Inhaled nitric oxide and heparin for infantile primary pulmonary hypertension

Abstract

Primary pulmonary hypertension in infancy is a rare and progressive disease with high mortality. The predominant histological finding is medial smooth-muscle hypertrophy which progresses with time to plexiform lesions. Inhaled nitric oxide (NO) inhibits smooth muscle growth and protein synthesis in the extracellular matrix and reduces hypoxic remodelling in the rat lung. Heparin also inhibits smooth muscle growth as well as promotes angiogenesis. Four seriously ill infants less than 4 months old were referred with severe unexplained pulmonary hypertension. Patients were catheterised after wedge lung biopsy showed medial smooth-muscle hypertrophy with scattered thromboemboli in small pulmonary arteries, confirming the diagnosis of primary pulmonary hypertension. Response to NO at 80 ppm was tested while patients were mechanically ventilated. Pulmonary vascular resistance (PVR) was calculated by the Fick equation with measured oxygen consumption. PVR decreased in all, from 1392, 1560, 960, and 1592 to 360, 1232, 328, and 504 dyn.s.cm .m, respectively. PVR returned to baseline levels when NO was withdrawn during acute testing. NO was restarted at 80 ppm, rapidly weaned to 10–20 ppm, and delivered continuously along with a low-dose heparin (10 U.kg.h) infusion for 25 days. This heparin dose was selected so that the partial thromboplastin time would not be prolonged. Methaemoglobin and nitrogen dioxide concentrations were followed regularly and remained low. At the end of 25 days, NO and heparin were stopped and patients were recatheterised. Two patients had sustained reduction of PVR and the other two had further reduction in PVR compared with measurements made during acute testing with NO (1232 to 632 dyn.s.cm .m in one, 504 to 216 dyn.s.cm .m in the other). Two patients were sent home on oral nifedipine and supplementary oxygen. One was recatheterised one year later with unchanged PVR (400 dyn.s.cm .m). He has not had recurrence of pulmonary hypertension during 32 months of follow-up. The other patient has been followed by serial echocardiograms suggesting right ventricular pressure less than a half systemic value during 18 months of follow-up. Both these patients remain on nifedipine but have been weaned from oxygen. A third patient was sent home on oxygen therapy alone. He presented with signs of right heart failure and was recatheterised 6 months after initial treatment. This child had recurrence of his pulmonary hypertension (PVR 1552 dyn.s.cm .m) that was refractory to treatment with NO and intravenous prostacyclin. He died while awaiting lung transplantation. The fourth patient was discharged home on no medication with normal pulmonary artery pressures following his 25day treatment, and awaits long-term follow-up. The presumed irreversibility and lethality of primary pulmonary hypertension early in life now needs further assessment. The antioxidant, antiproliferative, and