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Hormone Research in Paediatrics 2020Diazoxide is widely used to manage congenital hyperinsulinism and is generally well tolerated. Pericardial effusion is not a recognized side effect of diazoxide, apart...
BACKGROUND
Diazoxide is widely used to manage congenital hyperinsulinism and is generally well tolerated. Pericardial effusion is not a recognized side effect of diazoxide, apart from 2 single case reports.
CASE DESCRIPTION
Three patients with congenital hyperinsulinism developed pericardial effusion at the ages of 7 weeks, 8 months, and 17 years. The duration of diazoxide treatment (10-15 mg/kg/day) was 6.5 weeks, 5 months, and 17 years, respectively. There was no evidence of fluid overload or significant other cardiac anomaly. The 7-week-old patient presented with signs of cardiac failure, was treated with diuretics, and the effusion resolved after cessation of diazoxide. The 8-month-old patient required emergency subxiphoid drainage of the effusion due to hemodynamic compromise. The pericardial fluid had high numbers of polymorphonuclear cells, but did not grow any organisms, and histology showed non-specific chronic reactive changes; the effusion did not recur after cessation of diazoxide. The 17-year-old patient presented with atrial fibrillation, was treated with beta blockade and colchicine, and continues on diazoxide with monitoring of the effusion by ultrasound.
CONCLUSION
Patients on long-term diazoxide treatment may be at risk of pericardial effusion, the timing and significance of which is unpredictable. The duration of diazoxide treatment before presentation of pericardial effusion varied in our patients from weeks to years. We advise serial echocardiography 1-2 months after commencement of diazoxide and annually thereafter.
Topics: Adolescent; Congenital Hyperinsulinism; Diazoxide; Diuretics; Female; Humans; Infant; Infant, Newborn; Male; Pericardial Effusion
PubMed: 32580193
DOI: 10.1159/000507624 -
BMJ Open Aug 2022Infants with severe or recurrent transitional hypoglycaemia continue to have high rates of adverse neurological outcomes and new treatment approaches are needed that... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Infants 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 ANALYSIS
Phase 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 DISSEMINATION
This 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 NUMBER
ACTRN12620000129987.
Topics: Blood Glucose; Diazoxide; Double-Blind Method; Female; Fetal Diseases; Glucose; Humans; Hypoglycemia; Infant; Infant, Newborn; Infant, Newborn, Diseases
PubMed: 35977769
DOI: 10.1136/bmjopen-2021-059452 -
Revista de Medicina Interna, Neurologe,... 1974
Topics: Diazoxide; Humans; Hypertension; Hypoglycemia
PubMed: 4157097
DOI: No ID Found -
British Medical Journal Nov 1976
Topics: Diazoxide; Humans; Hypertension
PubMed: 990877
DOI: 10.1136/bmj.2.6046.1259 -
British Medical Journal Oct 1972
Topics: Abnormalities, Drug-Induced; Diazoxide; Female; Hair; Humans; Hyperglycemia; Hypertension; Pregnancy
PubMed: 5082554
DOI: 10.1136/bmj.4.5834.229-b -
British Medical Journal Feb 1973
Topics: Administration, Oral; Diazoxide; Drug Eruptions; Humans
PubMed: 4266186
DOI: 10.1136/bmj.1.5850.420-c -
British Medical Journal Dec 1972
Topics: Diazoxide; Female; Humans; Hypertension; Injections, Intravenous; Labor, Obstetric; Pregnancy; Pregnancy Complications
PubMed: 4645909
DOI: 10.1136/bmj.4.5841.669-a -
Hormone Research in Paediatrics 2017Diazoxide is the first-line treatment for pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to elucidate the pharmacokinetics of diazoxide in children with...
BACKGROUND
Diazoxide is the first-line treatment for pediatric hyperinsulinemic hypoglycemia (HI). This study aimed to elucidate the pharmacokinetics of diazoxide in children with HI.
METHODS
We obtained 81 blood samples from 22 children with HI. Measured serum diazoxide concentrations were used for population pharmacokinetic analysis. Patient factors influencing pharmacokinetics were estimated using nonlinear mixed-effects model analysis. Relationships between drug exposure and adverse drug reactions were also investigated.
RESULTS
Diazoxide disposition in the body was described by a 1-compartment model. Oral clearance (CL/F) and the volume of distribution were proportional to body weight (WT), as expressed by CL/F in males (liters/h) = 0.0358 + 0.00374 × WT (kg). CL/F in females was 39% greater than that in males. Steady-state concentrations of diazoxide were similar following twice- and 3 times-daily dosing when the total daily doses were comparable. A patient whose serum diazoxide concentration exceeded 100 μg/mL over a 4-month period developed hyperglycemia. No significant correlation was observed between severity of hirsutism and diazoxide concentration.
CONCLUSION
We have proposed for the first time a population pharmacokinetic model for diazoxide in children with HI. The potential risk of diabetes mellitus and/or hyperglycemia increases when serum concentrations of diazoxide exceed 100 μg/mL.
Topics: Adolescent; Child; Child, Preschool; Congenital Hyperinsulinism; Diazoxide; Dose-Response Relationship, Drug; Female; Humans; Infant; Infant, Newborn; Male; Models, Biological
PubMed: 28715810
DOI: 10.1159/000478696 -
JAMA Network Open Jun 2024Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Neonatal hypoglycemia is an important preventable cause of neurodevelopmental impairment, but there is a paucity of evidence to guide treatment.
OBJECTIVE
To evaluate whether early, low-dose oral diazoxide for severe or recurrent neonatal hypoglycemia reduces time to resolution of hypoglycemia.
DESIGN, SETTING, AND PARTICIPANTS
This 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 <22 mg/dL or <36 mg/dL despite 2 doses of dextrose gel) or recurrent hypoglycemia (≥3 episodes of a blood glucose concentration <47 mg/dL within 48 hours).
INTERVENTIONS
Newborns 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 MEASURES
The 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.
RESULTS
Of 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 RELEVANCE
In 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 REGISTRATION
ANZCTR.org.au Identifier: ACTRN12620000129987.
Topics: Humans; Diazoxide; Hypoglycemia; Infant, Newborn; Female; Male; New Zealand; Recurrence; Blood Glucose; Treatment Outcome
PubMed: 38869900
DOI: 10.1001/jamanetworkopen.2024.15764 -
Pediatrics Feb 2021The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to...
The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration-approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006-April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.
Topics: Congenital Hyperinsulinism; Diazoxide; Enterocolitis, Necrotizing; Fatal Outcome; Female; Humans; Incidence; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Retrospective Studies; Risk Factors
PubMed: 33483452
DOI: 10.1542/peds.2019-3202