REVIEW

Neurologic Deficits following Epidural or Spinal Anesthesia

Robert E. Kane, MS, MBA
OUR CASES of prolonged neurologic deficit following attempted epidural block with chloroprocaine were recently reported (I, 2). Two patients received epidural chloroprocaine during labor; following delivery, motor paralysis of the lower extremities was noted. Complete recovery of function was seen by 72 hours after delivery in one case. The other patient showed gradual partial recovery after 4 weeks. In the two other patients, total spinal anesthesia occurred following administration of 27 ml of 2% or 28 ml of 3%chloroprocaine for postpartum tuba1 ligation. Artificial ventilation was instituted and the operation was completed, but motor paralysis of the lower extremities was noted following regression of anesthesia in both patients, accompanied by urinary and fecal incontinence and partial sensory loss in one patient. Gradual return of function occurred over 72 hours in one case and over 4 weeks in the other, but tne latter patient developed symptoms of adhesive arachnoiditis 7 weeks following the operation. As part of the evaluation of these cases, a literature search was conducted for previous reports of similar sequelae following epidural or spinal anesthesia. The search was begun by consulting Index Medicus and computerized files including Medline, Toxline, and Excerpta Medica. Its purpose was to establish whether or not paralysis had been reported following epidural or spinal anesthesia with local anesthetics other than chloroprocaine. Reports of large series of epidural or
Received from the Pennwalt Pharmaceutical Division, Rochester, New York. Accepted for publication October 31, 1980. Reprint requests to Mr. Kane, Pennwalt Pharmaceutical Division, PO Box 1710, Rochester, NY 14603.

spinal anesthetics were collected to give an indication of the incidence of neurologic sequelae. Discussions of causative factors in published case reports led to literature dealing with spinal paralysis unrelated to local anesthesia and to pertinent experimental studies. This review summarizes the findings of published surveys of major regional anesthesia and lists case reports of severe neurologic sequelae in a series of tables. The signs and symptoms associated with known and suspected causes of neurologic deficit are described, and relevant experimental studies are discussed. Finally, previously reported cases are compared to the recently reported chloroprocaine cases in an effort to determine the etiology of the latter.

Neurologic Deficits following Epidural Anesthesia

Seven articles, which report on large series of patients undergoing epidural anesthesia, are summarized in Table 1. Local anesthetics included bupivacaine, chloroprocaine, hexylcaine, and lidocaine. In these surveys, the incidence of serious neurologic sequelae was low. Only three patients suffered persistent paralysis or paresis of the lower extremities in more than 50,000 cases. An extensive review of the literature by Dawkins (10) also indicates that paralysis occurs infrequently following lumbar or thoracic epidural block. Transient paralysis was reported in 48 cases @ I ) whereas seven patients suffered perma.%, nent paralysis in this series of 32,718 cases (0.02%).In his own series of 4,000 epidural blocks, Dawkins had one case of permanent paraplegia; a second patient suffered paresis that improved over 2 months.

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In contrast to the above surveys, a number of individual case reports have been published in which serious neurologic deficit has followed epidural anesthesia. Table 2 includes 30 cases of lower paralysis of undetermined etiology in addition to the four chloroprocaine cases cited above. Various local anesthetics were used, including lidocaine, procaine, trimecaine, mepivacaine, and hexylcaine. Many of the
TABLE 1 Survey Reports of Epidural Anesthesia
~~

solutions contained epinephrine. Six of the cases listed in Table 2 were unrelated to the anesthetic solution itself. Cord compression due to epidural hematoma occurred in four patients. All of these patients were receiving anticoagulant therapy. In one of the other cases, paralysis was due to unrecognized preexisting stenosis of the spinal canal. The patient reported by Craig et a1 (14)received a 40-mI epidural

Reference Bleyaert (3) Moore (4) Holdcroft (5) Moore (6)

No. of patients
3,000

Anesthetics Bupivacaine, 0.125%. 1:800,000 epinephrine Bupivacaine, 0.25%, 0.5%,or 0.75%. with or without epinephrine Bupivacaine. 0.5% or lidocaine, 1.5% (32 patients) Lidocaine + tetracaine with epinephrine in 6,270 patients, various agents in remaining cases Lidocaine, 2% (8,000 patients). chloroprocaine, 3% (700 patients), hexylcaine, 2% (200 patients) Lidocaine Various, mostly lidocaine

Procedures Obstetric Surgical, obstetric, diagnostic Obstetric Surgical, obstetric None None

Neurologic sequelae

11,080 1,000 7,286

1 foot drop; 1 paresthesia of thigh 1 bilateral paralysis of quadriceps muscles

Lund (7)

10,000

Surgical, obstetric, diagnostic

Eisen (8) Bonica (9)

9,532

Obstetric Surgical, obstetric. diagnostic

3.885

1 paresis of 1 leg (subarachnoid hexylcaine); 4 paresthesias o thigh; 1 persistf ent numbness; 3 bladder or rectal incontinence 16 paresthesias; 9 numbness of thigh; 1 paraplegia (one of 5,091 surgical cases) 1 hypalgesia of trunk, weakness of leg (subarachnoid lidocaine); 1 paresthesias. numbness weakness of leg

TABLE 2 Severe Neurologic Deficit following Epidural Block: Case Reports

Reference Braham (1 1)

