Included trials
Our literature search identified a total of 9133 studies. 1929 duplicates were excluded. 7204 studies were excluded based on the title or abstract. 21 studies were excluded based on the full text assessment. 24 trials met our inclusion criteria randomizing 3073 participants (27-50), of which 20 trials randomizing 2866 participants provided data for our predefined meta-analyses (27-43, 45, 47, 48). See PRISMA flowchart (Figure 1) for details regarding the literature search and the selection of trials.
The age groups of the randomized participants were infants (< 1 year) (38, 43, 44, 47) and children (age > 1 year and < 12 years) (27-37, 39-42, 45, 47, 48). All the trials assessed glucocorticosteroids as add on therapy of standard care. The glucocorticosteroids included were hydrocortisone (8 trials) (27, 42, 43, 46-50); dexamethasone (15 trials) (28-41, 43); and methylprednisolone (1 trial) (45) (Table 1). 18 trials used placebo plus standard care (27-31, 33, 35-37, 40-43, 45, 46, 48, 49) and 6 trials used only standard care as control intervention (16, 25, 32, 34, 38, 47). The follow-up ranged from one to 12 months. 19 trials reported all-cause mortality (27-43, 45, 47, 48); 20 trials reported serious adverse events (27-43, 45, 47, 48); 2 trials reported shock reversal (37, 42); 11 trials reported ototoxicity (29-31, 33-36, 39-41, 43); 9 trials reported adverse events not considered serious (29, 32, 35-37, 42, 43, 45, 48); and 12 trials reported neurological complications (28-34, 36, 38-41). No trials reported quality of life or organ failure. We created a ‘Summary of findings’ table (Table 2) using the prespecified outcomes all-cause mortality, serious adverse events, shock reversal, ototoxicity, and adverse events not considered serious. We also assessed neurological complications as a post-hoc analysis for trials including children with meningitis.
Six trials were assessed to be at overall low risk of bias (30, 36, 39, 41, 47, 48) whereas 18 trials were assessed to be at overall high risk of bias (27-29, 31-35, 37, 38, 40, 42-46, 49, 50) (Figure 2). The certainty of evidence according to GRADE ranged from very low to low.
The visual inspection of the forest plot and test for subgroup difference (P = 0.02) in the meta-analysis on our primary outcome serious adverse events showed that the effects of glucocorticosteroids seemed to differ between trials randomising participants with meningitis and trials randomising participants with sepsis of mixed focus (Figure 3 and 4). It was therefore not justifiable to pool trials including only children with meningitis with trials including children with difference underlying infections. Hence, we chose to report results separately for each group of trials (children with mixed focus of infection and children with meningitis). We have attached the results of the overall analyses in Appendix 1.
Effects of interventions
Glucocorticosteroids for sepsis with mixed focus
All-cause mortality
A total of 5/9 trials (55.6%), randomizing 358 participants, reported all-cause mortality. In the glucocorticosteroid group, 33/184 (17.9%) participants died compared with 27/174 (15.5%) participants in the control group. Meta-analysis showed no evidence of a difference when assessing all-cause mortality (RR 1.24, 95% CI 0.80 to 1.92; P = 0.34; I2 = 0%; 358 participants; 5 trials; very low certainty of evidence; Figure 5). Neither visual inspection of the forest plot nor tests for statistical heterogeneity (I2 = 0 %; P = 0.83) showed signs of heterogeneity.
Trial Sequential Analysis showed that we did not have sufficient data to confirm or reject that adding glucocorticosteroids to standard care reduced the risk of death by 20% and that the accrued information was compatible with either a reduced risk of death by 79% or an increased risk of death by 639% (TSA-adjusted CI 0.21 to 7.39) (Figure 6). Bayes factor (4.31) was above the Bayes factor threshold for significance of 0.1. Hence, the result confirmed the meta-analysis result showing no difference. We assessed the risk of bias of this outcome as high risk of bias. There were no missing data, so we did not perform 'best‐worst' and 'worst‐best' case meta‐analyses on this outcome. As we only included five trials, no funnel plot was constructed.
