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Hypoglycemia and Propranolol in Pediatric Behavioral Disorders

1999; American Academy of Pediatrics; Volume: 103; Issue: 6 Linguagem: Inglês

10.1542/peds.103.6.1290

1098-4275

Hector Chavez, Drew Ozolins, Joseph D. Losek,

Cardiovascular Syncope and Autonomic Disorders

Hypoglycemia is a metabolic imbalance that requires prompt recognition and treatment to prevent associated irreversible central nervous system damage. Hypoglycemia can be caused by decreased glucose intake (fasting), increased utilization (hyperinsulinemic state), or diminished production (enzymatic defects).1 One or more of these mechanisms can be responsible for hypoglycemia secondary to drug adverse reactions or overdoses. In pediatrics, drugs commonly associated with hypoglycemia include hypoglycemic agents, salicylates, and β-adrenergic blocking agents.2 We present two pediatric cases to illustrate the association between hypoglycemia and propranolol treatment in behavioral disorders.Case 1 is a 9-year-old white boy with a history of attention deficit disorder and anxiety disorder currently taking methylphenidate hydrochloride (10 mg po TID or 1.2 mg/kg/d), and propranolol (120 mg po every morning and 60 mg po every night or 7.2 mg/kg/d). Propranolol and methylphenidate hydrochloride were given on the day of admission. The patient was walking to a bus stop on the morning of admission and was noted to be confused and to have difficulty walking. Paramedics found the patient unresponsive with a heart rate of 47 beats per minute and systolic blood pressure of 160 mm Hg. Oxygen was given by mask, intravenous access was obtained, and the patient was transported to our emergency department. Physical examination on arrival to the emergency department showed a heart rate of 51 beats per minute, respiratory rate of 10 breaths per minute, blood pressure of 164/120 mm Hg, oxygen saturation was 99% on 12 L per minute oxygen by face mask. The patient's weight was 25 kg (10th percentile) and height was 124 cm (10th percentile). The Glascow Coma Score was 8. The pupils were 3 mm in diameter and reacted slowly to light. Funduscopic examination was not performed. There were small lacerations of the lower lip and an abrasion to the left knee. The remainder of the physical examination was normal. The presumptive diagnosis was possible intracranial injury or other pathology and increased intracranial pressure.Using rapid sequence induction, endotracheal intubation was performed for airway protection and hyperventilation. Heart rate was 160 beats per minute and blood pressure was 137/104 mm Hg. Thirty-two minutes after presentation to the emergency department, a critical glucose level of 27 mg/dL was called from the laboratory. The patient was given 60 mL D25 intravenously and about 3 minutes later began to struggle and equally move both arms and legs. Repeat serum glucose was 102 mg/dL 30 minutes after D25. Head computed tomography (CT) was obtained and the patient was transferred to the pediatric intensive care unit.The head CT was normal. The patient remained awake and alert and was extubated. Urine drug screen was positive for medications used in the emergency department and the patient's medications. Salicylates and ethanol blood levels were negative. A pediatric endocrine consult was obtained. Laboratory tests included the following with normal values in parenthesis: plasma acetoacetate 60 μg/mL (5–30 μg/mL), betahydroxybuterate 1.0 mmol/L (0.0–0.4mmol/L), insulin <1 uU/mL (2–13 uU/mL), growth hormone 15 ng/mL (1–6 ng/mL), and lactate 9.9 mg/dL (4.5–19.8 mg/dL). These tests were before treatment with D25. The approximate time from the onset of symptoms until obtaining the laboratory work was 45 minutes. Ten hours after administration of intravenous dextrose additional tests included Hgb A1C 4.9% (4.2%–6.3%), nonfasting C-peptide 7.8 ng/mL, and normal amino acids. Serum glucose levels remained normal during the hospital course, the high blood pressure resolved and remained normal. The patient was discharged from the hospital the next day on clonazepam and methylphenidate hydrochloride with home glucose monitoring. The patient has had no further hypoglycemic episodes.Case 2 is a 6-year-old white girl with a history of seizures of unknown type, attention deficit disorder, and oppositional disorder currently treated with propranolol (120 mg po BID or 14 mg/kg/d), methylphenidate hydrochloride (5 mg po QID or 1.2 mg/kg/d) and guanfacine hydrochloride (1 mg po qhs or 0.06 mg/kg/d). Medications were not given on the day of admission. On the morning of the day of admission the patient was found unarousable by the mother. Vital signs per paramedics at the scene were: pulse of 50 to 60 beats per minute, blood pressure of 124/74 mm Hg, and respiratory rate of 24 breaths per minute. Paramedics describe the patient as staring straight ahead. The paramedics administered 8 mg diazepam per rectum for possible seizure before transport to our emergency department.Physical examination on arrival to the emergency department showed no evidence of seizure activity. Vital signs were: heart rate of 60 beats per minute, respiratory rate of 4 breaths per minute, blood pressure of 134/90 mm Hg, with oxygen saturation of 98% on 15 L per minute oxygen via face mask. The patient's weight was 17 kg (25th percentile) and height of 112 cm (25th percentile). The child was ventilated by bag-valve mask and her heart rate increased to 80–90 beats per minute. The patient was combative to pain and unresponsive