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PEDIATRICS Vol. 111 No. 6 June 2003, pp. 1447-1452

EXPERIENCE AND REASON

Fatal Malignant Hyperthermia-Like Syndrome With Rhabdomyolysis Complicating the Presentation of Diabetes Mellitus in Adolescent Males

Abby S. Hollander, MD*, Robert C. Olney, MD{ddagger}, Piers R. Blackett, MD§ and Bess A. Marshall, MD*

* Division of Pediatric Endocrinology and Metabolism, Washington University School of Medicine and St Louis, Children’s Hospital, St Louis, MO 63110
{ddagger} Division of Pediatric Endocrinology, Nemours Children’s Clinic, Jacksonville, FL 32207
§ Department of Pediatrics, Diabetes and Endocrine Section, Children’s Hospital of Oklahoma, Oklahoma City, OK 73190


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 CASE REPORTS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. This report describes a new fatal syndrome observed in adolescent males at the initial presentation of diabetes mellitus. The features include hyperglycemic hyperosmolar coma complicated by a malignant hyperthermia-like picture with fever, rhabdomyolysis, and severe cardiovascular instability.

Design. Case series.

Setting. Pediatric intensive care units of 3 tertiary care facilities in the United States.

Patients. Six adolescent males, 5/6 obese with acanthosis nigricans, 4/6 black.

Results. Four of 6 patients died. Four of 6 patients did not have significant ketosis. Six of 6 patients had increased temperature after the administration of insulin.

Conclusions. The underlying etiology of this syndrome remains unclear. Possibilities include an underlying metabolic disorder such as a fatty acid oxidation defect, an unrecognized infection, exposure to an unknown toxin, or a genetic predisposition to malignant hyperthermia. Evaluation for all these possibilities and empiric treatment with dantrolene should be considered for this type of patient until this syndrome is better characterized.

Key Words: diabetes mellitus • rhabdomyolysis • malignant hyperthermia • obesity

Abbreviations: DKA, diabetic ketoacidosis • HHNS, hyperglycemic hyperosmolar nonketotic syndrome • BG, blood glucose


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
CASE REPORTS
 RESULTS
 DISCUSSION
 REFERENCES
 
Diabetes mellitus is one of the most common chronic disorders of childhood. It is rarely fatal at presentation. There are 2 well-described, life-threatening, acute metabolic complications of diabetes mellitus: diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar nonketotic syndrome (HHNS). Nausea, vomiting, dehydration, and weakness are common symptoms of DKA. Shock and coma are uncommon unless cerebral edema, which occurs in 1% to 2% of cases, develops. Fever is rare, and when present usually indicates an underlying infection.1 The overall mortality rate for DKA is estimated at 2% to 10%.2

HHNS is usually associated with type 2 diabetes mellitus. The incidence of type 2 diabetes has been increasing rapidly in children in the United States. The prevalence has been estimated at 2 to 50 per 1000, an increase of as much as 10-fold in the past 20 years.3 Despite the increasing incidence of type 2 diabetes in children, HHNS is rare in childhood.2 HHNS in adults generally presents in an insidious fashion, with increasing polyuria, polydipsia, and lethargy over several days. As with DKA, when fever is present in HHNS, an infection should be presumed.4 The mortality rate for HHNS has been reported as 12% to 46%,3 with the highest rates associated with age >75 years and serum osmolality >350 mOsm/L.5

In the past several years, 6 adolescent boys have presented with diabetes mellitus along with many features of HHNS. Their courses, however, were marked by development of high fever, rhabdomyolysis, and severe cardiovascular instability. The following report describes these cases as a new often-fatal presentation of diabetes mellitus in adolescents.


   CASE REPORTS
TOP
 ABSTRACT
 INTRODUCTION
 CASE REPORTS
RESULTS
 DISCUSSION
 REFERENCES
 
Case A
An 18-year-old obese black male with acanthosis nigricans presented with a flu-like illness. He was afebrile at presentation. The initial blood glucose (BG) was 1810 mg/dL with trace urine ketones. He developed fever and shock after initiation of therapy with intravenous (IV) fluid and IV insulin. He remained intubated for 44 days. Fever persisted for 48 hours. He had severe rhabdomyolysis and renal failure, and required dialysis for 5 weeks. He made a full recovery and was discharged after 104 days.

