The intrathecal lidocaine enigma: On the brink of cauda equinopathy

The Intrathecai Lidocaine Enigma: On the Brink of Cauda Equinopathy Rudolph H. de Jong HE 1990s have not been kind to spinal anesthesia, the introduction, via lumbar puncture, of local anesthetic into spinal fluid. The first of many tremors to come rumbled from over a dozen instances of persistent cauda equina syndrome following continuous catheter spinal anesthesia (mostly with hyperbaric 5% lidocaine). No sooner had the microbore catheter issue been resolved when "heavy xylocaine" itself was snared in controversy over alleged neurotoxicity. Aftershocks from that eruption fanned out when neurotoxicity was implied not only for 5%, but also for 2.5% and even plain 2% lidocaine. As if that weren't enough, yet another tremor hit home when other local anesthetics (bupivacaine, mepivacaine, and even tetracaine) too became implicated in neurotoxicity, although lidocaine still tops the list. With so many reports of radicular "irritation," venting one after another in short order, dawned a growing professional concern over the imputed radiculotoxicity of local anesthetics as a pharmacologic species. Ever since the seminal 1954 report by Dripps and Vandam? intrathecal injection of local anesthetics was considered both safe and efficacious, and lidocaine specifically so in the epochal 1969 multicenter study by Phillips et al.2 One cannot help but wonder what, if anything, has changed about spinal anesthesia in the intervening decades. Did the old masters, in searching out major neurologic complications perhaps overlook or shortchange the minor transient sequelae? Has our practice changed with new techniques, better drugs, and sharper tools for detecting borderline events? Or are we simply paranoid, hyping minor postoperative backache into a major media frenzy that threatens to deny future access to one of the safest and simplest methods of anesthesia? These are the fundamental issues that will be considered in this review.

T

HISTORY Over a century ago, Augustus Bier reported the first spinal anesthetic (with cocaine), adding, for good measure, a personal account of the agonizing

headache that followed. In 1943, young doctor Ekstam, co-developer with Nils L6fgren of lidocaine, bravely volunteered for the first spinal block with the newly synthesized local anesthetic. Twenty-five years later, a prospective study of over 10,000 lidocaine spinal anesthetics reported no major neurologic complications, two persistent radiculopathies, and just 30 minor transient sequelae. 2 By the drug's 50th birthyear, some 50 million lidocaine spinal anesthetics had been administered worldwide. 3 There is no way that this splendid success story could have been sustained were it not for lidocaine's consistent track record of efficacy, safety, predictability, and reliability. Not until the first few case reports of transient radicular irritation (TRI; see below) had appeared in 1993 did unease over lidocaine's potential for threshold neurotoxicity begin to surface. (Refer to the author's editorial 4 for pertinent citations.) Physicians and their patients, grudgingly to be sure, accept postoperative back pain, particularly after body positioning that would daunt a contortionist, as the stiff price to be paid for optimal surgical exposure. However, postspinal back pain does become a valid medical concern when it no longer is just simple musculoskeletal distress or needle-insertion discomfort, but rather a sharp shooting or stabbing pain that radiates down a radicular course from back to buttock and/or posterior thigh. That neuropathic pain pattern, moreover, is quite unlike simple postoperative positional backache as it is preceded by a multihour quiescent period before flaring up, often many hours after discharge home from anesthesia care. Even then TRI would not have become as contentious an issue were it not for initial association with one specific local anesthetic only. Now, a century after its introduction, con-

From Thomas Jefferson University, College of Medicine, Philadelphia, PA. Address reprint requests to Rudolph H. de Jong, MD, 261 Branch Hill Lane, Columbia, SC 29223. Copyright 9 1998 by W.B. Saunders Company 0277-0326/98/1704-000558.00/0

Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 17, No ,4 (December), 1998: pp 287-298

287

RUDOLPH H. DEJONG

288 cerns are being voiced over the safety of spinal anesthesia itself, not just with lidocaine but also with bupivacaine, mepivacaine, and even tetracaine. The Microcatheter Debacle

In May 1992, the Food and Drug Administration recalled microbore spinal catheters after more than a dozen cases of cauda equina syndrome had been reported following continuous spinal anesthesia. Adynamic maldistribution evidently sequestered a compact drug globule in the terminal thecal sac, placing unsheathed unprotected spinal roots of the cauda equina in direct contact with undiluted, fullstrength, local anesthetic solution. One unintended spinoff of the catheter device recall was the tacit implication that intrathecal local anesthetic drug injection remained an acceptably safe practice. As it turned out, however, when reports of transient postspinal radiculopathy began to surface shortly after the catheter recall, mainstream opinion began to swing away from faulting the delivery system device (catheter) and toward drug toxicity (local anesthetic). 5 In retrospect, while the microcatheter may have contributed to caudal drug pooling, actual injury of cauda equina rootlets likely was caused by local anesthetic puddled in a dead-end pocket.

TRANSIENT RADICULAR IRRITATION Background

In their now-classic survey of postspinal neurologic sequelae, Dripps and Vandam 1 described 85 patients (0.9%) who had transient dysesthetic sensations in the legs shortly after recovering from spinal block; they applied the term irritative to differentiate clearly these lesser symptoms from major and permanent sequelae. The term lay dormant for nearly 40 years until Swiss physicians documented four of 88 patients who reported one to several days of bilaterally radiating paresthesialike pain in the buttocks or legs after single-dose intrathecal hyperbaric lidocaine; these investigators coined the since-pervasive term transient radicular irritation (TRI) for this purely sensory postspinal sequel, attributing it to lidocaine neurotoxicity.6 Although the neurotoxic basis of TRI has been questioned (proponents 7'8 consider it just an unusually severe musculoskeletal backache), the per-

sonal account of a colleague9 leaves little doubt that he suffered radiating neuropathic radicular pain rather than localized musculoskeletal backache. Although lack of "hard" localizing physical findings often is called on to question the neurologic basis of TRI, that may be more indicative of the limited sensitivity of clinical sensory examination than of a clean bill of health (just ask any patient with chronic radicular pain despairing of "I can't find anything wrong, it must be all in your head"). Taxonomy