:;i : s
1 1 11 1 1 1 1 1 2 1 1 1 1 1 1 1 1

Anesthetics Procaine, 2% Procaine. 2% Lidocaine with epinephrine

Neurologic sequelae Permanent paraplegia, adhesive arachnoiditis Paralysis of iliopsoas and quadriceps muscles bilaterally Paraplegia

Etiologic factors Possible subarachonid injection Unknown High concentrations of epinephrine or circulatory deficit Stenosis of lumbar spinal canal Epidural injection of saline containing 1.5% of benzyl alcohol Hypotension Unknown Hypotension Epidural hematoma (anticoagulants) Epidural hematoma (anticoagulants) Hypotension Unknown Epidural hematoma (anticoagulants) Unknown Subarachnoid injection Unknown Hypotension Unknown

Catterberg (12) Chaudhari (13) Craig (14) Davies (1 5) Oawkins (10)

Gingrich (16) Harrison (17) Hellmann (18 ) Helperin (1 9) lagudin (20) Lund (7) Moore (6) Urquhart-Hay (21) Usubiaga (22)

Lidocaine. 1.5%, 1:200.000 Paraplegia epinephrine Lidocaine. 1.5%. 1:200,000 Severe paraparesis. very slow return of epinephrine function over 2 years. Lidocaine, 1.75% 1: Paraplegia, cellular degeneration of ante300,000 epinephrine rior spinal cord T-I0 downward Permanent paraplegia, gross T6-12 deLidocaine, 2% struction of spinal cord Lidocaine, 2%. 1:80.000 Partial sensory and motor loss of legs, epinephrine full recovery after 2 mo Not reported Temporary or permanent paralysis Lidocaine. 1% Paralysis of legs, sensory loss to T-I 0 Lidocaine, 1.5%. 1:200.000 Partial sensory and motor paralysis of epinephrine lower limbs, incomplete recovery. Not stated Paraplegia Lidocaine. 2%, 1:200,000 Moderate-severe weakness of legs, senepinephrine sory deficit Trimecaine. 2.5% Severe weakness of lower limbs, partial recovery over 2 mo Hexylcaine, 2% Partial paralysis of one leg Bilateral paralysis of quadriceps muscles Not stated Paraplegia, incomplete recovery, isLidocaine, 1.5%. and 1: 200,000 epinephrine chemic necrosis of lumbar spinal cord Lidocaine or mepivacaine Paraplegia. loss of sphincter control

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injection of saline containing the preservative benzyl alcohol. This was administered several hours after an inadvertent dural puncture and the authors speculate that the preservative may have caused the neurologic sequelae. In the remaining cases, the cause of residual paralysis was unknown or was considered to be related to the epidural anesthetic solution or procedure. Severe or prolonged hypotension resulting from the epidural anesthesia occurred in at least four patients, and may have resulted in cord ischemia or infarct. In the 11 cases reported by Catterberg and Insauti (14, the addition of epinephrine to the local anesthetic was suggested as being responsible for localized vasoconstriction and resulting spinal cord lesions. Inadvertent subarachnoid injection of local anesthetic was suspected in two cases. In one patient, 25 to 30 ml of 2% procaine was intended for epidural administration. Subarachnoid injection was suspected because of headache following the procedure. Weakness progressing to complete paralysis of the lower limbs developed over a period of weeks; laminectomy revealed arachnoiditis. The second patient experienced persistent partial paralysis of one leg following inadvertent subarachnoid block with 2% hexylcaine. In a monograph by Usubiaga ( 2 4 , 65 cases of neurologic complications following epidural anesthesia are presented. Many of these were previously unpublished. Probable causes included trauma, injected material, infection, vascular lesions, or preexisting pathology. In eight patients, the cause of paraplegia was unknown or undetermined.

Neurologic Deficits following Spinal Anesthesia

Seven survey reports of spinal anesthesia are listed in Table 3. Results of spinal anesthesia in more than 65,000 patients were reviewed in these studies. Various local anesthetics were used, including bupivacaine, dibucaine, lidocaine, mepivacaine, procaine, and tetracaine. Vasoconstrictors were added to the solutions in at least 10,000cases. From these reports, it appears that severe neurologic deficits following spinal anesthesia are rare, although several papers report only sequelae clearly related to the spinal anesthesia. As shown in Table 4, a number of individual case reports have appeared in which partial or, complete paralysis occurred following spinal anesthesia. Three types of syndromes appear to be represented by these cases. The most benign is aseptic meningitis characterized by high fever, headache, nuchal rigidity, and photophobia. The cerebral spinal fluid (CSF) pressure is increased, and CSF smears show high counts of polymorphonuclear cells; cultures of CSF are negative. Symptoms usually appear within 24 hours of spinal anesthesia and recovery occurs spontaneously within several days to a week
(38).

