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CARDIOVASCULAR ANESTHESIA

Severe Hypotension in a Patient Receiving Pemoline During General Anesthesia

Christian H. Bohringer, MBBS, FANZCA, FFICANZCA^*, Jonathan S. Jahr, MD^*, Susan Rowell, MD, and Kathrin Mayer, MD

Departments of *Anesthesiology and Pain Medicine and Surgery, University of California Davis Medical Center, Sacramento, California

Address correspondence and reprint requests to J. S. Jahr, MD, Department of Anesthesiology, UCDMC, 4150 "V" Street, Suite 1200, Sacramento, CA, 95817.

	Abstract

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Implications: This case reports hypotension under general anesthesia in a patient taking pemoline. Vigilance for unexpected hypotension is important in patients who are treated with psychostimulants. If hypotension occurs, vasopressors that act directly on adrenergic receptors should be used.

	Introduction

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Pemoline (2-imino-5-phenyl-4-oxazolidinone) is a central nervous system (CNS) stimulant used in the treatment of narcolepsy and attention deficit hyperactivity disorder (1). Although structurally dissimilar to amphetamines and methylphenidate, it has similar stimulating effects. The central stimulating effects of these drugs appear to be related to actions on CNS dopaminergic pathways. These lead to increased wakefulness, vigilance, and a decreased sense of fatigue (1).

In animal models, pemoline’s major action involves the presynaptic release and blockade of dopamine reuptake (2). Unlike other stimulants, pemoline has minimal peripheral sympathomimetic effects. The CNS effects of pemoline are less potent, and onset of action may take several weeks. In the United States, pemoline is listed as a Schedule IV drug, whereas the other stimulants are Schedule II.

	Case Report

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A 58-yr-old, 80-kg woman was scheduled for excision of a mass in her anterior right thigh. She denied any recent weight loss. The patient’s medical history included a 3-yr history of narcolepsy with two-three episodes of cataplexy every month. She was treated for 7 mo with pemoline, 75 mg twice a day, and imipramine 150 mg at bedtime. She also had hypertension, panic attacks, and chest pain. Her hypertension was well controlled on slow-release nifedipine 30 mg daily. Because of her recent chest pain, she had an extensive evaluation: a persantine-thallium scan was equivocal, coronary angiography demonstrated normal coronary arteries, and results of a dobutamine stress echocardiogram were negative for ischemia. She had episodic loss of vision; a magnetic resonance image of her brain showed periventricular lacunar infarcts consistent with her history of hypertension. Results of a magnetic resonance angiogram were normal and excluded basilar artery stenosis, with daily aspirin prescribed for stroke prophylaxis. She had smoked one pack of cigarettes a day for 30 yr and denied using alcohol. She had no known history of allergies to drugs. She consented to general anesthesia for the excision of the lipoma. She had declined a regional anesthetic, and in view of her history of panic disorder, this was not surprising.

