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University of Basel School of Medicine, Basel, Switzerland, and St. Luke’s-Roosevelt Hospital Center, College of Physicians and Surgeons of Columbia University, New York, New York
Address all correspondence to David J. Birnbach, MD, Department of Anesthesiology, St. Luke’s Roosevelt Hospital Center, 1000 Tenth Avenue, New York, NY 10019.
In the early 1990s, reports of cauda equina syndrome (CES) after continuous spinal anesthesia (CSA) surfaced (1,2) and startled a medical community that had become complacent about local anesthetic neurotoxicity. The safety of drugs used for spinal anesthesia has been debated since August Bier pioneered it in 1898. Originally, these emotional and polarized disagreements about the existence of neurotoxicity centered on permanent neurologic sequelae associated with the intrathecal administration of local anesthetics. Subsequently, the controversy extended to include both permanent and temporary sequelae as well as adverse outcomes observed after intrathecal administration of other drugs. Twenty years ago, the role of the dura mater as a protective barrier against neurologic injury was emphasized (3). Twelve years later, CES was reported after a large intrathecal dose of 2% lidocaine that was intended for epidural anesthesia (4). Is there is any evidence of a common denominator?
Neurotoxicity of local anesthetics per se "although largely ignored by clinicians, is not new" (5). Laboratory evidence suggests that local anesthetic neurotoxicity is, at least partially, dose- and concentration-dependent (6). With specific regard to lidocaine neurotoxicity, an irreversible block of impulse conduction was induced in the frog sciatic nerve within a clinical concentration range of 1% to 2% lidocaine (7). Similarly, exposure to solutions of 5% lidocaine caused an irreversible loss of electrical activity that was not a result of residual local anesthetic activity (8). More recently, direct neurotoxic effects on single crayfish giant axons were induced by lidocaine within the 1% to 2% concentration range (9). In addition, lidocaine-induced neuronal cell death was observed after a short exposure of isolated rat dorsal root ganglion cells to a 30 mM (approximately 1%) lidocaine solution (10).
Animal studies support the concept of concentration- and dose-dependence of local anesthetic neurotoxicity. In rats, increasing doses of intrathecal 5% hyperbaric lidocaine resulted in persistent sacral sensory deficits associated with motor weakness (11). Even when fixed doses of lidocaine were used, the 5% or 2.5% solution caused more severe spinal nerve root damage than the 1.25% solution (12).
It was probably not a coincidence that the reports of persistent neurologic deficits clustered shortly after the introduction of a new generation of fine-bore spinal catheters. CSA provided the advantage of a renewable block and also permitted unrestrained drug redosing. The repeated administration of large doses of lidocaine in a short period now appears ill considered. At the time, however, the practice was not questioned because there was no evidence for lidocaine-induced neurotoxicity. Only later was pooling of hyperbaric solutions demonstrated in a variety of spinal models, which provided evidence that maldistribution might be a key factor in jeopardizing the integrity of the spinal nerve roots of the cauda equina (13). Despite such complex and ambiguous information, acting to protect patients from what they considered a real risk, the Food and Drug Administration (FDA) issued a safety alert and withdrew spinal microcatheters from the United States market. This occurred despite the fact that there was no evidence to prove that large-bore catheters were not also capable of producing CES. In fact, one of the CES cases that precipitated the FDA decision occurred after CSA using a 20-gauge spinal "macro" catheter and 1% hyperbaric tetracaine (1). In retrospect, withdrawing these catheters may have been premature and may have even helped to foster complacency about lidocaine-induced neurotoxicity. After all, if the FDA suggested that spinal microcatheters were the culprit, the local anesthetic administered through those catheters must have been innocent. Did all cases of lidocaine-induced neurotoxicity disappear after removal of the spinal microcatheters? No. In fact, several reports of CES were observed after uneventful single-injection spinal anesthesia using 5% hyperbaric lidocaine within the recommended dose range (14–16). In the absence of other causes, the weight of the evidence points to local anesthetic neurotoxicity as the most likely, albeit not conclusive, etiology of injury in those cases (17).