A second type of neurologic deficit following spinal anesthesia has been called the cauda equina syndrome. The cases presented by Ferguson and Watkins (36)are characterized by urinary and fecal incontinence, localized sensory loss in the perineal area, and varying degrees of leg weakness. These symp-

TABLE 3 Survey Reports of Spinal Anesthesia

Reference No. of patients Anesthetics Procedure Neurologic sequelae

Kortum (23) Bergman (24) Phillips (25) Moore (26)

2,592 10.000 10,440 11,574

Bupivacaine, 0.5% Lidocaine, mepivacaine, bupivacaine Lidocaine Tetracaine, dibucaine; with epinephrine or phenylephrine in 8,852 Tetracaine, procaine, dibucaine Tetracaine. procaine, dibucaine; with epinephrine in 2,000 Tetracaine

Surgical Various Obstetric, surgical Surgical, obstetric

1 lumbar plexus injury None

8 persistent peripheral neuropathy 1 persistent muscular weakness of legs, impotence

1 paraplegia due to spinal tumor; 3 meningitis No major neurologic sequelae; 2 foot drop; 1 leg weakness (trauma); 12 exacerbation of previous neurologic disease 2 peroneal paresis. unilateral

Sadov (27) Dripps (28); Vandam (29-31 )

20,000 10,098

Various

Brown (32)

600

Surgical

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TABLE 4 Case Reports: Severe Neurologic Deficits following Spinal Anesthesia
Reference Bergner (33)

No. of patients
4 2 1 2 1

Anesthetics Tetracaine, 10 mg, in glucose, with 5 mg of ephedrine in 2 patients Dibucaine. 2.5 mg. in glucose Not stated Not stated Not stated Tetracaine. 1% in 10% dextrose "Heavy" durocaine (10% procaine glycerine and in 15% ethanol gliadin or gum acacia)

Neurologic sequelae Radiculitis, ascending myelitis, adhesive arachnoiditis. meningo encephalitis, death in 4 patients Incontinence of bladder and rectum Numbness, weakness, pain of lower extremities, adhesive arachnoiditis Quadraplegia. death, necrosis of central gray matter of cord Paraplegia developed 2-3 days after spinal anesthesia Urinary and fecal incontinence, sensory loss in saddle area, leg weakness of varying degree (cauda equina syndrome) Weakness of right quadriceps femoris muscle group Aseptic meningitis (fever, nuchal rigidity. headache, photophobia). recovery over several days to 1 week Flaccid paralysis of lower extremities, urinary retention, degenerative lesions in lower spinal cord Weakness of lower limbs progressing to paraplegia, adhesive arachnoiditis Flaccid paresis or paralysis of lower limbs, urinary incontinence, constipation Leg weakness, perianal numbness, constipation Bladder and bowel incontinence, marked weakness of legs, numbness, impotence in one patient Progressive weakness of legs, partial sensory loss Incontinence. paresis of one leg Permanent paraplegia Paralysis of lower limbs Paresis of lower limbs Paralysis of legs, incontinence Progressive adhesive arachnoiditis. leading to hydrocephalis and death Progressive weakness of legs, bladder incontinence, constipation: adhesive arachnoiditis Fever, headache, nuchal rigidity, photophobia, aseptic meningitis Weakness progressing to paraplegia, progressive arachnoiditis, death Weakness or paralysis of legs: gradual partial recovery Progressive weakness and sensory loss leading to complete paraplegia, adhesive arachnoiditis Transverse myelitis appearing 3 mo to 2% yr after spinal, constrictive arachnoiditis

Etiologic factors Unknown, undetected chemical contamination of the spinal solutions suspected Unknown Unknown Shock during operation Metastatic peridural tumor Authors consider high concentration of procaine as cause of the syndrome Unknown Problem attributed to soaking syringes with a phenolic disinfectant Vasospasm induced by ammonium sulfate or procaine suggested by pathology Unknown Unknown

Courville (34)

Desnoyers (35) Ferguson (36)

1 14

Finch (37) Goldman (38)

I
5

Tetracaine, 10 mg, phenylephrine, 4 mg in dextrose solution Tetracaine. 4 mg (4 patients) or procaine, 3.3% (1 patient) Procaine, 25 mg. ammonium sulfate, 400 mg. in 5 ml of sterile water Procaine Dibucaine. 1:1,500

Guttman (39)

Kennedy (40)

5
2

1 2

Piperocaine, 10% Tetracaine

Unknown Unknown

1
1

Procaine Not stated Tetracaine-dextrose Tetracaine-dextrose Procaine in CSF Tetracaine Tetracaine in dextrose

Unknown Unknown Unknown Metastatic carcinoma to cord, dura and vertebrae Unknown Possible contamination of local anesthetic with formaldehyde Authors postulate that detergent (Alkonox) used to wash syringes was responsible Unknown

Nicholson (41)

1 3

2
1 Paddison (42) 1

Payne (43)

Dibucaine. 0.2%

Seigne (44) Winkelman (45)

Tetracaine. 0.1 % Not stated

Unknown Sequelae attributed to inadequate rinsing of detergent solution from syringes

8
Williams (46)
1

Not stated Procaine

Patient received spinal anesthesia with procaine 3 times over 2 mo Unknown

Not stated

toms usually had their onset immediately after the effects of the spinal anesthesia had worn off, and may be permanent or show gradual regression over periods of weeks or months. Adhesive arachnoiditis is probably the most serious sequela of spinal anesthesia. Typical cases are de-

scribed by Bergner et a1 (33), Kennedy et a1 (40), and Winkelmen (45).Usually, gradual progressive weakness and sensory loss of the lower extremities occurs beginning several weeks to several months after spinal anesthesia. This may lead to complete paraplegia, and, in severe cases, to death. Laminectomy or auANESTHESIA AND ANALGESIA Vol 60, No 3, March 1981

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topsy reveals a proliferative reaction of the meninges with adhesive arachnoiditis and constriction of the spinal cord. In Table 4 are listed several cases in which paraplegia or paralysis following spinal anesthesia was due to preexisting pathology, such as metastatic lesions to the cord or meninges. These cases illustrate the potential ability for spinal anesthesia to precipitate neurologic deficits in patients with central nervous system pathology, or for spinal anesthesia to be temporally, but purely coincidentally, related to the onset of neurologic deficits due to other causes.

