Article, Endocrinology

Hyperosmolar hyperglycemic state secondary to neuroleptic malignant syndrome

Unlabelled imageHyperosmolar hyperglycemic state seconda”>Case Report

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American Journal of Emergency Medicine

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Hyperosmolar hyperglycemic state secondary to Neuroleptic malignant syndrome?,??

Abstract

Neuroleptic malignant syndrome (NMS) is often considered to be a precipitating factor for diabetic coma, such as a hyperosmolar hyperglycemic state (HHS). The combination of NMS and a systemic illness such as HHS can be difficult to diagnose because NMS may mask the coexisting condition. Although this coexistence is rare, it may be fatal if not detected early. We report a case of HHS in a 47-year-old male patient that developed after the distinguishing features of NMS had subsided. After the diagnosis of HHS, his recovery was a result of intravenous administration of soluble human insulin and fluid supplementation. Physicians caring for patients with diabetes who are also treated with neuroleptic agents should be aware that NMS may precipitate the development of secondary hyperglycemia despite a history of well-controlled blood glucose levels.

Neuroleptic malignant syndrome (NMS) is a rare but life- threatening neUrologic emergency associated with the use of neuroleptic agents and characterized by muscle rigidity, hyperther- mia, Autonomic dysfunction, and cognitive changes. Neuroleptic malignant syndrome has been proposed as a precipitating factor for ketotic or nonketotic diabetic coma such as a hyperosmolar hyperglycemic state (HHS) [1-3]. Although coexistence is rare, it can prove fatal if not identified early [2,4]. To the best of our knowledge, there are no reports indicating that NMS induces HHS after the distinguishing features of NMS subside rather than a simultaneous induction. Therefore, this is the first report to clearly indicate that NMS may trigger secondary hyperglycemia.

A 47-year-old man presented to his psychiatric hospital with a 2-day history of obtunded consciousness. He had a 30-year history of schizophrenia treated with antipsychotics such as haloperidol and risperidone. He had been diagnosed with mild diabetes mellitus 16 years prior, which had been controlled with diet therapy only. There was no history of other systemic disease. There was no family history of diabetes mellitus or diabetes insipidus. Two days before admission (day 1), he took 4 days’ worth of his medication (risperidone 24 mg, levomepromazine 200 mg, chlorpromazine 150 mg, promethazine 100 mg, phenobarbital 280 mg, flunitrazepam

16 mg, nitrazepam 40 mg, biperiden 4 mg, mianserin 120 mg, and an antiulcerative). He entered a twilight state, falling repeatedly at home. On day 3, his mother took him to the hospital.

On admission to the psychiatric hospital (day 3), he was lethargic and febrile (axilla temperature, 38.0?C) and complained of Muscle pain. All medication was discontinued. On day 4, blood biochemistry

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?? No conflict of interest or financial support declared.

revealed highly elevated Creatine phosphokinase (37801 IU/L; reference range, 15-110 IU/L). His urine appeared brown, and urinalysis was positive for occult blood on the chemical strip. Overdose-induced rhabdomyolysis was suspected. A fluid infusion was administered, and he was placed under observation.

Other blood tests showed the following: white blood cell count, 18900/uL (89% neutrophils); sodium, 111 mmol/L; potassium,

2.3 mmol/L; and C-reactive protein, 24.6 mmol/L. Electrolyte abnor- malities may have been induced by binge drinking in a lethargic state. The Serum glucose level was 118 mg/dL, and hemoglobin A1c (HbA1c) was 5.9%; a diabetic coma was ruled out. At this time, owing to an open wound on his left leg and the possibility of a life-threatening Systemic Infection, empiric broad-spectrum antibiotics were administrated.

On day 6, risperidone was administered again. On day 8, muscle rigidity, restlessness, and monology appeared. The psychiatrist suggested a diagnosis of NMS based on the prolonged high fever (N 38.0?C), muscle rigidity, disturbance of consciousness, and recent exposure to neuroleptics. The physician decided to transfer the patient to a general hospital, and on day 12, the patient was transported to our hospital by ambulance.

On admission to our hospital, the following clinical symptoms were observed: stupor; axilla temperature, 38.6?C; blood pres- sure, 156/85 mm Hg; pulse rate, 115 beats per minute; respiratory rate, 30/min; and oxygen saturation, 96% in room air. His skin was diaphoretic. An open wound and a pressure ulcer were observed on his left lower leg and sacral area, respectively. No muscle rigidity was observed. Neurologic examination revealed no focal motor or sensory deficits. The laboratory findings included the following: serum glucose level, 231 mg/dL; HbA1c, 6.5%; blood osmolality, 327 mOsm/L; hemoglobin, 12.3 g/dL; white blood cell count, 11160/uL (85.1% neutrophils); blood urea nitrogen, 26.5 mg/dL; creatinine, 0.9 mg/dL; sodium, 153 mmol/L; potassium, 4.1 mmol/L; and chloride, 113 mmol/L. There were no ketone bodies or pyuria on urinalysis. Electrocardiogra- phy and chest radiography showed no abnormalities. Computed tomography of the brain revealed no findings of note, and there was no meningeal irritation.

