Interactions of diazoxide with frusemide, spironolactone, and acetylsalicylic acid in a patient with hyperinsulinism of Infancy and Fallot tetralogy

Abstract

A neonate with hyperinsulinism of infancy and congenital heart disease (Fallot tetralogy) demonstrated marked sensitivity to diazoxide treatment when used in combination therapy with frusemide, spironolactone and acetylsalicylic acid. Hyperinsulinism of infancy (HI) is the commonest cause of recurrent and persistent hypoglycaemia in the infancy period and diazoxide is the drug of first choice for treatment. A term baby with a birth weight of 4.6 kg was noted to have tetralogy of Fallot with right ventricular outflow tract obstruction on a fetal echocardiogram at 30 weeks gestation. A right Blalock-Taussig shunt was inserted on day 1 of age. His blood glucose concentration was not detectable within 1 h after birth. His maximum glucose requirement was 18.5 mg/kg per min. Laboratory investigations confirmed HI: plasma glucose concentration 2.6 mmol/l (46.8 mg/dl), plasma insulin 28.2 mU/l, undetectable non-esterified fatty acids and total ketone body (acetotacetate and 3-b-hydroxybutyrate) concentrations. The serum ammonia concentration was 40 lmol/l. He was started on diazoxide (5 mg/kg per day) along with frusemide (1 mg/kg per day), spironolactone (0.4 mg/kg per day) and acetylsalicylic acid (5 mg/kg per day) for his congenital heart disease. He responded to diazoxide and full feeds were established. Six days after starting diazoxide he developed hyperglycaemia (Fig. 1) (21 mmol/l, 378.4 mg/dl), and diazoxide was stopped. Three days later he underwent a fast when he became hypoglycaemic at 3.5 h. Investigations again confirmed HI and he was restarted on diazoxide (3 mg/kg per day). He became hyperglycaemic (28.2 mmol/l, 508.1 mg/dl) within 24 h, requiring a single dose (0.4 U) of Actrapid and diazoxide was stopped again. Blood glucose concentrations returned to normal values within 48 h. However, on fasting he again became hypoglycaemic at 3 h (plasma glucose concentration 2.3 mmol/l (41.4 mg/dl), simultaneous plasma insulin 14.2 mU/l). He was now commenced on diazoxide at a sub-therapeutic dose of 1.5 mg/kg per day. On this dose the blood glucose concentrations were normalised and he was able to maintain normoglycaemia during a 6 h fast. The recommended starting dose of diazoxide for the treatment of HI is 5 mg/kg per day [2]. This patient demonstrated marked sensitivity to the hyperglycaemic action of diazoxide and needed only a sub-therapeutic dose of 1.5 mg/kg per day to maintain normoglycaemia. Whether this marked sensitivity is related to the interactions of diazoxide with diuretics and acetylsalicylic acid or intrinsic to this patient is unclear. In children, the half-life of diazoxide is thought to be about 9.5–20 h [5] with no data on neonates. After oral administration of diazoxide suspension, the hyperglycaemic effect begins within 1 h and lasts approximately 8 h [3]. The concentration of diazoxide required in the blood for the hyperglycaemic action in neonates is not known, although in adults a peak blood level of 16 lg/ml caused hyperglycaemia within 4 h after oral administration of a single dose of 10 mg/kg per day [3]. Significant interactions of diazoxide have been reported with diuretics [1]. The hyperglycaemic action of diazoxide is enhanced by the concurrent administration of thiazide and loop diuretics. The mechanism of hyperglycaemia due to thiazide diuretics such as chlorothiazide involves activation of potassium channels in the b-cell membrane [1] but the mechanism is unclear in the case of loop diuretics such as frusemide. Acetylsalicylic acid enhances the b-cell sensitivity to glucose as well as impairing glucose metabolism of insulin sensitive tissues [4]. Hence this action of acetylsalicylic acid is unlikely to explain the hyperglycaemia seen in our patient. Eur J Pediatr (2003) 162: 806–807 DOI 10.1007/s00431-003-1304-x

DOI: 10.1007/s00431-003-1304-x

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Cite this paper

@article{Alexander2003InteractionsOD, title={Interactions of diazoxide with frusemide, spironolactone, and acetylsalicylic acid in a patient with hyperinsulinism of Infancy and Fallot tetralogy}, author={Saji Alexander and Antoinette C Anazodo and Khalid Hussain}, journal={European Journal of Pediatrics}, year={2003}, volume={162}, pages={806-807} }