Possible Causes of Spinal Cord Injury

Spinal Cord Ischemia Four cases of lower limb paralysis following prolonged hypotension during surgery are summarized in Table 5. All patients received epidural anesthesia with lidocaine plus epinephrine, and systolic blood pressure remained below 100 mm Hg during surgery. After the effects of the anesthesia had worn off, a flaccid paralysis or paresis of the lower extremities was noted, with loss of bladder or rectal function in two cases. Neurologic examination revealed the ab-

sence of knee and/or ankle jerks. Sensation was impaired in two patients, and the outcome in these cases ranged from no change in neurologic signs to a gradual moderate return of motor function. In the two patients who died from intercurrent illness, autopsy revealed degenerative changes of the lower spinal cord indicative of ischemic necrosis. It has been suggested that the spinal cord infarction in these cases was associated with prolonged arterial hypotension during surgery (47). Other factors must have been involved, however, as epidural anesthesia is frequently employed to produce controlled hypotension during surgery without producing neurologic damage. In the above cases, factors such as posture, caval compression, and use of epinephrine may have contributed to a compromise of blood flow to the lumbosacral cord (47). Whatever the exact causes, partial or complete vascular occlusion may be responsible for spinal cord ischemia or infarct. The blood supply to the areas of the cord between adjacent radicular vessels is precarious (21). Individual anatomic differences may be important as well; a deficiency in segmental supplements of the anterior spinal artery may make some people especially vulnerable to spinal cord ischemia (48).

TABLE 5 Cases of Spinal Cord infarction Due to Arterial Hypotension during Epidural Anesthesia
Davies (1 5) Anesthesia Epidural at L1-2 with 27 ml of 1.75% lidocaine, 1: 300,000 epinephrine 80-90 mm Hg. 45 min 1st day after surgery Both legs paralyzed; very slight movement of right foot, left toes; loss of bladder and rectal function Knee and ankle jerks absent; no plantar responses Loss to pinprick to level of umbilicus: fine and course touch intact; Posture and vibration senses intact Harrison (1 7) Epidural at L4-5 with 30 ml of 1.5% lidocaine, 1:200,000 epinephrine 55-65 mm Hg, falling to 50 mm Hg after surgery Immediately after surgery Severe motor weakness of legs, hips and ankles, more oronounced on left Urquhart-Hay (21) Epidural at L3-4 with 36 ml of 1.5% lidocaine, 1:200.000 epinephrine 80-90 mm Hg Immediately after surgery Severe symmetrical motor weakness affecting cord segments Li-S1 with less involvement of L3-4 level, loss of bladder function Knee jerks brisk, ankle jerks absent, plantar responses absent Sensation to light touch and pinprick normal Usubiaga (22): case 35 Epidural at L3-4 with 25 ml of 1.5% lidocaine. 1: 200,000 epinephrine 60-85 mm Hg Immediately after surgery Both legs paralyzed: slight movement remained in left foot

Operative systolic BP Onset of paralysis Paralysis sites

Reflexes

Knee and ankle jerks absent: plantar responses flexor Loss to pinprick L4-5 segments; relative sparing below S-1 , paraesthesia of feet 1st day, pain in midlumbar region 7th day after surgery Gradual partial return of motor power over 4 weeks, no change m sensory deficit; motor weakness present at 2% yr

Loss of deep tenden reflexes

No sensory deficit

Sensation

Outcome

Postmortem findings

Very slight improvement; return of bladder control at 5 weeks; death from intercurrent disease nine months after surgery Bilateral degeneration of spinal cord from T-10 downwards, confined to distribution of anterior spinal artery; no evidence of arachnoiditis

Return of bladder control after 8 days; no change in neurologic signs in legs; death 14 mo later from intercurrent disease Bilateral necrosis of anterior and posterior horns and nerve roots of lower lumbar cord. degenerative changes of white matter; appearance of ischemic necrosis

Slight improvement in the left leg with physical therapy; permanent complete paralysis of right leg; partial paralysis the left

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Ditzler and McIlver (49) described a case of flaccid paraplegia following hypotension during general anesthesia. Neurologic examination led to a diagnosis of anterior spinal artery thrombosis. It was believed that preexisting arteriosclerosis of the anterior spinal artery and the period of serious hypotension during surgery permitted the thrombosis. Many cases of paralysis due to occlusion of the anterior spinal artery have been reported in addition to cases associated with hypotension during regional or general anesthesia. Various causes have been cited including vascular spasm, trauma, arteriosclerosis, syphilitic thrombosis, or interference with aortic blood flow (21). Steegman (50) has described six cases of anterior spinal artery syndrome in which thrombosis of the anterior spinal artery was due to syphilitic arteritis, spinal arteriosclerosis, or infection. Clinical signs varied with the level of the lesion. With lumbar cord involvement, a flaccid paralysis of the lower extremities with sphincter disturbance was seen, and pain and temperature sense was lost below the segmental level of the lesion. The usual outcome was the return of rectal and bladder control within a few days to months. Partial return of sensation and gradual recovery of motor power may occur. A similar pattern of flaccid paraplegia or quadraplegia, incontinence, and sensory loss was seen in the cases of anterior spinal artery thrombosis reported by Wells (51). Cross-clamping of the aorta above the renal arteries for prolonged periods during surgery can also produce spinal cord injury due to ischemia (22). Symptoms appear immediately after surgery and may be severe and permanent. These include flaccid paralysis, abolition of segmental reflexes, anesthesia, and sphincter incontinence. Similar symptoms have been reported following abdominal aortography (52, 53), shock due to cardiac arrest or coronary infarction (54), and damage to intercostal vessels by surgery, trauma, or diseases of the spine (55). Studies in animals have corroborated the propensity of cord ischemia for production of paralysis or paresis. In rabbits, compression of the abdominal aorta for 20 to 25 minutes produced flaccid paralysis of the hind limbs in some animals and paresis in others (56), ligation of the intercostal arteries led to paraplegia in dogs (57), obstruction of blood flow and to the surface vessels of the cervical cord in dogs produced myelopathy and hemiparesis (58). In a review of studies in various animal species, Heymans (59) noted that paralysis can be induced by interruption of blood flow to the spinal cord for periods ranging from 1 to 20 minutes. Histologically, the