Most postspinal backaches indeed are positional musculoskeletal 1~or needle-insertion trauma in origin. 11 Classic backache is a diffuse nonradiating pain that is often associated with local trigger points of tender paralumbar muscles in spasm. Characteristically, nonspecific postspinal backache starts shortly after normal sensation has returned, is aggravated by motion and eased by rest, and responds well to heat and simple analgesics. Although postspinal backache can be quite dysfunctional if left untreated, it ordinarily resolves spontaneously over a span of days to weeks. By the very prefix of "transient," TRI connotes mild reversible injury ("irritation") to one or more lumbosacral dorsal roots, thus tracing a strict neurotomal topography. A common description is of intense pain (6.2/10 on the verbal analog score 8) or dysesthesia originating in the lower back that radiates to the buttock and/or posterior thigh; less common is radiation to the anterior thigh, and very uncommon is radiation into the toes, signatures indicative of lumbosacral radiculopathy. Almost without exception, a pain-free interval of several hours (rarely a day) follows recovery of normal sensation and ambulation after spinal block. In fact, most outpatients already have been discharged street-fit to home before radicular pain strikes and thus may be lost entirely to follow-up. Unlike uncomplicated musculoskeletal backache, rest does not materially ease radicular pain, which, like other neuropathic pains, responds inadequately to simple analgesics. By the same token, spasm of lumbar muscles with local tenderness either is mild or absent. On occasion, the shooting pain is so distressing that opioids may be required for relief. Fortunately, as implied by "transient," pain is short-lived, commonly lasting a day or less, and seldom more than 3 days.

LIDOCAINE E N I G M A Transient radicular irritation characteristically presents as localizing upper-sacral radicular pain, without a "hard" neurologic component: intact sphincters, absent saddle anesthesia, normal reflexes, and unimpaired leg muscle function. (However, note the rather alarming appearance of postspinal ventral radiculopathies [see below] in prone-positioned patients.) While a lack of objective neurologic signs may be comforting, it should not be cause for trivialization, for TRI bespeaks the essential elements of a threshold neural inflammatory reaction. It is much like a mild sunburn: delayed onset, localizing pain, and complete swift recovery without residual. However, just a bit more sun exposure and the skin will be damaged and healing delayed. In fact, should postspinal localizing neurologic signs ever be elicited, there is just cause for concern over more extensive injury of cauda equina dorsal and ventral roots. 12'13 Local Anesthetic Dilution

When reports of TRI after single-dose hyperbaric lidocaine spinal block began to mount, the Food and Drug Administration reconvened its advisory committee in June 1994 to reconsider safety concerns and, if necessary, revise operational guidelines. By then it had become apparent that problems might be laid directly at lidocaine's door, whereas dextrose (added to render the anesthetic solution hyperbaric relative to spinal fluid) proved innocuous. (Lidocaine 2%, for instance, caused as many TRIs as 5% lidocaine, 14 whereas bupivacaine in a denser sucrose solution [8.25%] than lidocaine [7.5%] proved virtually trouble-free. Is) The committee formulated a consensus opinion that 5% lidocaine was too potent a solution for bare spinal roots, whence their recommendation to dilute 5% hyperbaric lidocaine to 2.5% by adding an equal volume of saline or spinal fluid before single-dose spinal injection. The package insert was altered accordingly and circulated with a "Dear Practitioner" letter to the anesthesia community. Nerve Root Stretching

Once again, tranquility was short-lived, Prospective clinical studies showed TRI inarguably linked to intrathecal lidocaine, but not to either bupivacaine, tetracaine, or dextrose (Tables 1 and 2) and that the incidence of TRI was as common with 2% lidocaine as it was with 5% lidocaine (Tables 2 and 3). More damning yet, was the

289 finding that stretching lumbosacral rootlets (as with knee arthroscopy or lithotomy positioning) renders neural tissue even more susceptible to chemical injury by lidocaine than in the supine recumbent position, 17 as demonstrated by a several-fold greater incidence of TRI after genitourinary/gynecological surgery or knee arthroscopy than after supine herniorrhaphy. Conversely, the neurotoxicity of local anesthetics other than lidocaine is not measurably intensified by positional stretching of cauda equina rootlets (Tables 1 and 2). Mechanical Trauma

In marked contrast to spinal root stretching, a recent survey 18 revealed that of the 12 neurologic deficits subsequent to spinal root needle trauma (leg paresthesia or pain on injection), 11 had received 0.5% bupivacaine and only one had received 5% lidocaine. Clearly, needle trauma of cauda equina rootlets during lumbar puncture, before intrathecal local anesthetic injection, predisposes to neurologic sequelae; worse, these posttraumatic radicular sequelae are not necessarily transient. A causal association between antecedent spinal root trauma, local anesthetic agent, and subsequent radiculopathy has been alluded to earlierl9; this now stands confirmed. Fortunately, needleinsertion nerve trauma is not that common, considering that cauda equina roots occupy one sixth the volume of the terminal thecal sac. 2~ Table 1. Postspinal Radicular Pain

Anesthetic Lidocaine Bupivacaine Tetracaine

Lithotamy(%) Supine (%) 29/133 (22) 1.75 (0) 0/23 (0)

5/175 (3) 1/195 (0) 0/52 (0)

Total (%) 34/308 (11.0) 2/270 (0.7%) 0/75 (0.0)

NOTE. Intrathecal local anesthetic drug (column 1) and cauda ecluina root stretching (column 2) each affect the incidence of TRI in 653 patients given spinal anesthesia. Columns 2 and 3 contrast the lithotomy position for gynecologic/ gynecologic surgery with the supine position for hernia repair. Major paints are that (1) there is a negligibly low incidence of TRI after intrathecal bupivacaine (< 1%) or tetracaine (none) compared with a greater than 10% combined incidence after intrathecal lidocaine, and (2) there is a striking sensitivity to spinal root stretching when lidocaine is the intrathecal local anesthetic (sevenfold increase in postlidocaine TRI when the cauda equina is stretched by legs-raised lithotomy positioning) and no difference whatsoever when either bupivacaine or tetracaine is used. Data from Freedman et alJ 6

RUDOLPH H. DE J O N G

290 Table 2. Postspinal Radicular Pain

Local Anesthetic 5% lidocaine + dextrose 2% lidocaine + saline 0.75% bupivacaine + dextrose Lidocaine totals

