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Anesthesia & Analgesia:
doi: 10.1213/ANE.0000000000000050
Critical Care, Trauma, and Resuscitation: Research Report

Low-Dose Hydrocortisone Therapy Attenuates Septic Shock in Adult Patients but Does Not Reduce 28-Day Mortality: A Meta-Analysis of Randomized Controlled Trials

Wang, Changsong MD*; Sun, Jiaxiao MSc*; Zheng, Juanjuan MSc; Guo, Lei MD*; Ma, Hongyan MD*; Zhang, Yang*; Zhang, Fengmin PhD‡§; Li, Enyou MD*

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Author Information

From the *Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University; Department of Medical Records, the First Hospital of Quanzhou, Quanzhou, China; Department of Microbiology, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin Medical University; and §Key Laboratory of Bio-Pharmaceutical, Harbin Medical University, Ministry of Education, Harbin, China.Jiaxiao Sun, MSc, is currently affiliated with Department of Anesthesiology, the First Hospital of Quanzhou, Quanzhou, China. Juanjuan Zheng, is currently affiliated with Department of Medical Records, the First Hospital of Quanzhou, Quanzhou, China.

Accepted for publication October 18, 2013.

Funding: Financial support by grants from the National Natural Science Foundation of China (No.30972839), China Postdoctoral Science Foundation (No. 2013M531069), Foundation of Heilongjiang Educational Committee (No.12531245) and Doctoral Fund of the First Affiliated Hospital of Harbin Medical University (No.2012B006) are gratefully acknowledged.

Dr. Changsong Wang and Jiaxiao Sun contributed equally to this work.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Enyou Li, MD, Department of Anesthesiology, The First Affiliated Hospital of Harbin Medical University, No 23 Youzheng St., Nangang District, Harbin, Heilongjiang 150001, China. Address e-mail to enyouli@aliyun.com.

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Abstract

BACKGROUND: The role of low-dose hydrocortisone in attenuating septic shock and reducing short-term mortality in adult patients with septic shock is unclear. We conducted a meta-analysis of previous studies to determine whether hydrocortisone could ameliorate the effects of septic shock at 7 and 28 days and reduce 28-day morality.

METHODS: Randomized controlled trials (RCTs) of corticosteroids versus placebo (or supportive treatment alone) were retrieved from electronic searches (Medline, Embase, and Cochrane Library databases; LILACS; and Web of Knowledge) and manual searches (up to May 2012). From a pool of 1949 potentially relevant articles, duplicate independent review identified 10 relevant, RCTs of low-dose hydrocortisone therapy in septic shock. Four pairs of reviewers agreed on the criteria for trial eligibility. One reviewer entered the data into the computer, and 3 reviewers checked the data. Missing data were obtained from the authors of the relevant trials. The primary outcome analyzed was an estimate of 28-day mortality.

RESULTS: Eight publications were included in the meta-analysis. Low-dose hydrocortisone therapy did not reduce 28-day mortality (N = 1063; odds ratio (OR) = 0.891, 95% confidence interval (CI), 0.69–1.15). Low-dose hydrocortisone therapy ameliorated shock at 7 days (6 RCTs, N = 964, OR = 2.078, 95% CI, 1.58–2.73, P < 0.0001, and I2 = 26.9%) and 28 days (6 RCTs, N = 947, OR = 1.495, 95% CI, 1.12–1.99, P = 0.006, and I2 = 0.0%).

CONCLUSIONS: Although low-dose hydrocortisone therapy ameliorates septic shock at 7 and 28 days, it does not reduce 28-day mortality.

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

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METHODS

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.

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Groups

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.

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Literature Search

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).

Figure 1
Figure 1
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Strategy Design

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.

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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

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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.

Table 1
Table 1
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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.

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Quality Assessment

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.

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Statistical Analyses

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.

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RESULTS

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.

Table 2
Table 2
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28-Day Mortality

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).

Table 3
Table 3
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Figure 2
Figure 2
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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).

