearly significant results (P = 0.057) do not comfortably exclude an increase in GI bleeding. The cumu lative analysis showed that the negative result became more stabilized in studies reported in recent years (Table 4).
Meta-analysis of hyperglycemia showed an OR = 2.143, 95% CI, 1.41–3.26, P < 0.0001, and I2 = 0.0%. The results were significant, indicating that low-dose hydrocortisone increases the incidence of hyperglycemia in patients with septic shock. Because only 3 studies were included, a cumulative analysis was not performed (Table 4).
This meta-analysis demonstrated that low-dose hydrocortisone therapy attenuated septic shock in adult patients at 7 and 28 days but did not reduce 28-day mortality. Hydrocortisone increased the blood glucose levels in patients with septic shock and was associated with increased GI bleeding, although this last finding did not reach statistical significance. The available evidence does not support the use of low-dose hydrocortisone as a routine treatment for adult patients with septic shock.
Our results are similar to those of Sligl et al.,29 who demonstrated that corticosteroid therapy does not reduce mortality rates but does appear to consistently reduce the time to shock reversal. The role of hydrocortisone therapy, in addition to fludrocortisone, was also evaluated in the COIITSS Trial.30 The authors failed to demonstrate a survival benefit associated with fludrocortisone treatment, but there may be a higher risk for increased infection.
Our results differ from the results of Annane et al.9 in 2009 because of different inclusion criteria. We limited our analysis to hydrocortisone therapy. Therefore, we excluded the 3 studies that Annane et al.9 included, Cicarelli et al.,31 Yildiz et al.,32 and Meduri et al.,33 because these investigators studied prednisolone, dexamethasone, and methylprednisolone, respectively. In addition, we included a 2010 report by Arabi et al.25
Yu et al.34 compared the effects of hydrocortisone and methylprednisolone on septic shock. They found that the survival rates for patients who received hydrocortisone were higher than for patients who received methylprednisolone, although the difference was not significant. These results suggest that different types of glucocorticoids may have different effects on septic shock treatment.
The study by Levy et al.35 was not included in our analysis because it was a retrospective cohort study; the steroid type, dose, and duration were also unspecified. The study by Raurich et al.36 was also excluded in our analysis because it was a case-control study. The study by Annane et al.22 was excluded because it evaluated hydrocortisone and fludrocortisone.
Cumulative meta-analysis showed that the OR value of 7-day shock reversal gradually decreased from 8.04 to 2.08, whereas the 95% CI decreased from (1.94–33.30) to (1.58–2.73) as a function of publication year. However, the OR values and 95% CI were both significantly higher than 1, indicating that although the positive results of 7-day shock reversal gradually weakened over the years, the results were still significantly positive and became stable in recent years. The cumulative analysis of 28-day shock reversal showed that the OR value decreased gradually from 3.67 to 1.49 and that the 95% CI decreased from (1.01–13.40) to (1.12–1.99) as a function of publication year. However, the OR values and 95% CI were both significantly higher than 1, indicating that although the positive results of 28-day shock reversal gradually weakened over the years, the results were still significantly positive and became stable in recent years.
It is not clear why mortality at 28 days did not decrease, since the data demonstrate that shock was ameliorated at 7 and 28 days in septic patients. This lack of an effect on 28-day mortality rate might be attributed to adverse events such as superinfection, GI bleeding, and hyperglycemia. In this study, we found that low-dose hydrocortisone increased blood glucose levels in patients, had a trend toward increased GI bleeding that was not statistically significant, and did not increase the risk of superinfection. Because of the small sample size and few adverse events in these studies, additional studies with increased sample sizes are warranted to explain the lack of improvement in mortality.
Our study demonstrates that although low-dose hydrocortisone therapy can improve shock reversal in patients with sepsis, the therapy has no significant impact on 28-day mortality rate. The new International Guidelines for Management of Severe Sepsis and Septic Shock suggest that it is not advisable to use IV hydrocortisone as a treatment for adult septic shock patients if adequate fluid resuscitation and vasopressor therapy can restore hemodynamic stability. If hemodynamic stability cannot be maintained, the guidelines suggest IV hydrocortisone alone at a dose of 200 mg per day.37 Our results are consistent with these new guidelines. The available evidence does not support the argument that low-dose hydrocortisone should be used as a routine treatment in adult patients with septic shock.
Name: Changsong Wang, MD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Changsong Wang has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Jiaxiao Sun, MSc.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Jiaxiao Sun has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Juanjuan Zheng, MSc.
Contribution: This author helped analyze the data.
Attestation: Juanjuan Zheng has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Lei Guo, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Lei Guo has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Hongyan Ma, MD.
Contribution: This author helped conduct the study.
Attestation: Hongyan Ma has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Yang Zhang.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Yang Zhang has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Fengmin Zhang, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Fengmin Zhang has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Enyou Li, MD.
Contribution: This author helped design and conduct the study and write the manuscript.
Attestation: Enyou Li has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Steven L. Shafer, MD.
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