Treatment

Early and adequate treatment of CHI is essential to prevent episodes of hypoglycemia and subsequent brain damage. The primary aim of the treatment is to monitor blood glucose frequently 1-2 hourly whilst aiming to maintain the blood glucose at normal levels i.e. at least >3.5 (63mg/dl) with normal feeding pattern for age as well as establish an appropriate fasting tolerance for age. The treatment measures include dietary, medicines as well as surgical approaches, and most commonly a combination of all. The acute treatment is identical in all forms of CHI, being the maintenance of adequate blood glucose levels. This also provides time to determine the specific cause and plan a long-term therapy. The treatment for CHI should always be guided by the specialist and children need regular monitoring as well as follow-up once discharged from the hospital. 

Frequent feeding

Feeding at regular, short intervals with high calorie carbohydrate feeds act as a very important supportive measure in reducing the frequency and severity of hypoglycemic episodes in CHI. However, feeding issues are known complications in CHI due to feeding disturbances, gastro-oesophageal reflux disease and other complications of CHI. Some of these complications are due to the administered medicines but some are also caused by unknown factors in all types of CHI. This often makes it necessary to deliver feeds through nasogastric tubes or percutaneous gastrostomy in order to keep blood glucose levels in a normal range.

Parenteral glucose infusion

Unlike other conditions that cause hypoglycemia, CHI also prevents the production of alternative fuels such as ketone or lactate leaving the brain without any source of energy. Normoglycemia (normal blood glucose levels) can be achieved by giving a fast-acting carbohydrate-containing glucose oral gel/drink by mouth or via feeding tube. Some children may need intravenous glucose bolus followed by delivering a continuous intravenous glucose infusion starting at 6-8 mg/kg/min to as high as 15-25 mg/kg/min. A higher threshold of blood glucose concentration should be aimed i.e. >3.5 mmol/L when monitoring blood glucose frequently and a central venous access may also be required in severe cases to deliver concentrated solutions of glucose.

Diazoxide

Oral administration of diazoxide, a KATP (ATP sensitive potassium channel) opener, is the first line therapy for all types of CHI. It binds to the SUR1 (sulfonylurea receptor – 1) subunit causing opening of the intact KATP channels, that results in the blockade of β-cell depolarization and subsequent reduction of insulin secretion. Thus, diazoxide is usually effective on a functionally intact KATP channels but patients with recessive or dominant KATP channel mutations do not respond to diazoxide. Clinical response to the therapy with diazoxide has been vital in terms of molecular genetic analysis, diagnosis and management strategies as patients can be divided into two sub-groups: diazoxide- responsive and diazoxide-unresponsive. In children with diffuse disease due to inactivating mutations in ABCC8 and KCNJ11 (genes coding the SUR1 subunit) and most with focal lesions are generally diazoxide-unresponsive. Whereas, children carrying mutations in the remaining genes known to cause CHI are generally diazoxide-responsive.

The initial dose of diazoxide should be started orally at 5mg/kg/day, in three divided doses which can be gradually increased, if needed, up to a maximum dose of 15-20 mg/kg/day. However, there are reports of lower doses of diazoxide 2-5mg/kg/day have been found effective in preterm and small for gestational age babies. The criteria for diazoxide-responsiveness include an age adjusted fasting tolerance, able to maintain normoglycemia and have a normal feeding plan. It should ideally be tried on the maximum dose for at least 5 subsequent days before the child is described as diazoxide-unresponsive.

Common side effects of diazoxide includes hypertrichosis (excessive hair growth of the eyebrows, forehead and back) that resolves completely, few to several months after discontinuation of therapy with diazoxide. Another commonly observed and a more severe side effect that limits and requires treatment withdrawal includes fluid retention, particularly in newborns that receive large amounts of intravenous glucose to maintain adequate blood glucose levels. This can also lead to an associated electrolyte imbalance, pulmonary hypertension and congestive heart failure. Hence, fluid restriction in neonates/infants along with a thiazide diuretic, such as chlorothiazide (7.5-10 mg/kg/day in to divided doses) is usually administered along with diazoxide, to prevent fluid retention. Stronger diuretics like spironolactone and furosemide 1mg/kg/dose twice a day (instead of chlorothiazide) may need to be used in conjunction with Diazoxide in babies who have risk factors of pulmonary hypertension. Less common side effects may include nausea, vomiting, feeding problems etc. Rare complications may include increase in pressure in the blood vessels in the lungs and heart. If the daily dose of diazoxide required to maintain adequate blood glucose levels fall below 3-5 mg/kg/day, then discontinuation with diazoxide therapy can be considered in a hospital setting.

Glucagon administration

Glucagon is a counter-regulatory hormone that induces glycogenolysis (breakdown of glycogen into glucose), gluconeogenesis (transformation of non-carbohydrate substrate into glucose) and lipolysis (breakdown of fat) that causes a rapid increase in glucose concentrations within a few minutes. Therefore, in cases of emergency, it is used as a first line therapy with symptomatic hypoglycemia and seizures, especially when the patients are unable to take oral feed and/or intravenous access is difficult. Intramuscular injection of glucagon in a single dose of 0.5-1 mg has been recommended for emergency cases. Subcutaneous glucagon infusion at a rate of 5-10 µg/kg/h in combination with octreotide has been recommended for long-term non-surgical management of CHI. Also, it is important to understand that glucagon, in high doses of over 1 mg, can cause rebound hypoglycemia due to paradoxical increase in insulin secretion and hence higher doses should be avoided.