Figure 3
Figure 3
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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.

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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.

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Shock Reversal

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).

Figure 4
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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.

Figure 5
Figure 5
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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.

Figure 6
Figure 6
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Cumulative Analysis

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).

Figure 7
Figure 7
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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.

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Complications

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).

Table 4
Table 4
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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).

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DISCUSSION

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.

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DISCLOSURES

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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REFERENCES

1. Matot I, Sprung CL. Definition of sepsis. Intensive Care Med. 2001;27(Suppl 1):S3–9

2. Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, Beale R, Svoboda P, Laterre PF, Simon S, Light B, Spapen H, Stone J, Seibert A, Peckelsen C, De Deyne C, Postier R, Pettilä V, Artigas A, Percell SR, Shu V, Zwingelstein C, Tobias J, Poole L, Stolzenbach JC, Creasey AAOPTIMIST Trial Study Group. . Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290:238–47

3. Dellinger RP. Cardiovascular management of septic shock. Crit Care Med. 2003;31:946–55

4. Cooperative Study Group. . The effectiveness of hydrocortisone in the management of patients with severe infections. JAMA. 1963;183:462–5

5. Russell JA. Management of sepsis. N Engl J Med. 2006;355:1699–713

6. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317:653–8

7. Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang MA, Fisher CJ Jr. Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature. Crit Care Med. 1995;23:1430–9

8. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ. 2004;329:480

9. Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De Gaudio R, Keh D, Kupfer Y, Oppert M, Meduri GU. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review. JAMA. 2009;301:2362–75

10. Moran JL, Graham PL, Rockliff S, Bersten AD. Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective. Crit Care. 2010;14:R134

11. Kalil AC, Sun J. Low-dose steroids for septic shock and severe sepsis: the use of Bayesian statistics to resolve clinical trial controversies. Intensive Care Med. 2011;37:420–9

12. Czock D, Keller F, Rasche FM, Häussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005;44:61–98

13. Lau J, Schmid CH, Chalmers TC. Cumulative meta-analysis of clinical trials builds evidence for exemplary medical care. J Clin Epidemiol. 1995;48:45–57

14. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1644–55

15. Kaufmann I, Briegel J, Schliephake F, Hoelzl A, Chouker A, Hummel T, Schelling G, Thiel M. Stress doses of hydrocortisone in septic shock: beneficial effects on opsonization-dependent neutrophil functions. Intensive Care Med. 2008;34:344–9

16. Bañares R, Albillos A, Rincón D, Alonso S, González M, Ruiz-del-Arbol L, Salcedo M, Molinero LM. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology. 2002;35:609–15

17. Peter JV, John P, Graham PL, Moran JL, George IA, Bersten A. Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ. 2008;336:1006–9

18. Spruance SL, Reid JE, Grace M, Samore M. Hazard ratio in clinical trials. Antimicrob Agents Chemother. 2004;48:2787–92

19. Moran J, Solomon P, Warn D. Methodology in meta-analysis: a study from Critical Care meta-analytic practice. Health Serv Outcomes Res Method. 2004;5:207–26

20. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60

21. Chawla K, Kupfer Y, Tessler S. Hydrocortisone reverses refractory septic shock (abstract). Crit Care Med. 1999;27:A33

22. Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaud P, Chaumet-Riffaut P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288:862–71

23. Mussack T, Briegel J, Schelling G, Biberthaler P, Jochum M. Effect of stress doses of hydrocortisone on S-100B vs. interleukin-8 and polymorphonuclear elastase levels in human septic shock. Clin Chem Lab Med. 2005;43:259–68

24. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel JCORTICUS Study Group. . Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111–24

25. Arabi YM, Aljumah A, Dabbagh O, Tamim HM, Rishu AH, Al-Abdulkareem A, Knawy BA, Hajeer AH, Tamimi W, Cherfan A. Low-dose hydrocortisone in patients with cirrhosis and septic shock: a randomized controlled trial. CMAJ. 2010;182:1971–7

26. Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, Hemmer B, Hummel T, Lenhart A, Heyduck M, Stoll C, Peter K. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med. 1999;27:723–32

27. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26:645–50

28. Oppert M, Schindler R, Husung C, Offermann K, Gräf KJ, Boenisch O, Barckow D, Frei U, Eckardt KU. Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Crit Care Med. 2005;33:2457–64

29. Sligl WI, Milner DA Jr, Sundar S, Mphatswe W, Majumdar SR. Safety and efficacy of corticosteroids for the treatment of septic shock: a systematic review and meta-analysis. Clin Infect Dis. 2009;49:93–101

30. Annane D, Cariou A, Maxime V, Azoulay E, D’honneur G, Timsit JF, Cohen Y, Wolf M, Fartoukh M, Adrie C, Santré C, Bollaert PE, Mathonet A, Amathieu R, Tabah A, Clec’h C, Mayaux J, Lejeune J, Chevret S. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010;303:341–8

31. Cicarelli DD, Vieira JE, Benseñor FE. Early dexamethasone treatment for septic shock patients: a prospective randomized clinical trial. Sao Paulo Med J. 2007;125:237–41

32. Yildiz O, Doganay M, Aygen B, Güven M, Keleştimur F, Tutuû A. Physiological-dose steroid therapy in sepsis [ISRCTN36253388]. Crit Care. 2002;6:251–9

33. Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ, Gibson M, Umberger R. Methylprednisolone infusion in early severe ARDS: results of a randomized controlled trial. Chest. 2007;131:954–63

34. Yu TJ, Liu YC, Yu CC, Tseng JC, Hua CC, Wu HP. Comparing hydrocortisone and methylprednisolone in patients with septic shock. Adv Ther. 2009;26:728–35

35. Levy H, Laterre PF, Bates B, Qualy RL. Steroid use in PROWESS severe sepsis patients treated with drotrecogin alfa (activated). Crit Care. 2005;9:R502–7

36. Raurich JM, Llompart-Pou JA, Ibáñez J, Frontera G, Pérez O, García L, Ayestarán JI. Low-dose steroid therapy does not affect hemodynamic response in septic shock patients. J Crit Care. 2007;22:324–9

37. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno RSurviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. . Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580–637

38. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg. 1976;184:333–41

39. Lucas CE, Ledgerwood AM. The cardiopulmonary response to massive doses of steroids in patients with septic shock. Arch Surg. 1984;119:537–41

40. Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, Duncan RC, Tendler MD, Karpf M. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. N Engl J Med. 1984;311:1137–43

41. Hughes GS Jr. Naloxone and methylprednisolone sodium succinate enhance sympathomedullary discharge in patients with septic shock. Life Sci. 1984;35:2319–26

42. Lederer V. Betamethasone sodium phosphate injection: high-dose regimen in septic shock. Clin Ther. 1984;6:719–26

43. Hellman A, Alestig K. High doses of corticosteroids in the treatment of septic shock. Acta Chir Scand Suppl. 1985;526:124–8

44. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med. 1987;317:653–8

45. Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray JF. Ineffectiveness of high-dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis. 1988;138:62–8

46. Marks JD, Marks CB, Luce JM, Montgomery AB, Turner J, Metz CA, Murray JF. Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration. Am Rev Respir Dis. 1990;141:94–7

47. Oppert M, Reinicke A, Gräf KJ, Barckow D, Frei U, Eckardt KU. Plasma cortisol levels before and during “low-dose” hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic shock. Intensive Care Med. 2000;26:1747–55

48. Briegel J, Jochum M, Gippner-Steppert C, Thiel M. Immuno modulation in septic shock: hydrocortisone differentially regulates cytokine responses. J Am Soc Nephrol. 2001;12(Suppl 17):S70–4

49. Annane D, Bellissant E. Impact of corticosteroids on the vascular response to catecholamines in septic shock. Réanimation. 2002;11:111–6

50. Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H. Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med. 2003;167:512–20

