Inhaled nitric oxide and heparin for infantile primary pulmonary hypertension

RESEARCH LETTERS

Research letters

Inhaled nitric oxide and heparin for infantile primary pulmonary hypertension Andrew M Atz, David L Wessel

Primary pulmonary hypertension in infancy is a rare and progressive disease with high mortality.1 The predominant histological finding is medial smooth-muscle hypertrophy which progresses with time to plexiform lesions.2 Inhaled nitric oxide (NO) inhibits smooth muscle growth and protein synthesis in the extracellular matrix3 and reduces hypoxic remodelling in the rat lung.4 Heparin also inhibits smooth muscle growth as well as promotes angiogenesis.5 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⫺5.m2, 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 PVR returned to baseline levels when NO was withdrawn during acute testing.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-1.h-1) 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⫺5.m2 in one, 504 to 216 dyn.s.cm⫺5.m2 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⫺5.m2). 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⫺5.m2) 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

THE LANCET • Vol 351 • June 6, 1998

antihypertensive actions of NO combined with the ability of heparin to inhibit smooth muscle hypertrophy and stimulate new vessel growth may provide a theoretical basis for prolonged treatment of primary pulmonary hypertension. This might be particularly applicable to infants who have substantial capacity for smooth muscle regression, alveolar growth, and angiogenesis. Moreover, the potential to induce accelerated maturation of the pulmonary vasculature in patients with congenital heart disease may make plausible certain surgical interventions previously thought impossible in the newborn baby. 1

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Cardelon CJ, Rylaarsdam M, Camacho L, Attie F, Zabal C, Buenida A. Primary pulmonary arterial hypertension in children under 2 years of age. Arch Inst Cardiol Mex 1991; 61: 533–37. Haworth SG. Pulmonary hypertension in childhood. Eur Respir J 1993; 6: 1037–43. Roberts JD, Roberts CT, Jones RC, Zapol WM, Bloch KD. Continuous nitric oxide inhalation reduces pulmonary arterial structural changes, right ventricular hypertrophy, and growth retardation in the hypoxic newborn rat. Circ Res 1995; 76: 215–22. Kolpakov V, Gordon D, Kulik T. Nitric oxide-generating compounds inhibit total protein and collagen synthesis in cultured vascular smooth muscle cells. Circ Res 1995; 76: 305–09. Rabinovitch M. Developmental biology of the pulmonary vasculature. In: Polin RA, Fox WW, eds. Fetal and neonatal physiology, 2nd edn. Philadelphia: WB Saunders, 1998: 913–23.

Department of Cardiology, Children’s Hospital, and the Departments of Paediatrics and Anaesthesia, Harvard Medical School, Boston, MA 02115, USA (D L Wessel)

Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients Roy Calne, Peter Friend, Susan Moffatt, Andrew Bradley, Geoff Hale, John Firth, John Bradley, Ken Smith, Herman Waldmann

Liver allografts in pigs and rats can induce tolerance; both hepatocytes and passenger bone-marrow-derived cells are necessary.1,2 Grafted livers recover spontaneously from histological and biochemical acute rejection. A short course of high-dose cyclosporin in renal allografted pigs given with donor splenocytes or donor blood resulted in “operational tolerance” with good graft function for more than 1 year in half the animals.3 These and other observations support the hypothesis that, in the absence of an aggressive T-cell response, an engagement of the immune system can lead to tolerance. Knechtle and colleagues found that T-cell depletion induced by a CD3-diphtheria immunotoxin given before renal allografting produced tolerance to renal allografts in rhesus monkeys. Prolonged donor-skin-graft survival in most of these animals was convincing evidence of a tolerant state.4 Campath 1H, a humanised anti-CD53

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