Epidural Ketamine in Healthy Children—What’s the Point?

In criticizing our study (1), Drs. Eisenach and Yaksh raise three main points: 1) that Anesthesia & Analgesia should not publish studies involving epidural or intrathecal injection of drugs for which sufficient preclinical data excluding toxicity is not available, 2) that the epidural injection of S(+)-ketamine in children does not offer a benefit substantial enough to justify its use, and 3) that the risk involved in our regimen, whether by ketamine alone or by its combination with clonidine, is an unknown quantity. Ketamine hasbeen used for neuroaxial anesthesia in children in several studies (2–8). Our own contribution basically was to add a new facet to what we regard as a noncontroversial topic. If the complete absence of neurotoxicity has never positively been established for ketamine, such positive proof has never been furnished for other commonly used local anesthetics either. As a matter of fact, most local anesthetics are known to induce morphological changes in nerve structures (9). As far as ketamine is concerned, a review article by Hodgson et al. published in Anesthesia & Analgesia in 1999 (10) on the neurotoxicity of intrathecally administered drugs persuaded us that a detailed discussion of potential risks is no longer required. Hodgson et al. concluded that “taken together, the rat, rabbit, and primate studies with intrathecal ketamine support its safety if used without a preservative [whereas] the commercially available preparation of ketamine contains an untested preservative (benzethonium chloride) and cannot be recommended for intrathecal use in humans”(10). We disagree with Drs. Eisenach and Yaksh that the six preclinical studies that they cite can be construed as suggesting that epidurally administered ketamine may induce neurotoxicity (11–16). To the contrary, the results of these studies strongly suggest that preservative-free ketamine in clinical doses has no neurotoxic effect: Borgbjerg et al. (11) administered repetitive intrathecal doses of preservative-free ketamine to 14 rabbits, concluding that preservative-free ketamine does not show neurotoxicity. Errando et al. (12) performed a histopathological study of 20 pigs, showing that subarachnoid ketamine without preservative is safe and effective without neurotoxic effects. Kristensen et al. (13) investigated the neuraxial effects of two NMDA receptor antagonists (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid and kynurenic acid) in rats, concluding that chronic intrathecal administration of pharmacologically active doses of these NMDA receptor antagonists did not produce neurotoxic effects in the spinal cord. Of the cited authors, only Brock-Utne et al. (14) and Malinovsky et al. (15) observed neurotoxicity that was potentially linked to ketamine. However, Brock-Utne et al. put their observation into perspective by indicating that the neurotoxicity they had observed in monkeys may well have been due to mechanical trauma during lumbar puncture (14). Malinovsky et al., in their turn, performed a follow-up study in which they demonstrated that the preservative solution chlorobutanol was responsible for the neurotoxicity they had observed in rabbits, whereas isomers of ketamine did not induce any spinal cord lesions (16). In our study, we did justice to this finding by using preservative-free S(+)-ketamine exclusively, administered in a single-shot technique in concentrations of 0.1%. There is no indication anywhere in the literature that this approach carries a risk of neurotoxicity. We also disagree with Drs. Eisenach and Yaksh that the unintentional administration of local anesthetics during caudal injection occurs so rarely as to be negligible. As a matter of fact, Dalens et al. (17) and Fisher et al. (18) reported that this type of accident occurs in up to 5.6% of children subjected to caudal and/or epidural anesthesia. Therefore, if we consider that 1 mg/kg preservative-free S(+)-ketamine is equipotent to 0.25% bupivacaine plus epinephrine 1:200,000 (6), the fact that intravasal S(+)-ketamine, contrary to bupivacaine (19,20), does not cause any serious cardiovascular and CNS complications in children is a major argument in favor of ketamine. Not even administration of an epidural test dose containing epinephrine to detect unintentional intravascular cannula placement could reliably produce hemodynamic responses in children (21). We therefore reaffirm our position that caudally administered preservative-free S(+)-ketamine is a good choice for protecting children against the serious consequences of accidental intravasal administration seen with the use of other local anesthetics, which is not a minor clinical problem (17,18). The risk of neurotoxicity by epidurally administered S(+)-ketamine is at least as thoroughly investigated as that of other local anesthetics. Its safety is supported by a reasonable number of clinical studies that have not shown any side effects whatsoever (1,2–8,22).