ArticlesInhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study
Introduction
Pulmonary hypertension is a major complication of surgery for congenital heart disease.1 The hallmark of this disorder in the early postoperative period is pulmonary hypertensive crisis (PHTC), characterised by an acute rise in pulmonary vascular resistance, which initiates a cycle of right-ventricular failure and poor cardiac output. If left untreated, cardiac arrest and death may follow.2 Despite traditional interventions, including parenterally administered vasodilators, hyperoxic hyperventilation, induced alkalosis, and inotropic support,3 the morbidity and mortality associated with PHTC remain unacceptably high.1
Advances in understanding the control of vasomotor tone have highlighted the role of endothelium-derived nitric oxide as a key vasodilator substance.4, 5 Basal release of endogenous nitric oxide by the pulmonary endothelium seems to be fundamental to constant active vasodilation in this circulation.6 Failure of nitric oxide bioavailability arises in children with congenital left-to-right shunt lesions, and this pre-existing endothelial dysfunction might be further exacerbated by congenital heart surgery.7, 8, 9 This postoperative deficiency of pulmonary nitric oxide availability might, therefore, be pathogenically linked to PHTC.
Inhaled nitric oxide is a selective pulmonary vasodilator that acts directly on pulmonary vascular smooth muscle but has no systemic effects, since it is rapidly inactivated when exposed to haemoglobin.10 We and others have previously reported the efficacy and safety of short-term inhaled nitric oxide in children with clinically apparent PHTC after corrective cardiac surgery.11, 12 Despite this treatment's apparent promise, complications (such as rebound pulmonary hypertension after inhaled nitric oxide being stopped13) have been reported. We aimed, therefore, in a prospective, randomised, double-blind, placebo-controlled trial, to study the routine use of inhaled nitric oxide after high-risk corrective congenital heart surgery and to assess its role in the prevention of pulmonary hypertension.
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Patients
Eligible patients were sequentially presenting infants suitable for corrective heart sugery with high pulmonary flow, pressure, or both, congenital heart lesions, such as non-restrictive ventricular septal defect, complete atrioventricular septal defect, truncus arteriosus, or total anomalous pulmonary venous drainage, with objective evidence of pulmonary hypertension at the immediate preoperative assessment. Pulmonary hypertension was defined as a mean pulmonary artery pressure higher than 25
Results
124 (95%) of 130 eligible infants were randomised at the start of surgery; the other six were excluded because parental consent could not be obtained. Baseline characteristics were similar for the two groups (table 2).
Infants who received inhaled nitric oxide had significantly fewer PHTC than those receiving placebo (median four [IQR 0–12] vs seven [1–19]; unadjusted relative risk 0·66 [95%CI 0·59–0·74] p<0·001; adjusted for dispersion 0·65 [0·43–0·99], p=0·045; figure 2).
The median time to
Discussion
Congenital heart disease is present in five to ten per 1000 livebirths.21 If surgery is required, the most common lesions (such as ventricular septal defect and atrioventricular septal defect) are characterised by raised pulmonary blood flow, pulmonary artery pressure, or both, which result in a high risk of potentially life-threatening postoperative PHTC.22
Children with high pulmonary flow, pressure, or both have impaired endothelium-dependent vasodilatation in the pulmonary circulation, which
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