Approach Considerations
Maintaining normoglycemia is essential to prevent neurologic sequelae. Infants with hyperinsulinism are at higher risk of neurologic sequelae than infants with hypoglycemia from other causes. Because insulin inhibits lipolysis and ketogenesis, hyperinsulinism results in the paucity of alternative fuel used by the brain.
The glucose output from the liver is 2-3 mg/kg/min in adults. Infants and children have a greater need for glucose and have a maximal output estimated at 5-7 mg/kg/min. Patients with hyperinsulinism may require very high glucose infusion rates (20-30 mg/kg/min) to maintain normoglycemia. Attempts should be made to keep blood glucose levels at 60 mg/dL or higher at all times.
Healthy neonates and infants can fast for 6 hours without experiencing hypoglycemia. This equates to skipping one feeding in the infant who is fed ad libitum.
Medications should be administered to suppress insulin secretion or stimulate glucose release. Patients with severe hyperinsulinism may be refractory to medical therapy and may require excision of a portion of or the entire pancreas. In general, maintenance of normoglycemia should be attempted before pancreatectomy is considered. At the same time, because hypoglycemia can result in irreversible brain damage, surgical excision should not be delayed in patients with severe hypoglycemia.
Blood glucose level should be determined before each oral feeding and when any symptom or sign of hypoglycemia is present. The most accurate blood glucose assessment is made by free blood drawn into an NaF-containing tube (gray top), with immediate processing to avoid spuriously low measurements resulting from glycolysis. A bedside glucometer can provide faster results, which need to be confirmed in the central laboratory only when the bedside value is below 60 mg/dL.
All portable glucometers are inaccurate by as much as 20% when the measured blood glucose level is below 70 mg/dL. To reduce the possibility of neurologic injury, the blood glucose level should be maintained above 60 mg/dL at all times.
Before discharging the patient from the hospital, perform a short fasting study (6-8 hr) to ensure that the infant can safely tolerate a missed or inadequate feeding at home. The infant must be able to maintain a blood glucose level above 60 mg/dL throughout the fast.
Ensure the training of caretakers and adequate home healthcare support for pump infusions (octreotide or glucagon) before discharging the patient from the hospital.
Medical Care
Medical therapy is the treatment of choice. [20] Patients with hyperinsulinism often require multiple medications to maintain normoglycemia. Medications used to treat hyperinsulinism include the following:
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Dextrose
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Diazoxide
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Octreotide
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Nifedipine
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Sirolimus
Dextrose is the most common initial approach to hypoglycemia in infants. [21] A 2 mL/kg to 3 mL/kg (200–300 mg/kg) intravenous bolus of 10% dextrose is given, followed by a continuous infusion. [22] Dextrose concentrations of up to 20-25% may be required in order to deliver glucose infusion rates in the 15-30 mg/kg/min range. If the infant’s serum glucose cannot be maintained above 60 mg/dL, other medications may be considered until a definitive diagnosis is made. [21]
Diazoxide is the first-line treatment for persistent HI and the only drug approved by the US Food and Drug Administration (FDA) for long-term treatment of hyperinsulinemic hypoglycemia. Initial administration is 10-15 mg/kg/day orally in 2 to 3 divided doses. Doses are titrated based on laboratory results. When effective, hypoglycemia normalizes within 2-4 days, although a trial of 5-8 days is required before treatment failure is determined. [22] Apart from hypertrichosis, adverse effects are generally limited to fluid retention, which, in infants needing high rates of IV dextrose, often requires prophylaxis with potent diuretics to avoid heart failure. [5]
In infants who fail to respond to diazoxide, octreotide is initiated. Initial dosage should not exceed 15 mcg/ kg/day, as serious adverse effects such as necrotizing enterocolitis (NEC), gallstones, and hepatitis are linked to higher doses. [23] Patients may have a good response to octreotide and can successfully be weaned off of dextrose infusions, while others may have no response or an incomplete response such that a continuous infusion of dextrose is still required. [22]
Nifedipine is a calcium channel antagonist used as an add-on treatment in partial diazoxide/octreotide resistance, and/or following partial pancreatectomy. [23]
Sirolimus, a mammalian target of rapamycin inhibitor, has been reported to be effective in treating congenital hyperinsulinism in infants and children unresponsive to maximal doses of diazoxide and octreotide. [24, 25, 26]
Surgical Care
Localized resection can be curative for focal-type congenital hyperinsulinism (CHI) and insulinomas refractory to medical treatment. [27] Near-total pancreatectomy is required for cure of diffuse-type CHI, but it is associated with complications such as diabetes, exocrine insufficiency, or persistent hypoglycemia. [27]
Gastrostomy tube
Gastrostomy tube placement may be indicated in extreme cases to administer food if the infant is unable to handle the increased glucose requirements. Frequent feedings by gastrostomy help maintain euglycemia but do not prevent the need for intravenous dextrose administration before surgery.
Partial or near-total pancreatectomy
Pancreatectomy is reserved for infants who fail to establish adequate control on medical therapy.
Although most surgeons initially remove 95% of the pancreas, a near-total (98%) pancreatectomy appears to be most effective in preventing hypoglycemia in the newborn period for those with diffuse potassium channel disease (SUR1 or Kir6.2 mutations). Remarkably, the elevated lifelong risk of diabetes mellitus is more closely related to the intrinsic error in regulated insulin release, rather than to the extent of pancreatectomy. [11] One study showed almost 94% of focal hyperinsulinism cases required no further treatment, versus 41% with diffuse hyperinsulinism that showed continued hypoglycemia postoperatively. [28]
Close monitoring of blood glucose levels is indicated to ensure glycemic control and to minimize hypoglycemia. If hypoglycemia persists, medical therapy should be reattempted. If medical therapy is unsuccessful, a second pancreatectomy may be indicated. The authors' experience indicates that clinically significant pancreatic regrowth can occur in infants after near-total pancreatectomy. A Whipple procedure is unwarranted because it cannot guarantee remission of diffuse disease.
Limited pancreatectomy is indicated for patients with focal disease.
Complications include pancreatic exocrine insufficiency, diabetes mellitus, and injury to the common bile duct.
Consultations
Consultation may be required with the following specialists for diagnosis and management of hyperinsulinism:
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Pediatric endocrinologist
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Pediatric surgeon
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Neonatologist
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Geneticist (if family history is present or suspected)
Transfer to a tertiary care facility (eg, academic children's hospital) is preferred for prompt diagnosis and medical treatment or surgical intervention and possible enrollment in clinical research protocols.
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Hyperinsulinism. Mechanisms of insulin secretion.
