RESUMO
OBJECTIVE: Transient hyperinsulinism (THI) is the most common form of recurrent hypoglycaemia in neonates beyond the first week of life. Although self-resolving, treatment can be required. Consensus guidelines recommend the lower end of the diazoxide 5-15 mg/kg/day range in THI to reduce the risk of adverse events. We sought to determine if doses <5 mg/kg/day of diazoxide can be effective in THI. DESIGN, PATIENTS, MEASURMENTS: Infants with THI (duration <6 months) were treated with low-dose diazoxide from October 2015 to February 2021. Dosing was based on weight at diazoxide start: 2 mg/kg/day in infants 1000-2000 g (cohort 1), 3 mg/kg/day in those 2000-3500 g (cohort 2) and 5 mg/kg/day in those >3500 g. RESULTS: A total of 73 infants with THI (77% male, 33% preterm, 52% small-for-gestational age) were commenced on diazoxide at a median age of 11 days (range 3-43) for a median duration of 4 months (0.3-6.8), with no difference between cohorts. The mean effective diazoxide dose was 3 mg/kg/day (range 1.5-10); 35% (26/73) required an increase from their starting dose, including 60% (9/15) of cohort 1. There was no association between perinatal stress risk factors or treatment-related characteristics and dose increase. Adverse events occurred in 13 patients (18%); oedema (12%) and hyponatraemia (5%) were the most common. Two infants developed suspected necrotising enterocolitis (NEC); none had pulmonary hypertension. CONCLUSION: Diazoxide doses <5 mg/kg/day are effective in THI. While the nature of the association between diazoxide and NEC was unclear, other adverse events were mild. We suggest considering starting doses as low as 2-3 mg/kg/day in THI to balance the side effect risk while maintaining euglycaemia.
Assuntos
Hiperinsulinismo Congênito , Hiperinsulinismo , Hipoglicemia , Lactente , Feminino , Recém-Nascido , Humanos , Masculino , Diazóxido/efeitos adversos , Hipoglicemia/tratamento farmacológico , Recém-Nascido Pequeno para a Idade Gestacional , Fatores de Risco , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo Congênito/tratamento farmacológicoRESUMO
The initial step for the differential diagnosis of hypoglycemia is to determine whether it is hyperinsulinemic or non hyperinsulinemic. Existing literature discusses drug-related hypoglycemia, but it misses a focus on drug-induced hyperinsulinemic hypoglycemia (DHH). Here we reviewed the association existing between drugs and hyperinsulinemic hypoglycemia. We primarily selected on the main electronic databases (MEDLINE, EMBASE, Web of Science, and SCOPUS) the reviews on drug-induced hypoglycemia. Among the drugs listed in the reviews, we selected the ones linked to an increase in insulin secretion. For the drugs missing a clear association with insulin secretion, we investigated the putative mechanism underlying hypoglycemia referring to the original papers. Our review provides a list of the most common agents associated with hyperinsulinemic hypoglycemia (HH), in order to facilitate both the recognition and the prevention of DHH. We also collected data about the responsiveness of DHH to diazoxide or octreotide.
