Review question
We reviewed the evidence on the effectiveness of inhaled nitric oxide for treatment of high blood pressure in the pulmonary vessels in infants and children born with heart disease.
Background
Pulmonary hypertension (PH) is an increase in blood pressure in the pulmonary vessels that affects various patient populations and can cause poor health and a significant number of deaths. PH can reduce cardiac function and precipitate a life-threatening crisis. Congenital heart disease (CHD) is a structural deformity of the heart that exists at birth, and often before birth. PH may arise because of increased pulmonary blood flow and persistent raised pulmonary arterial pressures, or following the use of cardiopulmonary bypass during surgical repair. Inhaled nitric oxide (iNO) is a therapy which causes a selective reduction in the high blood pressure of the pulmonary vessels without decreasing blood pressure in the rest of the body and, therefore, may have a treatment benefit in children with heart disease. In this review, we aimed to assess the benefits and harms of using iNO for postoperative management of PH in children with CHD.
Study characteristics
The evidence was current to December 2013. We found four randomized clinical trials involving 210 participants aged from one day to 17 years with PH either in the preoperative (one study) or postoperative period (three studies). Control groups received conventional management therapy (two trials) or nitrogen gas as placebo (two trials). Two trials compared changes in systemic and pulmonary arterial blood pressure and heart rate (haemodynamics). The other two trials compared the number of pulmonary hypertensive crises and deaths, with changes in haemodynamic measurements as secondary outcomes.
Key results
We found no differences between the groups of patients who received iNO and those that did not. Two trials reported on deaths before discharge, with none occurring in one of the trials. We observed no differences in the number of deaths (two trials); pulmonary hypertensive crises (one trial); changes in mean pulmonary arterial pressure (three trials), arterial pressure (three trials), or heart rate (HR) (three trials); or changes in oxygenation of the blood (one trial). However, no trials reported long-term deaths or neurodevelopmental disability. In addition, no data were available for analysis of length of hospital stay.
Although iNO has been studied as a postsurgical therapy in children with heart disease in order to assist recovery, this review showed no benefits with its use.
Quality of the evidence
Two trials had a low risk of bias. The quality of the evidence was, however, very low due to the small number of participants and low event rates. All trials utilized different concentrations of iNO, different durations of administration initiated at different times after the operation, and included patients with diverse congenital heart defects necessitating repair.
We observed no differences with the use of iNO in the outcomes reviewed. No data were available for several clinical outcomes including long-term mortality and neurodevelopmental outcome. We found it difficult to draw valid conclusions given concerns regarding methodologic quality, sample size, and heterogeneity.
Nitric oxide (NO) is a prevalent molecule in humans that is responsible for many physiologic activities including pulmonary vasodilation. An exogenous, inhaled form (iNO) exists that mimics this action without affecting systemic blood pressure. This therapy has been implemented in the treatment of pulmonary hypertension. This review examines the efficacy of iNO in the postoperative management of infants and children with congenital heart disease (CHD). The original review was published in 2005, updated in 2008 and again in 2014.
To compare the effects of postoperative administration of iNO versus placebo or conventional management, or both, on infants and children with CHD and pulmonary hypertension. The primary outcome was mortality. Secondary outcomes included length of hospital stay; neurodevelopmental disability; number of pulmonary hypertensive crises (PHTC); changes in mean pulmonary arterial pressure (MPAP), mean arterial pressure (MAP), and heart rate (HR); changes in oxygenation measured as the ratio of arterial oxygen tension (PaO2) to fraction of inspired oxygen (FiO2); and measurement of maximum methaemoglobin level as a marker of toxicity.
In this updated version we extended the CENTRAL search to 2013, Issue 12 of The Cochrane Library, and MEDLINE and EMBASE through to 1 December 2013. The original search was performed in July 2004 and again in November 2007. We included abstracts and all languages.
We included randomized and quasi-randomized controlled trials comparing iNO with placebo or conventional management, or both. Trials included only children with CHD requiring surgery complicated by pulmonary hypertension.
Two authors extracted data. Data were collected on mortality; number of PHTC; changes in MPAP, MAP, HR, and PaO2:FiO2; and maximum methaemoglobin level. Data on long-term mortality, neurodevelopmental disability, and length of hospital stay were unavailable. We performed subgroup analysis by method of control (placebo or conventional management).
We reran the searches to December 2013 and identified three new studies. These three studies did not fulfil our inclusion criteria. Therefore, no new studies were included in this updated review. In total four randomized trials involving 210 participants were included in this review. We observed no differences in mortality (OR 1.67, 95% CI 0.38 to 7.30; P = 0.50); PHTC (OR 0.80, 95% CI 0.15 to 4.18; P = 0.79); changes in MPAP (treatment effect -2.94 mm Hg, 95% CI -9.28 to 3.40; P = 0.36), MAP (treatment effect -3.55 mm Hg, 95% CI -11.86 to 4.76; P = 0.40), HR (treatment effect 0.02 bpm, 95% CI -8.13 to 8.18; P = 1.00), or PaO2:FiO2 (mean difference 17.18, 95% CI -28.21 to 62.57; P = 0.46). There was a significant increase in the methaemoglobin level (mean difference 0.30%, 95% CI 0.24 to 0.36; P < 0.00001) in patients treated with iNO, although levels did not reach toxicity levels. Data from long-term mortality, neurodevelopmental disability, and length of stay were not available. Two trials had a low risk of bias. Very low quality of the evidence was observed considering grading of the outcomes.