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and, on the day of transfer, had urinated in the middle of a room. He did not have access to any medications and instead they were administered daily to him by the staff at the assisted living facility. The valproate, in particular, was routinely given in the morning. He had not had any recent changes in his medications and had been taking the same dose of valproic acid for the past three years. His vital signs were: body temperature, 97.5F; pulse, 70 beats/ min; respiratory rate, 20 breaths/ min; blood pressure, 151/91 mm Hg; and pulse oximetry, 96% on room air. Physical examination revealed an unresponsive man with pupils that were 3 mm and reactive. The oral mucosa was moist. The lungs had rhonchi, more on the right than the left. Cardiovascular examination revealed a regular rate and rhythm with no murmurs. The abdomen had active bowel sounds with no palpable tenderness or masses. The neurologic exam revealed an obtunded man unable to obey any commands but withdrawing to pain. The patients occasional speech was inappropriate and incomprehensible. He opened his eyes only to pain. His Glasgow Coma Scale score was 8. He had brisk deep tendon reexes with no clonus. His gag reex was poor and Babinski reexes were downgoing bilaterally. During his evaluation, the patient had an episode of emesis and his oxygen saturation began to fall to 85%. It was decided to intubate the patient in order to protect the airway. After intubation, an orogastric tube was then inserted and a gastric lavage was performed without return of pill fragments. One hundred grams of activated charcoal with sorbitol was instilled down the gastric tube. A computed tomography (CT) scan of the head was performed, which was negative for acute pathology. The patients electrocardiogram showed a normal sinus rhythm at 86 beats/min with a narrow QRS complex and normal intervals. The patient had a normal complete blood cell count with a normal differential. The erythrocyte sedimentation rate was 7 mm/hr (<12

BRIEF REPORTS
Hyperammonemia and Coma without Hepatic Dysfunction Induced by Valproate Therapy
FERMIN BARRUETO JR, MD, JASON B. HACK, MD

Abstract. The authors report a case of a 41-year-old mentally disabled man with bipolar disorder who presented to the emergency department with altered mental status. He was found to have a signicantly elevated ammonia level (377 M/L) with no signs of hepatic insufciency. His coma and hyperammonemia were attributed to his chronic valproate therapy. This patient had the highest serum ammonia level ever reported with a therapeutic valproate level in the absence of any other anticonvulsant therapy, metabolic abnormality, or hepatic dysfunction. The authors discuss this case and review the current literature on hyperammonemia in valproic acid therapy and the use of L-carnitine in these patients. Key words: valproic acid; ammonia; carnitine; epilepsy; bipolar. ACADEMIC EMERGENCY MEDICINE 2001; 8:9991001

Valproic acid (2-propylpentanoic acid) is used commonly as an anticonvulsant in both the pediatric and adult populations.1 It has a broad spectrum of effects and is also used as a mood stabilizer in bipolar disease and other psychiatric disorders.2 Acute valproate toxicity from overdose has been shown to cause nausea, vomiting, ataxia, coma, and respiratory depression.3,4 Overdoses have also been associated with hyperammonemia, metabolic acidosis, and hepatic dysfunction.35 Hyperammonemia without hepatic dysfunction is an adverse effect that has been reported in the pediatric and adult populations at therapeutic valproate levels.611 Most of these reported cases occurred at initiation of valproate therapy or after an increase in dose.69 Additionally, all previous reports of hyperamFrom Pitt County Memorial Hospital, Brody School of Medicine, East Carolina University, Department of Emergency Medicine, Greenville, NC (FB, JBH). Received March 14, 2001; revision received June 26, 2001; accepted June 27, 2001. Address for correspondence and reprints: Fermin Barrueto Jr, MD, New York Poison Control Center, 455 First Avenue, Room 124, New York, NY 10016. Fax: 212-447-8223; e-mail: fbarrueto@ hotmail.com

monemia in valproate therapy involved patients with either marginal elevations in serum ammonia, concurrent administration of other anticonvulsants, or metabolic derangements.512 We report a case of an adult patient with severe hyperammonemia and coma that occurred with a therapeutic level of valproate, on no other anticonvulsant therapy, and without hepatic dysfunction or metabolic deciencies.

