Analgesic Efficacy of Adjuvant Medications in the Pediatric Caudal Block for Infraumbilical Surgery: A Network Meta-Analysis of Randomized Controlled Trials

Abstract

Various adjuvants are added to local anesthetics in caudal block to improve analgesia. The comparative analgesic effectiveness and relative rankings of these adjuvants are unknown. This network meta-analysis (NMA) sought to evaluate the comparative analgesic efficacy and relative ranking of caudal adjuvants added to local anesthetics (versus local anesthetics alone) in pediatric infra-umbilical surgery. We searched the United States National Library of Medicine database (MEDLINE), PubMed, and Excerpta Medica database (Embase) for randomized controlled trials (RCTs) comparing caudal adjuvants (clonidine, dexmedetomidine, ketamine, magnesium, morphine, fentanyl, tramadol, dexamethasone, and neostigmine) among themselves, or to no adjuvant (control). We performed a frequentist NMA and employed Cochrane's 'Risk of Bias' tool to evaluate study quality. We chose the duration of analgesia (defined as 'the time from caudal injection to the time of rescue analgesia') as our primary outcome. We also assessed the number of analgesic dose administrations and total dose of acetaminophen within 24 h. The duration of analgesia [87 randomized control trials (RCTs), 5285 patients] was most prolonged by neostigmine [mean difference: 513 min, (95% confidence interval, CI: 402, 625)]. Dexmedetomidine reduced the frequency of analgesic dose administrations within 24 h [29 RCTs, 1765 patients; -1.2 dose (95% CI: -1.6, -0.9)] and the total dose of acetaminophen within 24 h [18 RCTs, 1156 patients; -350 mg (95% CI: -467, -232)] the most. Among caudal adjuvants, neostigmine (moderate certainty), tramadol (low certainty), and dexmedetomidine (low certainty) prolonged the duration of analgesia the most. Dexmedetomidine also reduced the analgesic frequency and consumption more than other caudal adjuvants (moderate certainty).

Keywords: adjuvant; caudal; local anesthesia; network meta-analysis; pain; pediatric; post-operative.

Figure 1. PRISMA flow diagram of study inclusion and exclusion.

PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses.

Figure 2. Network geometry for each outcome.

The red circles represent interventions in each network, while a gray line connecting any work interventions represents a trial (or a trial arm in case of multi-arm studies). The total number of comparisons between any two interventions is printed as a number (in blue) on the respective gray line. Each intervention (red-circle) carries a label with its respective caudal adjuvant for each outcome. a. The network for primary outcome 'duration of analgesia' constituted 10 interventions and was assessed in 87 RCTs (n=5285 patients); b. The network for 'number of dose administrations' included eight interventions and was assessed in 29 RCTs (n=1765 patients), and c. The 'total dose of acetaminophen' network constituted ten interventions and was assessed in 18 RCTs (n=1156 patients).

Figure 3. Forest plots included -- a. Duration of analgesia; b. The number of dose administrations; c. The total dose of acetaminophen.

Each forest plot provides network estimates of included caudal adjuvants vs. control. A gray square represents the mean difference, while a black horizontal line represents the confidence interval. A vertical line represents the line of no effect. Units and values and the direction of the result are labeled below the x-axis for the respective outcome.

Figure 4. SUCRA (Surface Under the Cumulative Ranking curve) plots for outcomes -- a. Duration of analgesia; b. The number of dose administrations; c. The total dose of acetaminophen.

The x-axis shows the possible ranks, and the y-axis the ranking probabilities. Each colored line connects the estimated probability of being at a particular rank for a caudal adjuvant. The area under the cumulative rankograms is between 0 and 100%. The larger the SUCRA, the higher the treatment in the hierarchy for an outcome.

Figure 5. Rank heat plot.

Each circle ring represents a different outcome, while each section represents a different treatment or intervention. Each sector is colored according to the ranking of the treatment at the corresponding outcome. The scale consists of the transformation of three colors (red, yellow, and green) and ranges from the lowest to the highest value of the ranking statistic, such as 0%-100% according to the ranking statistics (e.g., Surface Under the Cumulative Ranking curve [SUCRA]) values. The red color corresponds to the smallest ranking statistic value (0%), values near the middle of the scale are yellow, and the green color corresponds to the highest-ranking statistic value (100%). The rank heat plot analysis suggests that dexmedetomidine is the best overall adjuvant for all three outcomes, followed by Tramadol and Neostigmine. Fentanyl was the worst adjuvant.

Figure 6. Comparison specific risk of bias for each outcome: a. duration of analgesia; b. number of dose administrations; and c. total dose of acetaminophen.

Studies at low, unclear, and high risk of bias are depicted in green, yellow, and red color, respectively. Overall bias for each comparison is estimated by the majority rule.

Figure 7. Comparison adjusted funnel plots for each outcome: a. duration of analgesia; b. number of dose administrations; and c. total dose of acetaminophen.

Figure 8. Forest plot showing pairwise analysis for each adjuvant vs. control for the duration of analgesia.

Figure 9. Publication bias assessment for all pairwise comparisons of caudal adjuvants vs. control for the duration of analgesia.

Figure 10. Forest plot showing pairwise analysis for each adjuvant vs. control for the number of dose administrations.

Figure 11. Publication bias assessment for all pairwise comparisons of caudal adjuvants vs. control for the number of dose administrations.

Figure 12. Forest plot showing pairwise analysis for each adjuvant vs. control for the total dose of acetaminophen.

Figure 13. Publication bias assessment for all pairwise comparisons of caudal adjuvants vs. control for the total dose of acetaminophen.