anterior horn cells were the most severely damaged, as in human cases. O n the other hand, restoration of function occurred in some species after interruption of circulation for as long as 40 minutes. Trauma Traumatic injury to the spinal cord or nerve roots during spinal or epidural anesthesia is an infrequent cause of neurologic disease. Vandam and Dripps (31) report one case in which paresthesias in legs, thighs, and feet occurred during multiple attempts at lumbar puncture. After surgery the patient developed leg weakness, loss of position sense, and backache. Symptoms improved over 3 months. In the same series of 10,098 patients given spinal anesthesia, there were 17 cases of minor sequelae after paresthesias was elicited during lumbar puncture. Symptoms included pain, paresthesias, or localized numbness of the feet or legs persisting for 1 day to 1 year. The occurrence of numbness, weakness, or pain in the legs following forceps delivery has been reported (60, 61). Symptoms are often in the distribution of the sciatic nerve and foot drop is common. Recovery is seen within several months. The most likely cause is said to be lumbosacral cord trauma by obstetric forceps (60). Murray (62) reviewed 201 published cases of postpartum paralysis of the lower extremities caused by injury to the sacral plexus. Bilateral lesions were rare, but did occur. Foot drop associated with nerve injury to the sacral plexus can be distinguished from the more frequent paralysis caused by compression of the common peroneal nerve between the head of the fibula and the stirrup used for maintenance of the lithotomy position (62). Pain is rare in the latter cases and motor loss is limited to the peripheral distribution of the peroneal nerve. Cases of nerve trauma due to the epidural catheter (63) or to abdominal retractors (64) have also been reported. Signs of localized weakness and hypoesthesia are seen, usually with complete recovery over a period of several weeks or months. Chemical Contamination of Local Anesthetic Solutions Contamination of local anesthetic solutions with detergents or other chemicals has often been blamed for production of neurologic sequelae to spinal anesthesia. The cases of aseptic meningitis reported by Goldman and Sanford (38) were attributed to soaking syringes with a phenolic disinfectant. A similar case reported by Seigne (44) was believed to be due to
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contamination with detergent, although no real evidence for this was presented. The irritant effect of contaminants in local anesthetic solutions can produce a progressive proliferative reaction of the meninges leading to adhesive arachnoiditis (65). Winkelman (45) reported 11 cases of progressive weakness following spinal anesthesia. These cases attributed to incomplete rinsing of detergent solutions from syringes. In these cases, symptoms usually were first noted within 1 or 2 weeks following spinal anesthesia. The milder cases resembled cauda equina syndrome, but others showed progressive severe impairment of function. Four patients died following ascending involvement of the cord and its membranes, eventually producing a fluid block over the vertex of the brain and internal hydrocephalus. Pathologic examination in one case showed hyperplasia of the pia mater with compression of nerve roots along the entire cord. Further cases of paraplegia due to adhesive arachnoiditis, sometimes resulting in death, have been reported. Bergner et a1 (33) suspected the cause in their six cases to have been an undetected chemical contaminant of the spinal solutions. The case reported by Paddison and Alper (42) was attributed to a detergent solution. Kennedy et a1 (40) and Williams (46) on the other hand, believed that the local anesthetic solutions were responsible for the sequelae, and Payne and Bergentz (43) recommended that large volumes or continuous injections of local anesthetics should not be used for spinal anesthesia.

Local Anesthetic Solutions

Central nervous system injury following spinal anesthesia has been attributed to a direct neurotoxic effect of local anesthetic agents or their vehicles. Ferguson and Watkins (36) reported 14 cases of cauda equina syndrome following spinal anesthesia with heavy Durocaine, a preparation in use in the 1930s that contained 10% procaine hydrochloride in 15% ethanol, glycerine, and gum acacia or gliadin. Onset of symptoms followed immediately after regression of the spinal anesthesia. The most constant finding was sphincter disturbances, but muscle weakness, usually of the lower legs, was sometimes present. Localized impairment of light touch, pinprick, and temperature sense was seen, mainly in the buttocks, but extending to the thighs in some cases. Knee and ankle jerk reflexes were diminished or absent. Most patients recovered bladder and rectal function over a period of weeks, as well as return of motor strength.

