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Three Part Question

In a [child with persistent hyperinsulinemic hypoglycaemia of infancy] can [nifedipine] [safely be given to treat hypoglycaemia]?

Clinical Scenario

A 5 year old boy, suffering from hyperinsulinemic hypoglycaemia and arterial hypertension secondary to polycystic kidney disease, was given nifedipine (0,3 mg/kg/TDS) to treat his high blood pressure. Normotension was restored and secondly, his blood sugar levels normalised. We wondered whether nifedipine could be used safely as long term treatment to counter hypoglycaemia in persistent hyperinsulemic hypoglycaemia of infancy (PHHI)?

Search Strategy

Cochrane Library and PubMed.
'persistent hyperinsulinemic hypoglycaemia of infancy' and 'hyperinsulinism' and 'nifedipine' and 'safety'.

Search Outcome

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 (7-12), one report on the safety of calcium channel blockers in children (2).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bas F et al, 1999	3 infants Intervention: Nifedipine0.7; 0.5 and 0.8 mg/kg/d	Case-series (Level 4)	Glycaemic control	Normoglycemia on therapy, hypoglycaemia after tapering of Nifedipine	Challenge-dechallenge-rechallenge studies.Follow up 12 months, side effects not reported (see (12))
Lindley KJ et al, 1996	1 preterm baby Intervention: Nifedipine 0.7mg/kg/d	Case report (Level 4)	Glycaemic control	Blood sugar increased (from 3.5 to 4.8 mmol/l), fasting tolerance from 3 to 10.5 hrs	Nifedipine introduced after Diazoxide, Glucagone, Steroids, ACTH and pancreatectomy were unsuccessful
Suprasongsin C et al, 1999	2 infants Intervention: Nifedipine0.5 and 0.7 mg/kg/d plus raw cornstarch 8g/kg/d	Case-series (Level 4)	Glycaemic control	Persistent rise in blood sugar from baseline 1.5 mmol/l and 1.9 mmol/l	Follow-up of 8 years and 14 months, side effects not reported
Eichmann D et al, 1999,	2 infants Intervention: Diazoxide and nifedipine 0.7 mg/kg/d and nifedipine 2 mg/kg/d	Case-series (Level 4)	Glycaemic control	One patient stable on nifedipine monotherapy, the other stable while diazoxide could be reduced	Very low base-line blood sugar levels: 0.78 mmol/l and 0.96 mmol/l, no side effects to nifedipine reported
Shanbag P et al, 2002	1 infant Intervention: Nifedipine 0.5 mg/kg/d	Case report (Level 4)	Glycaemic control	Blood sugar stable on nifedipine monotherapy	Follow up 9 months, no side effects reported
Darendeliler F et al, 2002	4 children Intervention: Nifedipine at a median of 0.65 mg/kg/dl	Case-series (Level 4)	Glycaemic control	All stable on nifedipine monotherapy	Follow-up 4 mo to 7.3 years 3 children from previous report (7) included

Comment(s)

Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) PHHI is the most common cause of persistent hypoglycaemia in infancy (1). In Central Europe it's 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 (Arabian peninsula or Scandinavia) (6). 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 (1,3,4). 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 ß-cell (1,2). Initially, high doses of glucose infusions are required to establish euglucaemia, traditionally followed by a treatment with either diazoxide or long acting somatostatin (octreotide), sometimes combined with dietary measures (high in starch, glucose or protein) (5). Partial to complete pancreatectomy is pursued in patients refractory to medical treatment, but complicated by high incidences of secondary diabetes mellitus later in life (3). Aims to answer our question regarding the medical treatment of PHHI by searching the Cochrane Collaboration's internet archive of systematic reviews lead to no positive result. A search of PubMed revealed no relevant controlled clinical studies. One consensus statement (evidence level 5) by Arvery-Green et al. (1) 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 (8-12). 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 (3). No severe episodes of hypoglycaemia or side effects to nifedipine (hypotension, nausea, dizziness) were reported, the longest period of follow up was 8 years (9,12). The author of the largest case-series (12) 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 (2). 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.

Clinical Bottom Line

Nifedipine has apparently been used successfully to treat persistent hyperinsulinemic hypoglycaemia in infancy. Without further study, the value of nifedipine in the treatment cascade for persistent hyperinsulinemic hypoglycaemia of infancy is unclear.

References

1. Bas F, Darendeliler F, Demirkol D, et al. Successful therapy with calcium channel blocker (nifedipine) in persistent neonatal hyperinsulinemic hypoglycaemia of infancy. J Pediatr Endocrinol Metab 1999;12:873-8.
2. Lindley KJ, Dunne MJ, Kane C, et al. Ionic control of beat cell function in nesidioblastosis. A possible role for calcium channel blockade. Arch Dis Child 1996;74:373-8.
3. Suprasongsin C, Suthutvoravut U, Mahachoklertwattana P, et al. Combined raw cornstarch and nifedipine as an additional treatment in persistent hyperinsulinemic hypoglycaemia of infancy. J Med Assoc Thai 1999;82 Suppl 1:S 39-42.
4. Eichmann D, Hufnagel M, Quick P, et al. Treatment of hyperinsulinemic hypoglycemia with nifedipine. Eur J Pediatr 1999;158:204-6.
5. Shanbag P, Pathak A, Vaidya M, et al. Persitent Hyperinsulinemic Hypoglycemia of Infancy- Successful treatment therapy with nifedipine. Indian J Pediatr 2002;69:271-2.
6. Darendeliler F, Fournet JC, Bas F, et al. ABCC8 (SUR1) and KCNJ11 (KIR6.2) mutations in persistent hyperinsulinemic hypoglycemia of infancy and evaluation of different therapeutic measures. J Pediatr Endocrinol Metab 2002;15:993-1000.
7. Thomas PM, Cote GJ, Hallman DM, et al. Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy. Am J Hum Genet 1995;56:416-21.
8. Menni F, de Lonlay P, Sevin C, et al. Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia. Pediatrics 2001;107:476-9.
9. Glaser B, Hirsch HJ, Landau H. Persistent hyperinsulinemic hypoglycemia of infancy: long-term octreotide treatment without pancreatectomy. J Pediatr 1993;123:644-50.
10. de Lonlay P, Touati G, Robert JJ, et al. Persistent hyperinsulinaemic hypoglycaemia. Semin Neonatol 2002;7:95-100.
11. Flynn JT, Pasko DA. Calcium channel blockers: pharmacology and place of therapy in pediatric hypertension. Pediatr Nephrol 2000;15:302-316.
12. Aynsley-Green A, Hussain K, Hall J, et al. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neonatal Ed 2000;82:F98-F107.