Twenty-one potentially relevant articles were identified from 115 citations. Twenty-one studies consisting of 1433 patients (Control group: 590 patients in twenty-one studies; Fentanyl group:199 patients in seven studies11–17; Sufentanil group: 156 patients in five studies18–22; Meperidine group: 488 patients in ten studies15,23–31) contained data regarding the effect of IT opioids on shivering (Flow chart: Figure 1).
Table 1a and 1b summarises the systematic review of the effects of IT fentanyl, sufentanil and meperidine on shivering in women undergoing cesarean delivery. Methodological validity scores determined by modified oxford score ranged from 3 to 7.
Network meta-analysis (NMA)
A total of twenty-one studies and three interventions (fentanyl, sufentanil and meperidine) with four comparison groups were included in the network meta-analysis. Six pairwise comparison and four direct comparisons were done in the network meta-analysis. Table 2 summarises the data on the effect of intrathecal opioids on the incidence of shivering. Out of the twenty-one studies with 1433 patients, 199 patients received the fentanyl,11–17 156 patients received the sufentanil,18–22 488 patients received meperidine15,23–31 and 590 patients in the control group.
Table 2 provides the effect estimates of direct, indirect and mixed network meta-analysis with quality of evidence rating according to the GRADE approach. Figure 2 displays the network diagram comparing the various intrathecal lipophilic opioids to prevent incidence of shivering in women undergoing cesarean delivery. Supplementary file S2 and S3 show the contribution matrix and league table for comparison of all classes of drugs
Fentanyl: Data on the incidence of shivering with IT fentanyl (7 RCTs, n=199 patients) were available in all the studies.11–17 The mixed evidence from the network meta-analysis showed that the incidence of shivering was significantly lower in the IT fentanyl group compared to the control group [IT Fentanyl vs. Control group: 22.11% vs. 51.94%; Pooled Odds Ratio (OR): 0.13; 95% Credible Interval (CrI): 0.04 to 0.35; P = 0.0004]. The funnel plot and influential analysis on the direct data identified Sadegh et al.2003 as the outlier and contributed the maximum heterogeneity to the end estimate. When this study was excluded and summary estimates were recalculated, the end estimate increased to 0.51(0.36 to 0.71); P<0.0001 and heterogeneity decreased to zero (not shown in the figure). The Begg’s test (P=0.089) and Egger regression test (P=0.2077) did not show any evidence of publication bias. Fail safe N test showed 113 studies required to increase the p value to more than alpha (>0.05), indicating the absence of the publication bias (not shown in the figure). Fentanyl was administered in the dose range of 7.5 to 25 microgram and there was no difference in the outcomes across this dose range (Coefficient -0.043; 95% CI: -0.0963 to 0.0103; P = 0.1139).
Sufentanil: Data on the incidence of shivering with IT sufentanil (5 RCTs, n=156 patients) were available in all the studies.18–22 The mixed evidence from the network meta-analysis showed that the incidence of the shivering was not significantly lower with the IT sufentanil when compared to the control group. (IT Sufentanil vs. Control group: 23.71% vs. 45.28%; OR: 0.37; 95% CrI: 0.11 to 1.22; P = 0.23). Metaregression analysis based on the IT sufentanil dose, did not change the final inference of the result (Coefficient 0.0919; 95% CI: -0.2495 to 0.4333; P = 0.5977)
Meperidine: Data on the incidence of shivering with IT meperidine were available in all the 10 studies. 15,23–31 The mixed evidence from the network meta-analysis showed that the incidence of shivering was lower in the meperidine group compared to the control group (IT Meperidine vs. Control group: 15% vs. 44.2%; OR: 0.12; 95% CrI: 0.05 to 0.29; P < 0.00001). for the direct data, the Begg’s test (P = 0.7544) and Egger regression test (P=0.1628) did not show any evidence of publication bias. Fail safe N test showed 85 studies required to increase the p value to more than alpha (>0.05), indicating the absence of the publication bias. Meperidine was used in the dose range of 5-35 mg and there was no difference in the outcomes across this dose range (Coefficient -0.0215; 95% CI: -0.0649 to 0.0219; P=0.3314). Metaregression and sensitivity analysis based on the quality of the study for the various subgroups slightly changed the end estimate, but did not change the final inference of our results (Table 3).
Side effects:
IT Fentanyl: The IT fentanyl group had a significantly lower incidence of intraoperative discomfort (IT fentanyl group vs. Control group: 6.89% vs. 34%; RR: 0.19; 95% CI: 0.10-0.35; P < 0.00001), but there was no significant difference in other maternal adverse events like pruritus (IT fentanyl group: 38.14% vs. 18.79%; RR: 2.03; 95% CI: 0.82-5.05; P = 0.13), nausea and vomiting (IT fentanyl group vs. Control group: 39.10% vs. 58.20%; RR: 0.66; 95% CI: 0.42-1.05; P = 0.08) and hypotension (IT fentanyl group: 43.57% vs. 54.47%; RR: 0.93; 95% CI: 0.78-1.12; P = 0.45) compared to the control group.
IT Sufentanil: The IT sufentanil group had a significantly higher incidence of pruritus (IT sufentanil vs. Control group: 20.87% vs. 2.12%; RR: 6.18; 95% CI: 1.18-32.46; P = 0.03), but there was no significant difference in other maternal adverse events like hypotension (IT sufentanil vs. Control group: 40.51% vs. 55.46%; RR: 0.74; 95% CI: 0.37-1.47; P = 0.39), nausea and vomiting (IT sufentanil group vs. Control group: 28.44% vs. 35.29%; RR: 0.83; 95% CI: 0.53-1.29; P = 0.40). IT sufentanil did not significantly decrease the intraoperative discomfort compared to the control group (IT sufentanil group vs. Control group: 36.84% vs. 59.09%; RR: 0.62; 95% CI: 0.31-1.24; P = 0.18).
IT Meperidine: The IT Meperidine group had significantly lower incidence of intraoperative discomfort (IT meperidine group vs. Control group: 2.7% vs. 13.6%; RR: 0.22; 95% CI: 0.09-0.55; P = 0.001) compared to the control group. There was a significant increase in nausea and vomiting (IT meperidine group vs. Control group: 42.7% vs. 19.4%; RR: 2.56; 95% CI: 1.14-5.75; P = 0.02), but there was no significant difference in other maternal adverse events like hypotension (IT meperidine group vs. Control group: 46.9% vs. 41.8%; RR: 0.96; 95% CI: 0.67-1.37; P = 0.82) and pruritus (IT meperidine group vs. Control group: 18.9% vs. 6%; RR: 0.63; 95% CI: 0.82-3.24; P = 0.17) between the two groups.
Quality of the evidence in network estimates:
Supplementary file S4 and S5 shows the rankogram and various domains examined to assess the quality of evidence in the network meta-analysis. Most of the included studies in the network meta-analysis were randomized double blind controlled studies with no, or some concerns in the study limitation. To assess the imprecision, effect estimates of the relative treatments lower than 0.95 and greater than 1.05 were considered to be clinically significant. The data were collected from different studies, across different countries, at varying time intervals and the network model showed some degree of incoherence (c2 statistics: 0.336; d(f): 2; p value: 0.846). The estimated value of between-study variance for the network meta-analysis is 0.412 indicating some heterogeneity and consistency in the network model. Overall, some of the comparisons were rated down for imprecision, heterogeneity and incoherence (inconsistency), thus the quality of the evidence for the effect estimates was low according to the GRADE approach.