Case Report of Olanzapine-Associated Elevation of Serum Creatine Kinase in a 16-Year-Old Boy With Heat Stroke

Sir: A potential common linkage has been proposed among hyperthermic syndromes such as neuroleptic malignant syndrome (NMS), malignant hyperthermia, and heat stroke.¹ These 3 syndromes may be induced by different mechanisms, but all involve breakdown in the normal thermogenic mechanisms responsible for maintaining body temperature. They all cause different degrees of central nervous system changes. Other physiologic abnormalities specific to each syndrome suggest that the hyperthermia is part of a more general hypermetabolic state. Marked elevation of serum creatine kinase (CK), in the absence of classic signs and symptoms of NMS, in patients treated with atypical antipsychotics has been described in the literature.^2–7 Newer atypical antipsychotics have potent serotonin (5-HT₂) and weaker dopamine (D₂) receptor binding properties, which are thought to contribute to lesser occurrence of extrapyramidal symptoms or NMS as opposed to conventional antipsychotics. Olanzapine has a particularly propitious ratio of serotonin to do-pamine. However, sporadic cases of NMS and isolated cases of CK elevation associated with olanzapine have been reported since the introduction of the drug in 1996. Here, we describe a case of marked reversible elevation of serum CK associated with olanzapine treatment in an adolescent boy with recent history of heat stroke.

Case report

Mr. A, a 16-year-old previously healthy boy, developed heat stroke while actively participating in a sporting camp. Initially, he was taken to a local hospital (in 2006), where he was found to be hyperthermic at 106° F and to have labile blood pressure and encephalopathy. He was intubated, rehydrated, and cooled. Computed tomography scan of the head did not reveal any abnormality. He had multi-organ failure and was transferred to our facility for further management after 6 hours.

On admission evaluation, he was afebrile, heart rate was 94 beats per minute, respiratory rate was 18 breaths per minute, and blood pressure was 140/80 mm Hg. He had bilateral subconjunctival hemorrhages, erythematous maculopapular rash, and, neurologically, had nonspecific responses to verbal stimulation. He was found to have respiratory failure, renal failure, hepatic dysfunction, and disseminated intravascular coagulation. Laboratory results at admission were as follows: sodium, 142 mEq/L; potassium, 5.4 mEq/L; blood urea nitrogen, 44 mg/dL; creatinine, 7.4 mg/dL; conjugated bilirubin, 6 mg/dL; unconjugated bilirubin, 2.4 mg/dL; aspartate transaminase, 6982 U/L; alanine transaminase, 5954 U/L; lipase, 2601 U/L; and amylase, 262 IU/L.

He was placed on continuous venovenous hemofiltration for acute renal failure secondary to severe rhabdomyolysis and was treated for liver insufficiency, disseminated intravascular coagulopathy, and metabolic disturbances. Two days after admission, he was extubated and placed on hemodialysis. Five days after admission, he remained insomnic and intermittently agitated with significant disorientation, confusion, delirium, and hallucinations. Magnetic resonance imaging of the head showed small areas of ischemia of unclear significance. Medication strategies were implemented in an effort to help the patient to reorient, sleep, and decrease his agitation. He became disinhibited when given a 1-time dose of lorazepam. Considering his agitation, visual hallucinations, and delirium, 7 days later he was started on treatment with olanzapine 2.5 mg orally, repeated twice during the night. The choice of haloperidol or other neuroleptics with higher D₂ affinity was deferred because of increasing evidence to support a link between thermodysregulation and NMS⁸ and his history of extreme sympathetic nervous system activation and/or dysregulation in response to physical and psychological stress, which could couple with haloperidol's potent dopaminergic blockade and serve as a predisposing factor. Since atypical antipsychotics have lesser incidence of extrapyramidal symptoms and development of NMS than the typical neuroleptics due to their unique mechanism of action on receptor blockage, we chose to try olanzapine for his delirium and sleep problem.

