KS Lun, LKH Poon, WH Lee

Abstract

We report here the use of continuous infusion of prostacyclin into the pulmonary artery in a newborn with severe pulmonary hypertension of newborn complicating meconium aspiration. Use of intravenous vasodilators failed to reverse the hypoxaemia while causing severe systemic hypotension. The use of prostacyclin infusion in the pulmonary artery decreased the pulmonary arterial pressure and significantly improved systemic oxygenation. There was no deterioration of blood pressure. The infant was successfully managed with good outcome.

Introduction

Severe persistent pulmonary hypertension of the newborn (PPHN) is associated with significant morbidity and mortality. The resulting hypoxaemia and acidosis produce further pulmonary vasoconstriction and lead to a vicious cycle of shunting, hypoxia and acidosis. Supportive treatment using hyperventilation, alkalinisation and inotropic medications are often ineffective in severe cases.

Intravenous vasodilators have been used with variable success, but they often cause drop of the systemic vascular resistance and severe hypotension. Intravenous prostacyclin (epoprostenol, PGI₂) has been used to reverse the pulmonary vasoconstriction in infants suffering from severe and refractory persistent pulmonary hypertension of the newborn.^1-2 We describe our experience of infusion of prostacyclin into the pulmonary artery in a neonate to achieve selective dilation of the pulmonary vessels.

Case Reports

A 3500g Chinese male was born at term by normal vaginal delivery to a 19-year-old primigravida. The amniotic fluid contained thick meconium. Apgar scores were 2 and 5 at one and five minutes respectively. Trachea was suctioned immediately after birth but he remained tachypnoeic and dyspnoeic. Chest roentgenogram revealed hyperinflated lungs and multiple areas of streaky atelectasis compatible with meconium aspiration syndrome. He stabilised initially with intubation and ventilation using an inspiratory pressure of 50 cmH₂O. He developed bilateral pneumothoraces and hypoxaemia (PaO₂ 4.36 kPa) got worse despite a FiO₂ of l00% ventilation and chest tube drainage. Conventional ventilation was switched to high frequency oscillatory ventilation at 16 hours after birth. Three doses of surfactant were given at 20, 26 and 32 hours of age.

Echocardiography revealed normal cardiac anatomy. Predominant right to left shunting was observed at the foramen ovate and ductus arteriosus. Right atrium, right ventricle and pulmonary arteries were dilated. Doppler study of the tricuspid regurgitation demonstrated a pressure gradient of 58 mmHg. This suggested systemic pulmonary arterial pressure with the simultaneous systemic pressure of 50/37 mmHg. Hypoxaemia and metabolic acidosis continued to deteriorate despite supportive treatment and alkalinisation. Intravenous tolazoline and magnesium sulphate failed to reverse the hypoxaemia but caused severe systemic hypotension and bradycardia requiring resuscitation. This necessitated discontinuation of these vasodilators. He required three inotropes including dopamine (15 mcg/kg/mm), dobutamine (15 mcg/kg/min) and adrenaline (1.2 mcg/kg/mm). Because of the catastrophic hypotension induced by intravenous vasodilators, we tried infusion of prostacyclin into the pulmonary artery as described by Lock et al.³ in 1979 at 24 hours of age.

A 4 French balloon wedge catheter was placed into the main pulmonary artery under echocardiographic guidance (Fig. 1). This revealed suprasystemic pulmonary arterial pressure (Table and Fig. 2). Prostacyclin was infused continuously into the main pulmonary artery over 10 days (maximum dosage 24 ng/kg/min). No deterioration of blood pressure was observed. Inotropic support could be decreased six hours after starting of prostacyclin. Pulmonary arterial pressure gradually declined to half systemic level three days after prostacyclin infusion. Systemic oxygenation improved significantly shortly after starting of prostacyclin (Table and Fig. 2). He had six episodes of pneumothoraces, which were managed by chest tube drainage. No further ventilatory support was required on day 27 of age. He was discharged from the hospital at day 44 old.

Fig. 1 The balloon wedge catheter is situated at the main pulmonary artery via left femoral puncture. UAC and UVC (later removed because of improper position) are shown. Central venous line is inserted via right femoral puncture. The lungs are hyperinflated with streaky atelectasis. Chest drains are inserted for bilateral pneumothoraces.

