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Professor of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, NC Professor of Anesthesiology, University of California, San Diego, San Diego, CA
To the Editor:
We note with concern, as we have in the past with regard to other agents (1,2), the continuing policy of this journal to publish clinical studies of epidural or intrathecal injection of drugs for which preclinical toxicity studies are lacking or have demonstrated toxicity. The current study (3) involves the epidural injection of S(+)-ketamine in healthy children undergoing inguinal hernia repair. This study was conducted with a double-blind methodology, and the concept of equipoise states that for a double-blind trial to be performed, the investigators must genuinely be uncertain as to which treatment is better. Undertaking such a study presumes a favorable risk-benefit ratio. In the case of healthy children, we must assume a particularly favorable ratio.
What is the risk of epidural injection of S(+)-ketamine? The article provides no citations or discussion regarding preclinical toxicity assessment or regulatory approval of the epidural administration of S(+)-ketamine. It should be noted that some but not all preclinical studies have indicated neurotoxicity as a result of neuraxial ly administered ketamine and other NMDA antagonists (4–9), and one case report (10) demonstrated neurotoxicity in postmortem spinal cord tissue, which is consistent with the neuropathology observed in animals studies. Although not all studies report neurotoxicity as a result of ketamine and some have speculated that the preservative present in some ketamine formulations may be responsible, there clearly is controversy in the preclinical literature as to the safety of this agent for either epidural or intrathecal injection. In general, repeated exposure for 28 days in two species of drug in concentrations or doses far exceeding the clinically anticipated dose is required for regulatory approval in the United States to proceed with clinical trials, and there is no such support in the published literature with regard to ketamine.
To move one step further, what is the risk of epidural injection of S(+)-ketamine combined with clonidine? Again, no citations or discussion is provided in the article. Have the compatibility and stability of such mixtures, even if acutely prepared, been established? Although clonidine lacks neurotoxicity when administered intrathecally alone (11), it does reduce spinal cord blood flow (12), which could potentiate toxicity from other agents. Given the conflicting nature of the neurotoxicity literature with ketamine alone, it seems only prudent to examine the toxicity of this combination before clinical trials.
Risk aside, what is the benefit of epidural injection of S(+)-ketamine, either alone or with clonidine, in these healthy children with minor surgery? Certainly, improved pain relief from lingering caudal analgesia compared with systemic therapy would not be expected to alter mortality in this healthy population, although it might reduce morbidity, such as sedation or nausea from systemic analgesics. The stated advantage is that accidental intravascular injection would not cause cardiovascular or central nervous system complications, as can occur with local anesthetics. Such events are a concern, particularly in anesthetized children. Yet, the incidence of this catastrophe is very small and known, compared with the unknown incidence (if any) of neurotoxicity from these drugs or of nightmares from central nervous system administration of ketamine.
We do not imply that the authors performed an improper study. Their institutional ethics committee approved the study, and informed consent was doubtless obtained. Nevertheless, we find it difficult to imagine the language of such a consent form that would not set off alarm bells, particularly if it included clear language that, in contrast to other therapies (e.g., local anesthetics), the safety of these drugs is completely unknown and that the risks include unanticipated side effects, including permanent paralysis.
Regardless of the nature of these issues, there is another party to this scenario, and that party is this journal. We think—and have previously stated so in letters to the editor (1,2)—that it is the ethical responsibility of the journal (i.e., its editors and referees) to insist on discussion of preclinical toxicity issues for epidural or intrathecal injection of novel drugs (even those with previous exposure in small numbers of humans) before acceptance and publication. This responsibility is not trivial, and its importance arises from the position of authority ascribed to a peer-reviewed paper in an authoritative journal. Reading the bottom line of this paper, one might conclude, as these authors stated, that ". . .(the combination of S(+)-ketamine with clonidine) is a safe and effective alternative to common local anesthetics for caudal blocks in pediatric anesthesia." Yet, in fact, this report establishes nothing of the kind, and such a statement is not supported by this report or any published report of which we are aware. The presence of such an assertion in the present case should be a source of concern to the journal and its editors.
References
Departments of Anesthesiology and Intensive Care Medicine, University of Vienna Medical School, Vienna, Austria
In Response:
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).
References
This article has been cited by other articles:
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  G. Blaise Should we use naloxone epidurally?/Devrait-on utiliser la naloxone dans l'espace peridural ? Can J Anesth, November 1, 2003; 50(9): 875 - 878. [Full Text] [PDF]
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