Necrotising enterocolitis in a newborn infant treated with octreotide for chylous effusion: is octreotide safe?

Abstract

Octreotide is a somatostatin analogue used for treating congenital chylothorax and congenital hyperinsulinism in infants. By increasing splanchnic arteriolar resistance and decreasing gastrointestinal blood flow, octreotide indirectly reduces lymphatic flow in chylous effusions.

Splanchnic ischaemia following octreotide predisposes infants to necrotising enterocolitis (NEC). Although NEC occurrence in infants treated with octreotide for hyperinsulinaemic hypoglycaemia has been reported widely, its incidence in infants with chylothroax is low. We describe a case of congenital chylothorax in a preterm infant who had poor response to thoracentesis. Although octreotide initiation lead to resolution of chylothorax, he developed NEC. Cessation of octreotide and medical management resulted in rapid resolution of NEC. Since octreotide is generally used as the first-line treatment for chylous effusion, the risk of NEC should be considered, especially when the dosage is increased. Infants on octreotide should be closely observed for early signs and symptoms of NEC to avert surgical emergency.

Background

Chylothorax is defined as accumulation of lymphatic fluid in the pleural space resulting from disruption or obstruction of the thoracic duct.¹ It affects 1 in 10 000 births and has a mortality rate of 20%–60%. If complicated by chylothorax, mortality can reach 98%.² Chylothorax is characterised by pleural fluid with a high protein level of >3 g/L, triglyceride levels of >1.1 mmol/L and absolute cell count of >1000 cells/µL with lymphocytic predominance (>80%) in milk-fed infant.³ Low triglyceride levels of <0.565 mmol/L excludes the diagnosis of chylothorax.¹

In addition to thoracentesis, octreotide has been used since the year 2000 for the management of congenital hyperinsulinism (CHI) and chylothorax.⁴ Octreotide is a long-acting somatostatin analogue that acts on the splanchnic vascular bed to reduce lymph fluid production. This leads to reduction in gastric, pancreatic and intestinal secretions, impairing intestinal absorption and collectively reducing the flow of chyle.⁵ However, reduction in splanchnic blood flow predisposes high-risk preterm infants to necrotising enterocolitis (NEC), as characterised by coagulation necrosis of the intestine, bacterial overgrowth and inflammation.⁶

Case presentation

A preterm male infant was born at 35+2 weeks gestation to a non-consanguineous couple. The antenatal ultrasound scans were unremarkable until 35+1 weeks. Fetal images showed signs of late onset hydrops including bilateral pleural effusion, ascites and skin oedema. Infant was delivered by emergency caesarean section and weighed 3000 g. His Apgar scores were 1 at 1 and 5 min of life. At birth, cord gases were unremarkable. He had respiratory depression and resuscitation included intubation, ventilation and bilateral thoracentesis. He was not dysmorphic and did not have any noticeable congenital anomalies.

Investigations

Postnatal chest radiograph and echocardiography confirmed hydrops with bilateral pleural effusion and a small posterior 2.4 mm pericardial effusion (figure 1). Abdominal ultrasound revealed minimal ascites. Although diagnostic workup for hydrops was conducted, it was unremarkable. In unfed state, the pleural fluid analysis had a protein level of 26.6 g/L, triglyceride of 0.82 mmol/L, with total white cell count of 2232/μL with 94% lymphocytes. The low triglyceride level is likely attributable to infant not being fed at the time of the pleural fluid analysis. Both liver and renal function tests remained unremarkable. His pleural fluid and blood cultures were sterile, and his karyotype was 46XY.

Figure 1.

Chest and abdominal X-ray done on day 1 of life showing bilateral chest tubes. A moderate right pleural effusion is noted. Mild airspace shadowing is also seen in the midzone of the right lung. There is left pneumothorax seen in the lower zone of the left hemithorax. The abdominal X-ray is unremarkable.

Treatment

Cardiorespiratory stability was achieved with thoracentesis and adequate ventilation. Initial management of chylothorax included gut rest and nutrition through total parenteral alimentation (TPA). The maximal pleural fluid loss was up to 144 mL/kg/day on day 3 of life. Pleural fluid loss was intermittently replaced with fresh frozen plasma and albumin. Because pleural fluid output remained high, intravenous octreotide was started on day 5 at 1 µg/kg/hour. The dose was gradually increased by 1 µg/kg/hour increment, up to a maximum dose of 9 µg/kg/hour over the next 9 days, with improvement in the pleural fluid output. Infant remained ventilated for 7 days and was extubated to continuous positive airway pressure support. He was further weaned to low flow nasal cannula by day 17 and eventually placed in room air by day 29.

