Seizures and Opisthotonos After Propofol Anesthesia Curtis B. DeFriez,

MD,

and Harry C. Wong,

MD

Department of Anesthesiology, University of Utah Medical Center, Salt Lake City, Utah

S

eizures occurring after general anesthesia are a rare event, and opisthotonos even more rare. Since its introduction in the United l n g d o m in June 1986, there have been several reports in the European literature of seizures and opisthotonos occurring after propofol anesthesia. Similar sequelae have yet to be reported in North America. Two cases are described of seizurelike activity associated with opisthotonic posturing that occurred in patients in our ambulatory surgery unit after they received propofol anesthesia.

Case Reports Patient 1 A healthy 34-yr-old, 85-kg man without a history of alcohol or drug use underwent arthroscopy and menisectomy of his left knee. Anesthetic induction consisted of intravenous midazolam (2 mg) and dtubocurarine (3 mg), followed 3 min later by propofol (2.4 mg/kg). Endotracheal intubation was facilitated by intravenous succinycholine (1.5 mg/kg). Anesthesia was maintained with 70% N,O in 0, and propofol infused at 200 pg.kg-'min-l for 15 min, then 150 pg' kg-l-min-' for an additional 30 min. Intravenous atracurium (20 mg, plus an additional 10 mg) was administered initially to facilitate controlled ventilation. After 40 min, spontaneous respiration was assisted with end-tidal CO, measured at 38 mm Hg. Muscle relaxant reversal was not deemed necessary at the end of surgery because the train-of-four ratio was 44, and unassisted respiratory effort and gas exchange were normal (end-tidal Pco, 3740 mm Hg). Intravenous ketorolac (60 mg) was administered for postoperative pain control, and the propofol infusion was discontinued 15 min before the trachea was extubated. The surgery was complicated by dissection of the isotonic irrigation fluid through the capsule of the knee, with Accepted for publication May 21, 1992. Address correspondence to Dr. DeFriez, Department of Anesthesiology, University of Utah Medical Center, 50 North Medical Drive, Salt Lake City, UT 84132.

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approximately 1L of lactated Ringer's solution extravasated within the tissues of the upper left thigh. The vital signs recorded on arrival in the recovery room were blood pressure (126/96mm Hg), heart rate (68 beatsimin), respiration (18 breathsimin), oral temperature (35.6"C), and oxygen saturation (96% on mask oxygen at 8 L/min). Approximately 2 min later, the patient had a generalized, tonic-clonic seizure that was temporarily ablated with intravenous midazolam (5 mg). Within 5 min, a second and then a third seizure, each lasting 1-2 min, were observed. Extension posturing of the head and neck immediately preceded and accompanied each event. The trachea was reintubated after intravenous thiopental(75 mg) and succinylcholine (80 mg). Spontaneous ventilation resumed within 10 min while 50% oxygen was administered through the endotracheal tube. The possibility of hyponatremia or hypoglycemia was excluded by normal electrolyte and serum glucose test results. An arterial blood gas sample drawn just after the first seizure revealed pHa 7.39, Paco, 40 mm Hg, Pao, 142 mm Hg, and hemoglobin level 14.3 g/dL. Auscultation of his chest was clear, with no wheezes or rales; he remained hemodynamically stable and well oxygenated for the entire episode. He was admitted to the University Hospital, where head computed tomography scan and electroencephalogram test results were unremarkable. Serum toxicology tests taken just after transport to the hospital showed no evidence of alcohol or illicit drug use. No further seizures were observed, and his sensorium cleared over 4-5 h. The fluid in his left thigh rapidly mobilized, and there was no indication of excessive circulatory volume or electrolyte imbalance. He was observed in the hospital overnight and discharged the next morning. This patient had been involved in a motor vehicle accident 15 yr earlier and had sustained a closed head injury from which he fully recovered. He denied any personal or family history of a seizure disorder.

Patient 2 An athletic 18-yr-old, 55-kg woman presented for diagnostic arthroscopy of the left knee. Anesthesia 91992 by the International Anesthesia Research Society

