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Department of Anesthesia and Perioperative Care, San Francisco General Hospital, San Francisco, California
Address correspondence and reprint requests to Kenneth Drasner, MD, Department of Anesthesia and Perioperative Care, San Francisco General Hospital, Room 3C-38, San Francisco, CA 94110. Address e-mail to kdrasner{at}anesthesia.ucsf.edu.
A decade ago, reports of neurologic deficits associated with spinally administered lidocaine generated concern regarding the potential toxicity of this anesthetic (1–3). Adding to this concern has been the recognition that transient neurologic symptoms (TNS), i.e., pain and/or dysesthesia in the buttocks and lower extremities, frequently follow spinal administration of lidocaine (4–7). The etiology and significance of these transient symptoms are unknown and a relationship to rare but more serious complications such as cauda equina syndrome remains highly speculative. Nonetheless, their common occurrence has heightened dissatisfaction with lidocaine and has generated interest in alternative anesthetics for spinal anesthesia. Where appropriate, most clinicians have substituted bupivacaine, a rational decision based on its infrequent incidence of TNS (5–7), experimental data indicating less toxicity (8), and the suggestion of less risk of clinical injury (2,3). However, identification of an alternative to lidocaine suitable for short surgical procedures has been more problematic. Although there are reports describing the use of small-dose bupivacaine combined with fentanyl (9), many practitioners report frequent failure with this technique, and complete recovery may still be delayed. Of other available options, neither procaine (10) nor mepivacaine (11) appears to offer a substantial advantage with respect to TNS. Although prilocaine may have promise—limited data suggest a less frequent, although perhaps not insignificant, incidence of TNS (12,13)—there is no formulation in the United States appropriate for intrathecal administration. Despite a rather blemished past, considerable attention is now focused on the possibility of using chloroprocaine to fill this anesthetic void.
Introduced into clinical practice more than 50 years ago, chloroprocaine quickly gained widespread popularity as an epidural drug, particularly in obstetrics, where its rapid hydrolysis by pseudocholinesterase virtually eliminated concern for systemic toxicity and fetal exposure. In 1952, shortly after it became available for clinical anesthesia, Foldes and McNall (14) reported a series of 214 cases in which chloroprocaine was used intrathecally for surgical anesthesia. Adequate block was achieved with doses ranging from 82.5 to 100 mg, and the duration of sensory anesthesia (defined as regression of pinprick anesthesia to the inguinal fold) was relatively brief: 82 ± 2.8 min with plain chloroprocaine and 121 ± 3.0 min with an epinephrine-containing solution. Despite these data and the lack of apparent adverse effects, chloroprocaine never evolved as a spinal anesthetic, perhaps because of the development and marketing of the amide lidocaine. In any case, reports in the early 1980s of neurologic deficits associated with possible intrathecal injection of epidural chloroprocaine raised concern regarding the potential neurotoxicity of this anesthetic (15–17), which, until recently, would have subdued any enthusiasm for deliberate intrathecal administration.
In this issue of Anesthesia & Analgesia, four articles now reexplore the use of spinal chloroprocaine: three report data from volunteer studies that examined the effect of adding clonidine (18) and compared chloroprocaine with small-dose bupivacaine (19) and with procaine (20), and the remaining article contains a retrospective review of a clinical experience encompassing 122 patients over 10 months (21). These reports are a logical extension of work by this group which was previously published in a volley of five articles in this journal (22–25). Taken together, the data and clinical experience reinforce and greatly extend the findings of Foldes and McNall (14) suggesting that chloroprocaine can produce effective spinal anesthesia with little, if any, risk of TNS (18–25). The duration of effect was shorter with chloroprocaine than with an equal dose of lidocaine (22), and institutional discharge criteria were achieved more rapidly with chloroprocaine than with lidocaine (22), procaine (20), or small-dose bupivacaine (19). As expected, anesthesia could be prolonged or enhanced by the coadministration of fentanyl (24), epinephrine (23), or clonidine (18). Somewhat surprisingly, reliable anesthesia could be achieved with doses of chloroprocaine as small as 30 to 40 mg (21), and the duration of anesthesia with a 60-mg dose was longer than that reported by Foldes and McNall despite the use of larger doses (82.5–100 mg) by these earlier investigators (14,23). Another unexpected, and potentially important, finding is the occurrence of "flu-like" symptoms in volunteers receiving chloroprocaine containing epinephrine (23), the implications of which we will return to shortly.