Before the induction of anesthesia, the patient’s blood pressure was 120/60 mm Hg, heart rate was 98 bpm, and temperature 36.5°C. Cefazolin 1g was administered IV in the preoperative holding area, without adverse effects. After routine monitors were placed and breathing of oxygen was started, general anesthesia was induced with midazolam 1 mg, fentanyl 50 µg, and propofol 100 mg. A size 4 laryngeal mask airway was placed, and the patient resumed spontaneous ventilation within 1 min. She was breathing oxygen/air in 2% sevoflurane. Within 5 min, her blood pressure decreased to 60/30 mm Hg despite rapid infusion of 1.5 L lactated Ringer’s solution. Her heart rate remained at 90 bpm, oxygen saturation at 98% to 100%. End-tidal carbon dioxide with spontaneous ventilation remained between 39 and 45 mm Hg, with a respiratory rate of 15–20 breaths/min. Ephedrine 50 mg in divided IV doses only transiently improved the hypotension (blood pressure to 85/40 mm Hg), and frequent phenylephrine boluses (100 µg/bolus) were required to maintain systolic blood pressure more than 90 mm Hg. Her skin was warm but not diaphoretic. Skin erythema, urticaria, bronchospasm, facial edema, and other features of potential anaphylaxis/anaphylactoid reaction were absent. There were no ischemic changes on a 5-lead electrocardiogram (ECG). She received prophylactic diphenhydramine 50 mg and calcium chloride 500 mg without improvement. The same anesthetic was maintained with the patient breathing spontaneously via a laryngeal mask airway with an end-tidal sevoflurane concentration of 2%. At this point, the differential diagnosis of the hypotension was primarily directed to deep anesthesia or hypovolemia. While these were being addressed, this surgeons were permitted to proceed. There was continuing hypotension requiring phenylephrine, and the patient moved slightly in response to surgical stimulation when the level of anesthesia was decreased. The duration of the surgery was 1.5 h. More than 1 mg of phenylephrine was required to maintain the systolic blood pressure more than 90 mm Hg. Arterial blood gases remained normal with no electrolyte abnormalities and a hematocrit of 34%. The emergence from anesthesia was smooth, except for continuing requirements of bolus phenylepherine.

On admission to the postanesthesia care unit, the patient initially continued to require phenylephrine boluses to raise arterial blood pressure to normal levels. When she became fully awake after 5 min, she complained of severe pain with a pain score of 10 of 10 (0 was defined as no pain and 10 as the worst pain imaginable). Her respiratory rate was 24 breaths/min. She required divided doses of 12 mg of morphine to relieve pain, without decreases in arterial blood pressure. Her blood pressure remained stable in the 120/70 mm Hg range throughout her postanesthesia care unit stay, with a stable heart rate in the range of 80 bpm. She then started to complain of sharp, left-sided chest pain without radiation. Several 12-lead ECGs demonstrated no evidence of ischemia, and a chest radiogram excluded a pneumothorax. She was admitted for observation to a telemetry unit. In the next 2 days, there were no changes on her ECGs, and the cardiac enzymes were normal. She resumed her regular medications, including pemoline, and was discharged home without further episodes of hypotension.

	Discussion

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Pemoline is used most commonly as an adjunct in the treatment of attention deficit hyperactivity disorder. It is also used as a treatment for narcolepsy in adults. Since its Food and Drug Administration approval in 1975, 13 cases of acute hepatic failure have been reported (3). It has, therefore, been removed from the market in England and remains a second-line drug in the United States. Increases in liver enzymes without hepatic failure may also occur. Insomnia is the most common side effect (3). Seizures, exacerbations of Tourette’s syndrome, tics, and other CNS effects may also occur.

A MEDLINE search from 1966 to present revealed no report of any adverse hemodynamic consequences of pemoline administration. Pemoline drug-drug interactions have not been studied in humans (4). However, a number of reports chronicle the apparently safe use of pemoline with other psychiatric medications (5). Reserpine, which may have similar characteristics to pemoline with regard to its potential depletion of stores of catecholamines in the brain and adrenal medulla, has been documented to interact during anesthesia with the narcotic, alfentanil, causing ventricular dysrhythmias (6). Sertraline, a selective serotonin reuptake inhibitor has been suggested to cause prolonged myoclonus in a patient undergoing a minor procedure (7). In this case, it was hypothesized that the other protein-bound drugs, namely lidocaine, midazolam, and fentanyl, caused an increased free fraction of sertraline caused by displacement from plasma proteins. Perhaps a similar situation occurred in our patient, increasing the effective concentration of pemoline in the circulation, decreasing the response to catecholamines.