Assuntos
Hiperinsulinismo , Hipoglicemia , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/complicações , Hipoglicemia/tratamento farmacológico , Hiperinsulinismo/induzido quimicamente , Hiperinsulinismo/complicações , Hiperinsulinismo/diagnóstico , Diazóxido/efeitos adversos , Secreção de InsulinaRESUMO
AIM/INTRODUCTION: Diabetes Mellitus is a chronic degenerative disease, and its main biochemical characteristic is hyperglycemia due to impaired insulin secretion, resistance to peripheral actions of insulin, or both. Hyperglycemia causes dyslipidemia and stimulates oxidative damage, leading to the main symptoms, such as fatigue and culminates in diabetic complications. Previous studies have shown that ATP-sensitive potassium channels counteract muscle fatigue and metabolic stress in healthy mouse models. To determine the effect of diazoxide on muscle strength development during diabetes, we tested the effect of diazoxide in streptozotocin-diabetic rats in muscle function, lipid profile and oxidative stress biomarkers. MATERIALS AND METHODS: Wistar rats were divided into 4 groups of six animals each: (1) Control group, (2) diabetes group, (3) Control group + diazoxide, and (4) Diabetic + diazoxide (DB + DZX). 4 weeks after rats were sacrificed, soleus and extensor digitorum longus muscles (EDL) were extracted to prepare homogenates and serum was obtained for biochemical measurements. Oxidative damage was evaluated by the thiobarbituric acid method and the fluorescent for reactive oxygen species (ROS) probe 2,4-H2DCFDA, respectively. RESULTS: Diabetic rats with diazoxide administration showed an increase in the development of muscle strength in both muscles; in turn, the onset of fatigue was longer compared to the group of diabetic rats without treatment. Regarding the lipid profile, diazoxide decreased total cholesterol levels in the group of diabetic rats treated with diazoxide (xÌ 46.2 mg/dL) compared to the untreated diabetic group (xÌ =104.4 mg/dL); secondly, diazoxide decreased triglyceride concentrations (xÌ =105.3 mg/dL) compared to the untreated diabetic rats (xÌ =412.2 mg/dL) as well as the levels of very low-density lipoproteins (xÌ =20.4 mg/dL vs. xÌ =82.44 mg/dL). Regarding the various markers of oxidative stress, the diabetic group treated with diazoxide was able to reduce the concentrations of TBARS and total reactive oxygen species as well as preserve the concentrations of reduced glutathione. CONCLUSION: Diazoxide administration in diabetic rats increases muscle strength development in EDL and soleus muscle, decreases fatigue, reduces cholesterol and triglyceride concentrations and improves oxidative stress parameters such as TBARS, ROS, and glutathione status.
Assuntos
Diabetes Mellitus Experimental , Hiperglicemia , Camundongos , Ratos , Animais , Diazóxido/efeitos adversos , Diazóxido/metabolismo , Estreptozocina/efeitos adversos , Estreptozocina/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Diabetes Mellitus Experimental/complicações , Substâncias Reativas com Ácido Tiobarbitúrico/efeitos adversos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Estresse Oxidativo , Hiperglicemia/complicações , Músculo Esquelético/metabolismo , Lipídeos , Triglicerídeos/efeitos adversos , Triglicerídeos/metabolismo , Colesterol/metabolismoRESUMO
Connexin43 (Cx43) exits as hemichannels in the inner mitochondrial membrane. We examined how mitochondrial Cx43 and mitochondrial KATP channels affect the occurrence of triggered arrhythmias. To generate cardiac-specific Cx43-deficient (cCx43-/-) mice, Cx43flox/flox mice were crossed with α-MHC (Myh6)-cre+/- mice. The resulting offspring, Cx43flox/flox/Myh6-cre+/- mice (cCx43-/- mice) and their littermates (cCx43+/+ mice), were used. Trabeculae were dissected from the right ventricles of mouse hearts. Cardiomyocytes were enzymatically isolated from the ventricles of mouse hearts. Force was measured with a strain gauge in trabeculae (22°C). To assess arrhythmia susceptibility, the minimal extracellular Ca2+ concentration ([Ca2+]o,min), at which arrhythmias were induced by electrical stimulation, was determined in trabeculae. ROS production was estimated with 2',7'-dichlorofluorescein (DCF), mitochondrial membrane potential with tetramethylrhodamine methyl ester (TMRM), and Ca2+ spark frequency with fluo-4 and confocal microscopy in cardiomyocytes. ROS production within the mitochondria was estimated with MitoSoxRed and mitochondrial Ca2+ with rhod-2 in trabeculae. Diazoxide was used to activate mitochondrial KATP. Most of cCx43-/- mice died suddenly within 8 weeks. Cx43 was present in the inner mitochondrial membrane in cCx43+/+ mice but not in cCx43-/- mice. In cCx43-/- mice, the [Ca2+]o,min was lower, and Ca2+ spark frequency, the slope of DCF fluorescence intensity, MitoSoxRed fluorescence, and rhod-2 fluorescence were higher. TMRM fluorescence was more decreased in cCx43-/- mice. Most of these changes were suppressed by diazoxide. In addition, in cCx43-/- mice, antioxidant peptide SS-31 and N-acetyl-L-cysteine increased the [Ca2+]o,min. These results suggest that Cx43 deficiency activates Ca2+ leak from the SR, probably due to depolarization of mitochondrial membrane potential, an increase in mitochondrial Ca2+, and an increase in ROS production, thereby causing triggered arrhythmias, and that Cx43 hemichannel deficiency may be compensated by activation of mitochondrial KATP channels in mouse hearts.