Case B
A 14-year-old obese black male with acanthosis nigricans presented with sore throat, vomiting, stumbling. He was afebrile at presentation. The initial BG was 970 mg/dL with 3+ urine ketones. His mental status deteriorated after initiation of therapy with IV fluid and IV insulin. Head computed tomography scan did not have dilated ventricles or other suggestion of cerebral edema. He developed fever and shock and was intubated. Creatinine rose from 1.0 mg/dL to 3.8 mg/dL during course. He remained febrile throughout his course. He developed refractory arrhythmias and died 20 hours after presentation. Postmortem examination did not elucidate a specific cause of death. No mention was made of skeletal muscle histology. There was no evidence of myocardial infarction or other underlying cardiac disease.

Case C
A 16-year-old obese black male with acanthosis nigricans presented with dizziness and no history of fever. The initial BG was 1381 mg/dL with 3+ urine ketones. He developed fever, shock, and mental status decline after initiation of IV fluids and IV insulin. Fever persisted for 19 hours. He had severe rhabdomyolysis and renal failure. He stabilized on day 2 of hospitalization. On day 3, he developed hypotension just after replacement of a femoral venous line with a dialysis catheter. He was taken to the cardiac catheterization lab to exclude a tear in the vein, and had a full cardiac arrest. Contrast injection during cardiopulmonary resuscitation revealed a large saddle pulmonary embolus. The resuscitation was not successful. The family did not want a postmortem examination.

Case D
A 14 year-old-obese black male with acanthosis nigricans presented with dizziness and vomiting. His appearance was remarkable for prominence of the mandible and large hands and feet. The initial BG was 1600 mg/dL with small urine ketones. Treatment was initiated with IV fluids and IV insulin. Fever developed over the first 12 hours. He became combative and was given haloperidol for sedation. Hypotension was a persistent problem. He had severe rhabdomyolysis and renal failure. Hemodialysis was complicated by hypotension. Hemodiafiltration was initiated. Pulmonary and cardiac function declined over the next 3 days, with development of pulmonary edema. He developed refractory hypotension and died on day 4 of hospitalization. The postmortem examination showed left ventricular hypertrophy, fatty liver, and nodular pituitary somatotroph hyperplasia. The psoas and diaphragm were described as having well-preserved cross striations, no necrotic change, and no inflammation.

Case E
A 16-year-old obese white male with acanthosis nigricans presented with vomiting, diarrhea, and severe lethargy. The initial BG was 1680 mg/dL, with trace urine ketones. He had hypotension, fever, and renal failure at presentation. A computed tomography scan did not have dilated ventricles or other suggestion of cerebral edema. He improved transiently after administration of IV fluids with decreased temperature and improved mental status. Hypotension worsened after initiation of IV insulin. He was intubated, with succinylcholine used for anesthesia. He then developed high fever, rhabdomyolysis, and ventricular arrhythmias. His rhythm deteriorated to asystole, and he died 13 hours after presentation. The postmortem examination did not reveal evidence of underlying cardiac disease and did not mention skeletal muscle histology.

Case F
A 14-year-old thin white male without acanthosis nigricans presented with vomiting, dizziness, and weakness. He was afebrile at presentation. The initial BG was 2580 mg/dL with 1+ urine ketones. Serum acetone was negative and urine organic acid profile showed minimal amounts of ß-hydroxybutryrate. He developed fever, hypotension, and mental status decline after administration of IV fluid and IV insulin. He received mannitol without obvious clinical improvement. He was intubated, then developed pulseless ventricular tachycardia responsive to cardioversion. Fever persisted for 5 hours. He remained intubated for 1.5 days. He had rhabdomyolysis but no renal failure. He made a full recovery and was discharged after 8 days.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 CASE REPORTS
 RESULTS
DISCUSSION
 REFERENCES
 
