Medications used in the treatment of hypoglycemia due to congenital hyperinsulinism of infancy (HI)

Congenital hyperinsulinism of infancy is the commonest cause of persistent and recurrent hypoglycaemia in the neonatal and infancy period. It is a heterogeneous disorder with respect to clinical presentation, histology, molecular biology and genetics. The biochemical profile is one of hypoketotic, hypofattyacidemic hypoglycemia. To prevent permanent brain damage from hypoglycemia, the treatment of infants with congenital hyperinsulinism must be prompt and aggressive. The drugs used in the medical therapy for congenital hyperinsulinism are diazoxide, octreotide, glucagon and nifedipine.     

Seizure due to somatostatin analog discontinuation in a case diagnosed as congenital hyperinsulinism novel mutation

The most common reason for refractory hypoglycemia in newborns is congenital hyperinsulinism. We report a girl with congenital hyperinsulinism due to novel homozygous mutation (c.2041-25 G>A; aberrant splicing mutation) in the ABCC8 gene encoding SUR1 and during somatostatin analog (octreotide) discontinuation developed by nonhypoglycemic seizures. The newborn (birth weight of 3,750 g) was referred to our clinic because of hypoglycemic seizures at 4 h postnatal. On admission, blood glucose was 24 mg/dL and intravenous glucose infusion was started. The patient's insulin level was 27 mIU/mL during the hypoglycemic period. Phenobarbital (5 mg/ kg/day) was added because of short-acting generalized clonic seizures. Although the patient received high doses of diazoxide, esidrex, and octreotide approximately for 2 months, hypoglycemic episodes continued. Then the patient had near-total pancreatectomy, and pathology confirmed a diffuse form of congenital hyperinsulinism. There was homozygous mutation in the ABCC8 gene encoding SUR1, which confirmed the diagnosis of autosomal recessive congenital hyperinsulinism. During octreotide discontinuation, the patient developed non-hypoglycemic seizures, which were controlled by restarting the previous doses. In the light of in vitro and in vivo studies on antiepileptic effects of somatostatin, we believe that seizures in our case have developed secondary octreotide discontinuity.     

Hypoglycemia in the neonate

Hypoglycemic episodes occurring during the newborn period are often due to transient immaturity of glucoregulatory pathways. Normal feeding is generally the only measure required to treat such episodes. After the first few hours of life, however, hyperinsulinism (HI) is the most common cause of neonatal hypoglycemia. HI may persist for the first weeks/months of life and then remit spontaneously, particularly in low birth weight neonates and those exposed to perinatal stresses; hypoglycemia in such infants can nearly always be medically controlled using diazoxide. There are also several forms of congenital hyperinsulinism presenting with hypoglycemia in neonates that does not remit. Depending on the type of genetic mutation, hypoglycemia in these infants with congenital hyperinsulinism may be controlled medically or may require surgery. The extent of surgery required in infants with ATP-dependent potassium channel mutations unresponsive to diazoxide is dependent upon histological subtype: focal vs. diffuse disease. Disease-specific diagnoses and treatments are therefore essential for effective management of the various forms of neonatal hyperinsulinism.     

Neonates with congenital heart disease

Early reparative surgery in neonates and infants with congenital heart disease, as opposed to initial palliation and later repair, is now commonplace. Changes to the conduct of cardiopulmonary bypass, timing of surgery and surgical techniques, and perioperative management substantially have reduced the postoperative mortality and morbidity for these patients. The success of this strategy of early reparative surgery now has been extended to the premature and low-birth-weight newborn, and, along with this, new challenges to postoperative care in the intensive care unit. However, the low mortality associated with two-ventricle repairs has not been the experience in newborns undergoing palliation for single-ventricle defects, in particular, hypoplastic left heart syndrome. A number of articles regarding management of newborns with single-ventricle defects have been published during the past 12 months, ranging from classification, prenatal diagnosis, treatment options, and predictors of both early and late outcome, which may provide a guide for patient management. As mortality has declined, there has been an increased emphasis on identifying indices that may predict outcome or morbidity both before and after surgery, along with possible strategies to attenuate adverse clinical responses. The inflammatory response to bypass is heightened in neonates and infants, and several reports have addressed possible techniques for attenuating the response. In addition, reports regarding the risk for necrotizing enterocolitis, the utility of lactate as an index of systemic perfusion, potential markers of myocardial and neurologic injury, and the use of mechanical support of the circulation in newborns with congenital heart disease are summarized.     

