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Regional Blockade in Patients with a History of a Seizure Disorder

Kopp, Sandra L. MD; Wynd, Kimberly P. MBBCh; Horlocker, Terese T. MD; Hebl, James R. MD; Wilson, Jack L. MD

doi: 10.1213/ane.0b013e3181a832da
Analgesia: Regional Anesthesia: Research Reports

BACKGROUND: Systemic local anesthetic toxicity is a potential complication in patients undergoing regional anesthesia, particularly during procedures requiring large doses of local anesthetic, such as epidurals, caudals, and peripheral nerve blocks. It is unknown whether patients with a history of a seizure disorder are at an increased risk of central nervous system toxicity (seizures) after local anesthetic administration.

METHODS: We retrospectively reviewed the medical records of all patients with documented history of a seizure disorder who underwent epidural, caudal, or peripheral nerve block from January 1, 1988 to December 31, 2001. Patient demographics, character of the seizure disorder, details of the regional procedure, and seizure activity in the perioperative period were recorded. The rate of seizure due to local anesthetic toxicity per 10,000 anesthetics was estimated using a point estimate and corresponding 95% confidence interval (CI).

RESULTS: During the 14-yr study period, 411 procedures in 335 patients with a seizure disorder were identified. Twenty-four patients experienced postoperative seizure activity. The timing of the most recent (preoperative) seizure was found to be significantly related to the likelihood of experiencing a postoperative seizure (P < 0.001). Based on the extended time interval between local anesthetic injection and/or termination of the infusion and the event, it was determined that the regional anesthetic was neither the primary etiology nor a contributing factor for the seizure in 19 of the 24 patients. In the remaining five patients, perioperative seizure activity was characteristic of their usual seizures. Although unlikely to be the cause of the seizure, local anesthetic toxicity could not be absolutely excluded as a contributing factor to the event in these five patients. Assuming that none of the seizures was related to local anesthetic toxicity the estimated incidence is 0 per 10,000 (95% CI 0–89 per 10,000). Conversely, if the seizures were related to local anesthetic toxicity in the five cases, the incidence is increased to 120 per 10,000 (95% CI 40–280 per 10,000).

CONCLUSIONS: We conclude that majority of seizures occurring in the perioperative period in patients with a preexisting seizure disorder are likely related to the patient’s underlying condition and that regional anesthesia in these patients is not contraindicated. Furthermore, because the likelihood of a postoperative seizure is increased in patients with a recent seizure, it is essential to be prepared to treat seizure activity, regardless of the anesthetic and analgesic technique.

From the Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota.

Accepted for publication January 21, 2009.

Terese T. Horlocker is the Section Editor of Regional Anesthesia. This manuscript was handled by Steven L. Shafer, Editor-in-Chief, and Dr. Horlocker was not involved in any way with the editorial process or decision.

Address correspondence and reprint requests to Sandra L. Kopp, MD, Department of Anesthesiology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905. Address e-mail to kopp.sandra@mayo.edu.

Local anesthetic toxicity is a potential risk for all patients undergoing regional anesthesia, particularly during procedures that require a large dose of local anesthetic, such as epidural, caudal, or peripheral nerve block. Systemic local anesthetic toxicity presents as a spectrum of neurologic signs and symptoms that worsen as plasma-drug levels continue to rise. Symptoms of central nervous system (CNS) toxicity generally follow a progression from lightheadedness, dizziness, and perioral numbness to visual or auditory disturbances and tinnitus. These are usually followed by peripheral muscle twitching and ultimately generalized tonic-clonic convulsions.

Previous studies have determined the time-to-peak plasma levels after a single bolus of local anesthetic to range from 15 to 120 min depending on anatomic location.1,2 The limited data available regarding continuous infusions of local anesthetics indicate that plasma levels continue to rise throughout the duration of the infusion.3,4 The published incidence of CNS local anesthetic toxicity (seizure) in the general population undergoing regional anesthesia ranges from 1.2 to 11 per 10,000 epidural anesthetics,5–9 1.3–69 per 10,000 caudal anesthetics,5,10 and 0–25.4 per 10,000 peripheral nerve blocks.5–7,9 However, these series did not report the number of patients with a preexisting seizure disorder. Although literature to support withholding a regional anesthetic from patients with a history of a seizure disorder is lacking, modifications to standard practice are recommended, such as selection of less potent local anesthetics, minimizing local anesthetic dose, and opting for a postoperative epidural infusion of opioid rather than local anesthetic.11

Historically, local anesthetics have been used to treat status epilepticus because of their concentration-dependent effect on seizures. At low blood levels, local anesthetics decrease cerebral blood flow, metabolism, and electrical activity, and are potent anticonvulsants. Conversely, at higher levels, they act as proconvulsants by lowering the seizure threshold within the cerebral cortex, amygdala, and hippocampus, usually leading to a generalized convulsion.12 As the serum drug level continues to rise, both the inhibitory and excitatory neural pathways are blocked, resulting in generalized CNS depression.

