Necrotising enterocolitis in newborns receiving diazoxide

Prado, Laura A; Castro, Maria del Carmen; Weisz, Dany E.; Jain, Amish; Belik, Jaques

doi:10.1136/archdischild-2020-319057

Cited by 20 publications

(31 citation statements)

References 35 publications

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“…Interestingly, the risk of NEC associated with diazoxide usage was increased in IUGR babies and developed within the first week of drug use as in our patient. 9,10 Our high-risk NICU cohort included two babies with aneuploidy. Patients with trisomy 13 tend to show higher insulin levels at hypoglycemia.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the risk of NEC associated with diazoxide usage was increased in IUGR babies and developed within the first week of drug use as in our patient. 9 , 10 …”

Section: Discussionmentioning

confidence: 99%

“… 6 Since it has been approved for HH, it is usually well tolerated except for some common side effects of hypertrichosis, edema, and electrolyte imbalance. 7 , 8 However, in the past decade, some cases have been reported suggesting severe adverse events (SAEs) including pulmonary hypertension, respiratory decompensation, necrotizing enterocolitis 9 , 10 and congestive heart failure related to the use of diazoxide specifically in neonates. 11 , 12 In 2015, the FDA issued a drug safety black box warning.…”

Section: Introductionmentioning

confidence: 99%

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The danger of diazoxide in the neonatal intensive care unit

Desai

Key

Swindall

et al. 2021

Therapeutic Advances in Drug Safety

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Background: The most common cause of persistent hypoglycemia in infancy is hyperinsulinemic hypoglycemia. When conservative measures fail, providers often use medications to treat persistent hypoglycemia. Diazoxide is first-line therapy for neonatal hypoglycemia and works by inhibiting insulin secretion. Diazoxide is associated with fluid retention, and less commonly with respiratory decompensation and pulmonary hypertension. Case reports documenting these severe adverse events exist in the literature, although the overall incidence, risk factors, and timing for these effects in a newborn are not clearly defined. Methods: We performed a retrospective chart review of all infants admitted to the neonatal intensive care unit (NICU) at Regional One Health from 1 January 2013 until 15 August 2019, who received diazoxide as a treatment for persistent hypoglycemia secondary to hyperinsulinism. Patients were stratified as either having no adverse event or having an adverse outcome to the medication. A severe adverse outcome was defined as any known major side effect of the medication, which a patient developed within 2 weeks of medication initiation that led to medication discontinuation. Results: From our pharmacy database, we identified a total of 15 babies who received diazoxide for persistent hypoglycemia. Of these patients, eight (53%) were classified as having a complication requiring discontinuation of the medication. Six out of eight patients required intubation with mechanical ventilation and five out of eight patients developed pulmonary hypertension. All patients returned to their baseline respiratory support after drug discontinuation. Conclusions: A total of 53% of our study population had an adverse outcome to diazoxide. Previous studies suggest 5% of patients may have respiratory decompensation and require ventilatory support while on diazoxide; however, 40% of our patients deteriorated and then required mechanical ventilation. Based on our data, respiratory deterioration may be more likely to occur when diazoxide is used in preterm infants, those with lower birth weight and intrauterine growth restriction. Plain language summary The dangers in diazoxide Newborns could experience a transient period of low blood glucose levels soon after birth. However, some may progress to persistent low blood glucose levels that cannot be controlled with adequate glucose infusion and may require other ways of treatment. Diazoxide is the first-line drug approved by the US Food and Drug Administration (FDA) for this condition. However, certain cases have reported the development of respiratory deterioration, including increased blood pressure in lung circulation after its use. This prompted a black box warning in 2015 by the FDA. The incidence of neonatal low blood glucose levels seems to have increased and so has the use of this drug. Our study identifies 15 newborns who received diazoxide at Regional One Health neonatal intensive care unit in the past 6 years and reports a significantly higher rate of adverse events in our population leading to drug discontinuation in almost 53% of our cases.

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, the risk of NEC associated with diazoxide usage was increased in IUGR babies and developed within the first week of drug use as in our patient. 9 , 10 …”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The danger of diazoxide in the neonatal intensive care unit

Desai

Key

Swindall

et al. 2021

Therapeutic Advances in Drug Safety

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“…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.…”

Section: Discussionmentioning

confidence: 79%

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

et al. 2022

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IntroductionInfants with severe or recurrent transitional hypoglycaemia continue to have high rates of adverse neurological outcomes and new treatment approaches are needed that target the underlying pathophysiology. Diazoxide is one such treatment that acts on the pancreatic β-cell in a dose-dependent manner to decrease insulin secretion.Methods and analysisPhase IIB, double-blind, two-arm, parallel, randomised trial of diazoxide versus placebo in neonates ≥35 weeks’ gestation for treatment of severe (blood glucose concentration (BGC)<1.2 mmol/L or BGC 1.2 to <2.0 mmol/L despite two doses of buccal dextrose gel and feeding in a single episode) or recurrent (≥3 episodes <2.6 mmol/L in 48 hours) transitional hypoglycaemia. Infants are loaded with diazoxide 5 mg/kg orally and then commenced on a maintenance dose of 1.5 mg/kg every 12 hours, or an equal volume of placebo. The intervention is titrated from the third maintenance dose by protocol to target BGC in the range of 2.6–5.4 mmol/L. The primary outcome is time to resolution of hypoglycaemia, defined as the first point at which the following criteria are met concurrently for ≥24 hours: no intravenous fluids, enteral bolus feeding and normoglycaemia. Groups will be compared for the primary outcome using Cox’s proportional hazard regression analysis, expressed as adjusted HR with a 95% CI.Ethics and disseminationThis trial has been approved by the Health and Disability Ethics Committees of New Zealand (19CEN189). Findings will be disseminated in peer-reviewed journals, to clinicians and researchers at local and international conferences and to the public.Trial registration numberACTRN12620000129987.

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“…Several case series have highlighted an array of possible side effects, including pulmonary hypertension, oedema, heart failure, neutropenia, hirsutism, acidosis, hyperglycemia, reopening of the ductus arteriosus, and necrotizing enterocolitis. [24][25][26][27][28] However, in other reports, serious side effects in otherwise well infants were rare. 12,29,30 Highquality, prospective, controlled data are needed to determine if there are any risks with short courses of diazoxide for transitional hypoglycemia.…”

Section: Discussionmentioning

confidence: 94%

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

Laing

Hanning

Harding

et al. 2021

Journal of Neonatology

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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.

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Necrotising enterocolitis in newborns receiving diazoxide

Cited by 20 publications

References 35 publications

The danger of diazoxide in the neonatal intensive care unit

The danger of diazoxide in the neonatal intensive care unit

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

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

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