Case report

Our patient was a twin, born at 30-weeks gestational age (424 g). He was intubated after birth and had evidence of pulmonary hypertension, which required inhaled nitric oxide for a short time. He was discharged home at approximately 4 months old in room air, without evidence of pulmonary hypertension by echocardiography. Shortly thereafter, he was readmitted due to acute respiratory failure, requiring non-invasive mechanical ventilation. His echocardiogram showed pulmonary hypertension, and he was started on sildenafil. He was not able to wean from ventilatory support, and, at 6 months old, he was transferred to our hospital for tracheostomy placement.

After tracheostomy placement, he developed respiratory deterioration. He was placed on inhaled nitric oxide and high frequency oscillatory ventilation. Echocardiography showed suprasystemic pulmonary hypertension with right heart hypertrophy and enlargement. NT pro-BNP values were between 2500 and 4000 pg/ml. Sildenafil was converted to an intravenous infusion (0.067 mg/kg/hour), and dopamine was initiated. He was receiving 100% inspired oxygen, and his oxygen saturation was difficult to maintain over 80%. His liver enzymes were elevated, and he had evidence of cholestasis due to prolonged parenteral nutrition after necrotizing enterocolitis; therefore, bosentan was not initiated. Dopamine was transitioned to milrinone, and a furosemide infusion was initiated.

At 7.5 months old (6.4 kg), an intravenous treprostinil infusion was initiated. Over the course of several weeks, the infusion was titrated to a maximal dose of 50 ng/kg/minute. He showed significant improvement in echocardiographic evidence of pulmonary hypertension, NT pro-BNP, and inspired oxygen requirement. His dose of treprostinil was held at the current dose and was not adjusted for weight gain. At approximately 11 months old, his NT pro-BNP was 85 pg/ml and he underwent cardiac catheterization. Hemodynamic assessment revealed a pulmonary vascular resistance (PVRi) of 1.8 woods units * m², while receiving 40 ng/kg/minute of treprostinil, adjusted for his current weight. He was tolerating full enteral feeds via gastrostomy tube, though his liver function testing remained elevated (supplemental figure 1). At this point, he was approaching readiness for discharge to a long-term care facility, but no local facility would accept the patient with a continuous treprostinil infusion, whether intravenously or subcutaneously administered. For this reason and with the recent positive reports of transition to enteral selexipag in children, the decision to attempt transition to enteral selexipag in our patient was made.

At 11.5 months old (8.6 kg), our patient began transition from continuous intravenous treprostinil to twice daily enteral selexipag. Transition occurred over an 8-day period and was well tolerated. The transition process is described later. He has been receiving enteral selexipag for over 12 months (since 3/30/2018) and continues to improve. He is now receiving 21% inspired oxygen and is weaning from ventilator support. His NT pro-BNP remains low (28 pg/ml), and his echocardiogram has shown no more than mild septal flattening (Fig 1 and supplemental figure 2).

Figure 1.

Parasternal short-axis end-systolic echocardiogram images over the course of therapy. ( a ) Severe septal flattening before administration of treprostinil. ( b ) Trivial septal flattening while receiving treprostinil 50 ng/kg/minute. ( c ) No septal flattening after transition to enteral selexipag. ( d ) Mild septal flattening 11 months after transition to enteral selexipag.

Preparation

To determine the proper method of medication preparation, the European Medicines Agency Assessment Report on selexipag was reviewed. ⁷ Selexipag is manufactured as immediate-release film-coated tablets of various strengths. Preparations with sterile water, Ora-Sweet®, and Ora-Plus® with various methods of suspension/dissolution were tested to find the optimal mixing procedure. The final method involves dissolving the tablet in sterile water over a 10–15-minute period. We tested 200 and 400 mcg tablets.

1. (1) Halve tablet.

2. (2) Pull out syringe plunger and place tablet halves in open syringe.

3. (3) Replace syringe plunger and fill to 4 ml with sterile water per tablet. Cap syringe.

4. (4) Intermittently shake and agitate syringe until tablet is dissolved (10–15 minutes).

5. (5) Administer required dose. Discard remaining solution.

Dose selection

Prior reports in children utilized the full final adult dose of 1600 mcg twice daily for children as young as 7 years old and 30 kg. With this information, we extrapolated our initiation and goal doses (Table 1). Our patient (8.6 kg) initially received 50 mcg twice daily, with a goal dose of 400 mcg twice daily.

Table 1.

Suggested paediatric dosing protocol.

Transition process

At transition, our patient was receiving 40 ng/kg/minute of intravenous treprostinil, adjusted for weight. He was receiving an H1- and H2-blocker to minimize systemic side effects as well. His pulmonary hypertension was well treated with his current therapies. Transition occurred over an 8-day period as follows. After each new dose strength was begun, the treprostinil infusion was decreased by 1 ng/kg/minute every 2 hours for 10 hours (5 ng/kg/minute over 10 hours), then held at that dose for the following 14 hours. This transition protocol continued daily until full dose selexipag (400 mcg twice daily) was achieved, and treprostinil was discontinued.

Monitoring and follow-up

During the initial cross-titration, vital signs were monitored continuously and recorded hourly. No significant changes to vital signs were observed during the transition. Echocardiography and NT pro-BNP were obtained throughout the transition and were similar to the previous testing.

The patient was subsequently discharged and follows up with a Cardiology office visit, echocardiogram, electrocardiogram, NT pro-BNP, comprehensive metabolic panel, and blood counts every 3 months. After 12 months of follow-up while receiving selexipag, his NT pro-BNP has remained low and his echocardiogram has shown no more than mild pulmonary hypertension. At his last visit, his dose was decreased from 400 to 200 mcg twice daily, which he has tolerated well. We plan to continue weaning selexipag slowly based on his echocardiogram, NT pro-BNP, and clinical symptoms. A follow-up catheterization will be performed after withdrawal of the medication to assure tolerance and assess vascular resistance.