Currently, it is unknown whether patients with a history of a seizure disorder are at an increased risk of CNS toxicity after the administration of large doses of local anesthetics. This retrospective study evaluated the frequency of seizure activity in patients with a history of a seizure disorder who subsequently underwent regional blockade.

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METHODS

After IRB approval, all patients with a documented history of a seizure disorder (seizure disorder listed as a medical diagnosis in the medical record) who subsequently underwent an epidural, caudal, or peripheral nerve block from January 1, 1988 through December 31, 2001 were identified. Patient demographics including age, gender, ASA physical status classification, and the urgency (elective or emergent) of the surgery were recorded. We recorded the characteristics and clinical course of the seizure disorder, including type of seizure disorder (absence, simple partial, complex partial, or convulsive), seizure frequency, most recent seizure, antiepileptic drug use, medication administration that may interact with antiepileptic drugs (e.g., antibiotics, anesthetics, antihistamines), and blood levels of antiepileptic drugs within 2 wk of the procedure. Details of the regional anesthetic technique were also documented, including procedure, type and dose of local anesthetic bolus, subsequent local anesthetic administration or infusions, adjuvants used, time of last sedative administration, and the presence of any CNS activity (tinnitus, perioral numbness, myoclonic jerks, tonic/clonic seizure, or partial seizure) during the block placement. For all patients experiencing seizure activity during their hospitalization, the circumstances surrounding the event were documented, including time of seizure, type of seizure, recent local anesthetic administration, antiepileptic drugs, medications administered at the time of seizure, and recent antiepileptic drug blood levels. Information pertaining to the seizure activity was derived from anesthetic records, postanesthesia care unit notes, and daily progress notes of the primary service, medical consultation team(s), and the anesthesia pain service. The cause of the seizure was determined using published data on the timing of peak blood levels, frequency of preoperative seizures, antiepileptic drug levels, results from neurology consultation, and documentation detailing the seizure activity.

Patient and procedure characteristics were summarized for the entire cohort using mean ± SD for continuous variables and percentages for categorical variables. The rate of seizure due to local anesthetic toxicity per 10,000 anesthetics was estimated using a point estimate and corresponding 95% confidence interval (CI).

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RESULTS

During the 14-yr study period, 411 caudal, epidural, or peripheral nerve blocks were performed in 335 patients with a documented history of a seizure disorder. Twenty-four patients had at least one episode of CNS (seizure) activity in the perioperative period. Sixteen patients had a single injection of local anesthetic and eight patients had a continuous infusion of local anesthetic. No patient experienced a seizure during or immediately after (<50 min) administration of the local anesthetic initial loading dose. The mean patient age was 42.8 ± 24.5 yr (range, 1 mo–94 yr). Patient characteristics including gender, ASA physical status, type of regional block, reason for surgery, seizure type, and seizure rates during hospitalization are provided in Table 1. Patients with a recent preoperative seizure were significantly more likely to experience a seizure during the perioperative period (P < 0.001) (Table 2).

Table 1

Table 1

Table 2

Table 2

Of the 24 patients who had a perioperative seizure, the regional anesthetic was determined to be coincidental and not causal in 19 patients due to the extended time interval between injection of local anesthetic and the seizure. Of these 19 patients, 15 received only a bolus dose of local anesthetic and four received a bolus of local anesthetic followed by a continuous infusion (Table 3). One patient experienced pseudoseizure activity 50 min after the local anesthetic bolus, four patients within 6 to 12 h, five patients within 12 to 24 h, and five patients more than 24 h after the local anesthetic bolus. In all four patients with a continuous infusion of local anesthetic, the seizure did not occur until more than 5 h after the infusion was discontinued.

Table 3

Table 3

Table 3

Table 3

In five of the 24 patients, local anesthetic toxicity could not be definitively excluded as a cause or contributing factor of the seizure activity (Table 4). Two patients experienced frequent (almost daily) seizures before hospital admission. Although the seizures noted postoperatively were similar to their “normal seizure activity” they occurred during the local anesthetic infusion and therefore CNS toxicity cannot be excluded. One patient who preoperatively experienced at least monthly seizures had bradycardia and facial twitching 90 min after a bolus of local anesthetic for an axillary block. Although the neurology consult documented this was likely not a seizure, preseizure activity facilitated by local anesthetic absorption cannot be absolutely excluded as a contributory factor. Two patients receiving antiepileptic medication who had not experienced a seizure for at least 1 yr preoperatively had an episode of seizure activity during an epidural infusion of local anesthetic. One patient with a subtherapeutic antiepileptic drug blood level had an epidural placed for pain control after a pneumonectomy and experienced a seizure 15 min after the infusion (bupivacaine 0.075%, 8 mL/h) had been discontinued. The second patient taking phenobarbital (unknown blood level) had been seizure-free for more than 6 yr and had an epidural placed for labor and delivery. Fifty minutes after the local anesthetic initial loading dose (bupivacaine 0.125%, 15 mL) and 40 min into the infusion (bupivacaine 0.125%, 10 mL/h), the patient felt that she had a seizure. However, there was no witnessed tonic-clonic activity, loss of consciousness, or postictal symptoms. The epidural infusion was stopped for 50 min and subsequently restarted with no further episodes of seizure activity.