There are a number of similarities in the presentation of these patients (Table 1). All 6 of these patients were adolescent males not previously known to have diabetes. Five of them were extremely obese and 4 of those 5 were black. All presented with extreme hyperglycemia and hyperosmolar states with moderate to severe acidosis. Only 1 had significant hypercarbia (case E), but 3 others had PCO2 that was inappropriately high for the degree of acidosis (cases B, C, and F). Four did not have significant ketonuria. Antibodies to islet antigens were not present in the 2 cases where they were checked. All had a strong family history of type 2 diabetes and 5 had acanthosis nigricans. All had a relatively sudden onset of hypotension associated with fever and required pressor support (Table 2). In all but 1 case, the patient presented afebrile and developed fever after therapy had begun (Fig 1). No patient had a positive blood or urine culture. All showed evidence of rhabdomyolysis and several developed arrhythmia or cardiac dysfunction (Table 3). Three died rapidly, while another died after initially stabilizing (case C). Two survived, 1 with residual hypertension but not requiring insulin (case A), 1 with mild unilateral upper extremity weakness and persistent diabetes mellitus (case F).


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  		TABLE 1. Characteristics of 6 Patients With Severe Hyperglycemia, and Malignant Hyperthermia-Like Syndrome

 

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  		TABLE 2. Modes of Therapy Used in 6 Patients With Severe Hyperglycemia, and Malignant Hyperthermia-Like Syndrome

 

Figure 1
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  		Fig 1. Body temperature of 6 pediatric patients with hyperosmolar nonketotic hyperglycemic coma before and after administration of insulin therapy. All points represent the mean temperature of all 6 patients at the given time except the time before insulin administration, which represents the 5 patients in whom temperatures were recorded before therapy. Data shown represent the mean ± the standard error of the mean.

 

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  		TABLE 3. Outcomes of 6 Patients With Severe Hyperglycemia, Malignant Hyperthermia-Like Syndrome

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 CASE REPORTS
 RESULTS
 DISCUSSION
REFERENCES
 
This report characterizes a fatal presentation of diabetes mellitus in adolescent boys that has not been previously described in the pediatric literature. Additionally, these cases represent the largest series of hyperosmolar coma in pediatric diabetes mellitus to date. The diagnosis of type 2 diabetes mellitus is being made with ever-increasing frequency in the pediatric population as the rate and degree of obesity in children rises. An increase in complications of type 2 diabetes in children can therefore be anticipated. The patients presented here had similar characteristics and developed a syndrome of severe hyperglycemia, fever, hypotension, and rhabdomyolysis with an extremely high mortality rate.

Two previous adult patients were reported with a similar syndrome at ages 32 and 22 years.6,7 The 32-year-old patient was African and obese, presented with polyuria, polydipsia, weight loss, confusion, and a BG of 1480 mg/dL.6 He was afebrile on admission but developed fever of 40°C as well as rhabdomyolysis after initiation of therapy. He was given chlorpromazine, haloperidol, and diazepam in addition to his fluid and insulin therapy but it appeared that the rhabdomyolysis had begun before administration of the psychotropic medication. He was given dantrolene late in the course of his illness (at 14 days) with unclear benefit, and he eventually died of cardiorespiratory arrest on day 15. The 22-year-old patient presented with report of gastrointestinal disorders and reduced level of consciousness.7 He had a BG of 1085 mg/dL and was afebrile on admission. After initiation of rehydration and insulin he developed fever with a peak temperature of 41.7°C. He developed evidence of rhabdomyolysis. He was treated within 2 hours with dantrolene 1.5 mg/kg body weight followed by 4.5 mg/kg/hour by infusion. He improved and survived. Susceptibility to malignant hyperthermia was diagnosed 5 months after his presentation by in vitro contracture test on a biopsy of the vastus lateralis muscle.

The 4 previously reported pediatric cases of rhabdomyolysis and diabetes include 2 with clear type 1 diabetes and DKA.8,9 Another was a 12-year-old who was not noted to be obese but who developed rhabdomyolysis after initiation of insulin and fluid therapy. The presence of fever was not noted, and the child survived after a course of acute renal failure.10 The fourth was reported in the German literature and presented at age 9 with apparent type 1 diabetes and ketoacidosis but who, like the patients presented here, developed fever and rhabdomyolysis after the administration of insulin.11

Malignant hyperthermia occurs when muscle calcium flux is disrupted leading to depleted calcium in the sarcoplasmic reticulum and increased calcium in the myoplasm. The known triggers include the anesthetics halothane and succinylcholine, neuroleptics, and stress. Malignant hyperthermia is known to be more common in young patients and there is a male predominance. In a review of malignant hyperthermia cases in Austria, only 3/160 crises occurred in patients over age 40. Of the 79 patients studied, 75% were male.12 The reason for male predominance is not known, but has also been reported in other populations.13,14