Knee

Hernia

Total

5/32

3/19

8/51

8/35

0/16

8/51

0/31 0/19 0/50 13/67 (19%) 3/35 (9%) 16/102

NOTE. The main points in this table are that (1) the overall incidence of TRI is identical (eight of 51 cases) irrespective of whether 5% or 2% lidocaine is the spinal anesthetic agent, (2) the addition of dextrose to intrathecal local anesthetic does not alter the incidence of postspinal TRI (it remains at eight of 51 cases whether lidocaine in saline or in dextrose is used), (3) cauda equina nerve root stretch sensitization by intrathecal lidocaine is demonstrated contrasting TRI after hernia repair in the supine neutral position with that after the hip and back twisting resulting from leg manipulation for knee arthroscopy, and (4) the remarkable difference in postspinal TRI between intrathecal lidocaine (16%) and intrathecal bupivacaine (0%) is again demonstrated. Data from Pollock et al. TM

What Has Changed? Accepting the preceding, a pivotal question arises: how could postspinal transient radicular irritation, possibly a surrogate marker for threshold local anesthetic myelotoxicity, ever have escaped scrutiny for nearly half a century, not to become a thorny issue until the 1990s? After all, the milestone prospective studies by Dripps and Vandam 1 and Phillips et al, 2 when combined, yield a mere 101 instances of postspinal paresthesias in over 20,000 procedures, for a gross rate of 1/200. As only 30 of the 101 paresthesias lasted a week or less, the net TRI frequency (as defined here) computes at just 1/670, substantially less than even the lowest post-lidocaine TRI value (1/250 on record. 21 Certainly not changed within memory are either the manufacturing process or the dosage formulation of lidocaine for intrathecal injection. So what then has changed in the intervening decades? For one, the classic landmark studies were designed to answer but one overriding question: Is spinal anesthesia with sterile prefilled ampules of local anesthetic solution any safer? Go back in time to the 1950s when the infamous Woolley and Roe incident of 1947 was still fresh in the mind. 22 From that stems the prevalent investigative emphasis on

permanent major postspinal neurologic sequelae, and the benign neglect of transient, comparatively trivial, minor symptoms that may well have fallen through the cracks. But the principal factor accounting for the greater incidence of TRI, however, surely must be heightened vigilance for postspinal neurologic complications (stemming from the unfortunate rash of mishaps after continuous spinal anesthesia), reinforced by quality improvement controls that demand persistent patient follow-up. Perhaps also contributing is the pivotal shift away from costly postoperative overnight hospital observation to early discharge from a bottom-line-driven short-stay facility. Pressured by demands for ever faster turnover, we may unwittingly have shortchanged elemental physiologic principles: that is, instituting a functional "warm-up" as part of the gradual postoperative recovery process that must be completed before allowing unrestricted resumption of full physical activity. Significant support for the latter, somewhat unorthodox, premise is obtained from the finding that transient radicular pain does not start until the patient is well on the way home after rushed discharge. It could be that the sudden strains of erect weightbearing on unwary musculoskeletal vertebral support structures are transmitted also to illprepared cauda equina rootlets, manifesting as sub-

TabLe 3. Postspinal Radicular Pain Local Anesthetic

5% lidocaine in 7.5% dextrose 2% lidocaine in 7.5% dextrose Lidocaine Totals

Dose

1 mg/kg 1 mg/kg --

TRI (d 1 )

TRI (d 3)

8/25

1/25

10/25 18/50 (36%)

2/25 3/50 (6%)

NOTE. Table 3 provides a different perspective on diluting the intrathecal lidocaine formulation. Unlike Table 2 (hyperbaric visobaric), the 5% and 2% lidocaine solutions both have been made hyperbaric with dextrose. The overall incidence of TRI actually is somewhat greater after 2% lidocaine (12 of 50 cases) than it is after 5% intrathecal lidocaine (nine of 50 cases). By definition, TRI is transient: although the overall incidence of TRI was 36% on the first postoperative day, it dwindled to 6% by the third day and had vanished by the fifth day. Because these gynecologic patients were placed in lithotomy stirrups, cauda equina root stretching accounts for the unusually high (36%) incidence of TRI on the first day. Data from Hampl et al) y

LIDOCAINE ENIGMA tie radicular irritation. (This reasoning is not unlike that of the "bad backache" proponents [see below], other than for invoking neural injury rather than musculoskeletal trauma.) The "Bad Backache" Hypothesis Even if more consistent patient follow-up were accountable for the current rash of TRI reports, it nevertheless stands as a rather lame excuse for want of a better explanation. And it instantly raises a most poignant question: Are we truly uncovering the new phenomenon of TRI (and, with it, perhaps a surrogate marker for radiculotoxicity) or are we merely crying wolf over altogether innocuous postpositional musculoskeletal back pain, such as the type of back pain that may be aggravated, as proposed, s by structural stresses secondary to the extreme lumbar muscle relaxation induced by intrathecal lidocaine? Stated differently, could TRI merely be a bland myoskeletal, rather than a worrisome neurologic, sequel of intrathecal local anesthetic administration? As discussed in more detail below, I view TRI as the threshold manifestation of an adverse neural response continuum to increasingly severe chemotoxic nerve injury. I offer two reasons for this stand, accepting that we do not as yet have the electrophysiologic tools to quantify fleeting sensory nerve root injury. First, if TRI were no worse than musculoskeletal back and leg pain, we would encounter it equally as frequently with local anesthetics other than lidocaine: as a matter of fact, we don't. Even when the burden of hypersensitization to local anesthetic neurotoxicity (induced by lumbosacral spinal nerve root stretching; see above) is superimposed, the incidence of TRI after intrathecal bupivacaine or tetracaine remains vanishingly low compared with that after lidocaine spinal block (Tables 1 and 2). More to the point perhaps is that anyone who has ever suffered the agony of acute radiating pain from spinal nerve root compression by a herniating lumbar disk is all too painfully aware of the vast qualitative difference between neuropathic pain and myoskeletal backache. The clever inference that intrathecal lidocaine relaxes lumbar muscles more profoundly than other local anesthetics (hence causing more intense postspinal TRI-like "backache") may well have merit. My quarrel is not so much with the causative mechanism itself as it is with the assumption that musculoskeletal stress ergo facto implies an exclu-

291 sively mechanical basis for TRI, thereby putting aside, all too conveniently, any notion of lidocaine neurotoxicity. Even if lidocaine-induced hyperrelaxation of musculoskeletal structures were the sole cause of TRI, why subject patients to the needless discomfort of an unwelcome backache? For TRI, as noted earlier, is a largely preventable complication: simply substitute almost any other intrathecal local anesthetic for lidocaine. Put bluntly, the prospect of a pain in the head after lumbar puncture is handicap enough; why compound that misery with an entirely avoidable pain in the butt? If you truly believe that TRI is myoskeletal, then stop using intrathecal lidocaine altogether.