After admission, his blood creatine kinase decreased to 149 mg/dL (day 14); muscle rigidity did not appear. However, a high fever more than 39?C persisted, and obtunded consciousness did not improve. The brown urine resolved, and repeated urinalysis was negative for ketone bodies or pyuria. His C-reactive protein levels were within 1 to

3 mmol/L. Hypernatremia and hyperchloremia had progressed (sodium elevated to 167 mmol/L). On day 15, his blood glucose level was 401 mg/dL, and his HbA1c level had increased to 7.0%. Blood osmolality increased to 402 mOsm/L. Urinalysis for ketone bodies was negative, and urinary glucose was positive (N 1000 mg/dL).

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Based on the above findings, he was diagnosed with HHS and promptly admitted to the intensive care unit (ICU). Soluble human insulin and fluid supplementation were administered intravenously. The glucose level dropped within normal limits, and he regained consciousness. Two days later (day 17), he was discharged from the ICU and returned to the psychiatric ward. Subcutaneous administra- tion of human insulin commenced. He was discharged 1 month later (day 50), after which antidiabetic medication was prescribed. Although drug adherence was poor, his blood glucose was well controlled. The antidiabetic medication was stopped, and his blood glucose was once again regulated with diet therapy only.

This patient presented with hyperthermia, muscle rigidity, Altered consciousness, and elevated creatine phosphokinase levels, all of which emerged within a week after exposure to a high dose of neuroleptic medications and resulted in a diagnosis of NMS [5]. The precise pathophysiology of NMS is not fully understood. However, it has been proposed that a high dose or rapid titration of neuroleptics may precipitate NMS [6] and may involve the central dopaminergic system, muscle cell membranes, and the sympathetic nervous system [7,8].

Hyperosmolar hyperglycemic state is characterized by severe hyperglycemia (blood glucose N 600 mg/dL), hyperosmolarity (serum osmolarity N 320 mOsm/kg), and dehydration without apparent ketoacidosis [9]. The precipitating causes of this hyperglycemic condition, whether it presents as a ketotic or nonketotic diabetic coma, include infection, dehydration, trauma, or Cardiovascular emergencies [9]. When this patient was admitted to our hospital (day 12) with NMS, his blood glucose level was 231 mg/dL, and urinalysis did not detect glucose or ketone bodies. We speculated that the elevation of blood glucose and osmolarity between days 12 and 15 resulted in HHS, when he was admitted to the ICU. The rapid elevation in the HbA1c levels (day 3, 5.9%; day 15, 7.0%) also supports this assumption.

It has been suggested previously that the hypermetabolic state in NMS can cause a ketotic or nonketotic coma even with a history of well-controlled blood glucose levels [2,3,10]. The hypermetabolic state likely activates the sympathetic system, suppressing insulin secretion and increasing stress hormone production, particularly that of glucagon and epinephrine [7]. An excess secretion of glucagon, catecholamines, cortisol, and growth hormone promotes gluconeo- genesis, glycogenolysis, and lipolysis, resulting in an insulin deficiency [11]. The hypermetabolic state in the present case was likely exacerbated by the presence of an open wound, rhabdomyolysis, electrolyte abnormalities, and an unconfirmed systemic infection. Moreover, it has been suggested that central hypodopaminergia can decrease peripheral glucose tolerance through alteration of the insulin-sensitive hypothalamic glucoregulatory system [12]. There- fore, with a background of impaired glucose tolerance owing to a long-term tonic dopamine blockade in the present case, the NMS- induced hypermetabolic state may have triggered HHS.

We present this case as a reminder to physicians that NMS might precipitate the development of HHS, even with previously well- controlled blood glucose. The combination of NMS and a systemic illness can be difficult to diagnose because of the masking effect that one may have on the other. Many conditions can mimic the presentation of both NMS and diabetic coma, including heatstroke, CNS infection, toxic encephalopathy, agitated delirium, and more

benign drug-induced extrapyramidal symptoms [13]. In addition, NMS and HHS can predispose each other, resulting in a vicious cycle and prolonging both NMS and diabetic coma [1,10]. Neuroleptic malignant syndrome-associated mortality is higher in the presence of other complicating illnesses such as HHS, rhabdomyolysis, or acute renal failure [2,4,14,15]. Consequently, it is important that physicians caring for Psychiatric patients with diabetes who are treated with neuroleptic agents be aware of this rare but potential association.

Keisuke Takanobu, MD? Daisuke Okazaki, MD Tomoo Ogawa, MD Shinya Watanabe, MD Matsuhiko Oka, MD

Department of Psychiatry, Kushiro City General Hospital, Kushiro

Hokkaido, Japan

?Corresponding author

Email address: [email protected]

Shinichi Murakami, MD

Department of Anesthetics, Kushiro City General Hospital, Kushiro

Hokkaido, Japan

Hideki Ura, MD

Department of Psychiatry, Tsurui Youseimura Hospital, Tsuruimura

Kushiro, Hokkaido, Japan

http://dx.doi.org/10.1016/j.ajem.2014.06.003

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