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Nitric oxide (NO) is a major regulator of vascular smooth muscle tone. Generated enzymatically by one of several NO synthases from L-arginine,1 NO activates guanylyl cyclase by binding to its haem component,2 leading to the production of cyclic GMP.3 4 This then relaxes vascular and bronchial smooth muscle by a mechanism which probably involves inhibition of an activation induced increase in cytosolic calcium concentration.5 NO has a high affinity for the iron of haem proteins, including reduced haemoglobin, forming nitrosyl haemoglobin (NOHb), which is then oxidised to methaemoglobin with the production of nitrate.6 7 As a result, when given as an inhalation, NO relaxes pulmonary vascular smooth muscle and is inactivated without altering the systemic vascular bed. NO mediates the reduction in pulmonary vascular resistance associated with birth.8-10 Inhalation of NO, in a variety of animal models, is an effective, selective pulmonary vasodilator which improves ventilation perfusion matching.11 12 In adults with severe respiratory distress syndrome treatment with inhaled nitric oxide (INO) reduced pulmonary arterial pressure and increased oxygenation secondary to a decrease in intrapulmonary shunting,13 with an improvement in oxygenation and a reduction in pulmonary vascular resistance (PVR) noted at INO doses as low as 1 ppm.14 15 The clinical use of INO in neonates has mushroomed since the original reports by Roberts16 and Kinsella17 which demonstrated sustained improvements in oxygenation in hypoxic near term infants with persistent pulmonary hypertension (PPHN), using 80 ppm and 20 ppm of INO, respectively. A subsequent preliminary dosing study did not demonstrate a significant dose effect in hypoxic neonates.18
Prospective controlled trials in neonates
As a result of these observations, a multicentre, multinational, prospective placebo controlled randomised trial was conducted to evaluate whether INO would reduce the incidence of death or the need for ECMO in …