Subgroup analyses
None of the planned subgroup analyses assessing risk of bias, age, type of steroids, and presence of shock showed evidence of a difference (Figure 7-10).
Serious adverse events
A total of 5/9 trials (55.5%), randomizing 358 participants, reported serious adverse events. In the glucocorticosteroid group, 37/184 (20.1%) participants experienced one or more serious adverse events compared with 30/174 (17.2%) participants in the control group. The trials including children with sepsis and mixed focus did not report any neurological events. The majority (80%) of these trials administered hydrocortisone (See Table 2). Meta-analysis showed no evidence of a difference when assessing serious adverse events (RR 1.24, 95% CI 0.82 to 1.87; P = 0.31; I2 = 0%; 358 participants; 5 trials; very low certainty of evidence; Figure 11). Neither visual inspection of the forest plot nor tests for statistical heterogeneity (I2 = 0%; P = 0.96) showed clear signs of heterogeneity. Trial Sequential Analysis showed that we did not have sufficient data to confirm or reject that adding glucocorticosteroids to standard care reduced serious adverse events by 20% and that the accrued information was compatible with either a decrease of serious adverse events by 77% or an increase of serious adverse events by 562% (TSA-adjusted CI 0.23 to 6.62) (Figure 12). Bayes factor (5.20) was above the Bayes factor threshold for significance of 0.1. Hence, the result confirmed the meta-analysis result showing no difference. We assessed the risk of bias of this outcome as high risk of bias. There were no dropouts, so we did not perform 'best‐worst' and 'worst‐best' case meta‐analyses on this outcome. As we only included five trials, no funnel plot was constructed.
Subgroup analyses
None of the planned subgroup analyses assessing risk of bias, age, type of steroids, and presence of shock showed evidence of a difference (Figure 13-16).
Secondary outcomes
Shock reversal
A total of 2/9 (22.2%) trials, randomizing 97 participants, reported shock reversal. In the glucocorticosteroid group 23/48 (47.9%) participants experienced shock reversal compared with 28/49 (57.1%) participants in the control group. Meta-analysis showed no evidence of a difference (RR 0.91, 95% CI 0.52 to 1.59; P = 0.74; I2 = 68%; 97 participants; 2 trials; very low certainty of evidence; Figure 17).
Adverse events
A total of 3/9 trials (33.3%), randomizing 159 participants, reported adverse events. In the glucocorticosteroid group 21/78 (26.9%) participants experienced one or more adverse events compared with 32/81 (39.5%) participants in the control group. Meta-analysis showed no evidence of a difference (RR 0.68, 95% CI 0.45 to 1.04; P = 0.08; I2 = 0%, 159 participants; 3 trials; very low certainty of evidence; Figure 18).
No trials assessed quality of life, organ failure, or ototoxicity. Hence, no meta-analysis was performed.
Dexamethasone for meningitis
Primary outcomes
All-cause mortality
A total of 14/14 trials (100%), randomizing 2449 participants, reported all-cause mortality. In the dexamethasone group, 193/1243 (15.5%) participants died compared with 191/1206 (15.8%) participants in the control group. Meta-analysis showed no evidence of a difference when assessing all-cause mortality (RR 0.97, 95% CI 0.78 to 1.21; P = 0.77; I2 = 7%; 2449 participants; 14 trials; low certainty of evidence; Figure 19). Neither visual inspection of the forest plot nor tests for statistical heterogeneity (I2 = 0 %; P = 0.58) showed signs of heterogeneity. Trial Sequential Analysis showed that we had did not have sufficient data to confirm or reject that adding glucocorticosteroids to standard care reduced the risk of death by 20% and that the accrued information was compatible with either a reduced risk of death by 41% or an increased risk of death by 58% (TSA-adjusted CI 0.59 to 1.58) (Figure 20). Bayes factor (4.23) was above the Bayes factor threshold for significance of 0.1. Hence, the Bayes factor result confirmed the meta-analysis result showing no difference. We assessed the risk of bias of this outcome as high risk of bias. The 'best‐worst' and 'worst‐best' case meta‐analyses showed that incomplete outcome data bias did not have the potential to influence the results (Figure 21 and Figure 22). Visual inspection of the funnel plots showed no clear signs of asymmetry (Figure 23).