Assuntos
Conexina 43 , Ventrículos do Coração , Camundongos , Animais , Ventrículos do Coração/metabolismo , Conexina 43/metabolismo , Diazóxido/efeitos adversos , Diazóxido/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Miócitos Cardíacos/metabolismo , Arritmias Cardíacas/metabolismo , Mitocôndrias , Trifosfato de Adenosina/metabolismoRESUMO
OBJECTIVES: Diazoxide (DZX) is the drug of choice for treating hyperinsulinaemic hypoglycaemia (HH), and it has potentially serious adverse effects. We studied the safety and efficacy of low-dose DZX in small-for-gestational-age (SGA) infants with HH. DESIGN: An observational cohort study from 1 September 2014 to 31 September 2020. SETTING: A tertiary Women's and Children's Hospital in Singapore. PATIENTS: All SGA infants with HH. INTERVENTION: Diazoxide, at 3-5 mg/kg/day. MAIN OUTCOME MEASURES: Short-term outcomes; adverse drug events and fasting studies to determine 'safe to go home' and 'resolution' of HH. RESULTS: Among 71 836 live births, 11 493 (16%) were SGA. Fifty-six (0.5%) SGA infants with HH were identified, of which 27 (47%) with a mean gestational age of 36.4±2 weeks and birth weight of 1942±356 g required DZX treatment. Diazoxide was initiated at 3 mg/kg/day at a median age of 10 days. The mean effective dose was 4.6±2.2 mg/kg/day, with 24/27 (89%) receiving 3-5 mg/kg/day. Generalised hypertrichosis occurred in 2 (7.4%) and fluid retention in 1 (3.7%) infant. A fasting study was performed before home while on DZX in 26/27 (96%) cases. Diazoxide was discontinued at a median age of 63 days (9-198 days), and resolution of HH was confirmed in 26/27 (96%) infants on passing a fasting study. CONCLUSION: Our study demonstrates that low-dose DZX effectively treats SGA infants with HH as measured by fasting studies. Although the safety profile was excellent, minimal adverse events were still observed with DZX, even at low doses.
Assuntos
Hiperinsulinismo Congênito , Diazóxido , Criança , Hiperinsulinismo Congênito/induzido quimicamente , Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido/efeitos adversos , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Pequeno para a Idade GestacionalRESUMO
Diazoxide is the first-line drug for treating hyperinsulinism and the only pharmacological agent approved for hyperinsulinism by the Federal Drug Administration. This systemic review and meta-analysis aimed to investigate the efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia (HH). The meta-analysis of the efficacy and safety of diazoxide in treating HH was performed by searching relevant studies in the PubMed, Embase, and Cochrane databases. The findings were summarized, and the pooled effect size and its 95% confidence interval (CI) were calculated. A total of 6 cohort studies, involving 1142 participants, met the inclusion criteria. Among the cohort studies, the pooled estimate of the response rate of diazoxide therapy was 71% (95% CI 50%-93%, Pheterogeneity< 0.001, I2 = 98.3%, Peffect< 0.001). The common side effects were hypertrichosis (45%), fluid retention (20%), gastrointestinal reaction (13%), edema (11%), and neutropenia (9%). Other adverse events included pulmonary hypertension (2%) and thrombocytopenia (2%). This meta-analysis suggested that diazoxide was potentially useful in HH management; however, it had some side effects, which needed careful monitoring. Furthermore, well-designed large-scale studies, such as randomized controlled trials, might be necessary in the future to obtain more evidence.
Assuntos
Anti-Hipertensivos/uso terapêutico , Diazóxido/uso terapêutico , Hiperinsulinismo/tratamento farmacológico , Hipoglicemia/tratamento farmacológico , Vasodilatadores/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Diazóxido/efeitos adversos , Humanos , Hipertricose/induzido quimicamente , Resultado do Tratamento , Vasodilatadores/efeitos adversosRESUMO
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.
Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido/efeitos adversos , Enterocolite Necrosante/induzido quimicamente , Diazóxido/uso terapêutico , Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/epidemiologia , Evolução Fatal , Feminino , Humanos , Incidência , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/induzido quimicamente , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/tratamento farmacológico , Doenças do Prematuro/epidemiologia , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Frequent and severe gastrointestinal disturbances have been reported with the use of diazoxide in adults and older children. However, no studies have investigated the incidence of necrotising enterocolitis (NEC) in diazoxide-exposed newborns. OBJECTIVE: To evaluate a possible association between diazoxide treatment for neonatal hypoglycaemia and the occurrence of NEC. DESIGN: Multicentre retrospective cohort study. SETTING: Three tertiary neonatal intensive care units in Toronto, Canada. PATIENTS: All patients treated with diazoxide for persistent hypoglycaemia between July 2012 and June 2017 were included. Overall incidence of NEC during those years on the participating units was obtained for comparison from the Canadian Neonatal Network database. MAIN OUTCOME: Incidence of NEC after diazoxide exposure. RESULTS: Fifty-five neonates were exposed to diazoxide during the study period. Eighteen patients (33%) showed signs of feeding intolerance, and 7 developed NEC (13%). A diagnosis of NEC was more prevalent in the diazoxide-exposed, as compared with non-exposed infants of similar gestational age (OR 5.07, 95% CI 2.27 to 11.27; p<0.001), and greatest among infants born at 33-36 weeks' gestation (OR 13.76, 95% CI 3.77 to 50.23; p<0.001). All but one of the neonates diagnosed with NEC developed the disease within 7 days from initiation of diazoxide treatment. CONCLUSION: The present data suggest a possible association between diazoxide exposure and the development of NEC in neonates. Further evaluation of the diazoxide-associated risk of NEC in neonates treated for persistent hypoglycaemia is warranted.
Assuntos
Diazóxido , Enterocolite Necrosante , Trato Gastrointestinal/efeitos dos fármacos , Hipoglicemia/tratamento farmacológico , Doenças do Prematuro/tratamento farmacológico , Canadá/epidemiologia , Correlação de Dados , Diazóxido/administração & dosagem , Diazóxido/efeitos adversos , Enterocolite Necrosante/induzido quimicamente , Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/epidemiologia , Feminino , Idade Gestacional , Humanos , Hipoglicemia/sangue , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Recém-Nascido , Doenças do Prematuro/sangue , Doenças do Prematuro/diagnóstico , Masculino , Moduladores de Transporte de Membrana/administração & dosagem , Moduladores de Transporte de Membrana/efeitos adversos , Neonatologia/métodos , Prevalência , Estudos Retrospectivos , Medição de RiscoRESUMO
BACKGROUND: Children with congenital hyperinsulinism (CHI), a severe orphan disease, are still one of the most demanding patients in the endocrinology practice. The use of first- and second-line drugs is not always effective and has a number of restrictions. Lanreotide - long-acting somatostatin - represents an alternative insulinostatic therapy. The main advantage of lanreotide is stable concentration of the drug in the blood that enables minimizing the number of injections. However, the experience of using lanreotide in the treatment of CHI is limited to small groups of patients. There is also a problem of the absence of a standardized regimen in clinical practice; and the calculator for evaluating the initial effective drug dose is needed.AIM of the study is to evaluate the effectiveness and safety of lanreotide therapy in the treatment of CHI in children. MATERIALS AND METHODS: An open single-center observational study was conducted on the basis of Endocrinology Research Centre. The study included diazoxide-unresponsive pediatric patients with CHI who were initially treated with octreotide in different modes: multiple daily subcutaneous injections or continuous subcutaneous infusion via pumps. The indicators of the effectiveness and safety of the lanreotide therapy were evaluated shortly after the first injection and lately on a regular visit after further injections. RESULTS: The study group included 12 patients. Persistent euglycaemia was achieved in 67% of the subjects (8/12). Complete effectiveness of the therapy was observed in 8/12 patients (67%), partial - in 3/12 (25%), and lack of effectiveness - in 1/12 of the patient (8%). The age of the patients at the time of lanreotide administration was 6 months (5; 15). According to the study, the most effective dose of lanreotide is 3.5-5.5 mg/ kg/ month. There were no significant side effects observed. CONCLUSIONS: The use of lanreotide in patients with diazoxide-resistant congenital hyperinsulinism was effective and safe in the vast majority of the patients. Moreover, we were able to calculate the effective dosage of lanreotide in CHI patients which fulfilled the clinical demand.