It is a bit ironic—to say the least—that chloroprocaine, the one-time poster child for anesthetic neurotoxicity, is now a candidate to replace lidocaine, an anesthetic that stood as the "gold standard" of safety for half a century over the course of 75 million spinal anesthetics. To understand the rationale for using chloroprocaine requires an appreciation of the nature of the early clinical injuries and the experimental investigations that have sought to understand their etiology.
As noted earlier, concern for neurotoxicity emerged two decades ago with a series of eight cases of neurologic injury associated with the use of Nesacaine-CE, a chloroprocaine solution containing the antioxidant sodium bisulfite (15–17). Review of these cases suggested that injury resulted because large volumes of anesthetic solution intended for the epidural space were inadvertently administered intrathecally, and this analysis inspired a number of studies directed at the relative toxicity of chloroprocaine and bisulfite. Of these, the most widely recognized were experiments conducted by Gissen et al. (26,27) in which exposure of isolated rabbit vagus nerve to the commercial solution of 3% chloroprocaine (containing 0.2% sodium bisulfite, pH 3) produced irreversible block, but exposure to the same solution buffered to pH 7.3 resulted in complete recovery. Additional experiments in this model demonstrated irreversible block with exposure to bisulfite without chloroprocaine, but only at a low pH, leading these investigators to suggest that liberation of sulfur dioxide was the etiology of injury.
On the basis of the foregoing material, the following considerations might lend support to clinical investigation of spinal chloroprocaine: 1) dosages used for spinal anesthesia are an order of magnitude lower than those used for epidural anesthesia; 2) there were no reported adverse neurologic effects in Foldes and McNall’s series of 214 chloroprocaine spinal anesthetics; and 3) bisulfite-free formulations of chloroprocaine are currently available. Unfortunately, the matter is a bit more complicated. First, although it has been assumed that injuries associated with chloroprocaine were the result of intrathecal injection of doses intended for the epidural space, not all of the reported cases contained strong evidence for inadvertent intrathecal injection (15–17). Second, although chloroprocaine was used for spinal anesthesia in more than 200 patients without neurologic sequelae in the 1950s (14), the early literature is replete with examples of apparently safe techniques that later proved to be otherwise. Finally, although data from several studies (28–31) supported Gissen et al.’s findings, data from others sharply conflicted (32–34). Moreover, recent in vivo data (published after the current volunteer studies were completed) not only conflict with Gissen et al.’s findings but, surprisingly, also suggest that bisulfite might be neuroprotective (35). Although it is not clear what accounts for such divergent findings, differences in the relative dosing of chloroprocaine and bisulfite and the susceptibility of the various model systems to sulfur dioxide are likely critical factors. The latter may arise from a disparity in levels or the activity of sulfite oxidase, the protective enzyme that catalyzes oxidation of sulfites to less toxic sulfates (36).
Despite the importance and relevance of the data, reviewer opinion was mixed regarding publication of the present clinical studies because of issues of process and consent. Some questioned whether the preclinical data and the historical information provided adequate support of chloroprocaine’s safety to justify clinical investigations and expressed concern that studies were initiated without resolution of the conflicting experimental toxicity data. Further, statements in the present publication and prior publications raised concern that uncertainties regarding the etiology of prior injuries might not have been adequately conveyed in the consent process. An additional issue of concern was the routine use of spinal chloroprocaine at the authors’ institution, which began in September 2002 (21). At that time, their experience with spinal chloroprocaine was apparently limited to a few dozen spinal anesthetics performed in volunteers (21)—a number barely sufficient to draw conclusions about a minor common problem like TNS and clearly inadequate to make meaningful statements regarding an acceptable incidence of rare major complications such as neurologic injury (e.g., a series of 3000 patients would be required to rule out an incidence of more than 1 in 1000 cases with a 95% confidence interval) (37). In the presentation of the data from their initial volunteer studies, the authors themselves comment on the limited number of subjects who received spinal chloroprocaine and the need for further study to establish safety (22–25).
