Structured clinical question

In a child with persistent hyperinsulinaemic hypoglycaemia of infancy [patient], can nifedipine [intervention] safely be given to treat hypoglycaemia [outcome]?

Search strategy and outcome

Search terms: “persistent hyperinsulinemic hypoglycaemia of infancy” and “hyperinsulinism” and “nifedipine” and “safety” and “calcium antagonist”.

Cochrane Library (nifedipine or persistent hyperinsulinemic hypoglycaemia of infancy): no relevant study found. PubMed (limits: language English; age 0–18 years): one practice guideline,¹ six case reports or patient series of PHHI treated with nifedipine,^2–7 one report on the safety of calcium channel blockers in children.¹² See table 2.

Commentary

Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is the most common cause of persistent hypoglycaemia in infancy.¹ In Central Europe it is a rare disorder, occurring sporadically (incidence approx. 1:50000), but has much higher incidences (1:2500 due to a familial form) in parts of the world with high consanguinity (for example, Arabian peninsula or Scandinavia).⁸ The majority of cases present in the neonatal period with pronounced hypoglycaemia. Severe long term neurological complications due to prolonged hypoglycaemia are common, hence treatment needs to be commenced immediately.^1,9,11 Genetic abnormalities of intracellular metabolic pathways or membrane cation transport have been found in 30–50% of cases, which cause constant insulin secretion through abnormally stimulated ATP-sensitive potassium channels and voltage-gated Ca²⁺ channels of the pancreatic β cell.^1,12 Initially, high doses of glucose infusions are required to establish euglycaemia, traditionally followed by a treatment with either diazoxide or long acting somatostatin (octreotide), sometimes combined with dietary measures (high in starch, glucose, or protein).¹⁰ Partial to complete pancreatectomy is pursued in patients refractory to medical treatment, but complicated by high incidences of secondary diabetes mellitus later in life.¹¹

Aims to answer our question regarding the medical treatment of PHHI by searching the Cochrane Collaboration’s internet archive of systematic reviews led to no positive result. A search of PubMed revealed no relevant controlled clinical studies. One consensus statement (evidence level 5) by Aynsley-Green and colleagues¹ discussed the treatment options for hyperinsulinism in childhood and was available in electronic form: among the standard treatments of PHHI were diazoxide, chlorothiazide, and somatostatin; Ca²⁺ channel blockers were not regarded a routine treatment due to lack of convincing studies. Since the time of publication of the consensus statement, however, several case reports and case series of nifedipine for PHHI have been published which showed encouraging results.^2,4–7 In these studies, nifedipine (either alone or in combination with other drugs or dietary measures) was introduced to avoid complications of diazoxide or somatostatin treatment (abdominal discomfort, vomiting, or anorexia).¹¹ No severe episodes of hypoglycaemia or side effects to nifedipine (hypotension, nausea, dizziness) were reported; the longest period of follow up was eight years.^4,7 The author of the largest case series⁷ was contacted and asked about his experience with nifedipine beyond the published cases. No complications in maintaining treatment were reported. A comprehensive review on the use of Ca²⁺ channel blockers in children convincingly illustrated the safety of nifedipine as long term treatment in childhood.¹²

Nifedipine has been successfully used to treat PHHI and increasing evidence from case reports suggests that it can safely be given as long term treatment without serious adverse effects. Facing the varied clinical severity of PHHI, it promises to become a valuable treatment option for some children. The mounting evidence from the quoted case reports suggests that nifedipine could be tried in patients failing the standard treatment before pancreatectomy is considered. A large, multicentre, randomised clinical trial would be desirable to elucidate the effectiveness and safety of nifedipine in this setting.