LOCAL ANESTHETIC SPECIFICITY Local Anesthetic Concentration Founded on anecdotal reports of the time, the 1994 Food and Drug Administration recommendation to dilute hyperbaric 5% lidocaine to half strength (2.5%) made good sense because even plain 2% lidocaine was said to offer as solid a spinal block, but with fewer adverse sequelae, as 5% hyperbaric lidocaine. However, that comforting assumption did not prove to be true once put to the clinical test. Independently, Pollock et a114 in the United States and Hampl et al ~7 in Switzerland demonstrated that 2% lidocaine yielded just about as high (if not higher) an incidence of TRI as did 5% lidocaine (Tables 2 and 3). That clinical observation seems to parallel laboratory findings that 2% lidocaine is threshold neurotoxic to isolated frog sciatic nerve. 23 As these same experiments 23 pegged lidocaine's neurotoxic threshold at approximately 1.5% one would anticipate comparable outcomes when transposed to the clinical setting. In fact, Drasner 24 editorialized that 1.5% lidocaine might well represent the upper nontoxic concentration threshold for intrathecal blockade in humans. However, will 1.5% lidocaine, less than one third the concentration of "gold standard" 5% lidocaine, prove sufficiently potent for satisfactory surgical anesthesia? The results of limited clinical studies comparing intrathecal 1.5% lidocaine with the 5% solution thus far are reassuring: analgesia to pinprick comes on as quickly, spreads as widely, and recedes as slowly with the former as with the latter. 25 Motor block too is said to be as solid with 1.5% as it is with 5% lidocaine, and time to streetfitness is com-

RUDOLPH H. DE J O N G

292 parable. In quite a turnabout, the weaker preparation offered more predictable spinal block: three of 26 subjects given 5% hyperbaric lidocaine had anesthesia inadequate for hernia surgery, whereas all 25 subjects given 1.5% lidocaine achieved solid surgical block. Whether reducing the intrathecal lidocaine concentration will correspondingly reduce the incidence of TRI still remains to be demonstrated*; experimental precedent leads to that anticipation, as local anesthetic neurotoxicity is decidedly concentration-dependent. 23'26 With that in mind, the high incidence of TRI after lidocaine merely could be an unfortunate outcome, reflecting more on the high drug concentration (5%) used than on an intrinsic neurotoxic property of lidocaine itself. Amino-Amide Local Anesthetics Lidocaine legacy. The original description of transient radicular irritation, comparing lidocaine and bupivacaine, was strongly suggestive that TRI occurred solely after intrathecal lidocaine; postbupivacaine T R I was not observed in this, admittedly small, population sample. 6 In all fairness, the waters have been muddied considerably in that TRI has been reported not just to follow intrathecal lidocaine, but also bupivacaine (Tables 1, 2, and 4), tetracaine (Table 1), prilocaine (Table 4), and mepivacaine (Table 5). Even so, TRI occurs far more frequently after lidocaine than after any other intrathecaUy injected local anesthetic. In a recent survey of over 40,000 spinal anesthetics, for instance, nine of the 12 neurologic deficits after atraumatic (ie, no nerve root needle contact) lumbar puncture had been given 5% lidocaine compared with the other three, who received 0.5% bupivacaine.18 Other amino-amides. For many years, virtually every publication implicated lidocaine, whether hyperbaric (5% to 2%) or isobaric (2%), as the villain responsible for TRI, with the occa-

*Editor's note: As this report went to press, conflicting results were reported for the incidence of TRI with 1% lidocaine. See Pavlin JD, Pavlin EG, FitzgibbonDR, et al: Effectof local anesthetic choice on voiding, duration of recovery, and transient radicular irritation after outpatient spinal anesthesia. Anesthesiology 89:A45, 1998 (abstr) and Pollock JE, Liu SS, Neal JM, et al: Is transient radiating back pain caused by concentration dependent neurotoxicityof spinal lidocaine? Anesthesiology 89:A1428, 1998 (abstr).

Table 4. Postspinal Radicular Pain

Local Anesthetic 2% lidocaine in 7.5% dextrose 2% prilocaine in 7.5% dextrose 0.5% bupivacaine in dextrose

Dose

Recovery

TRI

30 mg

Medium

7/24

30 mg

Medium

1/23

7.5 mg

Extended

0/20

NOTE. Another group of gynecologic patients, with the cauda equina stretched tout by lithotomy positioning, was challenged with intrathecal lidocaine or alternative local anesthetics. Once again note the very high incidence of TRI after lidocaine, even when diluted to 2%. Prilocaine, although closely related to lidocaine, has an acceptably low rate of TRI; its medium-long duration of action makes it a reasonable lidocaine alternative (prilocaine is not approved by the Food and Drug Administration for intrathecal use). Again note the vanishingly low TRI rate with bupivacaine, although the sample size is too small for significance. Data from Hampl et al. 2z

sional postbupivacaine TRI dismissed as a statistical fluke rather than as a trendsetter. This is true no longer. By 1996, a flurry of scientific abstracts had pointed the finger at intrathecal bupivacaine 16'29 (Table 1), prilocaine 27 (Table 4), and mepivacaine 28'29 (Table 5) during the process of evaluating lidocaine alternatives. Note well, too, the aforementioned disproportionately high frequency of neurologic sequelae (many more extensive and prolonged than TRI) that followed intrathecal bupivacaine when needle insertion during lumbar puncture inadvertently had grazed a spinal root. 18,19 Amino-Ester Local Anesthetics

Radicular irritation is not the sole province of amino-amide local anesthetics, for amino-ester agents such as procaine and tetracaine have proven to be marginally neurotoxic as well. Fourteen cases of cauda equina syndrome, for instance, were reported 60 years ago following intrathecal 10% procaine with 15% ethanol. 3~ Whether the preceding injuries were attributable to alcohol, procaine, or additives was never resolved. A retrospective Mayo Clinic review of 1,561 spinal anesthetics with a combination of 10% procaine and 1% tetracaine uncovered just one instance of transient cramping leg pain. 19 However, a later prospective pilot study was not nearly as encouraging, yielding one instance of TRI in 106 patients (0.9%) given