It is noteworthy that publication of the current articles follows on the heels of similar controversy regarding studies investigating intrathecal administration of midazolam. In one of the two accompanying editorials, Cousins and Miller (38) comment on the need to ensure a logical development of candidates for intrathecal drug delivery and state that publication of the material was not meant to condone the process by which it occurred. It is hoped that publication of the present material will serve to foster discussion rather than decrease the preclinical threshold for human trials of intrathecal drugs.
The issues surrounding the use of spinal chloroprocaine highlight substantial gaps in current knowledge and underscore the need for additional research regarding the toxicity of the anesthetics and bisulfite, the implications of which go well beyond the use of spinal chloroprocaine. This objective will require a better understanding of the strengths, limitations, and unique characteristics of the various experimental models, including species-dependent factors that may account for divergent findings. The current observation that epinephrine-containing solutions were associated with significant systemic side effects is puzzling and of considerable interest (23). The authors hypothesize that this might reflect a chemical meningitis induced by the combination of the low pH and the small amount of bisulfite present in the epinephrine solution. This cannot be ruled out and, if correct, would indicate a remarkable sensitivity—the amount of bisulfite that was administered is one tenth of that contained in just 1 mL of the current Abbott formulation of epidural chloroprocaine (Abbott Laboratories, North Chicago, IL). Such sensitivity would imply a risk of injury should even small or modest volumes of this anesthetic solution reach the subarachnoid space. Although this issue remains to be settled, there is little doubt that large doses of subarachnoid chloroprocaine (such as that achieved with inadvertent injection of a "full" epidural dose) can induce permanent neurotoxic injury. However, this toxicity is not unique to chloroprocaine. It has occurred clinically with lidocaine (39) and it is likely to occur with any of the currently available local anesthetics.
Although the process by which these studies were conducted will no doubt be the subject of much debate, the availability of the present data now place us beyond this issue. Although experience with bisulfite-free chloroprocaine as a spinal anesthetic remains limited, the rigorous systematic investigations of Kopacz et al. have gone far toward defining the characteristics of a drug that appears particularly well suited for outpatient spinal anesthesia. While there are many, myself included, who see the need for additional data collected under the umbrella of institutional approval and written informed consent, the safety profile of spinal chloroprocaine will likely be defined by off-label use in clinical practice. In any event, after 50 years on the bench, chloroprocaine may soon have an important position in clinical anesthesia as an intrathecal drug. Perhaps Yogi Berra wasn’t quite right when he lamented that "the future ain’t what it used to be."
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This article has been cited by other articles:
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  S. Evron, V. Gurstieva, T. Ezri, V. Gladkov, S. Shopin, A. Herman, A. Sidi, and S. Weitzman Transient Neurological Symptoms After Isobaric Subarachnoid Anesthesia with 2% Lidocaine: The Impact of Needle Type Anesth. Analg., November 1, 2007; 105(5): 1494 - 1499. [Abstract] [Full Text] [PDF]
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A. Casati, G. Danelli, M. Berti, A. Fioro, A. Fanelli, C. Benassi, G. Petronella, and G. Fanelli Intrathecal 2-chloroprocaine for lower limb outpatient surgery: a prospective, randomized, double-blind, clinical evaluation. Anesth. Analg., July 1, 2006; 103(1): 234 - 238. [Abstract] [Full Text] [PDF]
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P. J. Balestrieri Epidural Chloroprocaine-Standard of Care for Postpartum Bilateral Tubal Ligation Anesth. Analg., October 1, 2005; 101(4): 1241 - 1241. [Full Text] [PDF]
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