Single-shot caudal anesthesia is an established method of providing perioperative analgesia that is commonly performed in children undergoing penile surgery or inguinal hernia repair. There are several different local anesthetic agents available for this regional block. Bupivacaine, levobupivacaine, and ropivacaine are the long-acting agents most commonly encountered. All three agents have been used successfully for pediatric caudal anesthesia, but there may be some differences in their relative potency, efficacy, side effects, and toxicity. In this evidence-based clinical update, structured evidence-based methodology is used to compare the relative efficacy (onset time, quality of intraoperative analgesia, and duration of postoperative analgesia), side effects (including motor block), and toxicity (cardiac or neurological) of these three agents. It is important to appreciate the relative potency of bupivacaine, levobupivacaine, and ropivacaine in order to make a fair comparison of these three agents.

To provide an effective caudal block in children, local anesthetic agents must often be given at doses and volumes that approach the maximum recommended to avoid toxicity. Consequently, the balance between effectiveness, side effects, and toxicity becomes crucial when selecting one of these agents. After considering the findings of this review, anesthesiologists might be better able to make an informed decision regarding choice of local anesthetic for single-shot pediatric caudal anesthesia.

Clinical question

You are asked to provide anesthesia for a healthy three-year-old boy requiring bilateral inguinal hernia repair. You plan general anesthesia (sevoflurane, laryngeal mask), supplemented by a single-shot caudal block. You have three long-acting local anesthetics from which to choose, i.e., bupivacaine, levobupivacaine, or ropivacaine. You question which drug will provide optimal efficacy with the lowest incidence of side effects and toxicity.

Methods

A structured electronic literature search was conducted, using both PubMed and Medline (OVID). Search terms included “caudal” and combinations of at least two of “bupivacaine”, “ropivacaine”, and “levobupivacaine” (four separate searches). Search limits included “human” and “all child: 0-18 yr”. In the case of PubMed, publication limits were defined as “randomized controlled trials” (RCTs), “meta-analysis”, or “reviews”. With Medline (OVID), the publication limits were defined as “randomized controlled trials”, “evidence-based reviews”, or “reviews”. No limit was placed on publication date; the searches were completed in August 2010. A total of 28 references were obtained, and the abstracts were reviewed by two of the authors (E.F.A.M. and R.G.C.). Studies were identified that fit the criterion of a randomized controlled trial of at least two of the three local anesthetic agents when used for single-shot caudal anesthesia in children. Seventeen such RCTs were reviewed in detail using a structured methodology.1–17 Two review articles were also identified.18,19 The reference lists for all of these 19 publications were reviewed to identify any further RCTs that may have been missed with the initial search strategy; no such study was found. One meta-analysis was found using these search limits, but it did not specifically address single-shot caudal anesthesia in children. A separate search of the Cochrane Library did not identify any reviews that addressed our clinical question.

Each RCT was graded independently for quality using the Jadad score20 and Centre for Evidence-Based Medicine (CEBM)21 criteria (Appendices 1 and 2). The Jadad score only evaluates randomization, blinding, and handling of withdrawals. Scoring was performed independently by three experienced pediatric anesthesiologists (R.G.C., D.R.L., and A.E.). These reviewers not only took the Jadad score into account but they also used criteria such as allocation concealment, appropriateness of the statistical tests used, confidence intervals, quality of the sample size calculation, standardization of anesthetic technique, and validity of the pain score (if used). The three reviewers discussed any disagreement between the Jadad and CEBM scores and arrived at a consensus score. The papers were reviewed further by all of the authors, and data for anesthesia outcomes were extracted in the following domains:

  1. 1.

    Relative efficacy

    1. a)

      Onset time

    2. b)

      Intraoperative quality

    3. c)

      Duration of postoperative analgesia

  2. 2.

    Side effects

    1. a)

      Motor block

    2. b)

      Others

Characteristics of study design were documented, including the concentration and dose of drugs used, the number of subjects, age ranges, and surgical procedures performed. Finally, a review of the evidence was undertaken for the outcomes of interest, taking into account the quality of the studies involved. Recommendations were then made according to CEBM criteria (Appendix 2).

Comment on relative potency

Evaluating the efficacy and side effects of the local anesthetic agents must be viewed in the context of their relative potency. There is some uncertainty about the relative potency of these three drugs when used for single-shot pediatric caudal anesthesia. In labour, there appears to be a potency hierarchy of bupivacaine > levobupivacaine > ropivacaine, both with intrathecal22 and epidural23,24 administration. With neonatal spinal anesthesia, bupivacaine appears more potent than ropivacaine or levobupivacaine, but the difference is less marked at the effective dose (ED)95 than at the ED50.25 In the case of pediatric caudal anesthesia, levobupivacaine and ropivacaine have been shown to have a similar potency.26 The conclusion of an excellent review by Casati pointed to slight differences in anesthetic potency among the three agents, with bupivacaine > levobupivacaine > ropivacaine.27 This would give bupivacaine a slight advantage in terms of efficacy, if comparing identical doses of these drugs. Eleven of the studies in this review compared only identical concentrations and doses of the drugs (Table 1). The other six studies either included different concentrations or involved more than one concentration of the same drug. Overall, it appears that most of the studies (with two notable exceptions) included in this evidence-based clinical update compared “nearly” equipotent doses of the drugs.5,17 This then represents a slight weakness in the methodology of most of the studies reviewed.

