Continuous subcutaneous infusion of somatostatin analogues in the treatment of congenital hyperinsulinism

BACKGROUND: Congenital hyperinsulinism (CHI) is a severe disease with a high risk of development of neurological complications due to persistent hypoglycemia. The use of an analog of somatostatin (octreotide) in patients with the resistance to the first-line drug allows to avoid surgical intervention. However, the octreotide is currently used in the form of frequent fractional injections due to the short duration of it’s effect. We present in this article our own experience of using octreotide in continuous subcutaneous infusion in pediatric patients in order to improve the quality of life.

AIM To evaluate the efficiency and safety of the regime of continuous subcutaneous infusion of octreotide with the use of micro-dispensers (pumps) in children with diazoxide-resistant course of CHI.

MATERIALS AND METHODS: An observational single-centre dynamic research was carried out on the basis of the Federal State Budgetary Institution «Endocrinology Research Centre» of the Ministry of Health of the Russian Federation. The study included pediatric patients with CHI and proven diazoxide-resistant course who were initially treated with octreotide in the form of intermittent subcutaneous injections. The researches compared the indicants of efficiency and safety of therapy on treatment of intermittent injections and after transfer to continuous subcutaneous infusion of the drug. The duration of each method of administration was at least 2 weeks.

RESULTS: 16 patients took part in the research. The median for the total duration of octreotide usage in the examined patients was 3 months. According to the results of the work, the use of micro-dispensers for continuous subcutaneous administration of octreotide allowed to reduce the number of patients with episodes of hypoglycemia for more than 4 times (13/16 vs. 3/16); p=0,001). Also, there was a significant decrease in the number of patients with hyperglycemic episodes (4/16 vs. 0/16); p=0.000) and reduced dose of intravenous glucose (6.8 vs 5.2 mg/kg/min; p=0.042) as a result of continuous therapy, which indicates the advantages of smooth continuous administration comparing to single injections. We have not detected any significant side effects of the treatment. Elevated liver enzyme levels, dyspeptic symptoms and gallstone formation in some patients did not require cancellation of therapy. There were no hormonal disorders in the form of hypothyroidism and somatotropic hormone deficiency against the background of continuous octreotide infusion.

CONCLUSIONS: Thus, the use of octreotide in patients with diazoxide-resistant course of СHI in continuous subcutaneous infusion using pumps has a number of advantages over the standard method of intermittent subcutaneous injection. This method of administration allows to achieve better glycemic control and reduce the risks from infusion therapy with highly concentrated glucose solutions, which undoubtedly improves the quality of life of patients.

congenital hyperinsulinism, hypoglycaemia, octreotide, somatostatin analogues

1. Щедеркина И.О., Меликян М.А., Заваденко А.Н., и др. Неврологические пароксизмальные нарушения у детей с гипогликемией на фоне врожденного гиперинсулинизма: полиморфизм клинических проявлений // Эпилепсия и пароксизмальные состояния. — 2015. — Т.7. — №2. — С. 49−52. [Shchederkina IO, Melikyan MA, Zavadenko AN, et al. Neurological paroxysmal disorders in children with hypoglycemia in congenital hyperinsulinism: polymorphism of clinical implications. Epilepsy and paroxysmal conditions. 2015;7(2):49−52. (In Russ.)].doi: 10.17749/2077-8333.2015.7.2.049-058.

2. Muukkonen L, Männistö J, Jääskeläinen J, et al. The effect of hypoglycaemia on neurocognitive outcome in children and adolescents with transient or persistent congenital hyperinsulinism. Dev Med Child Neurol. 2019;61(4):451–457. doi: 10.1111/dmcn.14039.

3. De León DD, Stanley CA. Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates. Nat Clin Pract Endocrinol Metab. 2007;3(1):57–68. doi: 10.1038/ncpendmet0368.

4. Snider KE, Becker S, Boyajian L, et al. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013;98(2):E355−363. doi: 10.1210/jc.2012-2169.

5. Kapoor RR, Flanagan SE, Arya VB, et al. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrinol. 2013;168(4):557–564. doi: 10.1530/EJE-12-0673.

6. Vajravelu ME, de León DD. Genetic characteristics of patients with congenital hyperinsulinism. Curr Opin Pediatr. 2018;30(4):568–575. doi: 10.1097/MOP.0000000000000645.

