Minimal dose of octreotide causing necrotizing enterocolitis in a neonate with congenital hyperinsulinism – A rare case report

INTRODUCTION

Hyperinsulinism is the most common cause of persistent refractory hypoglycemia in the newborn.^[1] Attaining glycemic goals with parenteral fluids alone, often, is not possible and drugs such as diazoxide and octreotide (OTT) are required to be instituted. The somatostatin analog OTT has been used in the treatment of infants with congenital hyperinsulinism (CHI) since 1986.^[2] One of the major effects is a substantial reduction of arterial blood flow of the splanchnic arteries, predisposing to ischemic necrosis of the gut. All the reported cases of necrotizing enterocolitis (NEC) associated with OTT use in neonates with CHI have occurred when OTT was used at higher doses, suggesting a possible dose-dependent reduction of splanchnic blood flow by OTT.^[3]

We report a neonate with CHI who developed NEC with OTT at the minimal starting dose.

CASE REPORT

A male baby was born to a 27-year-old G2P1 mother, at 33⁺¹ weeks gestation with antenatal steroid coverage, weighing 2.75 kg (95^th centile), with a well 4-year-old female sibling. The neonate was a product of a non-consanguineous marriage and pregnancy was complicated by polyhydramnios and well-controlled gestational diabetes mellitus on metformin. The baby was born by an uncomplicated spontaneous vaginal delivery with Apgar scores of 6 and 9 at 1 and 5 min of life, respectively.

On day 1 of life, asymptomatic hypoglycemia was noted with blood sugar levels (BSLs) of 25 mg/dL. The hypoglycemia continued to persist despite adequate feeding and the baby had to be initiated on parenteral fluids with an increasing glucose infusion rate (GIR) requirement, going up to 18 mg/kg/min (administered through peripherally inserted central catheter [PICC] line) by day 3 of life. In view of persisting high GIR requirement, critical samples at the time of hypoglycemia were sent which revealed serum insulin levels of 5 mIU/L, with a simultaneous BSL of 33 mg/dL. Serum cortisol and growth hormone levels were normal and urinary ketones were negative. The required GIR reached a maximum of 25mg/kg/min during the course of illness. A repeat insulin level sent on day 10 of life revealed an inappropriately high insulin of 81.7 mIU/L with a corresponding BSL of 47 mg/dl; insulin: glucose ratio being 1.7, thus, confirming the diagnosis of hyperinsulinism.^[4] Genetic testing for CHI confirmed the diagnosis of autosomal recessive CHI. The neonate was found to have a homozygous aberrant splicing variant at intron 36 of ABCC8 gene on chromosome 11p15. Both the parents were genetically identified to be heterozygous carriers for the same mutation.

Diazoxide was commenced on day 12 of life but sugar levels remained intermittently low despite maximal dosing. On day 18, the neonate also developed Enterobacter sepsis and antibiotics as per culture sensitivity were commenced. The coagulogram was normal. In view of persistent high GIR requirement and non-responsiveness to diazoxide, subcutaneous OTT was started on day 21 at a dose of 4 mcg/kg/day administered subcutaneously six hourly. Oral feeds were being tolerated and therefore expressed breast milk was continued with a plan to gradually hike it up to full feeds. One week after starting treatment with OTT which was continued at the same dose as the blood sugars were maintained, the patient developed significant abdominal distension, feed intolerance, bilious vomiting, and bloody stools. Abdominal radiograph showed fixed dilated bowel loops, thickened bowel wall, and paucity of bowel gas [Figure 1]. Ultrasound revealed pneumatosis intestinalis and ascites. Clinical and radiological findings were consistent with NEC. Septic screen was on the improving trend with repeat blood culture being sterile. The patient was kept nil per oral and OTT was discontinued. Multiple blood component transfusions were given in view of anemia and thrombocytopenia. In view of a progressively fulminant course of the disease, the neonate was not deemed stable to undergo a laparotomy. The patient had a complicated course thereafter, requiring ventilation, inotropes and succumbed to the illness.

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Figure 1:

A 28-day-old male neonate with necrotizing enterocolitis. Abdominal radiograph showing dilated bowel loops and thickened bowel wall.

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DISCUSSION

OTT, a short-acting somatostatin analog, is commonly used as second-line treatment of CHI in patients unresponsive to diazoxide.^[5] A number of adverse events have been attributed to this drug, but a majority of them include laboratory abnormalities such as thrombocytopenia, leucopenia, raised liver enzymes, and abnormal renal functions. OTT also substantially reduces intestinal blood flow by vasoconstriction of the splanchnic vasculature causing concern that it may increase the risk of NEC.^[6] This is not only as a result of direct action on the vascular smooth muscle but is also related to its ability to modulate a variety of vasoactive hormones such as glucagon and vasoactive intestinal peptide.^[7]

In a summary of 8 cases of OTT-associated NEC, Laje et al. reported the age at starting OTT ranging from 4 to 21 days, with doses ranging from 15 to 27 mcg/kg/day (subcutaneous) and 4 to 8 mcg/kg/h of infusions.^[8] The neonates had been on OTT ranging from 1 to 15 days, before NEC being diagnosed. In our case, OTT was commenced on day 21, and interestingly, the baby developed features of NEC even at the minimal dose of OTT (4 mcg/kg/day), 7 days after commencement of OTT. In a retrospective analysis of 103 cases of CHI exposed to OTT, McMahon et al. noted only 1 case of NEC which developed 3 days after the commencement of OTT.^[9] This neonate had been on an OTT regimen of 12 mcg/kg/day administered in three divided doses.

Sepsis could often masquerade as NEC.^[10] Admittedly, it is difficult to state with certainty that OTT was the only causative factor for NEC in our case. Multiple risk factors for NEC may have had an additive effect. Prematurity and infant of diabetic mothers are known risk factors, which were present in our baby.^[11] Besides, the neonate had developed Enterobacter sepsis before commencement of OTT, though the septic screen was on the improving trend at the time of clinical deterioration. However, in the temporal profile of this case, appropriate antibiotics had been commenced for sepsis, the neonate continued to feed well, showed no abdominal symptoms or signs, until 7 days after administration of OTT. The sudden onset of abdominal distension and bloody stools suggested the development of NEC which could possibly be attributed to OTT.

In all the above-reported cases, OTT was considered a risk factor and all had OTT doses ≥12 mcg/kg/day.

CONCLUSION

We describe a rare case of NEC possibly associated with OTT use at the recommended initial starting dose. This could possibly suggest that the effect of OTT on the gut may not only be dose related, but idiosyncratic as well. Therefore, we advise caution and close monitoring of patients treated with this medication, even at low doses.