The sensory loss was permanent in 13 of the 14 cases. The incidence of cauda equina syndrome with spinal Durocaine was estimated to be between one in 90 and one in 155. MacDonald and Watkins (66) reported a study of spinal anesthesia in cats using heavy Durocaine. The vehicle components, alcohol and glycerine, did not cause paralysis, whereas 10% procaine or heavy Durocaine produced symptoms similar to cauda equina syndrome in some animals. Lower concentrations of procaine did not produce paralysis. Based on this study, Ferguson and Watkins (36) concluded that procaine itself was the causative agent in the production of the cauda equina syndrome, with paralysis of nerve roots exposed to the greatest concentration of the drug, and function of the smaller autonomic fibers being most impaired. Cauda equina syndrome has been reported following spinal anesthesia with drugs other than procaine. Ferguson and Watkins (36) cited seven cases published between 1907 and 1927 in which the anesthetic agent was Stovaine (amylocaine). Kennedy et a1 (40) and Nicholson and Eversole (41) reported cases in the 1940s in which cauda equina syndrome followed spinal anesthesia with piperocaine or tetracaine. Symptoms resembled those reported by Ferguson and Watson (36). Courville (34) in 1955 reported cases with similar symptoms, but the spinal anesthetic was not identified. In contrast to the above reports, the low incidence of complications following spinal anesthesia in the surveys listed in Table 3 is not strongly indicative of a direct neurotoxic effect of local anesthetic agents. Chloroprocaine appears to be similar to other agents in this respect. Foldes and McNall (67) administered 3.3% chloroprocaine intrathecally to 214 patients for various surgical procedures without evidence of neurologic sequelae. Greene (65) indicates that the incidence of complications due to spinal anesthesia has decreased since the 1940s, probably due to the use of lower concentrations of local anesthetics, and the fact that solutions containing such substances as alcohol, acacia, and strychnine are no longer used. The report of prolonged spinal anesthesia by Ansbro et a1 (68) supports the conclusion that local anesthetics in concentrations normally used in clinical practice produce no direct toxic effects on the cord. Continuous spinal anesthesia for ?,11, or 14 days was maintained with injections of procaine or dibucaine every 4 hours through a catheter. The only sequelae were transient fever, back pain, and stiff neck on day 14 in one patient; all symptoms cleared upon with-

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drawal of the catheter. Kamsler (69) found no increases in spinal fluid cell counts following single administrations of procaine, tetracaine, or hexylcaine, with or without dextrose, ephedrine, or epinephrine. However, catheter techniques produced large increases in spinal fluid leukocyte counts. These changes occurred in some cases in which no local anesthetic was injected, confirming that the catheter and not the local anesthetic was the causative factor. The lack of histologic changes in human spinal cords after spinal anesthesia with procaine (70) supports a similar conclusion. In another study (71), no histologic changes were seen in the spinal cord of a patient who had received 81 spinal anesthetics in 24 years. Animal Studies A number of animal studies have been conducted to investigate the possible neurotoxic effects of local anesthetics. Davis et a1 (72) in 1931 reported a study in which dogs were given intrathecal injections of Spinocaine, Gravocaine, and Scurocaine, three procaine preparations in use at that time. Dose-related but reversible histologic changes were seen, including an inflammatory meningeal reaction and secondary degenerative changes in the spinal cord. In contrast to the above results, Lundy et a1 (73) showed that the central nervous system of the dog is able to withstand large doses of procaine. Intradural injection of 5 ml of 25% or 50% procaine produced permanent paralysis of the hind limbs and degenerative changes of the myelin sheath. Lower concentrations or smaller volumes of the high concentrations had no permanent effects. The pia mater and arachnoid were not thickened in any animal, nor was inflammation observed in the subarachnoid space. Tui et a1 (74) did a similar study in cats and rabbits using various concentrations of procaine, monocaine, and dibucaine. All animals that survived the anesthetic recovered full sensory and motor function. Minimum anesthetic concentrations of the drugs produced no histologic changes of the cord or meninges. Reversible inflammatory and degenerative changes were seen following minimal lethal concentrations or half of minimal lethal concentrations. All changes were absent by 14 days after injection. Several animal studies have looked at the effects of possible contaminants of spinal solutions. Denson et a1 (75,76) soaked syringes in 1% 5%tribasic sodium or phosphate or various detergent solutions, then autoclaved them without rinsing before giving spinal anesthesia with 1%tetracaine to monkeys. Experimental

animals and control animals given spinal anesthesia without contaminants were observed for 3 to 14 months, then sacrificed. Examination of the spinal cord showed adhesive arachnoiditis in 12 of the 14 experimental monkeys, one of which became clinically paraplegic after 4 months. No gross or microscopic evidence of neuropathology was seen in the control animals. Hurst (77) studied the effects of various detergents and antiseptics injected into the cisterna magna of monkeys. There were no or few immediate symptoms, but progressive, severe neurologic signs occurred after a latent period. Histologically, the various agents damaged the superficial structures and elicited a cellular proliferation of the pia-arachnoid with consequent obstruction of CSF. Necrosis of meningeal arteries leading to obstruction of the lumen and restriction of blood supply to nervous tissues was also seen. Similar histologic changes have been reported in dogs given subarachnoid injections of anionic or cationic detergents (78).

