Diazoxide for the Treatment of Transitional Neonatal Hypoglycemia: A Systematic Review

Abstract

Background: Neonatal hypoglycemia is widely recognized as a common, preventable cause of brain injury in infants. Early use of diazoxide, which attenuates insulin secretion, is a possible treatment strategy for neonates that fail first-line management of hypoglycemia. Objective: To systematically evaluate the effectiveness and safety of diazoxide compared to placebo or no diazoxide treatment for improving short- and long-term outcomes in neonates born at ≥35 weeks’ gestation who require treatment for transitional hypoglycemia. Methods: MEDLINE, SCOPUS, EMBASE, and Cochrane databases were searched from inception until November 2020. We included all published randomized and nonrandomized controlled studies of diazoxide therapy in neonates that reported 1 or more prespecified outcomes. We excluded studies that primarily reported on neonates born at <35 weeks, with congenital hyperinsulinism or inborn errors of metabolism, or who started treatment after 1 month of age. Two authors independently performed screening, risk of bias assessment, data extraction, and rating of evidence certainty (GRADE). Meta-analysis was performed in RevMan (inverse variance, fixed effects). Results: A total of 161 studies were screened, 7 reviewed in full, and 1 included (N = 30). Low-certainty evidence suggested that diazoxide, compared with placebo, is associated with a shorter duration of intravenous fluids (mean difference [MD] –50 h, 95% confidence interval [CI] −94, −6), decreased time to achieve full enteral feeding (MD –49 h, 95% CI −91, −7), and euglycemia (MD –33 h, 95% CI −66, −0). Conclusions: Diazoxide may promote metabolic transition in late preterm and term neonates with transitional hypoglycemia. Further high-quality randomized trials are needed to assess short- and long-term effects of diazoxide therapy.

Oral diazoxide versus placebo for severe or recurrent neonatal hypoglycaemia: Neonatal Glucose Care Optimisation (NeoGluCO) study – a randomised controlled trial

“…A systematic review found low certainty evidence from one randomised trial that early use of diazoxide in SGA infants receiving intravenous dextrose for transitional neonatal hypoglycaemia decreased the duration of intravenous fluids and time to full enteral feeding by approximately 2 days. 29 Although there are no apparent adverse effects in this trial, several case series have highlighted a range of possible side effects, including pulmonary hypertension, oedema, heart failure, neutropenia, reopening of the ductus arteriosus and necrotising enterocolitis. 30–33 However, in other reports, serious side effects in otherwise well infants were rare, 16 34–36 suggesting that some of the conditions associated with diazoxide may reflect confounding.…”

Congenital hyperinsulinemic hypoglycemia (HH) requiring treatment as the presenting feature of Kabuki syndrome

“…Before starting treatment, a cardiac ultrasound should be performed to exclude pulmonary hypertension 24 . Finally, digestive disorders, hirsutism or cardiac disorders are other possible side effects of diazoxide treatment 25,26 . Somatostatin analogues are used as the second‐line treatment for diazoxide‐unresponsive cases of congenital HI.…”

Glucagon for Neonatal Hypoglycaemia: Systematic Review and Meta-Analysis

“…While low certainty evidence suggests that glucagon may raise BGC in many infants, several concerns remain, especially the high rate of recurrent hypoglycaemia. It remains unclear whether glucagon administration alters the course of metabolic transition and other approaches may be needed to directly address the underlying pathophysiology of transitional hypoglycaemia, particularly dysregulated insulin secretion [5]. It has been speculated that glucagon is less effective in infants with FGR, although this does not appear to be due to reduced glycogen stores [26].…”

“…Further, some infants have ongoing episodes of hypoglycaemia despite dextrose treatment, most likely due to failure to adequately suppress insulin secretion, thereby inhibiting hepatic glucose output [4]. Thus, new treatment approaches are needed that target the underlying pathophysiology and promote glycaemic stability [5].…”