LIDOCAINE E N I G M A

293

Table 5. Postspinal Radicular Pain

Local Anesthetic

Dose

Discharge Time

TRI

2% lidocaine in saline 1.5% mepivacaine

60 mg

213 min

6/27

45 mg

218 min

0/30

in saline

advocated. In fact, this disquieting observation should give pause for critical re-examination of the common practice of adding epinephrine (or for that matter, other vasoactive drugs, eg, clonidine) to the intrathecal local anesthetic solution. TRANSITIONAL TOXICODYNAMICS

NOTE. As in Table 4, the roots of the cauda equina were stressed during spinal anesthesia (this time by leg manipulation for knee arthroscopy) to maximize postlidocaine TRI. Mepivacaine may be another useful medium-duration lidocaine alternative, but be aware that mepivacaine is not approved by the Food and Drug Administration for intrathecal use in North America. Data from Liguori et al. 28

5% intrathecal procaine (fentanyl added for surgeries lasting longer than 45 minutes). 3~ Tetracaine appeared to be the one exception, faring better even than bupivacaine in skirting postspinal TRI. ~9 Perhaps no more, for Sakura et a132 presented 11 instances of TRI after intrathecal tetracaine (plus a 12th they reported the previous year). However, this is not all it seems to be, for of the 12 cases with TRI, 11 had phenylephrine added to the tetracaine, and of the 80 subjects given plain 0.5% tetracaine in saline, only one developed TRI, an outcome more in keeping with global experience. At the time of this writing, tetracaine (Pontocaine, Amethocaine, Winthrop Pharmaceuticals, New York, NY), without additives, still holds the crown as the least neurally irritating durable spinal anesthetic sanctioned in North America.

Vasoconstrictor Additive As noted above, 12 cases of TRI after intrathecal tetracaine have been reported by a single source; however, all but one of these had phenylephrine vasoconstrictor admixed to prolong duration of the spinal block. 32 That certainly makes a strong case against phenylephrine as an additive for tetracaine and, by extension, other long-lasting local anesthetics. In this context, it is significant to note that the one instance of "cauda equina syndrome" after single-dose intrathecal lidocaine occurred when epinephrine was added to the spinal anesthetic.33 Clearly, mixing any vasoconstrictor with the local anesthetic solution (to reduce systemic drug absorption and thereby prolong neural blockade) might not be quite as innocuous, as long has been

Although many of the investigators cited earlier assume pad passu a direct correlation between TRI and neurotoxicity (more accurately labeled "radiculotoxicity" or "myelotoxicity"), that correspondence remains to be demonstrated. The difficulty in establishing such linkage, if any, is that TRI pain is a symptom (a subtle sensory change) devoid of"hard" neurologic findings. Furthermore, the notion that transient radiculopathy is distanced from florid cauda equinopathy merely by duration and intensity of neurotoxic drug exposure takes some stretch of the imagination. Hence the prevailing perception that TRI is no worse than just a bad postspinal backache rather than the threshold expression of local anesthetic myelotoxicity (see above). What convinces many researchers (including this writer) that TRI represents the tip of a menacing pharmacotoxic iceberg is the surfacing of intermediate forms of postspinal sequelae. These sequelae manifest as persistent neurologic findings that represent a definitive continuum of radiculotoxicity, ranging from fleeting threshold irritation through persistent patchy sensory loss, and on up to permanent sensorimotor deficits.

Neurologic Continuum At first glance, TRI and cauda equinopathy appear to be totally disparate and unrelated neurologic sequelae of spinal anesthesia. And so they would have remained were it not for a seminal observation by Horlocker and her Mayo Clinic colleagues, who painstakingly analyzed neurologic sequelae of nearly 5,000 sequential spinal anesthetics. 19 With this decade's concern over local anesthetic neurotoxicity in mind, these investigators searched not just for major neurologic damages but dug especially deep for lesser fleeting postspinal sequelae. In their retrospective analysis, Horlocker et all9 uncovered a wide spectrum of cauda equinopathies ranging from minimal transient monoradicular dysesthesia at the symptomatic threshold to catastrophic overt cauda equina syndrome at the opposite pole. Intermediate in dysfunctionality between these delimiting bounds is a symptom

294 grouping they labeled "sensory cauda equina complex" in which dorsal, but not ventral, roots were compromised selectively. This symptom complex may be the keystone, perhaps the Rosetta stone, to span the perceptional jump from TRI to surrogate marker for threshold myelotoxicity.

Neurologic Findings To ensure a level playing field in the premise to follow, only those adverse outcomes confirmed by neurologic consultation after uncomplicated spinal anesthesia are considered, ie, uneventful lumbar puncture, no paresthesia(s) during needle placement, no catheter, and no combination techniques, such as spinal/epidural block. Additional transitional stages of polyradiculotoxicity, ranging from purely sensory to persistent sensorimotor, are starting to appear in the literature. Such clustering of reports of a hitherto rare complication is highly suggestive of a new, perhaps previously unnoted, complication. A landmark, as the 12 volunteer subjects were being observed prospectively for postspinal neurologic events, is the report of two instances of postspinal lower-sacral dorsal radiculopathy. 34 The first subject, after 100 mg of intrathecal hyperbaric lidocaine, had delayed onset perianal hypesthesia to pinprick with full recovery within 3 months. The second subject, after two closely spaced injections of 100 mg of intrathecal hyperbaric lidocaine each, had delayed onset saddle-area hypesthesia, spreading slowly over the perineum to include eventually the scrotum; although the circumference of the hypesthetic area receded gradually, residual perianal sensory deficit to pinprick still was demonstrable 6 months later. This report alone confirms a degree of dose dependence of symptoms in terms of spread and duration. In one retrospective analysis of adverse outcomes in Sweden, a patient retained residual L5 monoradiculopathy after 100 mg of intrathecal hyperbaric lidocaine. 35 A subsequent report listed two additional cases of confirmed sacral hypesthesia persisting longer than 6 months. 36 In a report cited earlier (see "Vasoconstrictor Additive"), the subject retained persistent (more than 5 months) difficulty in voiding and clinical hypesthesia in the $2 to $4 segments after 100 mg of intrathecal hyperbaric lidocaine (with epinephrine). 33 This also suggests that slowing absorption of (thereby