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was induced with intravenous midazolam (2 mg) and d-tubocurarine (3 mg), followed 3 min later by propofol (2.5 mg/kg) and succinylcholine (1.5 mg/kg) to facilitate endotracheal intubation. The anesthetic maintenance consisted of 70% N 2 0 in 0, and propofol infused at 200 pgkg-lamin-’ for 10 min, then decreased to 120 pg.kg-’.min-l for 15 min. After endotracheal intubation, atracurium (20 mg IV) was administered to control ventilation, maintaining endtidal CO, at 35 mm Hg. Intravenous ketorolac (60 mg) was administered to help manage postoperative pain. Vital signs and pulse oximetry readings were within normal limits during the operation. At the conclusion of surgery, the neuromuscular block was reversed with edrophonium (25 mg) and atropine (0.5 mg), and a normal ventilatory pattern was confirmed. After an uneventful tracheal extubation, the patient was transported to the recovery room. The patient’s emergence from the anesthesia was unexpectedly delayed, because she remained unconscious for >1 h in the recovery room with normal vital signs and pulse oximetry readings of 98%, with supplemental mask oxygen at 40%. She then awoke and seemed to respond appropriately for approximately 2-3 min, when she abruptly became restless and confused and exhibited pronounced athetoid movements of her head, neck, and limbs. She was given intravenous nalbuphine (10 mg), followed 5 min later by diphenhydramine (25 mg) to ameliorate what was thought to be an extrapyramidal type of dystonia. These drugs served only to temporarily sedate her. Approximately 15 min later, she reawakened more restless than before. Her arterial blood pressure increased to 140/100 mm Hg, and her pupils were widely dilated; but her heart rate and oximetry readings remained stable at 58 beats/min and 99%, respectively. Her agitation and abnormal posturing continued to worsen, progressing to frank opisthotonos with interspersed tonic-clonic seizurelike activity. Her trachea was reintubated after administration of intravenous propofol (90 mg) and succinylcholine (60 mg), and ventilation was assisted with a JacksonReese circuit and 100% 0, during transport to the University Hospital. The patient continued to manifest extension posturing and seizurelike movements, which were temporarily suppressed with three additional bolus doses of propofol (20-30 mg IV) while in the ambulance. In the emergency room, the opisthotonic posturing became severe, and she was given two intravenous doses of thiopental (75 mg) followed by midazolam (5 mg) by bolus and then by infusion at 4 mg/h overnight, which suppressed all abnormal movements. Head computer tomography scan and spinal fluid analysis were normal. Because of the severity of the opisthotonos, the patient received intravenous

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midazolam before an electroencephalogram could be obtained. The next morning, after the trachea was extubated, the patient was oriented and cooperative, with no recollection of the postanesthesia events. She developed a postdural puncture headache after a diagnostic spinal tap, which was relieved 2 days later by a lumbar epidural blood patch. She has since returned to normal activities. She has no personal or family history of a seizure disorder and denies any alcohol or illicit drug use. Neither patient received local anesthetics nor opiates in the operating room, and the second patient was given a single dose of nalbuphine only after the onset of her problems in the recovery room.

Discussion Seizures occurring during surgery often coincide with the administration of a specific anesthetic, whereas postoperative seizures are more commonly attributable to nonanesthetic causes. This does not seem to be the case with propofol, where the majority of neurologic complications reported to date, other than the minor muscle twitches seen during induction of anesthesia, have developed in the recovery period. Specifically, opisthotonos, previously a rare phenomenon in anesthetic practice, has been a recurrent finding in case reports from the European literature (1-6) and is listed in the packaging insert as a possible adverse reaction. The Committee on Safety of Medicines (the British regulatory body equivalent to the Food and Drug Administration) has received 37 reports of seizures, many accompanied by opisthotonic posturing thought to be due to propofol. Thirteen of these patients are known epileptics, which may represent a population at relative risk. The manufacturer has knowledge of six cases in the United States involving opisthotonos, myoclonia, and seizurelike behaviors that were spontaneously reported to them during the period of November 1989 to the present (personal communication with ICUStuart Pharmaceuticals, April 21, 1992). From this information, it appears that the incidence of severe postoperative myoclonic sequalae requiring intervention is very low. The mechanism by which propofol may act to produce these neurologic events is unclear. As pointed out by Modica et al. (7) in their recent review of the pro- and anticonvulsant effects of anesthetics, what we observe clinically as a ”seizure” may or may not represent the high-voltage electrical discharge characteristic of true cortical seizures. Without electroencephalographic monitoring, they conclude, ”it is extremely difficult to determine whether abnormal appearing seizure-like muscle movements are due to epileptiform activity or nonepileptic myoclonia.” Opisthotonos, for instance, is rarely seen with corti-