Assuntos
Hiperinsulinismo Congênito , Somatostatina , Criança , Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido/efeitos adversos , Humanos , Lactente , Injeções Subcutâneas , Octreotida/uso terapêutico , Somatostatina/uso terapêuticoRESUMO
Diazoxide, a drug used to treat hyperinsulinemic hypoglycemia (HH), is associated with pulmonary hypertension (PH), as reported by the US Food and Drug Administration. However, no report has detailed the association between diazoxide dose and PH development. We report a case of an infant with HH, subsequently complicated by diazoxide-induced PH. When diazoxide was introduced, PH did not appear initially, but it developed during increased dosing. We monitored PH via regular echocardiography examinations. PH gradually improved with tapering of the diazoxide dose and disappeared after drug discontinuation. Our case suggests a diazoxide dose threshold might induce PH. Therefore, close echocardiography examinations should accompany diazoxide treatment.
Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido/efeitos adversos , Hipertensão Pulmonar/induzido quimicamente , Fator Natriurético Atrial/sangue , Síndrome de Beckwith-Wiedemann/complicações , Cateterismo Cardíaco , Hiperinsulinismo Congênito/etiologia , Desprescrições , Diazóxido/administração & dosagem , Diuréticos/uso terapêutico , Relação Dose-Resposta a Droga , Ecocardiografia , Eletrocardiografia , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/tratamento farmacológico , Lactente , Recém-Nascido , Masculino , Peptídeo Natriurético Encefálico/sangue , Citrato de Sildenafila/uso terapêutico , Vasodilatadores/uso terapêuticoRESUMO
BACKGROUND: The diagnosis of hypoglycemia and the use of diazoxide have risen in the last decade. Diazoxide is the only Food and Drug Agency-approved pharmacologic treatment for neonatal hypoglycemia caused by hyperinsulinism (HI). Recent publications have highlighted that diazoxide has serious adverse effects (AEs) such as pulmonary hypertension (2-3%) and neutropenia (15%). Despite its increasing use, there is little information regarding dosing of diazoxide and/or monitoring for AEs. METHODS: We convened a working group of pediatric endocrinologists who were members of the Drug and Therapeutics Committee of the Pediatric Endocrine Society (PES) to review the available literature. Our committee sent a survey to its PES members regarding the use of diazoxide in their endocrine practices. Our review of the results concluded that there was substantial heterogeneity in usage and monitoring for AEs for diazoxide among pediatric endocrinologists. CONCLUSIONS: Based on our extensive literature review and on the lack of consensus regarding use of diazoxide noted in our PES survey, our group graded the evidence using the framework of the Grading of Recommendations, Assessment, Development and Evaluation Working Group, and has proposed expert consensus practice guidelines for the appropriate use of diazoxide in infants and children with HI. We summarized the information on AEs reported to date and have provided practical ideas for dosing and monitoring for AEs in infants treated with diazoxide.
Assuntos
Diazóxido/efeitos adversos , Hiperinsulinismo/complicações , Hipoglicemia/tratamento farmacológico , Antagonistas da Insulina/efeitos adversos , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Humanos , Hipoglicemia/etiologia , Lactente , MasculinoRESUMO
This case illustrates the importance of multidisciplinary counselling and management of pregnancies in women with complex medical conditions, especially concerning women with cognitive impairment. We present a woman with hyperinsulinism/hyperammonaemia (HI/HA) syndrome. This syndrome is characterised by recurrent episodes of hypoglycaemia and elevated ammonia levels, which are potentially harmful to both the patient and a developing fetus. We describe a successful multidisciplinary approach during the pregnancy of a mentally challenged patient with HI/HA syndrome. This case illustrates the importance of personalised counselling during the preconception period and emphasises to include all disciplines involved in the medical and daily care of such a patient. In our case, the extensive multidisciplinary care during the preconception period, pregnancy, delivery and postpartum period resulted in a good maternal and neonatal outcome.
Assuntos
Hiperamonemia/complicações , Hiperamonemia/terapia , Hiperinsulinismo/complicações , Hiperinsulinismo/terapia , Deficiência Intelectual/complicações , Complicações na Gravidez/terapia , Adulto , Diazóxido/administração & dosagem , Diazóxido/efeitos adversos , Dieta da Carga de Carboidratos , Aconselhamento Diretivo , Feminino , Humanos , Hiperamonemia/sangue , Hipoglicemia/etiologia , Hipoglicemia/prevenção & controle , Equipe de Assistência ao Paciente , Cuidado Pré-Concepcional , Gravidez , Resultado da Gravidez , SíndromeRESUMO
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.
Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido , Diuréticos/administração & dosagem , Derrame Pericárdico , Adolescente , Diazóxido/administração & dosagem , Diazóxido/efeitos adversos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Derrame Pericárdico/induzido quimicamente , Derrame Pericárdico/tratamento farmacológicoRESUMO
Diazoxide is a peripheral vasodilator that has been used for intravenous treatment of hypertensive emergencies. However, it is currently used mainly for hyperinsulinemic hypoglycemia in lower dose orally, and its major side effects are edema and pulmonary hypertension. Herein, we report the first association between periventricular leukomalacia (PVL) and intractable hypotension due to diazoxide. A Japanese female premature infant showed hypoglycemia concomitant with hyperinsulinemia. She was diagnosed with congenital hyperinsulinism, and oral diazoxide was started. Six days after starting diazoxide, she suddenly showed peripheral coldness, oliguria, and severe hypotension. The hypotension was refractory to general vasopressor therapies and persisted even after the discontinuation of diazoxide. Cranial echography showed periventricular echodensities followed by cystic PVL. Low-dose vasopressin effectively treated the hypotension. This single case reminds us the serious adverse events of diazoxide that have been forgotten, especially in premature neonates.
Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Diazóxido/efeitos adversos , Hipotensão/induzido quimicamente , Leucomalácia Periventricular/induzido quimicamente , Vasodilatadores/efeitos adversos , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Gravidez , Gravidez de GêmeosRESUMO
A 2.5-year-old boy with a history of (transient) congenital hyperinsulinism was admitted to the paediatric ward with recurrent hypoglycaemia. Diazoxide 5 mg/kg/day and hydrochlorothiazide 2 mg/kg/day were initiated. After increasing the dose of diazoxide to 10 mg/kg/day, the child developed mild rectal bleeding, petechiae, epistaxis and haematemesis. Blood screening showed severe thrombocytopaenia. Diazoxide and hydrochlorothiazide were stopped, and his platelet count normalised. Drug rechallenge was positive. Drug-induced immune thrombocytopaenia was diagnosed.
Assuntos
Anti-Hipertensivos/efeitos adversos , Diazóxido/efeitos adversos , Hidroclorotiazida/efeitos adversos , Trombocitopenia/induzido quimicamente , Pré-Escolar , Quimioterapia Combinada/efeitos adversos , Epistaxe/induzido quimicamente , Hematemese/induzido quimicamente , Humanos , Hiperinsulinismo/congênito , Hiperinsulinismo/tratamento farmacológico , Masculino , Doenças Retais/induzido quimicamenteRESUMO
OBJECTIVE: Diazoxide is first-line treatment for hyperinsulinaemic hypoglycaemia (HH) but diazoxide-induced pulmonary hypertension (PH) can occur. We aim to characterize the incidence and risk factors of diazoxide-induced PH in a large HH cohort to provide recommendations for anticipating and preventing PH in diazoxide-treated patients with HH. DESIGN AND PATIENTS: Retrospective cohort study involving four UK regional HH centres; review of case notes of HH patients on diazoxide. MEASUREMENTS: The diagnosis of PH was based on clinical and echocardiography evidence. Patient and treatment-related risk factors were analysed for association. RESULTS: Thirteen (6 men) of 177 HH diazoxide-treated patients developed PH, an incidence of 7%. In the PH group, HH was diagnosed at median (range) of 9 (1,180) days, with diazoxide commenced 4 (0,76) days from diagnosis and reaching a maximum dose of 7 (2.5,20) mg/kg/d. The majority (8 of 13 patients) developed PH within 2 weeks of diazoxide. Complete diazoxide withdrawal, but not dose reduction, led to PH resolution at 41 (3,959) days. In three patients, PH continued beyond 12 months. Risk factors for the development of PH included the presence of congenital heart disease (CHD) (P = .008), and total fluid volume exceeding 130 mL/kg/d in the immediate 24 hours preceding diazoxide (P = .019). CONCLUSION: Pulmonary hypertension can occur in 7% of diazoxide-treated HH patients. Risk factors include the presence of congenital heart disease and fluid overload. Recommendations include echocardiography and fluid restriction to 130 mL/kg/d prior to diazoxide treatment and immediate discontinuation of diazoxide if PH develops.