Ibrahim Gokce ( Department of Paediatrics, Erzurum District Training and Research Hospital, Erzurum, Turkey. )
Hasan Kahveci ( Nene Hatun Obstetrics and Gynaecology State Hospital, Neonatal Unit, Erzurum, Turkey. )
Zeynep Turkyilmaz ( Nene Hatun Obstetrics and Gynaecology State Hospital, Neonatal Unit, Erzurum, Turkey. )
Basak Adakli ( Nene Hatun Obstetrics and Gynaecology State Hospital, Neonatal Unit, Erzurum, Turkey. )
Cenap Zeybek ( Department of Paediatrics, Erzurum District Training and Research Hospital, Erzurum, Turkey. )
We treated 2 very low birth weight (VLBW) infants with respiratory distress syndrome suffering from refractory hypoxic respiratory failure complicated with severe pulmonary hypertension with inhaled iloprost. The first infant was an 800 gram male and the second case was a 920 gram female. Echocardiography revealed a right to left shunt through patent duct in the first case; suprasystemic pulmonary arterial pressure was estimated by using tricuspid regurgitation of moderate severity in the second case. Inhaled iloprost was started in those infants when conventional therapies including the administration of exogenous surfactant and high-frequency oscillatory ventilation failed. After the commencement of therapy, the clinical condition of the infants improved dramatically. Pulmonary arterial pressure returned to normal levels within five days. We suggest that inhaled iloprost may be helpful by improving oxygenation and reducing the need for aggressive mechanical ventilation in some cases of severe hypoxaemic respiratory failure in VLBW infants.
Keywords: Refractory hypoxic respiratory failure, Inhaled iloprost, Echocardiography, Exogenous surfactant.
Pulmonary artery hypertension (PAH) in preterm infants is characterized by an altered vasoreactivity with a marked pulmonary hypertension, which can lead to a right-to-left shunting of blood across the patent ductus arteriosus and foramen ovale. Preterm neonates with respiratory distress syndrome (RDS) may have elevated pulmonary vascular resistance soon after birth and this may be related to underdevelopment, including a decrease in the cross-sectional area and an abnormal muscularization of the pulmonary vasculature.1 In the clinical setting, the preterm or very low birth weight (VLBW) infant may manifest severe hypoxaemia, even after initial improvement following endotracheal surfactant instillation. This hypoxaemia often can be prolonged and unresponsive to conventional medical treatment and increasing respiratory support. Pulmonary artery hypertension may be a possible explanation and has been reported in preterm infants with RDS by many investigators.2
Inhaled iloprost recently has been introduced in the treatment of pulmonary hypertension, especially in adults. Iloprost is a stable prostacycline (PGI2) analogue with vasodilatory, anti-inflammatory and vascular remodeling properties. The systemic use of iloprost has been limited for causing hypotension in children and adults. Similar to nitric oxide (NO), when used by the inhaled route it selectively dilates pulmonary vessels and improves oxygenation.3 A few case reports have demonstrated the effectiveness and safety of inhaled iloprost in preterm infants, including extremely preterm ones and term infants with persistent pulmonary hypertension (PPHN) refractory to inhaled NO (iNO).3-8 Currently the use of inhaled iloprost has not been approved for premature neonates, and its therapeutic efficacy in this group remains controversial. Herein, we report the use of inhaled iloprost in treating pulmonary hypertension in two VLBW infants with RDS unresponsive to conventional treatment.