to voice. The patient's pupils were equal, round, and reactive to light. Fundoscopic examination was not performed. The rest of the physical examination was unremarkable. There was no evidence of trauma. The patient was assessed as being postictal.Intravenous access was established. The heart rate was 56 beats per minute and blood pressure was 118/67 mm Hg. Poor respiratory effort necessitated elective endotracheal intubation after rapid sequence induction. Sixty-five minutes from presentation to the emergency department, a rapid glucose test was 30 mg/dL. The patient was given 20 mL of D50 intravenously and became responsive almost immediately, attempting to pull out the endotracheal tube. Serum glucose level before treatment was 39 mg/dL. Repeat serum glucose 40 minutes after D50 was 98 mg/dL.The patient was transported to the pediatric intensive care unit, successfully extubated, and discharged the next day. The urine drug screen was only positive for drugs used in the emergency department and the patient's medications. The serum glucose levels remained within normal range during the hospital course. The patient was continued on propranolol (60 mg po QID), methylphenidate hydrochloride (5 mg po QID), and guanfacine hydrochloride (1 mg po qhs) and has had no further hypoglycemic episodes.Propranolol is a nonselective β-adrenergic blocking agent used in diseases of the cardiovascular system as well as in treatment of thyrotoxicosis, pheochromocytoma, migraine headaches, and behavior disorders.3,4 Hypoglycemia is a recognized, but uncommon, side effect of propranolol. Although there have been reports in the pediatric literature of propranolol-induced hypoglycemia, these cases have occurred in newborns of mothers prescribed propranolol or children with overdoses or with cardiac or renal disease.5–10 Of these reported cases, none underwent an endocrine evaluation for hypoglycemia as was performed in our first patient. The results of the evaluation were most consistent with propanolol-induced hypoglycemia.The recommended dose for propanolol in pediatrics is dependent on the disorder being treated. For arrhythmias, hypertension, and migraine headaches the recommended total oral daily dose ranges from 1 to 4 mg/kg/d.11–13 Propranolol has been used successfully in the treatment of rage, violence, and aggressive behavior in patients refractory to other therapies.414–22 The majority of these reports involve adult patients, but there have been pediatric case reports and studies that have shown effective control of aggressive behavior with propranolol.419–22 However, the efficacy, safety, and optimal dose of propranolol for behavior disorders has not been established. Thus, the dose of propranolol is dependent on therapeutic response and tolerance of side effects such as bradycardia and hypotension. Our patients were taking 7.2 and 14 mg/kg/d and single maximum doses of 4.8 to 7 mg/kg, respectively.Both of our patients presented early in the morning after fasting overnight. The low normal glucose that occurs after fasting can be exacerbated by β-adrenergic antagonist effect of propranolol blocking the catecholamine promotion of glycogenolysis and glucose mobilization in response to hypoglycemia.8 Furthermore, the early warning signs of hypoglycemia such as tachycardia, palpitation, and nervousness can be inhibited by β-adrenergic blocking agents.3The transient hypertension observed in our patients has not been discussed in other reports of propranolol and associated hypoglycemia in children. However, in review of previously reported cases (age range, 6 months to 9 years) blood pressures were abnormally high in 4 patients (above the 95th percentile per age and sex)23 and not reported in the remaining 5.5–10 Transient hypertension associated with propranolol-induced hypoglycemia has been reported in an adult patient.24 This is believed to be secondary to the constrictor effects of endogenous catecholamines released in response to hypoglycemia. Although the 2 patients we presented were also prescribed methylphenidate hydrochloride (which has the adverse effect of increase blood pressure), this is not the likely cause of hypertension in our patients because the blood pressure normalized with the resolution of hypoglycemia. Of note, the second patient we reported was also treated with a centrally acting antihypertensive guanfacine.There are no published reports of methylphenidate or guanfacine hydrochloride-induced hypoglycemia as isolated agents or in combination with propranolol25 However, the loss of appetite, which often occurs as an adverse effect of methylphenidate,26may make patients who are concurrently on propranolol at greater risk for hypoglycemia because patients on propranolol who are in a fasting state are at greater risk for hypoglycemia.In summary, children being treated with propranolol at doses greater than 4 mg/kg/d for behavior disorders may be at increased risk for hypoglycemia. Children in a fasting state and/or concurrently treated with methylphenidate are probably at increased risk. Hypertension is commonly associated with these hypoglycemic events but resolves with correction of the hypoglycemia. Awareness of this adverse effect will assist physicians in the emergent management of children on propranolol who present with altered mental status and should be considered by those treating aggressive behavior disorders in children with propranolol, especially those concurrently treated with methylphenidate.We thank Alice Sather for her help in the preparation of this manuscript.