Persistent pulmonary hypertension of the newborn (PPHN) affects about 2/1000 newborn. The mainstay of therapy is supportive high frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (NO), which have decreased the need for Extracorporeal membrane oxygenation (ECMO) in these patients [1].However, still there is significant mortality and affected infants are at risk of long-term neurological impairment. We present the case of a preterm infant with severe PPHN and shock that failed all available therapies and was successfully rescued with the administration of terlipressin.

A 33-week male preterm baby (birthweight 2010 g) was admitted to our neonatal intensive care unit. Soon after birth he developed respiratory distress and hypoxemia. He was intubated and a surfactant dose was administered but without significant improvement. An echocardiogram showed a structurally normal heart and a near-systemic pulmonary artery systolic pressure (PASP) of 55-60 mmHg. HFOV and inhaled NO (20 ppm) were then initiated. The infant was hypotensive (Mean arterial pressure, MAP <5th percentile) requiring inotropic support with dopamine and dobutamine. At 36 hours of life, the infant remained hypotensive and with oxygenation failure (oxygenation index 31). Sequential echocardiograms showed supra-systemic PASP (80-100mmHg), right heart failure and pure right-to-left shunts. Sildenafil was added and continuous prostaglandin E1 infusion was started to keep the ductus open and support cardiac output. Adequate MAP could not be maintained despite escalating inotropic support: norepinephrine (up to 0.8 µg/kg/min), epinephrine (up to 0.8 µg/kg/min) and hydrocortisone (1mg/kg/6h). In this context, bosentan (2mg/kg/12h) was added but neither improvement in pulmonary hypertension nor oxygenation was observed. Continuous epoprostenol infusion was initiated at 40 hours of life because of persistent right heart failure and shock. Pulmonary hypertension partially responded to this therapy with improved oxygenation (OI change from 40 to 24) but it was impossible to maintain systemic MAP at maximal inotropic support (vasoactive-inotropic score: 131). A contact with two ECMO transport teams was made at 2nd day of life but ECMO was considered not indicated because of prematurity and a poor expected survival. At 4th day of life, the child was in profound shock and it was decided, in agreement with parents, to use compassionate rescue treatment with terlipressin. A 5 µg/kg bolus dose was administered followed by 10 µg/kg/h continuous infusion. Terlipressin rapidly raised MAP to 60 mmHg, allowing escalation of epoprostenol up to 60 ng/kg/min. PASP decreased from 85 to 40 mmHg with improvement in oxygenation (OI from 38 to 15). In the next 24 hours, he developed left to right ductal shunt and he was progressively weaned from pulmonary vasodilators. Terlipressin was maintained for 48 hours and then tapered gradually (1 µg/kg/h) allowing the infant to be weaned from catecholamines (7th day of life) and finally extubated at 12th day of life. The child was discharged home without any clinically significant sequelae. At 2 years follow up, the child has age-appropriate developmental status.

With terlipressin we observed a rapid raise in MAP with a marked improvement in pulmonary hypertension and oxygenation, allowing tapering of catecholamines. Terlipressin has been used to treat catecholamine-resistant vasodilatory shock in adults, showing restoration of arterial blood pressure. Terlipressin has also been used in pediatric and neonatal refractory shock with unclear clinical benefits [2,3]. Unlike adults, pure vasodilatory shock is uncommon in the pediatric and neonatal population and in consequence excessive vasoconstriction can induce tissue ischemia and worsen heart function and is not generally recommended.

Terlipressin is a vasopressin analogue with long half-life that exerts effects via V1 and V2 receptors.The main clinical effect is mediated by V1-receptor that causes smooth muscle contraction and induces a potent increase in systemic vascular resistance (SVR) and blood pressure.Terlipressin is reported to increase SVR without a concomitant increase in pulmonary vascular resistance (PVR) [4]. In fact terlipressin may induce direct pulmonary vasodilatation via NO-release and lower pulmonary arterial pressure. Terlipressin-induced increase in SVR also improves coronary perfusion and right heart function contributing to increased pulmonary blood flow and oxygenation; which is newborn infants may be further facilitated by reversal of right to left intra-cardiac shunts as a consequence of increased MAP/PAP ratio [5].

Successful use of terlipressin in term infants with different causes of PPHN such as congenital diaphragmatic hernia has been reported [6]. However, its use has not been reported in preterm infants, in whom refractory PPHN is uncommon. In our patient, given the potentially reversible nature of idiopathic PPHN we decided to exhaust all therapeutic measures and try rescue treatment with terlipressin. We observed improved blood pressure, heart function, and oxygenation. During the infusion, cardio-respiratory monitoring, NIRS, ion control, echocardiography, troponin and serial clinical evaluations were used to monitor side effects. We only observed transient skin vasoconstriction and discoloration without development of skin necrosis or evidence of new-organ failure.

In conclusion we believe that terlipressin may be considered as a salvage therapy in severe PPHN and refractory hypotension when ECMO is not available or it is considered contraindicated.

1. Fuloria M, Aschner JL. Persistent pulmonary hypertension of the newborn.Semin Fetal Neonatal Med. 2017;22:220-6.

2. Masarwa R, Paret G, Perlman A, Reif S, Raccah BH, Matok I. Role of vasopressin and terlipressin in refractory shock compared to conventional therapy in the neonatal and pediatric population: A systematic review, meta-analysis, and trial sequential analysis. Crit Care. 2017;21:1.

3. Rodríguez-Núñez A, López-Herce J, Gil-Antón J, Hernández A, Rey C, RETSPED Working Group of the Spanish Society of Pediatric Intensive Care. Rescue treatment with terlipressin in children with refractory septic shock: A clinical study. Crit Care. 2006;10:R20.

4. Radicioni M, Troiani S, Camerini PG. Effects of terlipressin on pulmonary artery pressure in a septic cooled infant: an echocardiographic assessment. J Perinatol. 2012;32:89-5.

5. Evora PR, Pearson PJ, Schaff HV. Arginine vasopressin induces endothelium-dependent vasodilatation of the pulmonary artery. V1-receptor-mediated production of nitric oxide.Chest. 1993;103:1241-5.

6. Stathopoulos L, Nicaise C, Michel F, Thomachot L, Merrot T, Lagier P, et al. Terlipressin as rescue therapy for refractory pulmonary hypertension in a neonate with a congenital diaphragmatic hernia. J Pediatr Surg. 2011;46:e19-21.