On day 14 of life, he was fed with Monogen (Nutricia Medical, Ireland), a low-fat, whole-whey protein powdered milk high in medium chain triglycerides (MCT). Feeds were gradually increased to 128 mL/kg/day on day 19. However, on day 20, the infant had moderate to large amount of bloodstained stool, abdominal distension and increasing gastric aspirates. Blood counts were unremarkable. His abdominal X-ray showed pneumatosis intestinalis (figure 2) which was consistent with NEC (Bell’s stage 2A). Octreotide and oral feeds were discontinued, and TPA was restarted. His vital signs were closely monitored, and intravenous cloxacillin, amikacin and metronidazole were initiated.

Figure 2.

Chest and abdominal X-ray done on day 20 of life showing extensive pneumatosis predominantly in left bowel loop with involvement also seen in some loops in the right and central region of the abdomen. There is no pneumoperitoneum or portal venous gas.

Outcome and follow-up

With octreotide cessation and supportive management of NEC, the infant progressively improved. Haematochezia did not recur and his abdominal X-ray showed resolution of pneumatosis intestinalis with improvement in gut gas pattern within 72 hours of diagnosis (figure 3). Monogen was restarted on day 27 after 7 days of gut rest and oral feeding was well tolerated. The infant was discharged on day 53 on Monogen feeds. He was transitioned to standard infant formula by 3 months of age and started on weaning foods at 6 months. His growth and neurodevelopmental assessments are appropriate for age at the last review.

Figure 3.

Chest and abdominal X-ray done on day 22 of life showing complete resolution of the previously noted extensive pneumatosis. The chest X-ray shows a small residual right pneumothorax.

Discussion

Although congenital chylothorax is rare, it can be potentially fatal in infants. Fetal ultrasound can differentiate isolated hydrothorax from hydrops fetalis. The diagnosis of chylothorax can only be achieved by pleural fluid analysis. Fetal interventions including thoracoamniotic shunting or pleurodesis with OK-432 in chylothorax diagnosed before 34 weeks can improve the postnatal outcome.⁷ Once fetal diagnosis of pleural effusion is made, delivering the fetus at an optimal time frame is necessary to avoid life-threatening complications. After birth, treatment should continue with thoracentesis, adequate cardiorespiratory support and enteric rest. Optimal nutrition should be maintained with either TPA or MCT-based milk feeds.

Somatostatin (SST)/Octreotide in infants has shortened the duration of conservative management and facilitated early recovery. SST was initially used to treat patients with acromegaly. Over the last three decades, stronger and longer acting synthetic analogues have been developed (eg, octreotide, lanreotide and vapreotide). Their clinical use has been expanded for diverse medical conditions including portal hypertension, enterocutaneous fistulas, CHI and chylothorax. Besides its insulin-inhibitory effects, octreotide has other adverse effects including the suppression of luteinising hormone response to gonadotropin-releasing hormone and inhibition of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin and pancreatic polypeptide release.^{5 8}

Both SST and octreotide have side effects. However, the latter is preferred because of its relatively fewer side effects and its easy administration by the subcutaneous route. It is generally well tolerated though it may cause transient changes in blood glucose levels, abdominal distension and emesis.⁹ Octreotide reduces the splanchnic blood flow in a dose-dependent manner, affecting the entire gastrointestinal tract. Safety concerns have been raised on its potential impact on NEC development in infants receiving octreotide for chylous effusion management.¹⁰ Tyden et al demonstrated a 35% decrease in ileocolic and left colic blood flow in human volunteers following intravenous infusion of somatostatin. Nonetheless, the contribution of this haemodynamic alteration to NEC development is not dose dependent.¹¹

To date, there are only two cases of NEC in infants treated with octreotide for chylothorax reported in the literature. Mohseni-Bod et al reported NEC development in term infant with coarctation of the aorta treated with octreotide for postoperative chylothorax.¹² Buyuktiryaki et al described NEC development in a preterm infant with congenital chylothorax on day 4 of octreotide administration at 1 µg/kg/hour.¹³ Our’s is the third case of NEC report in infants treated for chylothorax using octreotide.