An 800 gram male infant was delivered spontaneously at 27 weeks gestation. Apgar scores were 5 at 1 minute and 8 at 5 minutes. The infant developed respiratory distress and required intubation in the first hour. Chest radiography on admission showed diffuse opacities in both lung fields, but laboratory findings were normal. The diagnosis was RDS and surfactant was applied 2 hours after birth. Initially, sufficient oxygenation was achieved on conventional ventilation, with approximately 40-50% inspired oxygen (FiO2). At the age of 8 hours, the patient deteriorated rapidly. Systemic arterial hypotension developed and in spite of increasing the inspired oxygen to 100% with conventional ventilation, the transcutaneous oxygen saturation (SaO2) decreased to 62%. We commenced high-frequency oscillatory ventilation (HFOV) with 100% oxygen. Surfactant was repeated 8 hours after birth. High dose vasopressors had been used for systemic hypotension. Treatment with surfactant, hyperventilation, and the elevation of systemic blood pressure had failed to improve oxygenation (SaO2 65-70%). Patient had an arterial oxygen tension (PaO2) / FiO2 ratio <60 despite optimum ventilator settings during at least 16 hours (Table). His clinical course was consistent with pulmonary hypertension. Echocardiography revealed a right to left shunt over a patent arterial duct (Figure-1).
Inhaled iloprost was started at a dose of 1 mcg/kg for each inhalation with 120-minute periods between inhalations. Iloprost was diluted with sodium chloride and administered endotracheally by an ultrasonic nebulizer integrated into the ventilator system. Oxygen saturation was normalized within 12 hours (SaO2 >90%). Control echocardiography the following day showed a complete conversion of right to left ductal shunting. Pulmonary artery systolic pressure was measured as 40 mmHg while systemic pressure was 70 mmHg. On the third day, the pulmonary to systemic pressure ratio decreased under the ratio of ½. The administration of iloprost decreased the oxygenation index (OI; ((FiO2 x mean airway pressure)/PaO2) x 100) from 44.23 to 3.4 and increased the ratio of PaO2 to FiO2 from 52 to 286 (Table).
The dose of iloprost was halved and then stopped on the fourth day. Echocardiography revealed normal pulmonary artery pressure on the fifth day and the patient began to be weaned from the ventilator. Clinical, haematologic, biochemical and radiological studies before discharge from the neonatal intensive care unit did not reveal any side effects.of iloprost.
A 920 gram female infant was delivered by emergency caesarean section for uncontrolled hypertension and spontaneous premature rupture of membranes at 28 weeks gestation. The mother had not received any antibiotics during pregnancy. The infant developed respiratory distress soon after birth. Chest x-ray revealed hazy, ground glass opacities consistent with RDS. Surfactant was applied. Despite effective conventional ventilation, her clinical condition deteriorated within hours. Oxygen saturation decreased to 60% with 100% FiO2. The systemic arterial blood pressure was 35 mmHg at the same time. Treatment with a second dose of surfactant, high frequency oscillation and elevation of systemic blood pressure to 68 mmHg had failed to improve oxygenation (SaO2 remained below 70%). The PaO2/FiO2 ratio was below 60 despite optimum ventilator settings during at least 16 hours (Table). Echocardiography on the second day of life revealed tricuspid regurgitation of moderate severity. Pulmonary artery systolic pressure calculated by using tricuspid regurgitation jet was 77 mmHg (Figure-2).
Suprasystemic pulmonary arterial hypertension was diagnosed and inhaled iloprost was started at a dose 1 mcg/kg. Oxygen saturation increased to 90% after the commencement of treatment. Pulmonary artery systolic pressure at control echo was measured as 47 mmHg while systemic pressure was 70 mmHg. On the third day, pulmonary arterial pressure was 24 mmHg. Inhaled iloprost therapy decreased the OI from 44.23 to 4.5 and increased the PaO2/ FiO2 ratio from 52 to 243 (Table). The dose of iloprost was halved and then stopped on the fourth day. The patient was weaned from the ventilator on the sixth day. The post-weaning period was non-eventful. We observed no side effects on blood pressure or on homeostasis.
Our clinical experience indicates that inhaled iloprost is a promising therapy for pulmonary hypertension unresponsive to conventional treatment in VLBW infants. In view of our findings, we believe that further studies with larger group should be conducted to fully elucidate the safety and efficacy of inhaled iloprost in comparison with other vasodilator drugs in VLBW infants.
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