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cal epilepsy but is a form of acute dystonic reaction that may be seen after administration of phenothiazinetype drugs acting at subcortical sites. Indeed, there is some evidence in a mouse model that propofol exerts effects at these deeper structures (8). Yet, Hodkinson et al. (9) reported three patients undergoing electrocorticographic mapping of seizure foci who developed true cortical epilepsy after a bolus dose of propofol (2 mgikg). In each instance, they observed complexes consisting of spikes, polyspikes, and spike and slow waves commencing 20-30 s after injection and persisting for up to 7 min. In contrast to these data, Lowson et al. (10) studied the protective effects of propofol against electrically and chemically induced seizures in mice and concluded that propofol possesses strong anticonvulsant properties. Propofol also diminishes seizure duration during electroconvulsive therapy in humans (11,12). Like other drugs that manifest both pro- and anticonvulsant activity, such as barbiturates, ketamine, enflurane, and etomidate, propofol has been used successfully to ablate status epilepticus refractory to other therapy (13’14). Although the dose of propofol used in our two patients tends toward the upper limit usually used in clinical practice, a review of the published literature fails to demonstrate a specific dose-response relationship to the events we are reporting. Although most of these patients, including the two discussed in this report, displayed only brief episodes of postanesthetic abnormalities, there have been reports of prolonged difficulties that cannot be directly related to the short hypnotic action or rapid elimination from blood of propofol. Hopkins (4)documents a case of a 29-yr-old woman who received 150 mg of propofol (2.5 mg/kg) and suffered apneic attacks, recurrent seizures, and opisthotonos for 23 days postoperatively. Another woman from Denmark reportedly had seizures for 7 days after propofol anesthesia despite antiepileptic medications (15). This leads some to speculate that a metabolite may be at fault. To our knowledge, none of the known metabolic by-products (several propofol glucuronides and the 4-sulfate conjugates of 1,4-quinol) are epileptogenic. We report these two cases to raise the awareness of anesthesiologists to the possibility of seizurelike activity and opisthotonos associated with the use of propofol in combination with many anesthetic techniques. Many anesthetic and analgesic drugs are known to produce seizure activity clinically, but the emergence of opisthotonos, and a variety of other

athetoid behaviors in the postoperative period, is almost uniquely associated with the use of propofol. The adjuvant drugs used during anesthesia were administered in small quantities, whereas the propofol was infused at rather high doses. We noted a striking exacerbation of symptoms in our second patient after administration of repeated boluses of propofol during the recovery period. Also, propofol is implicated in a number of similar reports from Europe, where it has been in clinical use since 1986. Although clinical evaluation of these two patients does not conclusively demonstrate the administration of propofol to have caused the neurologic aberrations we report, we could not find other likely explanations. Unfortunately, the current paucity of information with regard to these phenomena and how they may relate to different dosages and methods of administration of propofol, as well as differences in patient populations, makes it difficult to draw definitive conclusions or make treatment recommendations.

References 1. Dingwall AE. Oculogyric crisis after day case anaesthesia. Anaesthesia 1978;42:565. 2. Cameron AE. Opisthotonos again. Anaesthesia 1987;42:1124. 3. Laycock GJA. Opisthotonos and propofol: a possible association. Anaesthesia 1988;43:257. 4. Hopkins CS. Recurrent opisthotonos associated with anaesthesia. Anaesthesia 1988;43:904. 5. Jones GW, Boykett MH, Klok M. Propofol, opisthotonos, and epilepsy. Anaesthesia 1988;43:905. 6. Saunders PRI, Harris MNE. Opisthotonos and other unusual neurological sequelae after outpatient anaesthesia. Anaesthesia 1990;45:552-7. 7. Modica PA, Tempelhoff R, White PF. Pro- and anticonvulsant effects of anesthetics (part I). Anesth Analg 1990;70:303-15. 8. Smith MB, Soar J, Morris PJ, Dolin J. Propofol induced seizurelike behavior in mice. Br J Anaesth 1990;64:369-97. 9. Hodkinson BP, Frith RW, Mee EW. Propofol and the electroencephalogram. Lancet 1987;8574:1518. 10. Lowson S, Gent JP, Goodchild CS. Anticonvulsant properties of propofol and thiopentone: comparison using two tests in laboratory mice. Br J Anaesth 1990;64:59-63. 11. Bone ME, Wilkins CJ, Lew JK. A comparison of propofol and methohexitone as anaesthetic agents for electroconvulsive therapy. Eur J Anaesthesiol 1988;5:279-86. 12. Simpson KH, Halsall PJ, Carr CME, Stewart KG. Propofol reduces seizure duration in patients having anaesthesia for electroconvulsive therapy. Br J Anaesth 1988;61:34?4. 13. Yanny HF, Christmas D. Propofol infusions for status epilepticus (letter). Anaesthesia 1988;43:514. 14. Thomas DC, Morgan P. Propofol infusions for the treatment of status epilepticus. Today’s Anaesthetist 1989;4106-7. 15. Bredahl C . Seizures and opisthotonos after propofol anesthesia. A possible connection. Ugeskr Laeger 1990;152:748-9.

Seizures and opisthotonos after propofol anesthesia.

Seizures and Opisthotonos After Propofol Anesthesia Curtis B. DeFriez, MD, and Harry C. Wong, MD Department of Anesthesiology, University of Utah...
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