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).
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.
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.
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.
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.
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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