CASE HISTORY
A 41-year-old mildly obese male resident of a local nursing home was sent for evaluation of inappropriate behavior and increased somnolence. He arrived to the emergency department (ED) in the late afternoon unresponsive and had an episode of emesis. He was disheveled and was unable to give any history. The documentation that accompanied him stated that his past medical history included psoriasis, bipolar disorder, gout, and hypertension. His medication list consisted of acebutolol, hydrochlorothiazide, ibuprofen, haloperidol, benztropine, gembrozil, lorazepam, valproic acid and multivitamins. He was allergic to penicillin. He normally ambulated with a cane and was able to feed himself. Recently, he had become lethargic

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VALPROATE

Barrueto, Hack HYPERAMMONEMIA IN VALPROATE THERAPY

mm/hr*). His arterial blood gas, after intubation, showed a pH of 7.43, pCO2 of 39 torr, and pO2 of 441 torr. His electrolytes were within normal limits, with a normal anion gap. His liver function tests showed a protein level of 6.3 g/dL (6.28.3 g/dL), an albumin level of 3.0 g/dL (3.44.9 g/dL), a mildly elevated SGOT of 70 U/L (1037 U/L), and an SGPT of 30 U/L (040 U/L). Amylase was 26 U/L (<115 U/L) and lipase was 87 U/L (<82 U/L). The prothrombin time (PT) was 11.4 sec (9.712.5 sec) and the international normalized ratio (INR) was 1.0. The prothrombin time (PTT) was 35.5 sec (21.030.6 sec). The valproic acid level was 73.5 g/mL (50100 g/mL) and within therapeutic limits. Serum osmolarity was 254 mosm/kg and creatine kinase was elevated at 3,085 IU/L. His venous ammonia level was 377 M/L (<35 M/L). Carnitine therapy was initiated in the ED. The patients weight was estimated to be 100 kg and he was therefore given 10 g of L-carnitine intravenously (100 mg/kg) over one hour. The patient was transported to the medical intensive care unit. The venous ammonia level declined to 47 M/L seven hours after initiation of carnitine therapy. The patient awoke and was extubated 14 hours after presentation to the ED. He became completely alert and responsive with a normal physical examination within 24 hours. He denied any suicidal ideation and stated that everything just became fuzzy over the past two days. He was not given any further charcoal or carnitine after he left the ED but remained on lactulose. He had an increase in his ammonia the second hospital day to 89 M/L, but with continued lactulose administration this decreased to 46 M/L during the third and fourth hospital days. A urine screening test for abnormal amino acids was performed to detect any urea cycle deciencies and none were detected. His valproate was discontinued and

he was transferred to the psychiatric unit at his baseline mental status to further manage his bipolar disorder and adjust his medications.

DISCUSSION
The metabolism of valproic acid is complex and still not completely understood. Valproate is metabolized mostly by fatty acid -oxidation and glucuronic acid conjugation with a minimal contribution by -oxidation.13 There is evidence that during chronic or high-dose valproate therapy, hypocarnitinemia may be induced, which may inhibit -oxidation.14 This causes a decrease in -oxidation metabolites, which are considered benign, and -oxidation increases to compensate.13 The metabolites of -oxidation appear to have a toxic effect on the liver.1315 It has also been hypothesized that this maybe a contributing factor to the hyperammonemia seen in chronic valproate therapy and thus may be one of the mechanisms in which carnitine therapy helped our patient lower his ammonia level. The cause of hyperammonemia without hepatic dysfunction appears to be multifactorial and not well elucidated. It has been shown that valproate indirectly inhibits carbamoyl phosphate synthetase I (CPS I) in the urea cycle by decreasing synthesis of N-acetyl glutamate, the activator of CPS I, causing the breakdown in the urea cycle and subsequent increase in ammonia.16,17 The kidneys also contribute to the hyperammonemia by increasing glutamine uptake and ammonia release into the serum from the kidneys via glutaminase stimulation.18 Neither of these reactions appears to affect hepatic function. Hyperammonemia without hepatic dysfunction has also been reported in inherited metabolic disorders such as X-linked ornithine transcarbamylase deciency.12,19,20 In these patients, the hyperammonemia occurs during the initiation of therapy and is quickly reversible upon discontinuation of therapy. All of the rest of the reported cases of hyperammonemia either were mild (46 to 105 M/L) or were seen in patients with concomitant anticonvulsant therapy, although the relationship between the two is unclear.37,9,10 There is a reported case