RUDOLPH H. DEJONG prolonging exposure to) lidocaine increases the severity of radicular injury. Selective radiculotoxicity certainly is not the sole province of lidocaine, for another report finds residual low-sacral sensorimotor deficits persisting 2 years after 18 mg of intrathecal hyperbaric bupivacaine. 37 In the aforementioned Swedish analysis, three patients given in excess of 15 mg of intrathecal bupivacaine had neurologic deficits lasting more than 6 months, ranging from lumbosacral dysesthesias with tendon reflex asymmetry to limited motor and/or sphincter impairment. 36 In contrast, analysis of a comparable Finnish database yielded two cases meeting our strict exclusion criteria: the first, after 13.5 mg of intrathecal bupivacaine, with initial unilateral L3-4 radiculopathy, resolving after 1 month to an L4 monoradiculopathy; the other, after 20 mg of intrathecal bupivacaine, with peroneal monoparesis resolving over 3 months. 38 The preponderance of current evidence increasingly points to a drug-mass exposure-time-related radiculotoxicity of intrathecal local anesthetics, that is, the denser and the longer the drug exposure, the more extensive and irreversible the neural injury. A progressive symptom continuum of neurotoxic cauda equinopathies now begins to unfold: starting with mild transient monoradiculitis at the threshold lower asymptote, increasing through bilateral sensory cauda equina complex midway up the curve, thence advancing inexorably to permanent lumbosacral root injury at the upper asymptotic bound. The resultant (hypothetical) drug-exposure/neural injury cumulative dose effect curve is illustrated in Fig 1 and is diScussed in the following section.

CAUDA EQUINOPATHIES Chemical Radiculitis The dorsal and ventral lumbosacral roots are the longest and thinnest intraspinal nerves; their high surface to volume ratio, and scanty investment by connective tissue collagen, render the cauda equina singularly vulnerable to chemical injury by penetrating pharmaceuticals (in this instance, local anesthetics). 2~ As reports of transient postspinal neurologic sequelae spring up from around the world, it becomes ever more evident that transient radicular irritation is the symptom of a mild inflammatory response to threshold neurotoxic irritation of one or more cauda equina dorsal roots. Cauda

LIDOCAINE ENIGMA

295 Equina Syndrome Triad 97%--

Fig 1. A proposed cumulative probability curve correlatA ing adverse radlculotoxic red sponse with periaxonal local V anesthetic drug mass ("concene tration'). The vertical axis r grades the severity of postspiS nal neurologic sequelae on an e ascending scale, ranging from threshold radicular irritation at /~ the lower boundary to overt e catastrophic cauda equina synS drome at the upper boundary, p A continuum of progressive O neural injury unfolds between /.j these scale-defining asympS totes. The horizontal axis e ("Drug Concentration") represents the toxicodynamic product of local anesthetic concentration at the drug/nerve interface, multiplied by the duration of drug/nerve contact in units of time. In short, the more concentrated the local anesthetic in the spinal fluid and the 3%-longer cauda equina roots re- Back Ache main in contact with the dissolved drug mass, the more intense the chemical inflammatory reaction.

Spotty Sphincter/Leg Weakness

50%--

]

SensoryCauda Equina Complex

Patchy Numbness Groin/Leg

Transient Radicular Pain

Drug Concentration

equina syndrome, conversely, is the overt manifestation of a far-reaching, near-irreversible chemical burn of sensory, motor, and preganglionic parasympathetic cauda equina axons, presenting as the infamous triad of saddle anesthesia, hemiparesis, and sphincter incompetence. ~2 An early series of 14 cases of cauda equina syndrome following hospital-compounded intrathecal "heavy duracaine" (10% procaine, 15% ethanol, glycerine, and "thickener"), published more than 60 years ago, makes for troubled reading. 3~

Silent Period Curiously, the full extent of neurotoxic radicular damage may not manifest immediately, the symptom-free interval perhaps mirroring evolution of an inflammatory reaction to chemical injury, progressing from initial endoneural edema to eventual axonal disruption. 27 Classic TRI, for instance, characteristically does not begin to hurt until sev-

eral hours after spinal anesthesia has dissipated, by which time the patient already will have been discharged as street-fit from medical care. Even the more extensive root injuries, which take from weeks to months or longer to recover, manifest that deceptively silent initial symptom-free period. 34-37

Dependent Radiculotoxicity An altogether different perspective on neurotoxic radiculitis emerges from the dynamic local anesthetic/nerve root contact interface. Uniquely characteristic of "classic" TRIs are the purely sensory (dorsal root) symptoms of pain and/or dysesthesia. This makes intuitive sense as, in the supine recumbent position, the dorsal roots dip deep into the bottom of the spinal fluid well, immersed fully in densely concentrated local anesthetic solution. The ventral (motor) roots, conversely, float to the surface, where local anesthetic, in rising to the top, is diluted by fresh spinal fluid. Intrinsic anatomic

296

RUDOLPH H. DE J O N G Table 6. Postspinal Radicular Pain

Local Anesthetic

Dose

SensoryTRI

Motor TRI

3% lidocaine in 7.5% dextrose

30 to 45 mg

4/1045

42/1045

NOTE. A fascinating tale, with an unexpected twist: in their huge sample (over 1,000 lidocaine spinal anesthetics), the investigators find an incidence of just 0.4% "classic" TRI ["sensory TRI'), a rate far lower than seen anywhere else, even with patients in the neutral supine position. Is the Japanese dosage form of lidocaine different from elsewhere? No, they used a product of European manufacture. Different, as the story unfolds, is that these were patients who had anorectal surgery in the prone position. The 1O-fold higher incidence of transient leg weakness ("motor TRI") is the give-away; in the prone face-down position, dorsal and ventral roots change location within the spinal sac so that ventral roots become dependent, dipping deep into the local anesthetic well, and dorsal roots float on top of the spinal fluid out of harm's way (see text for details). Data from Morisaki et al. 21