51. Laterre PF, Levy H, Bates BM. Steroid use in prowess patients with septic shock (abstract). Intensive Care Medicine. 2003;29:S89

52. Guzman JA, Bander JJ, Guzman CB.. Steroids in septic shock; Limited value of cortisol testing to guide replacement therapy. Critical Care Medicine. 2005;33:A169

53. Tandan SM, Guleria R, Gupta N. Low dose steroids and adrenocortical insufficiency in septic shock: a double-blind randomised controlled trial from India. Proceedings of the American Thoracic Society Meeting. 2005 New York, NY American Thoracic Society:A24

54. Rinaldi S, Adembri C, Grechi S, De Gaudio AR. Low-dose hydrocortisone during severe sepsis: effects on microalbuminuria. Crit Care Med. 2006;34:2334–9

55. Loisa P, Parviainen I, Tenhunen J, Hovilehto S, Ruokonen E. Effect of mode of hydrocortisone administration on glycemic control in patients with septic shock: a prospective randomized trial. Crit Care. 2007;11:R21

56. McGee WT, Higgins TL, Jodka P. Optimal steroid therapy may improve outcome in septic shock (abstract). Crit Care Med. 2007;12:A117

57. Cicarelli DD, Vieira JE, Benseñor FE. Comparison of C-reactive protein and serum amyloid a protein in septic shock patients. Mediators Inflamm 2008 2008:631414.

58. Kurugundla N, Irugulapati L, Kilari D. Effect of steroids in septic shock patients without relative adrenal insufficiency-a pilot study [abstract]. American Thoracic Society: International Conference. 2008:A116

59. Büchele GL, Silva E, Ospina-Tascón GA, Vincent JL, De Backer D. Effects of hydrocortisone on microcirculatory alterations in patients with septic shock. Crit Care Med. 2009;37:1341–7

60. Hayashi M. Activated protein c and corticosteroids decrease the rate of albumin transudation in septic shock (abstract). Crit Care Med. 2009;34:A407

61. Hu B, Li JG, Liang H, Zhou Q, Yu Z, Li L, Luo Y, Liu C, Gan Q. [The effect of low-dose hydrocortisone on requirement of norepinephrine and lactate clearance in patients with refractory septic shock]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2009;21:529–31

62. Russell JA, Walley KR, Gordon AC, Cooper DJ, Hébert PC, Singer J, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJDieter Ayers for the Vasopressin and Septic Shock Trial Investigators. . Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock. Crit Care Med. 2009;37:811–8

63. Valoor HT, Singhi S, Jayashree M. Low-dose hydrocortisone in pediatric septic shock: an exploratory study in a third world setting. Pediatr Crit Care Med. 2009;10:121–5

64. Beale R, Janes JM, Brunkhorst FM, Dobb G, Levy MM, Martin GS, Ramsay G, Silva E, Sprung CL, Vallet B, Vincent JL, Costigan TM, Leishman AG, Williams MD, Reinhart K. Global utilization of low-dose corticosteroids in severe sepsis and septic shock: a report from the PROGRESS registry. Crit Care. 2010;14:R102

65. Jung B, Nougaret S, Chanques G, Mercier G, Cisse M, Aufort S, Gallix B, Annane D, Jaber S. The absence of adrenal gland enlargement during septic shock predicts mortality: a computed tomography study of 239 patients. Anesthesiology. 2011;115:334–43

66. Schelling G, Briegel J, Roozendaal B, Stoll C, Rothenhäusler HB, Kapfhammer HP. The effect of stress doses of hydrocortisone during septic shock on posttraumatic stress disorder in survivors. Biol Psychiatry. 2001;50:978–85

67. Huh JW, Choi HS, Lim CM, Koh Y, Oh YM, Shim TS, Lee SD, Kim WS, Kim DS, Hong SB. Low-dose hydrocortisone treatment for patients with septic shock: a pilot study comparing 3 days with 7 days. Respirology. 2011;16:1088–95

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