The mechanism that was responsible for the malignant hyperthermia-like syndrome that occurred in the patients presented here is not known. Succinylcholine may have played a role in the course of case E. None of the other cases received succinylcholine. Rhabdomyolysis, not necessarily with hyperthermia, has been repeatedly reported in DKA15–19 as well as in diabetic hyperosmolar coma in adults.6,20–27 A number of inborn errors of metabolism have been found in patients with rhabdomyolysis occurring in situations other than diabetes, not associated with fever or hyperthermia, including disorders of glycogen metabolism.28–31 Disorders of fatty acid metabolism have also been associated with the occurrence of rhabdomyolysis, including carnitine palmitoyltransferase I or II deficiency,29 very long chain acyl-coenzyme A dehydrogenase deficiency,32,33 medium chain acyl-coenzyme A dehydrogenase deficiency,34 and the trifunctional protein of ß-oxidation.35 Carnitine palmitoyltransferase II deficiency has additionally been shown to have an association with malignant hyperthermia.36 There is increasing evidence that there are defects in fatty acid oxidation in the skeletal muscle of obese individuals with type 2 diabetes leading to accumulation of lipid within the myocytes.37 Perhaps this disordered metabolism in the skeletal muscle makes the myocytes more susceptible to subsequent damage.

In the case of the patients presented here, no enzyme studies were done to test for inborn errors of metabolism. These disorders remain as possible contributors to the occurrence of rhabdomyolysis. Unfortunately, in most of these disorders no proven specific therapy exists. However, as noted in Table 2, carnitine was given in 2 cases in an attempt to ameliorate the course in the event that one of these inborn errors of fatty acid oxidation was present. The efficacy of carnitine in this situation is not known.38 One might speculate that the premature appearance of type 2 diabetes in an adolescent suggests the presence of a predisposing metabolic defect, though none have to date been reported except in cases of autosomal dominant maturity onset diabetes of youth.

Wappler et al7 have proposed that a preservative, m-cresol, which is present in most commercially prepared insulin, may have been the triggering agent for malignant hyperthermia in at least 1 patient. His group has subsequently shown that 4-chloro-m-cresol can initiate malignant hyperthermia in swine susceptible to the syndrome39 and that it can be used reliably for diagnosing malignant hyperthermia susceptibility.40 Dantrolene, a diphenylhydantoin analog, is the drug of choice in the treatment of acute malignant hyperthermia crisis. Its mechanism of action is not precisely known, but the drug appears to act on the myocyte to inhibit release of calcium from the sarcoplasmic reticulum.41 In the 1 case in which dantrolene was given as therapy for malignant hyperthermia associated with DKA, the patient improved and survived.7 M-cresol is present in all commercially available preparations of regular insulin in the United States, so it would have been present in the insulin administered in all of the current cases.

We propose that the syndrome which occurred in our patients may have been malignant hyperthermia. The combination of severe physiologic stress with administration of IV insulin containing m-cresol may have triggered the malignant hyperthermia syndrome, or an underlying inborn error of metabolism may have been present that predisposed to the syndrome in the setting of diabetic hyperosmolar coma. Should a similar syndrome of hyperosmolarity and fever appear in the setting of adolescent type 2 diabetes, particularly if rhabdomyolysis is present, a trial of dantrolene may be beneficial in addition to the usual considerations of sepsis and toxic exposure. In addition, until a diagnosis of an error of fatty acid metabolism has been ruled out, treatment with carnitine should be considered. In patients presenting with new-onset diabetes, DKA, or particularly HHNS, a family history of malignant hyperthermia or rhabdomyolysis should be sought.


   FOOTNOTES
 
Received for publication Sep 7, 2002; Accepted Nov 12, 2002.

Reprint requests to (A.S.H.) Division of Pediatric Endocrinology and Metabolism, Box 8116, St Louis Children’s Hospital, One Children’s Place, St Louis, MO 63110. Email: hollander{at}kids.wustl.edu


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 INTRODUCTION
 CASE REPORTS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics




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