Neurologic Deficit following Epidural or Subarachnoid Administration of Chloroprocaine

Clinical descriptions of the cases recently reported by Reisner et a1 (1) and Ravindran et a1 (2) are presented in Table 6. Chloroprocaine was administered for epidural anesthesia in all four patients, but inadvertent subarachnoid injection resulting in total spinal block occurred in two patients. In the case reported by Reisner et a1 (I), mechanical ventilation was required for 5% hours following administration of 25 ml of 3%chloroprocaine. In case 3 of Ravindran et a1 (2) artificial ventilation was continued for 2% hours after injection of 23 ml of 2% chloroprocaine. In the other two cases reported by Ravindran et al, total spinal anesthesia did not occur. The only indication of subarachnoid administration was very rapid onset of perineaI anesthesia foilowing injection of 10 to 12 ml of 3% chloroprocaine. Motor weakness was seen in all four patients, sensory loss was reported in three patients, and sphincter disturbances occurred in two. Recovery from anesthesia was very slow in cases 2 and 3 of Ravindran et a1 (4,with a gradual return of motor function over 3 days. These two cases resemble previous reports of delayed recovery after epidural block with bupivacaine. Six patients reported by Cuerden et a1 (79), Maycock (BO), and Pathy and Rosen (81) experienced sensory and motor deficit for between 11 and 60
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TABLE 6 Neurologic Deficit following Epidural or Inadvertent Subarachnoid Block with Chloroprocaine
Reisner et al (I) Anesthesia 3% chloroprocaine with 1 : 200,000 epinephrine, 3 4 test dose, then 25-ml single injection Postpartum tubal ligation Respiratory arrest shortly after injection; mechanical ventilation for 5% hr, blood pressure stable; operation completed under ketamine, nitrous oxide Immediately following procedure Marked weakness of the lower extremities, urinary retention, fecal incontinence Ravindran et al , (2): case 1 3% chloroprocaine, total of 1 6 ml over 90 min by catheter Labor and vaginal delivery Minimal dyspnea; given supplemental oxygen; blood pressure at 100/70 to 110/80, patient conscious throughout delivery Immediately following regression of anesthesia Paralysis of lower extremities Ravindran et al(2): case 2 0.5% bupivicaine with 1 : 200.000 epinephrine, 11 ml for labor, then 12 ml of 3% chloroprocaine Labor and vaginal delivery Systolic blood pressure fell to 90 mm Hg; quickly controlled with fluids and uterine displacement Immediately following delivery Paresis of lower extremities 3 hr after delivery; incontinence Knee and ankle jerks absent Intact touch, vibration, pressure, position senses Ravindran et al(2): case 3 2% chloroprocaine, 4 4 test dose followed by 23 ml Postpartum tubal ligation Dyspnea progressing to apnea; mechanical ventilation for 2% hr

Procedure Operative course

Onset of sequelae Motor function Reflexes Sensation

Immediately following procedure Paralysis of lower extremities 7% hr after epidural injection

Outcome

Loss of pinprick senses below T-12 level at 20 hr. below 5-2 at 25 hr after anesthesia: vibratory and position sense intact Gradual return of muscle power over 4 weeks; return of bowel function at 3 wk; 7 wk after surgery, patient developed back pain, marked paresis of lower extremities and patchy sensory loss to T-12; urinary and fecal incontinence; diagnosis of adhesive arachnoiditis or arachnoid cyst by myelography

Knee and plantar reflexes absent bilaterally Intact pressure, touch, vibration and position sense; tactile discrimination and temperature senses absent below L-1 Gradual partial return of motor function; walking with aid of crutches and brace on left leg at 4 wk

Tingling sensation in right lower extremity

Complete recovery of neurologic function by 72 hr after delivery

Recovery of motor function by 72 hr after surgery; residual numbness of heels and buttocks subsided over 6 mo

hours after epidural injection of 10 to 36 ml of 0.375% or 0.5%bupivacaine, with or without epinephrine. In case 2 of Ravindran et a1 (2) 11 ml of 0.5%bupivacaine with 1:200,000 epinephrine was used for relief of labor pains before injection of chloroprocaine for perineal analgesia. It is possible that the epidural bupivacaine played a role in prolonging anesthesia in this patient. The case reported by Reisner et a1 (1)and case 1of Ravindran et a1 (2) also showed early onset of sensory and motor deficit. Gradual recovery was seen over a period of several weeks, but after 4 weeks, leg weakness persisted in case 1 of Ravindran et al, and Reisners patient required intermittent bladder catheterization and had loss of pinprick sensation to 5-4. This patient returned to the hospital 7 weeks after surgery with back pain, marked paresis of the lower extremities, and patchy sensory loss to T-12. A myelogram was consistent with a diagnosis of adhesive arachnoidosis or an arachnoidal cyst. Some return of sensory and motor function was seen, but after 9 weeks the patient remained markedly paretic, incontinent of feces, and unable to void. At this time there was some return of sensation to legs and buttocks.

Etiology of Neurologic Deficit

Comparison of the clinical findings in the two cases of prolonged sequelae following injection of chloroprocaine to those of the previously described syndromes may provide clues to the etiology of the former. The immediate onset of neurologic sequelae most closely resembles cases of paralysis due to hypotension during surgery, following either epidural anesthesia (Table 5 ) or general anesthesia. The pattern of motor and sensory loss with gradual recovery over a period of weeks is similar to that seen in cases of cord infarction due to hypotension or anterior spinal artery thrombosis. Cauda equina syndrome following spinal anesthesia is also usually characterized by immediate onset and gradual recovery of sphincter control. However, sensory loss was said to be permanent in the cases reported by Ferguson et a1 (36).In Reisners (1) patient, the paresis and incontinence that developed after 7 weeks is consistent with the delayed onset seen in adhesive arachnoiditis, but the early symptoms could not have been produced by arachnoiditis. Trauma cannot be completely ruled out in the

