Heat stroke associated with topira”>Case Report

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American Journal of Emergency Medicine

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Fatal heat stroke associated with topiramate therapy?,??,?

Abstract

A 40-year-old man with diabetes and seizure disorder was found at home unresponsive and “very hot to touch” by his father 40 min- utes before emergency medical services arrival. His usual medica- tions included topiramate, divalproex sodium, and rosiglitazone/ metformin. Paramedics administered oxygen, intravenous fluids, and naloxone. They did not witness or report Seizure activity. Upon emergency department arrival, the patient was unresponsive (Glas- gow Coma Scale 3), hypotensive (94/50 mm Hg), and tachypneic (32 breaths per minute), with a heart rate of 60 beats per minute and elevated rectal temperature peaking at 43.2?C. His skin was hot and dry, without rash; physical examination was otherwise normal. Labo- ratory studies revealed severe metabolic acidosis with acute renal failure and rhabdomyolysis. In spite of sedation, intubation, and ag- gressive cooling measures, the patient had cardiac arrest and died approximately 2 hours after arrival. Serum topiramate and valproate concentrations were within therapeutic ranges at 8.8 ug/mL (thera- peutic 2-12) and 97 ug/mL (therapeutic 50-100), respectively.

Previously reported cases of oligohydrosis and fever associated with topiramate (TPM) have been reported in children and, in general, have been mild and reversible when the drug was decreased or withdrawn. We believe this to be the first reported death due to heat stroke in a patient taking TPM. Topiramate inhibits carbonic anhy- drase, potentially leading to oligohydrosis and hyperthermia in some patients. Although fever due to divalproate hypersensitivity has been described, we find it to be an unlikely etiology in this case. With the growing list of indications and widespread usage of TPM, physicians should be aware of the risk of oligohydrosis and hyperthermia, par- ticularly in warm climates.

Topiramate is a sulfamate-substituted monosaccharide of D- fructose, approved by the United States Food and Drug Administration in 1996, first as an antiepileptic drug for adults and children and subsequently for migraine prophylaxis in adults. Off-label indications for TPM include psychiatric disorders, eating disorders, Neuropathic pain, alcohol and drug dependency, and treatment for refractive scars [1]. The FDA estimates that in a 4-year period from 2007 to 2010, some 32 million TPM prescriptions were dispensed, and 4.3 million patients filled TPM prescriptions at outpatient pharmacies.

? Sources of support: None.

?? Conflict delineations: The authors have no conflicts of interest to disclose.

? This article was presented as a poster at the North American Congress of Clinical Toxicology in Washington, DC, on September 24, 2011.

In July 2003, following several case reports of TPM-associated oligohydrosis and fever [2,3], the FDA issued a warning recommend- ing Close monitoring of TPM-treated patients, especially children, for reduced sweating and increased body temperature, particularly in hot weather [4]. Dodgson et al [5] previously demonstrated that TPM inhibits carbonic anhydrase isoenzymes II and IV, preferentially. These isoenzymes are found in human eccrine sweat glands. This is believed to be the mechanism of sweat suppression and fever in patients taking TPM. Although most reported cases have been mild and reversible with cessation of TPM therapy, Galicia et al [6] reported a case of severe hyperthermia resulting in long-term neurologic sequelae. We present what we believe to be the first case of fatal heat stroke associated with therapeutic use of TPM.

A 40-year-old man was found at home unresponsive and “very hot to touch” by his father some 40 minutes before evaluation by emergency medical services (EMS). His medical problems included a seizure disorder and diabetes, for which he was taking TPM, dival- proex sodium, and rosiglitazone/metformin. Medical history included a gunshot wound to the head. No seizure activity was reported to or witnessed by EMS. Capillary glucose at the scene was 122 mg/dL. Emergency medical services administered oxygen, a 500-mL intrave- nous bolus of normal saline, and naloxone 4 mg IV with no discernible improvement. Upon emergency department arrival, the patient was unresponsive (Glasgow Coma Scale 3), with decreased air movement bilaterally and regular heart rhythm. The vital signs included a heart rate of 60 beats per minute, blood pressure of 94/50 mm Hg, res- piratory rate of 32 breaths per minute, and rectal temperature of 42.2?C, later peaking at 43.2?C. Oxygen saturation by pulse oximetry was 93% on 15 L/min by bag valve mask. The skin was hot and dry without rash, and the examination was otherwise normal. The patient was given lorazepam 4 mg IV, fosphenytoin 1 g IV, and placed on a cooling blanket. Etomidate 30 mg and rocuronium 100 mg were administered intravenously, and the trachea was intubated. Addi- tional lorazepam, 4 mg, then 2 mg, was given intravenously. Dan- trolene was considered, but withheld. A Foley catheter was placed with no urine return. Additional fluid boluses of normal saline were administered, and cold compresses were placed on the body. The patient’s blood pressure dropped to 78/36 mm Hg shortly after arrival. A central line was placed. In addition to intravenous fluid boluses, dopamine was initiated at 10 ug/kg per minute. The heart rate dropped, prompting administration of atropine and epinephrine, without response. The patient deteriorated into cardiac arrest 54 minutes after arrival. An electrocardiogram revealed a wide complex supraventricular tachycardia with 3:1 block and frequent premature ventricular contractions, right bundle-branch block, and left axis deviation, with T-wave abnormalities suggestive of lateral ischemia and possible acute or recent Inferior myocardial infarction. Chest