7. Salomon-Estebanez M, Flanagan SE, Ellard S, et al. Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time. Orphanet J Rare Dis. 2016;11(1):163. doi: 10.1186/s13023-016-0547-3.

8. Stanley CA, de Leon DD, ed. Monogenic hyperinsulinemic hypoglycemia disorders. Frontiers in Diabetes. 2012. doi: 10.1159/isbn.978-3-8055-9944-3.

9. Banerjee I, Salomon-Estebanez M, Shah P, et al. Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia. Diabet Med. 2019;36(1):9–21. doi: 10.1111/dme.13823.

10. McMahon AW, Wharton GT, Thornton P, de Leon DD. Octreotide use and safety in infants with hyperinsulinism. Pharmacoepidemiol Drug Saf. 2017;26(1):26–31. doi: 10.1002/pds.4144.

11. Katz MD, Erstad BL. Octreotide, a new somatostatin analogue. Clin Pharm. 1989;8(4):255–273.

12. Doyle ME, Egan JM. Pharmacological agents that directly modulate insulin secretion. Pharmacol Rev. 2003;55(1):105–131. doi: 10.1124/pr.55.1.7.

13. Laje P, Palladino AA, Bhatti TR, et al. Pancreatic surgery in infants with Beckwith-Wiedemann syndrome and hyperinsulinism. J Pediatr Surg. 2013;48(12):2511–2516. doi: 10.1016/j.jpedsurg.2013.05.016.

14. Van der Steen I, van Albada ME, Mohnike K, et al. A multicenter experience with long-acting somatostatin analogues in patients with congenital hyperinsulinism. Horm Res Paediatr. 2018;89(2):82–89. doi: 10.1159/000485184.

15. Demirbilek H, Hussain K. Congenital hyperinsulinism: diagnosis and treatment update. J Clin Res Pediatr Endocrinol. 2017;9(Suppl 2):69–87. doi: 10.4274/jcrpe.2017.S007.

16. Yau D, Salomon-Estebanez M, Chinoy A, et al. Central venous catheter-associated thrombosis in children with congenital hyperinsulinism. Endocrinol Diabetes Metab Case Rep. 2019;2019(1). doi: 10.1530/EDM-19-0032.

17. Edelson JB, Orenstein EW, Zaoutis LB, Copelovitch L. Intravenous fluid management in the pediatric hospital setting: is isotonic fluid the right approach for all patients? Curr Treat Options Pediatr. 2015;1(1):90–99. doi: 10.1007/s40746-014-0006-0.

18. Avatapalle B, Padidela R, Randell T, Banerjee I. Drug-induced hepatitis following use of octreotide for long-term treatment of congenital hyperinsulinism. BMJ Case Rep. 2012;2012:bcr2012006271. doi: 10.1136/bcr-2012-006271.

19. Jack M, Greer R, Thomsett M, et al. The outcome in Australian children with hyperinsulinism of infancy: Early extensive surgery in severe cases lowers risk of diabetes. Clin Endocrinol (Oxf). 2003;58:355–364. doi: 10.1046/j.1365-2265.2003.01725.x.

20. Yorifuji T, Kawakita R, Hosokawa Y, et al. Efficacy and safety of long-term, continuous subcutaneous octreotide infusion for patients with different subtypes of KATP-channel hyperinsulinism. Clin Endocrinol (Oxf). 2013;78(6):891–897. doi: 10.1111/cen.12075.

21. Koren I, Riskin A, Barthlen W, Gillis D. Hepatitis in an infant treated with octreotide for congenital hyperinsulinism. J Pediatr Endocrinol Metab JPEM. 2013;26(1-2):183–185. doi: 10.1515/jpem-2012-0372.

22. Ben-Ari J, Greenberg M, Nemet D, et al. Octreotide-induced hepatitis in a child with persistent hyperinsulinemia hypoglycemia of infancy. J Pediatr Endocrinol Metab JPEM. 2013;26(1-2):179–182. doi: 10.1515/jpem-2012-0349.

23. Glaser B, Hirsch HJ, Landau H. Persistent hyperinsulinemic hypoglycemia of infancy: long-term octreotide treatment without pancreatectomy. J Pediatr. 1993;123(4):644–650. doi: 10.1016/s0022-3476(05)80970-9.