of haloperidol-induced hyperammonemia in a child with citrullinemia.21 This patients reaction was immediate, within hours, once haloperidol was started. Our patient had no known metabolic derangements, including citrullinemia, and had been taking this combination of haloperidol and valproate for several years. An interesting aspect of this case was how rapidly the patient responded to the carnitine therapy. Ishikura et al. measured the metabolites from and -oxidation before and after carnitine therapy in an acute overdose of valproate. They showed how the metabolites from -oxidation increased after administration of L-carnitine and the metabolites from -oxidation decreased. Murakami et al. were also able to show the same pattern of metabolites in a patient receiving chronic valproate therapy. We know of no randomized controlled studies that compare carnitine therapy with other traditional treatment regimens for hyperammonemia. However, there is growing evidence that carnitine therapy may be helpful both in the prevention and in the treatment of hyperammonemia secondary to valproate therapy.1315,22 Our patient had altered mental status and coma due to his chronic valproic acid therapy and severe hyperammonemia. He also appears to have had extended periods of unresponsiveness prior to being evaluated in the ED, since his creatinine kinase level was elevated to 3,085 IU/L. The patient quickly returned to baseline following gastrointestinal decontamination with charcoal, discontinuation of valproate, and administration of L-carnitine. Severe hyperammonemia occurred in our adult patient who was receiving chronic valproate therapy with a therapeutic drug level. Also, this patient was not taking any other anticonvulsant medication or had a metabolic derangement, as all of the previously reported patients did.

CONCLUSIONS
Valproic acid can cause hyperammonemia in the setting of both high and therapeutic drug levels without evidence of hepatic dysfunction. Obtaining an ammonia level in patients who present with altered

*Normal values are shown in parentheses. SGOT = serum glutamate oxaloacetate transaminase (aspartate aminotransferse); SGPT = serum glutamate pyruvate transaminase (alanine aminotransferase).

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15. Murakami K, Sugimoto T, Woo M, Nishida N, Muro H. Effect of L-carnitine supplementation on acute valproate intoxication. Epilepsia. 1996; 27:6879. 16. Stephens JR, Level RH. Effects of valproate and citrulline on ammoniuminduced encephalopathy. Epilepsia. 1994(1); 35:16471. 17. Coulter DL. Carnitine deciency in epilepsy: risk factors and treatment. J Child Neurol. 1995; 10(Nov. suppl 2): s3239. 18. Marini AM, Zaret BS, Beckner RR. Hepatic and renal contributions to valproate-induced hyperammonemia. Neurology. 1998; 38:36571. 19. Leao M. Valproate as a cause of hyperammonemia in heterozygotes with ornithine-transcarbamylase deciency. Neurology. 1995; 45:5934. 20. Forget PP, van Oosterhout M, Bakker JA, Wermuth B, Vles JS, Spaapen LJ. Partial N-acetyl glutamate synthetase deciency masquerading as a valproic acid-induced Reye-like syndrome. Acta Paediatr. 1999; 88:140911. 21. Rubenstein JL, Johnston K, Elliot GR, Brusilow SW. Haloperidol-induced hyperammonaemia in a child with citrullinaemia. J Inher Metab Dis. 1990; 13:7545. 22. Raskind JY, El- Chaar GM. The role of carnitine supplementation during valproic acid therapy. Ann Pharmacother. 2000; 34:6308.

mental status and receiving valproate therapy maybe warranted. Resolution or prevention of hyperammonemia may be enhanced with the administration of L-carnitine, but further study is required.