Fig. 2 Graphic representation of the response to prostacycline.

Up to 12 months of follow-up, the patient showed no sign of neurological sequelae. Developmental assessment was normal. CT scan of brain was normal. There was no evidence of chronic respiratory complication.

Discussion

Prostacyclin, a metabolite of arachidonic acid, is a potent short acting vasodilator and inhibitor of platelet aggregation that is produced by the vascular endothelium. It is a normal constituent of neonatal pulmonary vessels that has been used in the treatment of severe persistent pulmonary hypertension of the newborn.^1-3 Clinical studies have also demonstrated the "relative" specific pulmonary vasodilation effect in pulmonary hypertensive crisis of infants after cardiac surgery,⁴ primary pulmonary hypertension in children and adult.^5-8 No severe toxicity has been reported. However, prostacyclin in the systemic circulation can result in hypotension. Intravenous infusion could result in right to left shunting of prostacyclin at atrial level and induce systemic hypotension. Theoretically, infusion of prostacyclin into the pulmonary artery should avoid systemic hypotension. Lock reported in 1979 the clinical success of using infusion of prostacyclin into the pulmonary artery in a neonate with refractory persistent pulmonary hypertension of newborn complicating meconium aspiration.³ The catheter was placed during cardiac catheterisation. We placed the balloon wedge catheter at bedside under echocardiogram guidance. This prevented the high risk of transferring a critically ill neonate to the cardiac catheterisation laboratory. Care was taken to avoid placement of the catheter too close to the ductus arteriosus hoping to decrease the infusion of prostacyclin into the systemic circulation. We found no difficulty and complication during the procedure.

Most studies reported effective pulmonary vasodilation using intravenous prostacyclin without major side effects.^1-2 Because our patient had experienced catastrophic hypotension while using intravenous vasodilators, we decided to infuse prostacyclin directly into the pulmonary artery. We observed no deterioration of blood pressure. We were able to use a lower dose (maximum 24 ng/ kg/mm) compared to the study which required a mean intravenous dose of 60 ng/kg/min (range 30-120 ng/kg/ mm).² This can probably be explained by the loss of drug to the systemic circulation through the right to left atrial shunt.

Another way to achieve selective pulmonary vasodilation is to use aerosolised prostacyclin. Bindl et al. reported their success in managing two neonates with persistent pulmonary hypertension of the newborn using aerosolised prostacyclin.⁹ The systemic blood pressure remained stable while pulmonary arterial pressure declined. In our patient, it is not possible to deliver aerosolised prostacyclin into the high frequency oscillatory ventilator circuit.

High frequency oscillatory ventilation and surfactant therapy served to maintain lung volume by adequate lung recruitment. We believed this might enhance the effect of prostacyclin. Appropriate ventilation strategy appears to be synergistic to prostacyclin therapy.

During the past decade, interest has been focused on the inhalation nitric oxide for treatment of severe persistent pulmonary hypertension of the newborn. Inhaled nitric oxide causes selective pulmonary vasodilation. Multicenter prospective study had demonstrated inhaled nitric oxide improved systemic oxygenation in infants with persistent pulmonary hypertension of newborn.¹⁰ Unfortunately, nitric oxide was unavailable in our institution when the patient presented.

Some infants do not response to inhaled nitric oxide. The thickened pulmonary arteries of these infants may continue to restrict blood flow when they are relaxed by nitric oxide. Inflammation of the airways due to pneumonia or meconium aspiration may decrease the response to nitric oxide. Clinical study had shown the additive effect of using prostacyclin and nitric oxide.⁶ Infusion of prostacyclin may be beneficial in infants who are not responsive to nitric oxide. This requires further clinical studies.

In conclusion, our experience suggests continuous infusion of prostacyclin in the pulmonary artery is useful for treating refractory persistent pulmonary hypertension of the newborn while avoiding the complication of systemic hypotension that may be associated with intravenous infusion. It may also have the advantage of using smaller dose. Prostacyclin may be an alternative to inhaled nitric oxide if this is not available.

References

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