Cholelithiasis in a newborn following treatment with the somatostatin analogue octreotide

We report the case of a newborn infant affected by congenital hyperinsulinism who developed cholelithiasis associated with cholestatic jaundice following treatment with octreotide, a somatostatin analogue.     

Hyperinsulinism and hyperammonaemia syndrome due to a novel missense mutation in the allosteric domain of the glutamate dehydrogenase 1 gene

Abstract:   Congenital hyperinsulinism is one of the causes of persistent hypoglycaemia in neonates and infants. We describe a one-month-old boy with a rare form of congenital hyperinsulinism characterised by hypoglycaemia and hyperammonaemia.     

Pitfalls in the diagnosis of congenital hyperinsulinism: a case report and review of the literature

BACKGROUND: Congenital hyperinsulinism is the most common cause for recurrent hypoglycaemia in neonates and infants. Uncontrolled hypoglycaemia leads to seizures and long-term cerebral damage. Often, the diagnosis is delayed because of nonspecific symptoms and confusing laboratory results. PATIENT: We report a patient with hyperinsulinism who was initially wrongly diagnosed as having idiopathic cerebral convulsions and treated accordingly. CONCLUSIONS: Diagnosis of congenital hyperinsulinism is based on a strong suspicion and a thorough family history. Normal random blood glucose or random insulin levels are not helpful in excluding this disease.     

Octreotide as therapeutic option for congenital idiopathic chylothorax: a case series

Background: Octreotide, a somatostatin analogue, is used for the management of patients with refractory chylothorax although its safety and efficacy in neonates have not been evaluated in controlled clinical trials. We present one of the largest case series about the use of octreotide in congenital idiopathic chylothorax. Methods: Six cases of congenital chylothorax (CC) were prospectively collected, who were managed with same unit protocol for octreotide. Mean (SD) gestation was 34.5 (±2.2) weeks, and birthweight was 3410 (±840.4) g. All infants required chest drains from day 1 of life, and the mean (SD) duration of insertion was 36.1 (±8.5) days. Octreotide was commenced at a median age of 13.5 days (range 8–22), given for a median duration of 20 days (range 12–27). The starting dose was 0.5–1 μg/kg/h with an increment of 1–2 μg/kg/day to a maximum of 10 μg/kg/day. Resolution of chylothorax was achieved in five patients, being resistant to treatment in the sixth patient. None had adverse effects from octreotide. Full enteral feeds were reached at a mean age of 44 days. Conclusion: Early commencement of octreotide is recommended although further reports to evaluate the safety and efficacy would add to the profile of this medication in the treatment of CC.     

Congenital Hypoglycemia Disorders: New Aspects of Etiology,Diagnosis, Treatment and Outcomes

Hypoglycemia continues to be an important cause of morbidity in neonates and children. Prompt diagnosis and management of the underlying hypoglycemia disorder is critical for preventing brain damage and improving outcomes. Congenital hyperinsulinism (HI) is the most common and severe cause of persistent hypoglycemia in neonates and children. Recent discoveries of the genetic causes of HI have improved our understanding of the pathophysiology, but its management is complex and requires the integration of clinical, biochemical, molecular, and imaging findings to establish the appropriate treatment according to the subtype. Here we present a summary of a recent international symposium on congenital hypoglycemia disorders with emphasis on novel molecular mechanisms resulting in HI, genetic diagnosis, overall approach to management, novel therapies under development, and current outcomes.     

Life-threatening hyperkalemia following partial pancreatectomy for neonatal hyperinsulinism.