Parents and staff noted improvement in the form of less agitation, better sleep, and absence of hallucination. However, laboratory results drawn the next day showed a significant elevation in CK; from 808 U/L at baseline to 2133 U/L (normal range: 35–230). Prior to administration, aspartate transaminase and ala-nine transaminase were 266 and 393 U/L, respectively, and conjugated bilirubin was 19.9 mg/dL. Post administration enzyme levels were 638 and 493 U/L, respectively, with a conjugated bilirubin of 17.5 mg/dL. Blood urea nitrogen and creatinine were unchanged from pretreatment levels. Because of the concerns that olanzapine may have exacerbated his hypermetabolic state and induced further rhabdomyolysis, it was immediately discontinued. The patient did not meet any criteria of NMS as per DSM-IV-TR and did not show any sign of developing muscle rigidity, temperature elevation, extrapyramidal symptoms, or new change in mental status. Creatine kinase levels further increased to 4681 U/L before beginning to drop again to normal levels over a period of 1 week. During this time, the patient did not have any type of intramuscular injections, new medications, or restraints, which could potentially cause muscle injury leading to a rise in CK levels. The patient's mental status began to improve each day. After a 23-day hospitalization, he was transferred to a facility near his home for rehabilitation. Mental status on discharge was oriented with cognitive abilities grossly intact.

Isolated marked elevation of CK associated with atypical antipsychotics, without other features of NMS, has been reported in the literature. One study found transient increases in CK in 10% of patients treated with both conventional and newer atypical antipsychotics.⁹ Exact pathophysiology and clinical implications of isolated elevation in CK remain unclear. Meltzer¹⁰ has demonstrated 5-HT–induced toxicity to skeletal muscle in rodents leading to necrosis and massive increase in CK. On the basis of this evidence, it is postulated that atypical antipsychotics could interact with endogenous 5-HT to cause some skeletal muscle injury. Dopaminergic receptor blockade is believed to be the main pathophysiology for signs and symptoms of NMS; however, some authors advocate for dysregulated sympathetic nervous system hyperactivity in cases of NMS.⁸ Some authors have suggested that elevated CK may be the beginning of potential NMS, and early diagnosis and immediate discontinuation of the offending drug may prevent the fatal condition.¹¹

Several diagnostic criteria for NMS are used in the literature, but the most commonly employed are the DSM-IV-TR research criteria, which define the syndrome as severe muscle rigidity and elevated temperature associated with taking neuroleptics and, in addition, having 2 of the following: diaphoresis, dysphagia, tremor, incontinence, changes in level of consciousness, mutism, tachycardia, elevated or labile blood pressure, leucocytosis, and laboratory evidence of muscle injury. However, our patient did not show any features of full blown NMS. In the literature, there is increasing evidence¹² to support a link between several hyperthermic syndromes, including NMS and serotonin syndrome. Both involve a breakdown in the normal thermogenic mechanisms responsible for maintaining body temperature. The hypothalamus and sympathetic nervous systems are primarily involved and are regulated by levels of serotonin, dopamine, and norepinephrine. It has been suggested that some patients could be more vulnerable to medication-induced hyperthermic syndromes. For example, elevated body temperature has been associated with increased toxicity of the serotonergic agent 3,4-methylenedioxymethamphetamine (MDMA) in studies looking at causes of serotonin syndrome.¹² It does not seem unreasonable to hypothesize that an elevated or dysregulated body temperature would also make a patient more susceptible to the effects of neuroleptic medication and may even increase the risk of NMS. Our patient had recently been treated for heat stroke, a break down of the body's ability to dissipate heat. This may have made him more vulnerable to the effects of neuroleptic medication on the hypothalamus and sympathetic nervous system. At the time of administration, the potential benefits of olanzapine far exceeded the risk of developing complications. However, careful monitoring of liver function and CK levels was required.

One should be aware of the fact that atypical neuroleptics, the use of which is becoming increasingly common in inpatient and outpatient settings, can cause complete or partial NMS-like presentation or an isolated increase in CK, which could herald the onset of full blown NMS. Great care should be taken in treating delirium with atypical antipsychotics in a patient with a history of heat stroke. Awareness of a triad of heat stroke, malignant hyperthermia, and NMS should always be kept in mind. Baseline pretreatment CK levels and frequent monitoring during the treatment period could avoid this potentially dangerous syndrome. Further research is warranted to investigate the precise pathophysiology and clinical implications of isolated CK elevation and to identify patients who are at higher risk of developing complications from neuroleptic medications.