IJTCVS 2006; 22: 19–21 Case reports
Misra et al 19 Acute phenytoin toxicity
Acute phenytoin toxicity mimicking stroke following cardiopulmonary bypass Malempati Amaresh Rao, MS, Manoranjan Misra, M.Ch., Rajnish Duara, MS, Karunakaran Jayakumar M.Ch., Kurur Sankaran Neelakandhan, M.Ch. Department of Cardio-Vascular & Thoracic Surgery, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala Introduction Presentation of neurological complications following CPB ranges from acute stroke to subtle neurocognitive changes1. We report a case following coronary artery bypass surgery under CPB when Phenytoin toxicity in early postoperative period mimicked a neurological stroke leading to delay in its diagnosis. Case Report A 55-year-old diabetic, hypertensive and dyslipidemic male with functional class III angina was admitted for coronary revascularization. Patient had a history of stroke with left hemiparesis five years ago, with complete recovery within a year. He had one episode of seizure three years back but did not seek any medical advice. Cardiac evaluation revealed triple vessel disease with fair left ventricular function without any intracardiac clots. Liver function test revealed SGOT of 48 u/L and SGPT of 56 u/L (normal range up to 40 u/l). Ultrasonography of abdomen showed fatty liver. Carotid artery duplex scanning showed 30% stenosis of right and 45% stenosis of left internal carotid artery. Computerised tomography (CT) of brain revealed chronic infarct in right frontal and gangliocapsular region. Electroencephalogram three weeks prior to surgery showed a spike and wave discharge over temporal areas consistent with seizure disorder, and patient was started on oral Phenytoin 100 mg thrice daily. He underwent coronary artery bypass grafting Address for correspondence: Manoranjan Misra Department of Cardio-Vascular & Thoracic Surgery Sree Chitra Tirunal Institute for Medical Sciences and Technology Trivandrum, Kerala, India 695011 Tel: +91-471 2524 551 Fax: +91-471 2550 728 E-mail:
[email protected] © IJTCVS 097091342210305/38 Received - 05/05/05; Review Completed - 02/11/05; Accepted - 21/11/05.
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under CPB. Postoperatively hemodynamics remained stable. Oral aspirin and Phenytoin were restarted on first postoperative day. He was initially in a state of confusion, and, on the 3rd postoperative day, developed pronounced ataxia, nystagmus, dysarthria and vomiting. A likely clinical diagnosis of posterior circulation stroke was considered. CT scan ruled out a hemorrhagic stroke but could not rule out new embolic phenomena. Heparin infusion was thus started empirically. The neurological status was slowly deteriorating. MRI done on the fifth postoperative day revealed no fresh structural lesions in the brain. At this stage a likely possibility of Phenytoin toxicity was considered. Serum total Phenytoin concentration estimation revealed a toxic level of 40 microgram/ deciliter. (Therapeutic range 10-20 mcg/dl) which clinched the diagnosis. Patient also had hyponatremia requiring frequent corrections, however levels of urinary sodium were low. Phenytoin was stopped and patient showed good recovery with no residual neurological deficit within 15 days. At discharge his serum Phenytoin level was within normal range and he was advised to remain under a neurologist follow up. Discussion Phenytoin (Diphenyl hydantoin) is often used for perioperative seizure prophylaxis. Pharmacology and toxicology of Phenytoin is well described. However, acute Phenytoin toxicity with therapeutic doses given orally is extremely rare. We believe it has happened due to the effect of CPB on the pharmacology of Phenytoin2. While no studies have specifically been done for behavior of Phenytoin on cardiopulmonary bypass, the effect of drugs with similar pharmacological qualities can be used as a comparable model 3 . The use of Phenytoin, therefore, in the setting of open-heart surgery under cardiopulmonary bypass calls for some special consideration Levels of Phenytoin may have risen due to CPB
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20 Misra et al Acute phenytoin toxicity
IJTCVS 2006; 22: 19–21
A
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Fig. 1. A,B,C Pre operative CT scan showing old stroke in gangliocapsular area
D
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Fig. 1. D,E,F Post operative CT scan showing no fresh changes
induced hypoproteinemia (with the subsequent rise in free unbound fraction) and concomitant medications such as Heparin, Cefotaxime and Aspirin4,5. As the hepatic function was marginally compromised, induction of enzymes to metabolize Phenytoin may have been inadequate. The confusional state associated with narcotic analgesia in the post extubation period confounded the initial features of toxicity, and symptoms manifested only after they became significant mimicking an acute posterior circulation stroke. With
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patient already having history of neurological events and carotid lesions, the obvious inference was that of an embolic stroke. At this stage, Phenytoin toxicity was not thought of as the previous two doses of Phenytoin were omitted, and such a scenario is extremely rare with oral doses we had started the patient on. Heparin started in view of suspected embolic stroke might have further displaced Phenytoin from the bound albumin and lead to increase in the symptoms. Once MRI totally ruled out embolic phenomenon, metabolic causes were sought
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IJTCVS 2006; 22: 19–21
Misra et al 21 Acute phenytoin toxicity
for. Low urinary excretion of sodium ruled out syndrome of inappropriate antidiuretic hormone secretion. Nystagmus, only when obvious on the fifth day, was the important clue to suspect Phenytoin toxicity6. The clinical correlation compounded by the raised serum Phenytoin levels guided prompt withdrawal of the drug avoiding possible mortality reported even at levels over 50 mcg/dl7. We believe that peri-operative assessment of serum Phenytoin levels and a reduced dose of Phenytoin just prior to surgery, especially in the setting of borderline hepatic function would have helped prevent significant morbidity. A higher index of suspicion of Phenytoin toxicity would have resulted in significantly early recovery. We recommend a low threshold for serum Phenytoin monitoring for any perioperative change in neurological status. The effect of CPB on Phenytoin has not been well studied. Thus a detailed and in depth analysis of the behavior of a vital drug as Phenytoin during and in the post cardiopulmonary bypass period will refine its use in the high risk groups.
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References 1. I.Toner, K.M.Taylor, S.Newman, and LC. Smith Cerebral functional changes following cardiac surgery: Neuropsychological and EEG assessment Eur. J Cardiothorac Surg, 1998; 13: 13–20. 2. Mets B The pharmacokinetics of anesthetic drugs and adjuvants during cardiopulmonary bypass.Acta Anaesthesiol Scand. 2000; 44: 261– 73. 3. Hynynen M, Hynninen M, Soini H, Neuvonen PJ, Heinonen J. Plasma concentration and protein binding of alfentanil during high-dose infusion for cardiac surgery. Br J Anaesth. 1994; 72: 571–76. 4. Dasgupta A, Dennen DA, Dean R, McLawhon RW. Displacement of phenytoin from serum protein carriers by antibiotics: studies with ceftriaxone, nafcillin, and sulfamethoxazole. Clin Chem. 1991; 37: 98–100. 5. Olanow CW, Finn AL, Prussak C. The effects of salicylate on the pharmacokinetics of phenytoin. Neurology. 198; 31: 341–42. 6. Murphy JM, Motiwala R, Devinsky O. Phenytoin intoxication. South Med J. 1991; 84: 1199–204. 7. Subik M, Robinson DS. Phenytoin overdose with high plasma levels (case report). WV Med J 1982; 78: 281–82.
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