Elsevier

The Lancet

Volume 356, Issue 9240, 28 October 2000, Pages 1464-1469
The Lancet

Articles
Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study

https://doi.org/10.1016/S0140-6736(00)02869-5Get rights and content

Summary

Background

Pulmonary hypertensive crises (PHTC) are a major cause of morbidity and mortality after congenital heart surgery. Inhaled nitric oxide is frequently used as rescue therapy. We did a randomised double-blind study to investigate the role of routinely administered inhaled nitric oxide to prevent pulmonary hypertension in infants at high risk.

Methods

We enrolled 124 infants (64 male, 60 female; median age 3 months [IQR 1–5]), 76% with large ventricular or atrioventricular septal defects, who had high pulmonary flow, pressure, or both, and were undergoing corrective surgery for congenital heart disease. They were randomly assigned continuous low-dose inhaled nitric oxide (n=63) or placebo (n=61) from surgery until just before extubation. We measured the numbers of PHTC, time on study gas, and hours spent in intensive care. Analysis was done by intention to treat.

Findings

Compared with placebo, infants receiving inhaled nitric oxide had fewer PHTC (median four [IQR 0–12] vs seven [1–19]; relative risk, unadjusted 0·66, p<0·001, adjusted for dispersion 0·65, p=0·045) and shorter times until criteria for extubation were met (80 [38–121] vs 112 h [63–164], p=0·019). Time taken to wean infants off study gas was 35% longer in the nitric oxide group than in the placebo group (p=0·19), but the total time on the study gas was still 30 h shorter for the nitric oxide group (87 [43–125] vs 117 h [67–168], p=0·023). No important toxic effects arose.

Interpretation

In infants at high risk of pulmonary hypertension, routine use of inhaled nitric oxide after congenital heart surgery can lessen the risk of pulmonary hypertensive crises and shorten the postoperative course, with no toxic effects.

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.

Section snippets

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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