Prevalence and safety of diazoxide in the neonatal intensive care unit

Gray, Keyaria D.; Dudash, Kathryn; Escobar, Carmen; Freel, Colman; Harrison, Tylah; McMillan, Chandler; Puia‐Dumitrescu, Mihai; Cotten, C. Michael; Benjamin, Robert; Clark, Reese H.; Benjamin, Daniel K.; Greenberg, Rachel G.

doi:10.1038/s41372-018-0218-4

Cited by 30 publications

(43 citation statements)

References 30 publications

(56 reference statements)

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“…In a paper describing the pharmacokinetics of diazoxide from Kizu et al [14], a high incidence of hypertrichosis in 17 out of 19 patients was reported, but no major SAEs. In the recent analysis of the use of diazoxide in NICUs by Gray et al [18], they found that pulmonary hypertension occurred in 2% of patients treated with transient neonatal hypoglycemia and that worsening of fluid overload and worsening respiratory status occurred in 14 and 12% respectively. This is a different group of patients than those reported in our paper because only 68 of 868 patients who were discharged home remained on diazoxide.…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…There is no obvious explanation for why diazoxide would cause necrotizing enterocolitis, so we feel in these circumstances, it is likely not related to the drug. Gray et al reported 1% rate of necrotizing enterocolitis in their 1,066 babies but felt the diazoxide was not causative and that many factors were likely to be in play, specifically all but one of their patients who got necrotizing enterocolitis were < 37 weeks gestation [18]. …”

Section: Discussion/conclusionmentioning

confidence: 99%

“…The use of diazoxide has increased in the new-born population since 1997 [18]. The side effect profile of diazoxide has been well noted but not until recently were studies published that define the likelihood of developing serious adverse events (SAE) in order to better guide the prescribing physician with analysis of the risk-benefit ratio in the treatment of patients with hyperinsulinism.…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…A recent study by Gray et al [18] in 2018 showed that since 1997, the percentage of infants exposed to diazoxide in neonatal units has increased and they speculate that since the publication of the American Academy of Pediatrics guidelines in 2011, both the frequency of diagnosis of hypoglycemia and rate of treatment with diazoxide has doubled. They report overall that 1066 infants were exposed to diazoxide out of approximately 1.25 million babies admitted to the neonatal intensive care unit (NICU).…”

Section: Introductionmentioning

confidence: 99%

“…They report overall that 1066 infants were exposed to diazoxide out of approximately 1.25 million babies admitted to the neonatal intensive care unit (NICU). In their review, Gray et al [18] reported that pulmonary hypertension occurred in 2% of patients treated with diazoxide. Herrera et al [19] recently reported the prevalence of adverse events in 295 patients diagnosed with hyperinsulinism over a 12-year period from 2003 to 2014.…”

Section: Introductionmentioning

confidence: 99%

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Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism

Thornton¹,

Truong²,

Reynolds³

et al. 2019

Horm Res Paediatr

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Introduction: Diazoxide is the first line and only Federal Drug Agency approved pharmacological agent for the treatment of hyperinsulinism. Its use has increased over the years to include patients with various genetic forms of hyperinsulinism, perinatal stress hyperinsulinism and infants of diabetic mothers with more babies than ever being exposed to this therapy. Methods: We performed a retrospective analysis of 194 patients with hyperinsulinism in our clinic and looked for those who had experienced serious adverse events (SAE) including pulmonary hypertension and neutropenia. We compared the rates of SAE in the different types of hyperinsulinism. Results: Out of 194 patients with hyperinsulinism, 165 (85.1%) were treated with diazoxide. There were 17 SAEs in 16 patients including 8 cases of pulmonary hypertension and 8 of neutropenia. These data show that overall the frequency of SAE associated with diazoxide use is 9.7%, but that those with perinatal stress hyperinsulinism have a much higher rate than those with genetic forms of hyperinsulinism (16.7 vs. 3.6%; p = 0.01). We also found diazoxide is associated with pulmonary hypertension (4.8% of patients treated). Although more patients with perinatal stress hyperinsulinism (7.6%) were affected than genetic hyperinsulinism (1.2%), the difference was not significant (p = 0.088). Conclusion: The rate of SAEs associated with (not necessarily caused by) diazoxide has been demonstrated. The rate of SAE in newborns with perinatal stress hyperinsulinism is significantly higher than that of otherwise healthy babies with genetic forms of hyperinsulinism, suggesting that caution should be used when prescribing diazoxide to this population. This information should help balance the risk benefit of treatment and provide guidance on screening for these complications in the population of treated patients.

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Section: Discussion/conclusionmentioning

confidence: 99%

Section: Discussion/conclusionmentioning

confidence: 99%

Section: Discussion/conclusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism

Thornton¹,

Truong²,

Reynolds³

et al. 2019

Horm Res Paediatr

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Diazoxide for Severe or Recurrent Neonatal Hypoglycemia