OBJECTIVE: To alert readers to the possibility of rebound hyperkalemia following pancreatic resection for neonatal hyperinsulinism. DESIGN: Case report. SETTING: Intensive care unit of tertiary pediatric hospital. PATIENT: A term neonate with severe hyperinsulinism complicated by hypokalemia, fluid overload, and necrotizing enterocolitis. INTERVENTIONS: Preoperative management consisted of glucose 20.8 mg/kg/min, diazoxide 15 mg/kg/day, octreotide 27 mug/kg/day, and potassium (>10 mmol/kg/day) to maintain normoglycemia and normokalemia. The large glucose requirement, administered as 20% glucose, contributed to congestive heart failure, which was treated with frusemide. Attempts to feed enterally were abandoned because of necrotizing enterocolitis. Partial colectomy and subtotal pancreatectomy were performed on day 20. MEASUREMENTS AND MAIN RESULTS: Serum potassium rose rapidly within 2 hrs of surgery to reach 12.3 mmol/L, causing ventricular tachycardia (240 beats/min) on electrocardiogram. There was no evidence of renal failure or adrenal insufficiency. Management consisted of insulin 0.1 units/kg intravenously, 10% calcium gluconate 0.1 mmol/kg intravenously, sodium bicarbonate 3 mmol/kg intravenously, frusemide 2 mg/kg intravenously, and resonium 0.6 g/kg per rectum with good outcome. CONCLUSIONS: This report highlights the rapid electrolyte shifts possible after sudden cessation of hormones regulating Na/K-ATPase activity.     

Successful Treatment of Neonatal Chylothorax with Octreotide

Chylothorax is a relatively uncommon, but a common form of pleural effusion in the neonates. It may be either congenital or acquired. The efficacy of octreotide therapy for chylothorax is controversial. Herein the authors report successful suppression of chylothorax by octreotide in a newborn who had undergone thoracostomy tube.     

Outcome of primary peritoneal drainage for perforated necrotizing enterocolitis: comparison between laparotomy and drainage.

Perforation of the gastrointestinal tract in neonates is still associated with high mortality rates. Laparotomy is usually required to treat gastrointestinal perforation, however peritoneal drainage under local anesthesia has been also described as an alternative mode of treatment. In our institute, laparotomy was the first choice for the management of gastrointestinal perforation in neonates until 1999. Because of the high mortality rates in this group of patients, our policy has since changed to the use of primary peritoneal drainage instead. The aim of this study is to compare the effectiveness of primary peritoneal drainage (PPD) and primary laparotomy (PL) procedures in the management of gastrointestinal perforation due to necrotizing enterocolitis in neonates. Between 1994 - 1998, ten babies with intestinal perforation underwent PL, whereas fifteen newborns with similar findings were treated with PPD between 1999 and 2003. Eight (80 %) of the patients died in the PL group prior to 1999. In the PPD group 8 (53.3 %) of babies required no further treatment and were discharged without any complications. Four (26.7 %) patients in this group needed laparotomy later, and three (75 %) of them survived. In conclusion, we believe that PPD is more effective than PL for the management of perforated necrotizing enterocolitis in neonates. Laparotomy can be used in particularly unresponsive cases after primary peritoneal drainage.     

Severe transient hyperinsulinaemic hypoglycaemia: two neonates without predisposing factors and a review of the literature

We report on transient hyperinsulinism (HI), presenting as severe congenital HI, in two neonates born without intrauterine growth restriction, maternal diabetes, perinatal asphyxia or Rhesus/platelet isoimmunisation. The neonates developed early (<6 h of life), symptomatic, non-ketotic hypoglycaemia (0–0.66 mmol/l), associated with elevated insulin levels (40–200 mU/l), and required high glucose infusion rates (22–24 mg/kg per min) to maintain normoglycaemia. However, both babies were diazoxide-sensitive and did not require glucose infusions beyond 2 weeks of life. Neither neonate had elevated serum ammonia levels or evidence of a metabolic disorder. Conclusion:transient hyperinsulinism can occur in newborns delivered uneventfully without significant perinatal complications. The unusual sensitivity to medical treatment in these cases of neonatal-onset hyperinsulinaemic hypoglycaemia underscores the importance of careful medical management of severe congenital hyperinsulinism. Careful consideration of the indication and if necessary, timing and extent of pancreatectomy is required, while maintaining euglycaemia to protect the developing brain.Abbreviations AGA appropriate for gestational age - BGL blood glucose level - BWS Beckwith-Wiedemann syndrome - HI hyperinsulinism - HI/HA hyperinsulinism/hyperammonaemia - IUGR intrauterine growth restriction - PHHI persistent hyperinsulinaemic hypoglycaemia of infancy - SGA small for gestational age - SUR sulphonylurea receptor - TNHI transient neonatal hyperinsulinism - UVC umbilical venous catheter     

Congenital chylothorax in a late preterm infant and successful treatment with octreotide

