Background

Severe heat stroke tends to be complicated with rhabdomyolysis, especially in patients with exertional heat stroke [1–4]. Rhabdomyolysis may lead to systemic effects, including the local occurrence of compartment syndrome, hyperkalemic cardiac arrest, and/or lethal disseminated intravascular coagulopathy [5–7]. Rhabdomyolysis usually occurs in the acute phase of heat stroke. We herein report a case of heat stroke in a patient who experienced bimodal rhabdomyolysis in the acute and recovery phases.

Case presentation

A 34-year-old male patient was found lying unconscious with a head injury on the road after participating in a half marathon in the spring. It was a sunny day with a maximum temperature of 24.2 °C and a humidity of 54%. A physician who was transported by helicopter to check on the patient reported that his Glasgow Coma Scale score was 6 and that he presented marked restlessness. His blood pressure was 110/80 mmHg, his heart rate was 140 beats per minute (BPM), his respiratory rate was 40 breaths per minute (BPM), and his axillary temperature was 40.8 °C. He was transported to our hospital by a ground ambulance after the infusion of a sedative agent and the rapid infusion of cooled lactated Ringer. His medical and family history was unremarkable. He did not have sign of flu in a few days. Upon arrival, his Glasgow Coma Scale score was 10. His blood pressure was 116/86 mmHg, his heart rate was 164 BPM, his respiratory rate was 36 BPM, his SpO2 level was 95% with oxygen (8 l/min by mask), and his bladder temperature was 40.2 °C. The physiological findings included hyperhidrosis with restless confusion. After the rapid infusion of 3500 ml of cooled lactated Ringer and gastric lavage with iced water, his bladder temperature decreased to 38.8 °C within 30 min of his arrival and the patient became calm. A chest roentgen revealed no abnormal findings, while an electrocardiogram showed sinus tachycardia without a change in the ST segments. Head CT, which was performed to determine the cause of the patient’s unconsciousness, revealed no brain abnormalities; however, the patient’s marked restlessness and confusion returned. To secure the patient’s safety, a sedative was administered and tracheal intubation was performed. The main results of a blood analysis are shown in Table 1. On the second day of hospitalization, a blood analysis revealed the following findings: aspartate aminotransferase (AST), 144 IU/L; alanine aminotransferase (ALT), 86 IU/L; prothrombin activation ratio, 22%; platelet count, 5 × 104/mm3; and ammonia level, 108 μg/dl. These values were compatible with a diagnosis of acute hepatic failure (according to the Japanese guidelines) [8]; thus, he received fresh frozen plasma and a platelet transfusion was performed. On the third day of hospitalization, a blood analysis revealed the following findings: AST level, 14,894 IU/L; ALT level, 14,355 IU/L, prothrombin activation ratio, 43.8%; and platelet count, 3.8 × 104/mm3; thus, plasma exchange was performed for 2 days, followed by continuous hemodiafiltration for 3 days. The time course of the changes in the patient’s creatinine phosphokinesis (CPK) levels is shown in Fig. 1. The patient’s CPK level increased to 8832 IU/L on the fifth day of hospitalization and then showed a tendency to transiently decrease. The patient was extubated on the eighth day of hospitalization, after showing the ability to respond to commands and the improvement of his laboratory data. From the ninth day of hospitalization, gradual rehabilitation was initiated; this included transferring to a wheelchair or standing at his bedside. However, he felt pain in both legs and his CPK level increased again. Despite the cessation of all drugs and rehabilitation, his CPK level increased to 105,945 IU/L on the 15th day of hospitalization. During this period, he had a low-grade fever ranging from 37.2 to 37.8 °C. Fortunately, his CPK level decreased with a fluid infusion, which was administered to prevent renal failure. The patient’s rehabilitation was restarted after his CPK level fell to <10,000 IU/L. On the 31st day of hospitalization, his CPK level decreased to 623 IU/L and he was discharged on foot. Later, a genetic analysis revealed that he had a thermolabile genetic phenotype of carnitine palmitoyltransferase II (CPT II).