Octreotide

Octreotide, is an eight amino acid, synthetic, long-acting somatostatin analogue that is the second line of medical therapy of children with diazoxide-unresponsive CHI. Octreotide inhibits insulin secretion from pancreatic β-cells by binding to somatostatin receptor SSTR2 and SSTR5 which in-turn inhibits calcium mobilization and acetylcholine activity thereby decreasing the insulin gene promoter activity resulting in reduced insulin biosynthesis. Somatostatin may also inhibit insulin secretion through its action on KATP channel. The recommended initial dose of octreotide is 5 μg/kg/day with a maximum dose of 30-35 μg/kg/day delivered at 6-8 hours’ interval through subcutaneous injections or a continuous subcutaneous infusion. Long-term, continuous, subcutaneous octreotide infusion with an insulin pump has also been reported as a feasible alternative to surgery for patients with monoallelic KATP channel mutations. Octreotide is very effective initially with the first response usually being rapidly increasing blood glucose levels. But the initial effectiveness may wane off followed by a rapidly diminishing effect (tachyphylaxis) 24-48 hours after the initiation of therapy. This mandates dose adjustments with octreotide to moderate the tachyphylaxis. Side effects with octreotide include nausea, abdominal pain, diarrhea, alteration in gut motility, bile sludge, gall stones drug-induced hepatitis, necrotizing enterocolitis and may also produce hypothyroidism and short stature through suppression of growth hormone and thyroid stimulating hormone. Hence, children need regular follow-up to monitor for side effects of these medications.

Long acting Somatostatin Analogues

Long-acting octreotide release (LAR) and lanreotide are two prolonged release formulations of synthetic somatostatin analogues that have been successfully used in children with CHI even during early infancy over last few years. These are similar to octreotide that have a longer duration of action and can be used once in a month. LAR is formulated with biodegradable microspheres which increases its half-life, whereas lanreotide is a synthetic octa-peptide, both of these can be administered as intramuscular or deep subcutaneous injections every 28 days. This dose regime increases the treatment adherence and improves the quality of life for the patient and their family. These longer acting preparations are generally reserved for use in patients that have responded with short acting octreotide and are on a stable regimen and should be initiated by the specialist after discussing with the family. The side effects of these formulations are similar to octreotide and children need regular follow-up to monitor for side effects of these medications.

Nifedipine

Nifedipine is an L-type calcium channel blocker that inhibits insulin secretion from the pancreatic β-cells by inactivating the voltage-gated calcium channels. Though there have been several cases demonstrating the effectiveness of nifedipine in CHI, vast majority of the CHI patients do not show any response. However, given the role of voltage-gated calcium channels in regulating insulin secretion, the role of nifedipine cannot be completely ruled out and needs more standardized studies and trials. It is recommended in a dose of is 0.25-2.5 mg/kg/day divided into 2-3 doses. Hypotension is an uncommon side-effect, especially at doses above 0.5 mg/kg/day.

Cases with confirmed focal disease on 18F-DOPA PET/CT scan and medically unresponsive diffuse disease are classical indications for surgery in CHI patients. Surgery should be conducted by an experienced pancreatic surgeon in a tertiary hospital setting.

Partial Pancreatectomy

Partial pancreatectomy is the treatment of choice for patients with focal form of CHI. The surgical procedure aims to remove only a small part of the pancreas, the exact localization of which can be made using 18F-DOPA PET-CT scan that helps to guide the surgeon during the surgery. The majority of the patients with focal form of CHI are generally cured completely and do not require any medical therapy after surgery. However, focal lesions located in the head of the pancreas are generally difficult to operate on since many important structures such as the bile duct and duodenum lie close to the head of the pancreas. For lesions located in the body or tail of pancreas, laparoscopic approach is generally preferred to benefit from a minor patient trauma and shorter post-operative care.

Near-total Pancreatectomy

Patients with diffuse or atypical disease usually require a subtotal or near-total-pancreatectomy. It is an extensive surgery in which the tail, body, uncinated process and part of the pancreatic head are resected leaving a rim of pancreatic tissue surrounding the common bile duct and along the duodenum. However, despite extensive resection some children may continue to require frequent feeds and medical therapy to prevent hypoglycemia. They may also require repeat surgeries or total pancreatectomy to control severe CHI. Moreover, this procedure also carries the risk of developing pancreatic exocrine insufficiency and diabetes which requires life-long pancreatic enzyme replacement and insulin therapy. But the surgery definitely helps in reducing the severity of the hypoglycemic episodes and lessening the intensity of medical regimen to maintain normoglycemia.

Considering the risks involved with surgical procedures and the recent advances in the pharmacotherapy, medical therapy is preferred when possible.

Given the fact that CHI is a relatively rare condition with a challenging management requiring a multidisciplinary team of pediatric endocrinologists, neonatologists, radiologists, pathologists and surgeons specialized in the treatment of these children, it is recommended that these patients are referred to tertiary centers that the necessary experience and expertise in managing this condition.