Chylothorax is defined as abnormal accumulation of lymphatic fluid in the pleural space and is a rare condition in neonates. Chylothorax causes respiratory and nutritional problems and a significant mortality rate. Octreotide is a long-acting somatostatin analog that can reduce lymphatic fluid production and has been used as a new strategy in the treatment of chylothorax. Here, we report a premature baby with severe bilateral pleural effusion diagnosed by prenatal ultrasound and subsequently confirmed to be congenital chylothorax after birth. This newborn baby was initially treated with bilateral chest tube insertion to relieve severe respiratory distress. However, the chylothorax recurred after a medium-chain-triglyceride-enriched formula was initiated. The accumulation of chylothorax diminished after the administration of octreotide. Therefore, octreotide may allow the patient to avoid invasive procedures, such as reinsertion of chest tubes or surgery.     

Octreotide in the treatment of neonatal postoperative chylothorax: report of three cases and literature review

Chylothorax is a well-recognized complication after neonatal cardiothoracic surgery. Management strategies include cessation of enteral feedings, repeated aspiration, chest drainage, and total parenteral nutrition. Somatostatin and its analogue, octreotide, have been used with promising results. The authors present three cases of neonatal postoperative chylothorax in which octreotide was used. After literature review, we can say that octreotide is relatively safe, and may reduce clinical course and complications associated with neonatal postoperative chylothorax. One should be aware of possible association between octreotide and necrotizing enterocolitis. Prospective controlled trials supporting octreotide use are lacking.     

Systemic arterial pneumatosis in a neonate with necrotizing enterocolitis

Ultrasound is exquisitely sensitive for the identification of portal vein pneumatosis, which in neonates is commonly caused by necrotizing enterocolitis. We describe the ultrasound finding of systemic arterial pneumatosis in a case of necrotizing enterocolitis associated with congenital heart disease. A combination of a patent ductus venosus and an extracardiac right-to-left shunt via the great vessels through a patent ductus arteriosus provided a pathway for the pneumatosis from the portal vein to the abdominal aorta.     

The evidence base for neonatal surgery

The practise of evidence based medicine means integrating the clinical expertise with the best available external clinical evidence from systematic research. There is a lack of supporting scientific evidence from rigorous trials in neonatal surgery. The indications for surgery and the type of operation performed in neonates are rarely supported by randomised controlled trials. As a consequence, the majority of the operations performed in neonates are supported by retrospective studies and surgeon preference.This review article is focussed on operations in neonates which are performed by general paediatric surgeons. Only a few randomised controlled trials have been performed in neonatal diseases such as congenital diaphragmatic hernia, necrotizing enterocolitis, pyloric stenosis and inguinal hernia. All of these trials have been based on collaboration between paediatric surgical units highlighting the importance of creating a network of centres that will promote multicentre prospective studies.     

Congenital hyperinsulinism

Congenital hyperinsulinism is a cause of persistent hypoglycaemia in the neonatal period. It is a heterogeneous disease with respect to clinical presentation, molecular biology, genetic aetiology and response to medical therapy. The clinical heterogeneity may range from severe life-threatening disease to very mild clinical symptoms. Recent advances have begun to clarify the molecular pathophysiology of this disease, but despite these advances treatment options remain difficult and there are many long-term complications. So far mutations in five different genes have been identified in patients with congenital hyperinsulinism. Most cases are caused by mutations in genes coding for either of the two subunits of the beta-cell K(ATP) channel (ABCC8 and KCNJ11). Two histological subtypes of the disease - diffuse and focal - have been described. The preoperative histological differentiation of these two subtypes is now mandatory as surgical management will be radically different. The ability to distinguish diffuse from focal lesions has profound implications for therapeutic approaches, prognosis and genetic counselling.     

Treatment of postoperative enterocutaneous fistulas with octreotide in two neonates.

Enterocutaneous fistula (EF) in newborns and prematures is a well-recognized complication after necrotizing enterocolitis and other abdominal surgical procedures. Conservative management consists of bowel rest, antibiotics, wound care, and the administration of drugs that either reduce gastrointestinal motility or secretions. Octreotide decreases gastrointestinal secretions, inhibits or blocks the effects of gastrointestinal hormones, diminishes gut motility and thus reduces the flow through the fistula. We used octreotide and were able to report successful spontaneous closure of a fistula in our 2 neonatal patients, one a premature neonate with necrotizing enterocolitis (NEC) and the other with meconium peritonitis.