segregation within the thecal sac of dorsal from ventral roots may explain the exclusively sensory presentation of "classic" TRI; for, in the supine position, dorsal roots and ganglia soak in a puddle of local anesthetic solution that is far more concentrated than that in which the ventral roots soak. This explains the dominance of transient sensory symptoms, and the auspicious absence of transient leg muscle weakness, in conventional TRI. Clinching the notion of preferential neurotoxic injury to dependent spinal roots is the stunning symptom reversal when ventral roots are rotated into, and dorsal roots lifted out of, hyperbaric solution layered at the bottom. In a provocative report, Morisaki et a121 described an astoundingly low incidence (4 of 1,045 cases) of transient dorsal root irritation after hyperbaric lidocaine (Table 6). Why would TRI be so much less prevalent in Japan than elsewhere in the world; was drug formulation modified, perhaps? Not at all, for, in lieu of transient radicular pain (dorsal roots), an alarmingly high frequency (4%) of transient leg muscle weakness (ventral roots) was observed in patients receiving a modest (30 to 45 mg) dose of 3% hyperbaric lidocaine (Table 6). The difference, as it turns out, is in spinal cord transverse alignment; for the spinal anesthetics were given for anorectal surgery in the prone jackknife position. When the patient lies face-down on the abdomen, it is the ventral roots that now soak in the dense drug layer puddled

at the bottom of the spinal fluid well, whereas the dorsal roots float out of harm's way near the top of the spinal fluid surface.

Dose-Effect Curve The ominous caveat that ventral radiculitis lurks not far behind transient dorsal radiculitis leaves ever less doubt that TRI is the first-stage marker of a chemically induced mild inflammatory reaction ("irritation") of intrathecal lumbosacral spinal roots-a radiculitis that is transient only because it barely skirts the threshold neurotoxic exposure limit. As in the earlier analogy with solar exposure, the lower the sun in the sky, the longer one can stay outside before the skin becomes irritated. That is: drug dose and local anesthetic concentration together determine the total drug mass targeting the nerve, while duration of exposure determines the severity of injury. Said differently, the greater the local anesthetic dose, the higher its concentration, and the longer the axonal exposure, the more extensive and persistent the neural damage. Accept for the moment that transient radiculitis and overt cauda equina syndrome represent opposite poles of local anesthetic-induced myelotoxicity: Are these just two unrelated, altogether different outcomes, or do TRI and cauda equina syndrome represent instead the lower and upper bounds of a continuum of increasingly more severe myelotoxicity that stretches between these two extremes? In other words, can one identify interim milestones that fall between the lower and upper asymptotes of myelotoxicity thereby, in effect, creating a genuine dose-effect curve? So it would seem, for the above-noted (see "Neurologic Continuum" section) isolated case reports form the framework for a spectrum of cauda equinopathies: patchy groin or saddle numbness, monoradicular or unilateral myotomal weakness, sensory cauda equina complex, mixed sensorimotor disorders, and eventually, progressive sphincter and skeletal leg muscle paresis. Figure 1 illustrates a (hypothetical) cumulative dose effect curve constructed from the preceding elements; while exact location on the vertical percentage axis remains tentative, the upward progression in spread and severity of myelotoxic injury is readily evident. If the assumption of a dose-effect continuum of myelotoxic injury indeed is correct, all falls into place. For instance, a sobering corollary of operating on the radiculotoxic edge is that

LIDOCAINE ENIGMA the inexorable laws of probability eventually will catch up-some day, an uncommonly susceptible luckless patient will sustain a not-so-transient cauda equinopathy when given a routine dose of intrathecal local anesthetic.

RECOMMENDATIONS At the end of a century of growth, spinal anesthesia has arrived at a crossroad, for the realization is dawning that intrathecal local anesthetics have a finite, albeit limited, capacity for radicular irritation. It may well be, as is most obviously the case with lidocaine, that the concentration of intrathecal drug, as presently administered, skates uncomfortably close to the radiculotoxic threshold. Rather than dismissing intrathecal lidocaine out of hand, consider stepping down the concentration of intrathecal local anesthetic formulations to retain optimal clinical efficacy with less threat to patient safety. As documented here, there is ample reason for concern, but no need for alarm. A corollary of"the longer the drug exposure, the more severe the adverse effect" is the disproportionate jump in TRI occurrence when spinal blockade is extended with phenylephrine; adding phenylephrine to prolong spinal blockade can no longer be recommended. Whether that caveat extends to other vasoconstrictors, epinephrine for instance, remains to be determined; for the present, due caution is advised.

CONCLUSIONS The incidence of transient postspinal radicular leg or buttock dysesthesias is consistently greater after intrathecal lidocaine than after bupivacaine or tetracaine; TRI is about as frequent after 2.5% (or even 2%) as it is after 5% lidocaine. Whatever the local anesthetic drug or its concentration, the addition of dextrose to render the solution hyperbaric does not materially affect the frequency of postspinal TRI. Conversely, the incidence of postlidocaine TRI increases sharply when lumbosacral dorsal roots are stretched, as in lithotomy positioning or knee arthroscopy. Although TRI could be the innocuous cohort of an unusually severe musculoskeletal backache, the wide-ranging spectrum of postspinal neurologic sequelae is in all likelihood the clinical presentation of a pharmacologic continuum of myelotoxicity. More likely than not, TRI represents an early warning sign (a marker) of threshold drug-mass

297 exposure-time-related myelotoxicity. In short, TRI is just the tip of a massive iceberg of potential cauda equinopathies. Rather ominous is the recent description of muscle weakness (ie, transient ventral radiculitis) after spinal anesthesia in the prone position; whereas, transient dysesthesias (ie, TRI) are rare in the prone position. Transient ventral, rather than dorsal, radiculitis in prone subjects suggests that the chemical burn is position related. The highest drug exposure occurs at dependent spinal roots, where local anesthetic is layered densely at the bottom of the thecal sac.