Table 1 Summary of study characteristics
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Review of current best evidence

The characteristics of the 17 RCTs reviewed are summarized in Table 1. Of note, only four of these studies were found to be of high quality (CEBM 1b), and only three had a Jadad Score of 5/5 (Table 2). Several studies had small sample sizes, and sample size calculations were not performed in all cases. Only four studies compared all three drugs. Fifteen studies evaluated bupivacaine, seven evaluated levobupivacaine, and sixteen evaluated ropivacaine; this may reflect the fact that levobupivacaine is less widely available than the other two drugs. Although most comparisons involved “nearly” equipotent doses of the agents, some studies included a group with an unusually low concentration (e.g., 0.1% ropivacaine)5 or an unusually high concentration (e.g., 0.5% ropivacaine)17 of drug. Most studies included a pain score in the postoperative period as an outcome finding and/or as a trigger for the administration of rescue analgesia. Remarkably, there were ten different scores used in this series (Appendix 3), mostly objective/behavioural, which raises questions as to the comparability of pain data among the studies.

Table 2 Principal findings of studies reviewed
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The principal findings of the 17 studies are summarized in Table 2, together with their Jadad Scores and CEBM ratings. The findings are discussed in relation to relative efficacy and side effects.

Relative efficacy

In nine studies that examined onset time to surgical anesthesia, seven showed no difference among the three agents. One study1 showed that levobupivacaine had a slower onset time compared with bupivacaine or ropivacaine; however, the difference was not clinically important. Another study13 showed that bupivacaine had a slower onset time compared with ropivacaine, but again, the difference was not clinically important.

Fourteen studies evaluated the quality of intraoperative anesthesia. Five of these studies based the assessment on the need for additional analgesia, typically fentanyl. One of these studies11 showed a difference in the need for intraoperative fentanyl, with ropivacaine requiring more intraoperative analgesia than either of the other agents. Another study5 showed that ropivacaine was associated with more intraoperative fentanyl requirement, but only with a 0.1% concentration. In four studies, intraoperative analgesia was evaluated by hemodynamic measures, and none of these showed a difference among the agents. Seven studies made general statements as to intraoperative efficacy, such as “all blocks were clinically successful”; no difference among the agents was identified in these qualitative assessments. In summary, only one study suggested a difference in intraoperative quality,11 with the other thirteen studies showing no difference among the three drugs.

Duration of postoperative analgesia was evaluated in all 17 studies. Thirteen studies showed no difference in the duration; four studies showed a difference. Of these four, the first study2 showed a longer duration of analgesia with bupivacaine compared with levobupivacaine or ropivacaine, as judged by Children’s and Infant’s Postoperative Pain Scale score and the need for analgesia. Somewhat predictably, the second study5 showed a shorter duration of postoperative analgesia with 0.1% ropivacaine compared with 0.2% ropivacaine or bupivacaine. A third study comparing bupivacaine with ropivacaine showed a longer duration with ropivacaine, evidenced by the need for, and time of, first analgesia.13 Unsurprisingly, a fourth study showed that 0.5% ropivacaine had a longer duration than 0.25% ropivacaine or bupivacaine.17 In essence, only two studies showed a difference in duration when “nearly” equipotent doses of drug were used; one showed a longer duration with bupivacaine,2 and one showed a longer duration with ropivacaine.13

Side effects

Motor block was evaluated in 16 of the studies. Eight studies showed no difference in motor block. Two of the other eight studies showed that bupivacaine caused more motor block than levobupivacaine or ropivacaine,1,2 and four showed that bupivacaine caused more motor block than ropivacaine.4,5,7,9 Two studies showed motor block in only one subject, one with 0.2% bupivacaine16 and one with 0.5% ropivacaine.17 It would appear from these data that bupivacaine has a greater tendency to cause motor block than ropivacaine, and levobupivacaine lies somewhere between the two in this regard. In general, when motor block did occur, it tended to be short-lived and not associated with complete paralysis.

Adverse events or complications were reported in 16 studies; however, there were no serious adverse events reported (e.g., cardiac or neurological toxicity) in any subject studied. Postoperative nausea and vomiting was reported in four studies; no difference was shown among the agents. Six studies reported specifically on hemodynamic changes, with four subjects overall showing self-limited sinus bradycardia, two with bupivacaine2,11 and one each with levobupivacaine11 and ropivacaine.11 Seven studies reported in general terms only, such as “no apparent side effects”.

Given the very low incidence of serious toxicity associated with single-shot caudal anesthesia in children, it is not surprising that none of these relatively small human studies demonstrated a difference among the three agents in terms of cardiac or neurologic toxicity. Animal research does exist, however, that points to a safer profile of ropivacaine and levobupivacaine compared with bupivacaine.28,29

Conclusions

There is no evidence to suggest that any one of bupivacaine, levobupivacaine, or ropivacaine is preferable over the other(s) in terms of clinical efficacy when used for single-shot caudal anesthesia in children. Adverse events appear to be rare, minor in nature, and comparable in incidence among the three agents. Bupivacaine may be the drug of choice if motor block is desired; when motor block is to be minimized, ropivacaine may be the preferred option. The theoretical increased safety profile of levobupivacaine and ropivacaine, evidenced by animal studies, may be a consideration when selecting a local anesthetic agent. It is important to note that the studies included in this review did not address additives (e.g., ketamine, clonidine, or opiates), caudal anesthesia in the neonate, continuous epidural infusions, or other forms of nerve block.

Recommendations

  1. 1.

    The choice of a long-acting local anesthetic for single-shot pediatric anesthesia in children includes bupivacaine, levobupivacaine, and ropivacaine, with no agent being clearly superior in terms of efficacy or side effects. (Grade B recommendation);

  2. 2.

    Bupivacaine is preferred if motor block is desirable; ropivacaine if motor block is to be minimized. (Grade B recommendation);

  3. 3.

    Levobupivacaine and ropivacaine show less toxicity in animal studies compared with bupivacaine. This finding might be considered when making the choice of agent. (Grade D recommendation).