In our level IV tertiary neonatal unit, we manage more than half a dozen cases of chylous effusions every year. We have used the same regimen for more than a decade. Octreotide is initiated at 1 µg/kg/hour as a continuous infusion and gradually increased at 1 µg/kg depending on the response, to a maximum 10 µg/kg/hour. The dose of octreotide used ranges from 10 to 70 µg/kg/day subcutaneously or 0.3–10 µg/kg/h intravenously.³ The recommended dose for octreotide in CHI is 5–35 µg/kg/day.^{14 15} NEC incidence in infants treated with octreotide for CHI has been reported.^{6 15} Although the recommended dose for octreotide treatment in chylothorax is several fold higher than that for CHI, NEC occurrence in infants with chylothorax on octreotide is sparse. The rarity of chylothorax and variability in dose response may have contributed to this outcome.³

A systematic review by Das et al reported that response to chylothorax treatment was effective with octreotide. However, there were significant discrepancies among the dose, duration and frequency used. In addition, the trials reviewed were not randomised. The authors concluded that ‘no practice recommendation can be made based on the evidence identified and suggested for a multicentre randomised controlled trial to assess the safety and efficacy of octreotide in the treatment of chylothorax in neonates’.³

Our infant was started on octreotide according to our unit’s protocol. We increased the dose to 9 µg/kg/hour for treatment response. He developed haematochezia, abdominal distension and pneumatosis intestinalis after 15 days on parenteral octreotide. Six cases of octreotide-associated NEC has been reported in infants with CHI; all of which occurred within 15 days of treatment.^{15 16} McMahon et al studied the safety of octreotide in 103 infants (mostly born at term) with CHI¹⁷ and reported only one fatal case of severe NEC. Laje et al reported 2% of NEC occurrence in neonates treated with octreotide for CHI. Four of 197 infants, all born at term and developed NEC did not have risk factors for developing NEC other than octreotide.¹⁵

Because no randomised controlled trials have been conducted to validate the safety and risk of octreotide, other risk factors may contribute to NEC development. However, if we consider that all infants are reasonably homogeneous in terms of age, diagnosis and treatment, octreotide might be the only significant risk factor and has played a substantial role due to its haemodynamic effects on splanchnic vascular bed.

Naranjo et al designed a questionnaire to determine the likelihood of whether an adverse drug reaction is actually due to drug rather than the result of other factors. To assess whether there is a causal relationship between octreotide and NEC in our case, we used Naranjo score, which showed a probable association with a score of 3.¹⁸

Newer medications, such as sildenafil and Sirolimus, are also available for chylothorax treatment. Sildenafil prevents cyclic guanosine monophosphate (cGMP) degradation by selectively inhibiting phosphodiesterase-5, thereby facilitating lymphatic vessel growth to resolve lymphatic obstruction and chylothorax.¹⁹ It was described to be effective in the case of a preterm infant with congenital chylothorax associated with pulmonary lymphangiectasia which was unresponsive to octreotide. Sirolimus, an inhibitor of the mammalian target of rapamycin, has successfully treated chylothoraces associated with lymphatic malformation in both adults and older children.²⁰ A recent study by Mizuno et al reported age-adjusted sirolimus dosing regimens for neonates and infants. However, further studies are warranted to validate its use in newborn infants.²¹

In conclusion, octreotide use may increase the risk of NEC, especially when administered in higher dosage for chylothorax treatment. Additional predisposing risk factors include prematurity, intrauterine growth restriction with abnormal doppler studies, haemodynamically significant patent ductus arteriosus and perinatal asphyxia. We recommend judicious escalation of the dose of octreotide as clinically indicated together with vigilance and close monitoring of signs and symptoms for early identification of NEC (Bell’s stage 1 and 2). Immediate cessation of octreotide, adequate parenteral nutrition during enteric rest and respiratory/haemodynamic support for maintaining gut perfusion and oxygenation should be undertaken to maximise the chances of recovery from NEC.

Learning points.

• Pleuroamniotic shunts or pleurodesis with OK-432 can be done during midtrimester if the fetal scan detects chylous effusion. In newborns, conservative management of chylothorax includes thoracentesis, enteric rest, medium chain triglycerides-based milk feeds/total parenteral alimentation and octreotide.

• Octreotide causes gut ischaemia by splanchnic vasoconstriction. Hence, it should be used with caution in preterm, small for gestational age infants and those born with cyanotic congenital heart diseases or large patent ductus arteriosus, as they are more susceptible to necrotising enterocolitis (NEC).

• Compared with congenital hyperinsulinism, higher dose of octreotide is typically used in infants with chylothorax. They should be closely observed for early signs and symptoms of NEC to avert a surgical emergency.