Nitric Oxide

The main effect of nitric oxide (NO) is smooth muscle relaxation by increasing intracellular cGMP. Vasodilation mainly occurs in areas that are adequately ventilated causing blood to shunt away from poorly ventilated areas [119]. Its use in ARDS may therefore be considered to reduce ventilation/perfusion mismatch by reducing dead space ventilation and, thereby, improving oxygenation. The clinical response to iNO has been reported in various (individual) case series, demonstrating a rapid improvement in oxygenation even with a concentration as low as 1 part per million (ppm) [1, 111, 129, 138]. Day and co-workers compared the effects of 10 ppm iNO in ten paediatric patients with acute bilateral lung disease requiring a positive end-expiratory pressure (PEEP) > 6 cmH₂O and a fraction of inspired oxygen (FiO₂) > 0.5 for > 12 h with 12 control patients [38]. Although there was an immediate, but unsustained improvement in pulmonary vascular resistance and systemic oxygenation defined by the OI, no beneficial effect on mortality was observed although this study was not designed to assess mortality. Dobyns et al. performed a prospective, multicentre, placebo-controlled RCT of 108 children > 1 month of age with severe acute hypoxaemic respiratory failure (i.e. OI > 15) randomised to iNO 10 ppm (N = 53 children) or control (N = 55) [43]. Patients with a congenital heart defect or after cardiac surgery were not included in this study, and nearly half of the patients suffered from underlying diseases (i.e. chronic lung disease or immunodeficiency). The positive effect of iNO on oxygenation was confirmed in just about half of the patients. Mortality was comparable between the two groups, although again this trial was also not designed to assess this. Subgroup analysis revealed a possible beneficial effect of iNO in immunocompromised patients and those with severe hypoxaemia (i.e. OI > 25), although the small sample size in these analyses precludes the robustness of these findings. Ibrahim et al. randomised 32 children aged 2 months-10 years with severe ARDS (PaO₂/FiO₂ < 200 mmHg, positive inspiratory pressure > 30 cmH₂O and a FiO₂ > 0.5) to one of the three groups: (1) 24 h of iNO at 5 ppm in the prone position, (2) 24 h of iNO at 5 ppm in the supine position or (3) no iNO in the prone position [73]. In line with the two other studies, these investigators observed a significant improvement in oxygenation, but not in mortality. It may thus be concluded that although iNO improves oxygenation in PARDS, it does not positively affect patient outcomes. This conclusion is strengthened by the outcome of a Cochrane analysis of 604 children and adults with ARDS [3]. Oxygenation was improved, but there was no improvement in mortality, duration of mechanical ventilation, ventilator- free days or length of intensive care unit (ICU) or hospital stay in the iNO cohort [3]. Additionally, there appeared to be an increased occurrence of renal impairment in patients managed with iNO. Therefore, the use of iNO for PARDS should only be considered in patients with documented pulmonary hypertension or severe right ventricular dysfunction [99]. In patients with intractable hypoxaemia, iNO may be considered as rescue therapy from or as a bridge to extracorporeal life support (ECLS).