As discussed above, permanent neurologic sequelae after spinal anesthesia is a serious and well-defined problem. The two studies reported in this issue (18,19), however, refer not to that problem but to transient neurologic symptoms (TNS), a somewhat less severe and far more frequent side effect of spinal anesthesia. This syndrome is characterized by short-lived painful sensations in the buttocks or lower extremities after full recovery from uneventful single-shot spinal anesthesia (20). Previously, the syndrome was known as transient radicular irritation, but because the etiology is still unclear, this label has been abandoned (21). Since the first report in 1993 (22), numerous similar cases have been published, with the vast majority occurring after the administration of hyperbaric lidocaine for spinal anesthesia (23). The risk of TNS was not eliminated by a reduction of lidocaine concentration from 5% to 2% and even as small as 0.5% (24,25). Moreover, neither the concentration of glucose (21,26) nor the osmolarity of the local anesthetic solution (21) affected the incidence of TNS. According to randomized and nonrandomized studies, the risk of TNS associated with bupivacaine (20,26–30), tetracaine (30,31), mepivacaine (27,32), prilocaine (33–35), or procaine (36) was significantly less than with lidocaine.
With the exception of two reports of TNS that occurred after the administration of hyperbaric 5% lidocaine in pregnant patients undergoing cervical cerclage (37) and a single nonrandomized prospective study consisting of only a small number of obstetric patients receiving lidocaine for various surgical procedures (38), data on lidocaine neurotoxicity in obstetric patients are lacking. Therefore, the studies by Philip et al. (18) and Aouad et al. (19) commendably increase our knowledge of this subject. That said, there is some cause for concern that anesthesiologists will interpret these two studies as justification for routine use of 5% hyperbaric spinal lidocaine in obstetrics. Can we conclude from these two studies that spinal lidocaine is safe for use in the obstetric population? The question is not easily answered, and as recently suggested in this journal "the higher the risk, the greater must be the benefit." Are there appreciable benefits for spinal lidocaine in obstetrics? The findings of the Aouad article suggest that bupivacaine is the better spinal drug for cesarean delivery. It gives a more dependable block of optimal duration and is associated with fewer complications. The question of which spinal anesthetic to administer for very short obstetric procedures such as cerclage or tubal ligation, however, is more difficult to answer. There are no very short-acting hyperbaric spinal local anesthetics that have taken the place of lidocaine for these short procedures and many believe that spinal bupivacaine lasts too long to be a reasonable choice of anesthetic for a procedure that will last <20 min. Because Philip et al. (18) did not evaluate the duration of the block, the study unfortunately cannot address this issue. Further studies evaluating the quality and duration of motor block when smaller doses of bupivacaine are used should be undertaken. In the meantime, should anesthesiologists use hyperbaric lidocaine for these procedures? This question must be answered by individual anesthesiologists who may come to different conclusions based on their interpretation of the current data. Because of the potential for neurotoxicity, we wonder is everything all right even if nothing goes wrong?
Both articles published in this issue (18,19) suggest that TNS may represent pain related to musculoskeletal strain resulting in myofascial pain rather than a transient neurotoxic drug effect (39,40). Such an explanation would certainly simplify much of the problem (41) and might even restore lidocaine’s former reputation of a "gold standard." However, should we not be concerned about prematurely closing the black box of neurotoxicity by once again bypassing the debate that started a decade ago? Moreover, the pathogenesis of myofascial pain syndrome is not known and diagnostic methods, including trigger point injection, are not consistently positive (42). This may be related to the fact that trigger point palpation is particularly unreliable when performed by nonexpert physicians and only marginally reliable after training (43). Because electrophysiologic testing in volunteers experiencing TNS was normal (44), what is the evidence for TNS being related to some kind of neural dysfunction? The tests used may not have been appropriate to test for changes in small-fiber sensory function (45). Because functionally different small-fiber afferents may be affected independently and small-fiber neuropathy has to be considered in the differential diagnosis of burning limb pain without routine electrophysiologic or pathologic abnormalities, TNS "could well be an early warning sign of ominous dose-time related lidocaine neurotoxicity" (46). Although the pain threshold is enhanced in late pregnancy, it seems absurd to infer that the potential risk of neurotoxicity would be reduced concomitantly.
Would a patient given all of the current available information and the choice of lidocaine or bupivacaine choose the former? We think not. Because pregnant patients represent a population that lies to the extreme in terms of the criteria for safety and lack of morbidity, we believe that for the present, there is still insufficient safety evidence to suggest that spinal hyperbaric 5% lidocaine be routinely used in obstetrics. Complacency should not blind us to the potential for patient risk nor delay us from evaluating this issue in further studies. Perhaps William Shakespeare summed it up best when he wrote "the best safety lies in fear."
Acknowledgments
We would like to thank Peter Fuhr, MD, neurologist, for his advice.
References
This article has been cited by other articles:
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  W. R. Lewis and A. C. Perrino Jr. Transient Neurological Symptoms After Subarachnoid Meperidine Anesth. Analg., January 1, 2002; 94(1): 213 - 214. [Abstract] [Full Text] [PDF]
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