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chloroprocaine cases, although paresthesias were not elicited, and the distribution of motor and sensory loss was not localized. With regard to the possible direct neurotoxic effect of chloroprocaine, solutions of this agent have been used for spinal anesthesia without adverse effects (67). Moreover, prolonged exposure of the sciatic nerve in rats to 1% chloroprocaine produced no evidence of nerve injury (82). The low pH of chloroprocaine solutions (pH 2.7 to 4.0) has been suggested as a possible causative factor (83). Other local anesthetic solutions are also acidic. For example, the pH of lidocaine solutions containing epinephrine is in the range of 3.5 to 4.0 (84).Intrathecal injections of solutions with pH less than 4.0produced no residual effects in monkeys (85). The fact that large volumes of local anesthetic are sometimes used for epidural anesthesia may contribute to neurologic damage following inadvertent subarachnoid injection. In the two cases of total spinal block following chloroprocaine, more than 20 ml was administered. If all of this volume was injected intrathecally, the local anesthetic would escape the dilutional and buffering effects to be expected with the small volumes normally employed in spinal anesthesia. Thus the lumbar cord would be exposed to a high concentration of chloroprocaine at a low pH. Another possibility involves ischemic injury to the cord. As noted above, the early symptoms in the cases reported by Reisner (1)and Ravindran et a1 (2) resemble those of anterior spinal artery syndrome or paresis caused by hypotension during surgery. The administration of a large volume of solution into the subarachnoid space may have produced spasm of the spinal arteries with resulting ischemia or infarct. The effects of local anesthetics on the spinal vasculature are unknown. Certain agents including chloroprocaine and bupivacaine have been shown to cause vasoconstriction in gravid uterine blood vessels (86). The presence of epinephrine in the anesthetic solution in the patient reported by Reisner (1) may have contributed to a vasospastic reaction. A vascular mechanism for the spinal cord injury is an attractive hypothesis for several reasons. The lower spinal cord is vulnerable to ischemic injury because of the anatomy of its blood supply (55). A deficiency in segmental supplements to the anterior spinal artery may make some people more prone to ischemic injury to the spinal cord than others (46). The fact that all of the cases were obstetric may also be significant in that hemodynamic changes due to pregnancy may have compromised circulation to the spinal cord. Pedersen and Finster (87)report that diversion of venous blood

via the intervertebral venous plexus and azygos vein to the superior vena cava occurs in late pregnancy and results in engorgement of the intervertebral plexus and reduction in the size of the epidural and subarachnoid spaces. In addition, the lower aorta may be compressed in the supine position. The coincidental occurrence of paralysis folIowing spinal anesthesia has been reported (88). In an evaluation of the electromyelogram, Marinacci and Courville (89) found that of 482 patients whose neurologic complaints seemed to be related to spinal anesthesia, 478 turned out to be caused by concurrent and unrelated conditions. Thus the possibility that a preexisting condition played a role in one or more of the chloroprocaine cases cannot be excluded.

Conclusions
Four cases of prolonged neurologic deficit following the use of chloroprocaine for epidural block have been reported. Inadvertent subarachnoid administration occurred in at least two of these patients. The literature on neurologic sequelae following epidural or spinal anesthesia has been reviewed. Clinical descriptions and possible etiologic factors are presented for cases resembling the four recent cases. Most survey reports indicate that the incidence of severe neurologic deficit following epidural or spinal block is very low; however numerous published case reports describing temporary or permanent paralysis following these procedures have appeared. Paraplegia may be due to cord ischemia or infarct caused by arterial hypotension during surgery, or compromise of blood supply to the cord by the procedure or condition of the patient, or by production of an epidural or subdural hematoma. Injury to the spinal cord or the nerve roots has also occurred following inadvertent subarachnoid administration of toxic chemicals or chemical contamination of anesthetic solutions. Chemical contaminants such as detergents or antiseptics act as irritants and induce a meningeal reaction which may progress to constrictive adhesive arachnoiditis. The pattern of symptoms and the timing of their onset in the recently reported cases appears to resemble most closely cases of cord ischemia following spinal or epidural anesthesia. Symptoms are also similar to cord ischemia produced by other causes, such as shock or aortography. Anterior spinal artery spasm may have been produced by one or more of the following factors: subarachnoid administration of a large volume of anesthetic solution, the vasoconstricANESTHESIA AND ANALGESIA Vol 60, No 3. March 1981

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tive effects of chloroprocaine, the possible vasoconstrictive effect of the vehicle or its pH, and the addition of epinephrine to the anesthetic solution. Special susceptibility to cord ischemia may have been present due to hernodynamic changes during pregnancy. In view of the fact that causation of adverse reactions to inadvertent subarachnoid introduction of local anesthetics is conjectural, the precautions iterated by Covino et a1 (83) should be kept in mind when using any of these agents epidurally. These precautions include use of an adequate test dose to rule out inadvertent intrathecal placement of the catheter, injection of repeated fractional doses rather than large single doses, and, in the case of intrathecal injection of a full anesthetizing dose, withdrawal of a similar volume of CSF. Clearly, further work is needed in order to determine the factors associated with the fortunately rare but severe neurologic complications associated with epidural or spinal anesthesia. It is especially desirable that animal studies be conducted to explore the possible role of local anesthetics, vehicle components, injection volume, and intraoperative blood pressure in producing prolonged neurologic sequelae.
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