Table 1 The laboratory analysis results
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Fig. 1
figure 1

The time course of the changes in the patient’s creatinine phosphokinesis (CPK) data. The patient’s CPK level increased to 8832 IU/L on the fifth day of hospitalization and then showed a transient tendency to decrease. From the ninth day of hospitalization and following the start of rehabilitation, the patient’s CPK level increased again to reach 105,945 IU/L on the 15th day of hospitalization. PE plasma exchange, CHDF continuous hemodiafiltration

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Discussion

We herein report a case of heat stroke in a patient with bimodal rhabdomyolysis in the acute and recovery phases. We performed a PubMed search to identify any related articles using the key words “heat stroke” and “rhabdomyolysis”. As a result, we found 110 articles about heat stroke with rhabdomyolysis. Among these cases, we found 17 cases involving individuals with heat stroke complicated with rhabdomyolysis in which the time course of the CPK level was described [1, 9–24]. We summarized these cases, including the present case, in Table 2. Among them, only two reports from Japan showed bimodal rhabdomyolysis [15, 22]. In one of these two reports, Takahashi et al. described a 16-year-old male patient who experienced convulsions 3 days after living donor liver transplantation [22]. After the convulsions on postoperative day 5, the patient’s CPK level, which had been showing a tendency to decrease, increased from 715 to 24,985 IU/L. Convulsions can cause rhabdomyolysis; thus, this case report was excluded from the studies that described the natural course of bimodal rhabdomyolysis induced by heat stroke [25]. Two reports by Miura et al. described the case of 38-year-old man who experienced a life-threatening flare-up of rhabdomyolysis (CPK level of 84,612 IU/L on the third hospital day) and who was treated by plasma exchange, hemodiafiltration, steroid pulse therapy, and anticoagulant treatment [15]. His general condition was initially thought to be improving; however, his smoldering rhabdomyolysis suddenly flared up with a marked increase in his CPK level (105,231 IU/L on the 18th day of hospitalization) when the steroid dosage was reduced and rehabilitation was initiated. Thereafter, his condition rapidly deteriorated and he eventually died, despite the provision of aggressive treatment. In addition, Fink et al. reported the case of a 16-year-old male athlete with heat stroke and rhabdomyolysis [19]. The patient survived and was discharged on day 14, but his CPK level was more than 1000 IU/L for several weeks after his discharge. Their report did not indicate whether the patient’s rhabdomyolysis was bimodal. Similarly to our case, in the four Japanese reports of six patients who suffered bimodal rhabdomyolysis in the acute and recovery phases (more than 2 weeks after severe heat stroke), all of the patients could survive and start rehabilitation (Table 3) [26–29]. Accordingly, the authors’ hypothesized that during the recovery phase, the stress of rehabilitation exercises can cause collapsed muscles that are injured by heat stroke to repeatedly flared up. Drugs that are administered during intensive treatment in the acute phase may be involved in the occurrence of bimodal rhabdomyolysis. However, this possibility was considered to be unlikely in the present case because drug-induced rhabdomyolysis usually subsides when the drugs are stopped [30]. In our search of the literature, heat stroke-induced bimodal rhabdomyolysis was only described in Japanese case reports; thus, genetic differences may affect this phenomenon.

Table 2 A summary of the reports on heat stroke in which the time course of rhabdomyolysis was described
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Table 3 The Japanese reports of bimodal rhabdomyolysis after heat stroke
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CPT II is a pivotal enzyme in mitochondrial fatty acid oxidation, which is essential for energy production during simultaneous glucose sparing and a requirement for major energy supply, such as during prolonged fasting or exercise [31]. Cases with the thermolabile genetic phenotype of CPT II have been described mainly in Japan and China. Recent studies have suggested the association of this phenotype with influenza-associated encephalopathy, encephalopathy during a high-grade fever caused by human herpesvirus-6, enterovirus 71, Echo virus, Coxsackievirus, rotavirus, respiratory syncytial virus, adenovirus infection, or sudden unexpected death in infancy [31–40]. Generally, CPT II deficiency has three clinical presentations: a lethal neonatal form, a severe infantile hepatocardiomuscular form, and a myopathic form (which is usually mild and can manifest from infancy to adulthood) [41]. While the former two are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death, the latter is characterized by recurrent exercise-induced muscle pain and weakness, sometimes associated with myoglobinuria, resembling our case [41]. The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting the skeletal muscle and is the most frequent cause of hereditary myoglobinuria, and males are more likely to be affected than females [41]. Accordingly, the thermolabile genetic phenotype of CPT II in the present case might have affected the occurrence of bimodal rhabdomyolysis, even during mild exercise like rehabilitation after depletion of energy in the muscle due to an initial attack of heat stroke [42]. Oda et al. also suggested that the thermolabile genetic phenotype of CPT II was a risk factor for severe heat stroke [43]. Like Reye syndrome, heat stoke induced by thermolabile genetic phenotype of CPT II might be classified as a fatty acid oxidation disorder in the future [44].

Conclusions

Physicians should pay special attention to the stress of rehabilitation exercises, which may cause collapsed muscles that are injured by severe heat stroke to repeatedly flare up.