References
1. Coulter DL, Wu H, Allen RJ. Valproic acid therapy in childhood epilepsy. JAMA. 1980; 244:7858. 2. Lennkh C, Simhandi C. Current aspects of valproate in bipolar disorder. Int Clin Psychopharmacol. 2000; 15:111. 3. Anderson GO, Ritland S. Life threatening intoxication with sodium valproate. J Toxicol Clin Toxicol. 1995; 33: 27984. 4. Thabet H, Brahmi N, Amamou M, Ben SN, Hedhili A. Hyperlactatemia and hyperammonemia as secondary effects of valproic acid poisoning. Am J Emerg Med. 2000; 18:508. 5. Lee WL, Yang CC, Deng JF, Chen YF, Lin HD, Weng PH. A case of severe hyperammonemia and unconsciousness following sodium valproate intoxication. Vet Hum Toxicol. 1998; 40:3468. 6. Hamer HM, Knake S, Schomburg U, Rosenow F. Valproate-induced hyperammonemic encephalopathy in the pres-

ence of topiramate. Neurology. 2000; 54: 2302. 7. Rawat S, Borkowski WJ, Swick HM. Valproic acid and secondary hyperammonemia. Neurology. 1981; 31:11734. 8. Ohtani Y, Endo F, Matsuda I. Carnitine deciency and hyperammonemia associated with valproic acid therapy. J Pediatr. 1982; 101:7825. 9. Pannikkar GP, Gilman SM. Valproate-induced hyperammonemia in the psychiatric setting: 2 cases. J Clin Psychiatry. 1999; 60:55760. 10. Williams CA, Tiefenbach S, McReynolds JW. Valproic acid-induced hyperammonemia in mentally retarded adults. Neurology. 1984; 34:5503. 11. Zaret BS, Beckner RR, Marini AM, Wagle W, Passarelli C. Sodium valproate-induced hyperammonemia without clinical hepatic dysfunction. Neurology. 1982; 32:2068. 12. Bogdanovic MD, Kidd D, Briddon A, Duncan JS, Land JM. Late onset heterozygous ornithine transcarbamylase deciency mimicking complex partial status epilepticus. J Neurol Neurosurg Psychiatry. 2000; 69:8135. 13. Ishikura H, Matsuo N, Matsubara M, Ishihara T, Takeyama N, Tanaka T. Valproic acid overdose and L-carnitine therapy. J Anal Toxicol. 1996; 20(1):558. 14. Murakami K, Sugimoto T, Nishida N, et al. Abnormal metabolism of carnitine and valproate in a case of acute encephalopathy during chronic valproate therapy. Brain Dev. 1992; 14:17881.

Clinical Pearls

(cont. from page 997) veal any complicating pneumothorax but suggests a basal inltrate in the right lung eld. Because of the hemodynamic instability in the face of suspected endocarditis, immediate cardiology consultation is requested. Prior to cardiology evaluation, an electrocardiogram shows the presence of ST elevation in the inferior leads II, III, and AVF, with reciprocal depression in the anterior leads. Because of persistent hypotension, a radial arterial line is inserted to monitor arterial pressure, and this tracing not only conrms hypotension, but also shows the presence of a pulsus paradoxus. The cardiology fellow eventually conrms this via standard auscultation, conrming the arterial line tracing value of 22 mm. Bedside echocardiography by the cardiology consultant shows the presence of a large mitral valve vegetation, with the surprise nding of a large pericardial effusion that completely surrounds the cardiac silhouette (ultrasound image not available). There is some dysfunction of the right ventricular wall, but this also corresponds to inferior wall motion abnormalities. The cardiologist does not detect any atrial collapse, and thinks that the right ventricular wall motion abnormality

Laboratory Evaluation and ED Course. Central venous access is obtained via right subclavian technique, after failure to cannulate the right internal jugular vein successfully. The right carotid artery is inadvertently entered with the nder needle, and a substantial right-sided neck hematoma develops. The patient undergoes a standard rapidsequence intubation using etomidate and succinylcholine, and the endotracheal tube is secured after conrmation of tube placement by auscultation and end-tidal carbon dioxide monitoring. Even prior to obtaining central venous access, the order is sent to pharmacy for nafcillin 2 grams, gentamicin 100 mg, and vancomycin 1 gram. As soon as these are available they are administered via the central line, after obtaining baseline laboratory results and blood cultures (Table 1). Once back, these labs show a marked leukocytosis and left shift in the differential, but no signicant metabolic abnormality is noted that would account for such altered mental status in this patient. Prior to the administration of these antibiotics, the patient becomes hypotensive with systolic blood pressures in the 80s (mm Hg). This hypotension temporarily responds to IV crystalloid bolus administration, and conrmatory chest radiography does not re-