This case may illustrate a drug interaction between pemoline and general anesthetic drugs. Sevoflurane is the most likely anesthetic drug to have interacted because the phenylephrine requirement lasted until the end of the case and was not apparent when sevoflurane was stopped. The hypotension in this patient may have been caused by chronic use of this psychostimulant. Pemoline inhibits uptake of dopamine competitively and norepinephrine noncompetitively in the CNS (8). Over time, this will lead to neurotransmitter depletion at the synaptic vesicles and leave the patient’s circulation unable to respond to the vasodilatory effects of general anesthetic drugs. This may explain why ephedrine, which is an indirect-acting sympathomimetic agonist, failed to normalize the blood pressure when phenylephrine, which acts directly on adrenergic receptors, was effective. Ephedrine was given initially because the differential diagnosis at that time was an excessive depth of anesthesia or hypovolemia. When neurotransmitter depletion was subsequently suspected, phenylephrine was used instead. Our patient remained vasodilated and hypotensive although she moved in response to surgical stimulation under general anesthesia at less than one minimum alveolar concentration. The exhaled sevoflurane concentration was 1.5%.

Nifedipine may have exacerbated the intraoperative hypotension, but does not account for its severity. Hess and Meyer (9) found that blood pressure was decreased only preoperatively in the nifedipine rather than the placebo group and recommended continuing nifedipine in the perioperative period.

Imipramine may cause orthostatic hypotension, but a MEDLINE search did not reveal any case reports of hypotension under anesthesia with this drug at therapeutic concentrations.

The degree of hypotension was exceptional with this anesthetic technique, especially when considering the light level of anesthesia and the small dose of opioid used intraoperatively. The differential diagnosis for this vasodilated hypotensive state includes anaphylaxis, anesthetic overdose, and myocardial ischemia. As the patient did not have other features of anaphylaxis, continued to move in response to surgical stimulation, and had a subsequent negative cardiac examination, these alternative diagnoses were rejected.

As a result of the recent increase in prescriptions of psychostimulants for a growing number of indications (10), hypotension under anesthesia associated with these drugs may occur more often in the future. To remove pemoline from the circulation would require several days of abstinence because pemoline has a long half-life of 16–18 hours (11). Catecholamine repletion of synaptic vesicles may take even longer.

In summary, this case reports vasodilatation and hypotension in a patient on pemoline under general anesthesia. Other factors may have contributed to the decreased blood pressure, and pemoline cannot be implicated definitively. This case nevertheless demonstrates the importance of vigilance for unexpectedhypotension in patients taking psychostimulants. If hypotension does develop in these patients, a direct-acting vasopressor such as phenylephrine should be used.

	References

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1. Fry JM. Treatment modalities for narcolepsy. Neurology 1998; 50: S43–8.
2. Holmes VF. Medical use of psychostimulants: an overview. Intern J Psychiatr Med 1995; 25: 1–19.[Web of Science][Medline]
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4. . American hospital formulary service drug information. 40th ed. Bethesda: American Society of Health-System Pharmacists, 1999.
5. Markowitz JS, Morrison SD, De Vane CL. Drug interactions with psychostimulants. Int Clin Psychopharmacol 1999; 14: 1–18.[Web of Science][Medline]
6. Jahr JS, Weber S. Ventricular dysrhythmias following an alfentanil anesthetic in a patient on reserpine for hypertension. Acta Anaesthesiol Scand 1991; 35: 788–9.[Medline]
7. Jahr JS, Pisto JD, Gitlin MC, O’Neill PT. The serotonin syndrome in a patient receiving sertraline after an ankle block. Anesth Analg 1994; 79: 189–91.[Abstract/Free Full Text]
8. Molina VA, Orsinger OA. Effects of Mg-pemoline on the central catecholaminergic system. Arch Int Pharmacodyn Ther 1981; 1: 66–79.
9. Hess W, Meyer C. Hemodynamic effects of nifedipine in patients undergoing cardiopulmonary bypass surgery. Acta Anesthesiol Scand 1986; 30: 614–9.[Medline]
10. Beck C, Silverstone P, Glor K. Psychostimulant prescriptions by psychiatrists higher than expected: a self-report survey. Can J Psychiatr 1999; 44: 680–4.[Medline]
11. Goenechea S, Wagner GM. Quantitative determination of pemoline in serum and urine after ingestion of therapeutic doses. Arzneimittelforschung 1977; 27: 1604–5.[Medline]

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