Table 4

Table 4

Assuming that local anesthetic toxicity did not play a role in any of the seizures (0 of 24 events), the seizure incidence during the perioperative period would be 0 per 10,000 (95% CI 0–89 per 10,000) anesthetics. Although unlikely, if local anesthetic toxicity contributed to the five seizures described above, the incidence would be 120 per 10,000 (95% CI 40–280 per 10,000) anesthetics.

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DISCUSSION

Seizure is defined as the clinical manifestation of abnormally hyperexcitable cortical neurons. Although all patients with epilepsy have seizures, many patients have a single seizure during their lives and are not considered to have epilepsy. A population-based epidemiologic study from Rochester, MN, found that the cumulative incidence of epilepsy through 74 yr of age is 3.0%, with an incidence of any convulsive disorder approaching 10%.13 Therefore, it is not uncommon for a patient with the diagnosis of a seizure disorder to present for a surgical procedure in which regional anesthesia or analgesia may be considered. Furthermore, there are no data regarding the overall incidence of perioperative seizures in patients with a history of a seizure disorder and the effect of anesthetic and analgesic management on seizure risk.

Our investigation identified 24 patients who experienced perioperative seizure activity. It is difficult to determine whether a perioperative seizure is due to the seizure disorder itself, or any of the numerous factors that influence the frequency of seizures in this population. Common factors that may provoke seizure activity include fluctuations in antiepileptic drug blood levels, sleep deprivation, fatigue, stress, excessive alcohol intake, and menstruation.14,15 The reduction in antiepileptic drug serum levels is a well known cause of seizure provocation during the perioperative period.16 Factors that have been shown to contribute to fluctuations in antiepileptic drug levels during the perioperative period include preoperative antiepileptic drug noncompliance, changes in the antiepileptic dosing schedule, anesthetic drugs, perioperative medications, and alteration of gastric motility leading to delayed absorption and reduced bioavailability.15,17

Conversely, results from animal studies suggest that specific anticonvulsants may provide a degree of protection against lidocaine-induced seizures. For example, benzodiazepines (diazepam and clonazepam) seem to confer the greatest protection against local anesthetic-induced neurotoxicity within animal models. Phenobarbital and carbamazepine are also protective; however, phenytoin and primidone may enhance local anesthetic convulsions.18

Four patients experienced a postoperative seizure during or immediately after an epidural/caudal infusion of local anesthetic. One patient experienced bradycardia and facial twitching 90 min after an axillary block. Although the cause of the seizures was likely multifactorial, local anesthetic toxicity could not be absolutely excluded in these patients. In the remaining 19 patients who experienced a postoperative seizure, local anesthetic toxicity was determined to be unlikely based upon published data estimating time to peak blood levels after local anesthetic administration or a combination of variables, such as altered administration of antiepileptic drugs and overall preoperative seizure frequency. Previous studies have determined that the time to peak plasma levels after a bolus of local anesthetic varies from 15 to 120 min (Table 5). A limited number of studies evaluating infusions through continuous catheters indicate that local anesthetic plasma levels continue to rise throughout the duration of the infusion (Table 6). The peak blood level measured in patients with a continuous psoas or femoral 3-in-1 block occurred at 48 h, which also corresponded to the time that the infusion was discontinued.3 As the use of prolonged perineural infusions increases, further studies are needed to determine the risk of local anesthetic toxicity in this patient population. Patients who had frequent seizures near the time of admission were significantly more likely to experience a seizure during their hospital course when compared to patients with less frequent seizures.

Table 5

Table 5

Table 6

Table 6

A previous study at our institution, during the same time period, reported the incidence of CNS toxicity among all patients undergoing regional anesthesia (epidurals, caudals, and peripheral nerve blocks) to be 10 per 10,000 regional anesthetics.5 It is difficult to interpret whether our results represent an increased risk, because determining the exact etiology of the perioperative seizure in this population is challenging. The difficulty arises due to incomplete documentation regarding the preoperative and perioperative seizure, as well as limited information on local anesthetic and antiepileptic blood levels.

In summary, we conclude that regional anesthesia in patients with a history of a seizure disorder is not contraindicated. However, the relative risk of inducing seizure activity with a regional anesthetic technique in patients with a diagnosis of seizure disorder, compared with patients without such a diagnosis, is unknown. Furthermore, because the likelihood of a postoperative seizure is increased in patients with a recent seizure, it is essential to be prepared to treat seizure activity, regardless of the anesthetic or analgesic technique.

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