REFERENCES 1. Dripps RD, Vandam LD: Long-term follow-up of patients who received 10,098 spinal anesthetics: Failure to discover major neurological sequelae. JAMA 156:1486-1491, 1954 2. Phillips OC, Ebner H, Nelson AT, et al: Neurologic complications following spinal anesthesia with lidocaine: A prospective review of 10,440 cases. Anesthesiology 30:284289, 1969 3. Renck H: Neurological complications of central nerve blocks. Acta Anaesthesiol Scand 39:859-868, 1995 4. de Jong RH: Last round for a "heavyweight"? Anesth Analg 78:3-4, 1994 (editorial) 5. Horlocker TT, McGregor DG, Matsushige DK, et al: Neurologic complications of 603 consecutive continuous spinal anesthetic using macrocatheter and microcatheter techniques. Anesth Analg 84:1063-1070, 1997 6. Schneider M, Ettlin T, Kauffmann M, et al: Transient neurologic toxicity after hyperbaric subarachnoid anesthesia with 5% lidocaine. Anesth Analg 76:! 154-1157, 1993 7. Carpenter RL: Hyperbaric lidocaine spinal anesthesia: Do we need an alternative? Anesth Analg 81:1148-1153, 1995 (editorial) 8. Pollock JEo de Jong RH: Hyperbaric lidocaine for spinal anesthesia? Am J Anesthesiol 24:161-165, 1997 9. Wong CA, Benzon H, Kim C: Bilateral radicular pain after epidural lidocaine. Reg Anesth 21:600-601, 1996 (letter) 10. Hartrick CT: Transient radicular irritation: A misnomer? Anesth Analg 84:1392-1393, 1997 (letter I I. Stevens RA: Back pain following epidural anesthesia with 2-chloroprocaine. Reg Anesth 22: 299-302, 1997 12. Haerer AF: Disorders of the spinal cord, in DeJong's The Neurologic Examination (Sth ed). Philadelphia PA, Lippincott, 1992 13. Jaradeh S: Cauda equina syndrome: A neurologist's perspective. Reg Anesth 18:473-480, 1993 14. Pollock JE, Neal JM, Stephenson CA, et al: Prospective study of the incidence of transient radicular irritation in patients undergoing spinal anesthesia. Anesthesiology 84:1361-1367, 1996 15. Hampl KF, Schneider MC, Thorin D, et al: Hyperosmolarity does not contribute to transient radicular irritation after spinal anesthesia with hyperbaric 5% lidocaine. Reg Anesth 20:363-368, 1995

298 16. Freedman J, Li D, Jaskela M, et al: Risk factors for transient neurologic symptoms after spinal anesthesia. Anesthesiology 85:A741, 1996 (abstr) 17. Hampl KF, Schneider MC, Pargger H, et al: A similar incidence of transient neurologic symptoms after spinal anesthesia with 2% and 5% lidocaine. Anesth Analg 83:1051-1054, 1996 18. Auroy Y, Narchi P, Messiah A, et al: Serious complications related to regional anesthesia. Results of a prospective survey in France. Anesthesiology 87:479-486, 1997 19. Horlocker TT, McGregor DG, Matsushige DK, et al: A retrospective review of 4767 consecutive spinal anesthetics: Central nervous system complications. Anesth Analg 84:578584, 1997 20. Hogan Q: Size of human lower thoracic and lumbosacral nerve roots. Anesthesiology 85:37-42, 1996 21. Morisaki H, Masuda J, Kaneko S, et al: Transient neurologic sequelae in 1,045 patients undergoing spinal anesthesia with 3% hyperbaric lidocaine. Anesthesiology 87:A781, 1997 (abstr) 22. Cope RW: The Woolley and Roe case: Woolley and Roe versus Ministry of Health and others. Anesthesia 9:249-270, 1954 23. Bainton CT, Strichartz GR: Concentration dependence of lidocaine-induced irreversible conduction loss in frog nerve. Anesthesiology 81:657-667, 1994 24. Drasner K: Lidocaine spinal anesthesia: A vanishing therapeutic index? Anesthesiology 87:469-472, 1997 (editorial) 25. Markey JR, Montiague R, Winnie AP: A comparative efficacy study of hyperbaric 5% lidocaine and 1.5% lidocaine for spinal anesthesia. Anesth Analg 85:1105-1107, 1997 26. Kalichman MW: Physiologic mechanisms by which local anesthetics may cause injury to nerve and spinal cord. Reg Anesth 18:448-452, 1993 27. Hampl KF, Heinzmann-Wiedmer S, Luginbuehl I, et al: Transient neurologic symptoms after spinal anesthesia: A lower incidence with prilocaine and bupivacaine than with lidocaine. Anesthesiology 88:629-633, 1998

RUDOLPH H. DE JONG 28. Liguori GA, Zayas VM, Chisholm MF: Transient neurologic symptoms after spinal anesthesia with mepivacaine and lidocaine. Anesthesiology 88:619-623, 1998 29. Hiller A, Rosenberg PH: Transient neurologic symptoms after spinal anesthesia with 4% mepivacaine and 0.5% bupivacaine. Br J Anesth 79:301-305, 1997 30. Ferguson R, Watldns K/I: Paralysis of the bladder and associated urological sequelae of spinal anaesthesia (cauda equina syndrome). Br J Surg 25:732-752, 1937 31. Axelrod EH, Alexander GD, Brown M, et al: Procaine spinal anesthesia: A pilot study of the incidence of transient radicular irritation. Anesth Analg 86:$2, 1998 (abstr) 32. Sakura S, Sumi M, Sakaguchi Y, et al: The addition of phenylephrine contributes to the development of transient neurologic symptoms after spinal anesthesia with 0.5% tetracaine. Anesthesiology 87:771-778, 1997 33. Gerancher JC: Cauda equina syndrome following a single spinal administration of 5% hyperbaric lidocaine through a 25-gauge Whitacre needle. Anesthesiology 87:687-689, 1997 34. Beardsley D, Holman S, Gantt R, et al: Transient neurologic deficit after spinal anesthesia: Local anesthetic maldistribution with pencil point needles? Anesth Analg 81:314-320, 1995 35. Dahlgren N, Ttirnebrandt K: Neurological complications after anesthesia. A follow-up of 18000 spinal and epidural anaesthetics performed over three years. Acata Anaesth Scand 39:872-880, 1995 36. Pleym H, Spigset O: Peripheral neurologic deficits in relation to subarachnoid or epidural administration of local anesthetic for surgery. A survey of 21 cases. Acta Anaesthesiol Scand 41:453-460, 1997 37. Kubina P, Gupta A, Oscarsson A, et al: Two cases of cauda equina syndrome following spinal-epidural anesthesia. Reg Anesth 22:447-450, 1997 38. Aromaa U, Lahdensuu M, Cozanitis DA: Severe complications associated with epidural and spinal anaesthesias in Finland 1987-1993. A study based on patient insurance claims. Acta Anaesthesiol Scand 41:445-452, 1997