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x-ray revealed satisfactory endotracheal tube placement and no infiltrate. ABG during cardiac arrest revealed pH 7.12, pCO₂ 39.1 mm Hg, pO₂ 31.4 mm Hg, and base excess -16.0 mEq/L. Serum creatinine was 3.7 mg/dL; serum lactate, 4 mmol/L; and serum creatine kinase was 6101 IU/L. Serum TPM was 8.8 ug/mL (therapeutic 2-12); serum valproate was 97 ug/mL (therapeutic 50-100). Despite advanced cardiac life support measures and active cooling, the patient died approximately 2 hours after arrival.

Although most reported cases of oligohydrosis and fever associ- ated with TPM have been reported in children and have, in general, been mild and reversible when the drug was decreased or withdrawn [2,3], we believe that TPM contributed to fatal heatstroke in an adult in this case. Drugs may induce body temperature elevations by a number of mechanisms. Eyer and Zilker [7] describe 7 toxic causes of hyperthermia, including adrenergic fever (cocaine and amphet- amines), antidopaminergic fever (neuroleptic malignant syndrome associated with phenothiazines and butyrophenones), anticholinergic fever (antihistamines), Serotonin syndrome (monoamine oxidase inhibitors, Selective serotonin reuptake inhibitors and cyclic antide- pressants), uncoupling of oxidative phosphorylation (salicylates), malignant hyperthermia (volatile anesthetics), and drug-induced fever (anticonvulsants, heparin). Topiramate, which causes oligohy- drosis and fever through inhibition of sweat gland carbonic anhy- drase, appears to fall into this last “catch-all” category. This category likewise includes hypersensitivity syndromes, such as the DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome. The DRESS syndrome has been reported after use of Valproic acid, one of the medications consumed by our patient. Indeed, our patient had some of the clinical features of DRESS syndrome (fever and elevated Liver enzymes and acute renal failure) but lacked the charac- teristic eosinophilia (0.5%), atypical lymphocytes, and severe skin eruption at the time of presentation. In fact, in published cases of sodium valproate hypersensitivity, skin lesions have been a common finding. Furthermore, valproate hypersensitivity generally occurs in patients within 8 weeks of initiating the drug. Our patient had been taking it for several months. Lymphadenopathy, another common finding in DRESS, was not noted on this critical patient’s examination either. For these reasons, we doubt valproate is the etiology of this patient’s hyperthermia.

The incidence of TPM-associated oligohydrosis and fever has

generally been considered to be low, with the manufacturer citing 35 spontaneous reports per 1000000 patients treated [4]. However, Ziad et al [8] found that 10.5% of all patients taking TPM in an epilepsy clinic in Beirut spontaneously reported hyperthermia when asked generically about adverse experiences, compared with 0.15% of patients taking other Antiepileptic drugs. Furthermore, temperatures between 39?C and 39.5?C were reported in 15.4% of those taking TPM and reporting hyperthermia. As in previous reports, the higher body temperatures typically occurred in warm months (May-October) [8]. The present case occurred in July. The peak temperature on that day was 93?F. Of greater concern, Galicia et al [6] reported the case of a 27-year-old man found in continuous Generalized seizures. His body temperature on hospital arrival was 42.9?C. In spite of reducing his body temperature and providing aggressive supportive care, the patient had persistent balance problems and tremors with slurred speech 11 months after the event. More recently, Nolla-Salas et al [9] have reported on 3 cases of heat stroke associated with adult patients taking TPM. A 69-year-old woman, a 24-year-old man, and a 32-year-

old man, all with temperatures exceeding 40?C and Mental status changes, all recovered to be discharged home [9]. Children are not exempt either from serious outcomes. Boussemart et al [10] reported the case of a 10-year-old boy with anoxic encephalopathy who deve- loped fever above 41?C on multiple occasions until TPM was withdrawn. Finally, Strawn et al [11] reported on a 14-year-old adolescent girl riding a bicycle in high ambient temperature (90?F) some 8 weeks after starting TPM therapy for bipolar disorder. She was found unresponsive, with a temperature of 42.2?C. She developed rhabdomyolysis and hypotension. Topiramate was stopped, and divalproex started in its place. She was discharged home in stable condition.

In summary, this case is, to our knowledge, the first report of lethal heat stroke associated with TPM therapy. With the growing list of indications and widespread usage of TPM, physicians should be aware of the risk of oligohydrosis and hyperthermia, particularly in warm climates.

Stephen W Borron MD

Division of Medical Toxicology, Texas Tech University Health Sciences

Center, Paul L. Foster School of Medicine

El Paso TX 79905, USA

Department of Emergency Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine

El Paso TX 79905, USA

Robert Woolard MD Susan Watts PhD

Department of Emergency Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine

El Paso TX 79905, USA

E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2013.07.013

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