Laing,

Walsh,

Alsweiler

et al. 2024

JAMA Netw Open

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ImportanceNeonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment.ObjectiveTo evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia.Design, Setting, and ParticipantsThis 2-arm, placebo-controlled randomized clinical trial was conducted from May 2020 to February 2023 in tertiary neonatal units at 2 New Zealand hospitals. Participants were neonates born at 35 or more weeks’ gestation and less than 1 week of age with severe hypoglycemia (blood glucose concentration &lt;22 mg/dL or &lt;36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration &lt;47 mg/dL within 48 hours).InterventionsNewborns were randomized 1:1 to receive diazoxide suspension (loading dose, 5 mg/kg; maintenance, 1.5 mg/kg every 12 hours) or placebo, titrated per protocol.Main Outcome and MeasuresThe primary outcome was time to resolution of hypoglycemia, defined as enteral bolus feeding without intravenous fluids and normoglycemia (blood glucose concentration of 47-98 mg/dL) for at least 24 hours, compared between groups using adjusted Cox proportional hazards regression. Hazard ratios adjusted for stratification variables and gestation length are reported. Prespecified secondary outcomes, including number of blood glucose tests and episodes of hypoglycemia, duration of hypoglycemia, and time to enteral bolus feeding and weaning from intravenous fluids, were compared by generalized linear models. Newborns were followed up for at least 2 weeks.ResultsOf 154 newborns screened, 75 were randomized and 74 with evaluable data were included in the analysis (mean [SD] gestational age for the full cohort, 37.6 [1.6] weeks), 36 in the diazoxide group and 38 in the placebo group. Baseline characteristics were similar: in the diazoxide group, mean (SD) gestational age was 37.9 (1.6) weeks and 26 (72%) were male; in the placebo group, mean (SD) gestational age was 37.4 (1.5) weeks and 27 (71%) were male. There was no significant difference in time to resolution of hypoglycemia (adjusted hazard ratio [AHR], 1.39; 95% CI, 0.84-2.23), possibly due to increased episodes of elevated blood glucose concentration and longer time to normoglycemia in the diazoxide group. Resolution of hypoglycemia, when redefined post hoc as enteral bolus feeding without intravenous fluids for at least 24 hours with no further hypoglycemia, was reached by more newborns in the diazoxide group (AHR, 2.60; 95% CI, 1.53-4.46). Newborns in the diazoxide group had fewer blood glucose tests (adjusted count ratio [ACR], 0.63; 95% CI, 0.56-0.71) and episodes of hypoglycemia (ACR, 0.32; 95% CI, 0.17-0.63), reduced duration of hypoglycemia (adjusted ratio of geometric means [ARGM], 0.18; 95% CI, 0.06-0.53), and reduced time to enteral bolus feeding (ARGM, 0.74; 95% CI, 0.58-0.95) and weaning from intravenous fluids (ARGM, 0.72; 95% CI, 0.60-0.87). Only 2 newborns (6%) treated with diazoxide had hypoglycemia after the loading dose compared with 20 (53%) with placebo.Conclusions and RelevanceIn this randomized clinical trial, early treatment of severe or recurrent neonatal hypoglycemia with low-dose oral diazoxide did not reduce time to resolution of hypoglycemia but reduced time to enteral bolus feeding and weaning from intravenous fluids, duration of hypoglycemia, and frequency of blood glucose testing compared with placebo.Trial RegistrationANZCTR.org.au Identifier: ACTRN12620000129987

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Genotype and phenotype analysis of a cohort of patients with congenital hyperinsulinism based on DOPA-PET CT scanning

Zhang

et al. 2019

Eur J Pediatr

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Congenital hyperinsulinism (CHI) is a clinically, genetically, and morphologically heterogeneous disorder. 18 F DOPA-PET CT scanning greatly improves its clinical outcome. Here, we presented the first Chinese 18 F DOPA-PET CT scanning–based CHI cohort highlighting the variable ethic clinical phenotypes and genotypes. Fifty CHI patients were recruited. Median age at presentation was 2 days. Median fasting time was 2 h. Mean insulin level was 25.6 μIU/ml. Fifty-two percent of patients were diazoxide-unresponsive with significantly shorter fasting tolerance time and higher serum insulin level compared with the responsive patients. Seventy-four percent of patients experienced at least one adverse drug reaction. Tremendously increased focal lesions (32%) were detected and 75% of them were cured through surgery. Thirty-one nucleotide sequence changes were identified in 48% patients. Four novel variants (Q608X, Q1347X, Q289X, F1489S) in ABCC8 gene and 2 novel variants (G132A, V138E) in KCNJ11 gene were detected. Of the variants, 87.1% harbored in ABCC and KCNJ11 genes. T1042Qfs*75 in ABCC8 gene was the most common mutation. Conclusion : Highly increased portion of focal lesion was presented in Chinese CHI patients compared with that of the previous reports. Intolerance to diazoxide was much more evident in Chinese or East Asian than other populations. Certain hotspot mutations harbored in Chinese CHI patients. What is Known: • 18 F DOPA-PET CT scanning can provide informative guidance for surgical procedure when medical therapy is not well responded in CHI patients . What is New: • Intolerance to diazoxide is much more evident in Chinese and East Asian CHI patients compared with the other ethnic populations . • Novel mutations were detected in ABCC8 and KCNJ11 gene. Hotspot mutations such as T1042Qfs*75, I1511K, E501K, G111R in ABCC8 gene, and R34H in KCNJ11 gene are predominantly responsible for Chinese CHI patients .

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Prevalence and safety of diazoxide in the neonatal intensive care unit

Abstract: Diazoxide use in NICU settings has increased over time. Infants receiving diazoxide commonly received diuretics.

Cited by 30 publications

References 30 publications

Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism

Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism

Diazoxide for Severe or Recurrent Neonatal Hypoglycemia

Genotype and phenotype analysis of a cohort of patients with congenital hyperinsulinism based on DOPA-PET CT scanning

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