Subgroup analyses
None of the planned subgroup analyses assessing risk of bias, age, and dose showed evidence of a difference (Figure 24-26).
Serious adverse events
A total of 14/14 trials (100%), randomizing 2379 participants, assessed serious adverse events. In the dexamethasone group, 370/1210 (30.6%) participants experienced one or more serious adverse events compared with 435/1169 (37.2%) participants in the control group. The trials primarily reported neurological complications, hearing loss/ ototoxicity, or a combination of both (see Table 1). Meta-analysis showed evidence of a difference when assessing serious adverse events (RR 0.68, 95% CI 0.53 to 0.86; P = 0.001; I2 = 64%; 2379 participants; 14 trials; very low certainty of evidence; Figure 27). There were signs of statistical heterogeneity (I2 = 64%; P = 0.0006), however, visual inspection of the forest plot did not show clear signs of heterogeneity. Trial Sequential Analysis showed that we did not have sufficient data to confirm or reject that adding glucocorticosteroids to standard care reduced serious adverse events by 20% and that the accrued information was compatible with either a decrease of serious adverse events by 75% or an increase of serious adverse events by 80% (TSA-adjusted CI 0.25 to 1.80) (Figure 28). Bayes factor (0.02) was under the Bayes factor threshold for significance of 0.1. Hence, the result confirmed the meta-analysis result suggesting a difference. We assessed the risk of bias of this outcome as high risk of bias. The 'best‐worst' and 'worst‐best' case meta‐analyses showed that incomplete outcome data bias did not have the potential to influence the results (Figure 29 and Figure 30). Visual inspection of the funnel plots showed clear signs of asymmetry (Figure 31) confirmed by Harbord test (P=0.0009).
Subgroup analyses
None of the planned subgroup analyses assessing risk of bias, age, and dose showed evidence of a difference in intervention effects (Figure 32-34).
Secondary outcomes
Hearing loss or ototoxicity
A total of 11/14 (78.6%), randomizing 1825 participants, reported hearing loss or ototoxicity. In the dexamethasone group 130/941 (13.8%) participants experienced ototoxicity compared with 174/884 (19.7%) participants in the control group. Meta-analysis showed evidence of a beneficial effect of adding dexamethasone to standard care (RR 0.63, 95% CI 0.45 to 0.88; P = 0.007; I2 = 44%; 1825 participants; 11 trials; low certainty of evidence; Figure 35). Trial Sequential Analysis showed that we did not have sufficient data to confirm or reject that adding glucocorticosteroids to standard care reduced serious adverse events by 20% and that the accrued information was compatible with either a reduced the risk of ototoxicity by 84% or an increased the risk of ototoxicity by 148% (TSA-adjusted CI 0.16 to 2.48) (Figure 36).
Adverse events
A total of 5/14 trials (35.7%), randomizing 582 participants, reported adverse events. In the dexamethasone group 126/293 (43.0%) participants experienced one or more adverse events compared with 97/289 (33.6%) participants in the control group. Meta-analysis showed no evidence of a difference (RR 1.15, 95% CI 0.76 to 1.75; P = 0.52; I2 = 69%, 582 participants; 5 trials; very low certainty of evidence; Figure 37).
No trials assessed quality of life, organ failure or shock reversal. Hence, no meta-analysis was performed.
Post-hoc analysis of neurological complications
The trials including children with meningitis reported many neurological complications as serious adverse events. We therefore decided to analyze that outcome separately as well.
A total of 12/14 (85.7%) trials, randomizing a total of 1866 participants, assessed neurological complications. In the dexamethasone group 123/950 (12.9%) participants experienced neurological complications compared with 140/916 (15.3%) participants in the control group. Meta-analysis showed no evidence of a difference (RR 0.79, 95% CI 0.58 to 1.05; P = 0.12; I2 = 20%; 1866 participants; 12 trials; low certainty of evidence; Figure 38).