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April 1997
Inhaled Nitric Oxide in Full-Term and Nearly Full-Term Infants with Hypoxic Respiratory Failure.
The Neonatal Inhaled Nitric Oxide Study Group
The New England Journal of Medicine 1997;336:597-604.
Roberts JD, Fineman JR,
Morin FC, Shaul PW, Rimar S, Schreiber MD, Polin RA, Zwass MS, Zayek MM,
Gross I, Heymann MA, Zapol WM.
New England Journal of Medicine1997; 336:605-610.
[ see abstract below ]
Two original articles appeared back-to-back in the New England Journal, both dealing with clinical applications of nitric oxide in the treatment of newborn infants with pulmonary hypertension related to respiratory failure. These articles are remarkably parallel in nature and arrive at similar conclusions and recommendations related to the evolving practice of administering inhaled nitric oxide therapeutically to infant patients. It is now recognized that inhaled nitric oxide is a selective pulmonary vasodilator.
Many have assumed that appropriate relief of pulmonary hypertension would result in improved oxygenation and decreased mortality in the newborn. Both these studies reflected controlled trials of inhaled nitric oxide in patients with pulmonary hypertension, examining a variety of physiologic features, but primarily focusing upon the effects of inhaled nitric oxide on (a) systemic oxygenation, (b) the requirements for extracorporeal membrane oxygenation (ECMO), and (c) mortality.
Although some debate exists regarding the maximal effective concentration of nitric oxide which may be used in the treatment of pulmonary hypertension, both studies used concentrations sufficient to produce a pharmacologic effect. Both studies conclude that inhaled nitric oxide improves systemic oxygenation in these patients, that it may reduce the need in some cases for extracorporeal membrane oxygenation, that it offers no apparent benefit affect on mortality (vs. patients treated with ECMO), and that, under the conditions described in both studies, it does not produce significant hypotension or metabolic toxicity. In both studies, it is reported that nitric oxide treatment can be relatively safe in critically ill patients.
Additionally, these studies provide a more objective basis for some intuitive recommendations for practice in the use of nitric oxide in this patient population, as well as serving to formulate avenues for focused future research. In one study the suggestion is made that greater advantages with nitric oxide administration may accrue to those patients who are initiated earlier in this therapy. It is emphasized that nitric oxide therapy should not be delayed until the time an infant�s condition is highly unstable.
The first article recommend that �Appropriate support by conventional means, including the use of surfactant and high-frequency ventilation by experienced practitioners, should precede the administration of inhaled nitric oxide. If such management does not lead to improvement, however, treatment with nitric oxide, whether there is echocardiographic evidence of pulmonary hypertension or not, will substantially reduce the number of infants who receive extracorporeal membrane oxygenation.�
Additionally, the authors of the second article emphasize an advantage of nitric oxide over ECMO in that while extracorporeal membrane oxygenation may save the lives of some newborn infants with severe systemic hypoxemia, �it is invasive, expensive, and unavailable in many intensive care units, and is associated with substantial morbidity.�
Both these articles tend to help define the relative role of nitric oxide as another modality in the continued efforts improve the high mortality rate associated neonatal pulmonary hypertension.
Return to the Current Literature Review Front Page, or read the abstract:
ABSTRACT: The Neonatal Inhaled Nitric Oxide Study Group
Background: Neonates with pulmonary hypertension have been treated with inhaled nitric oxide because of studies suggesting that it is a selective pulmonary vasodilator. We conducted a randomized, multicenter, controlled trial to determine whether inhaled nitric oxide would reduce mortality or the initiation of extracorporeal membrane oxygenation in infants with hypoxic respiratory failure.
Methods: Infants born after a gestation of >34 weeks who were 14 days old or less, had no structural heart disease, and required assisted ventilation and whose oxygenation index was 25 or higher on two measurements were eligible for the study. The infants were randomly assigned to receive nitric oxide at a concentration of 20ppm or 100 percent oxygen (as a control). Infants whose partial pressure of arterial oxygen (PaO2) increased by 20 mm Hg or less after 30 minutes were studied fro a response to 80-ppm nitric oxide or control gas.
Results: The 121 infants in the control group and the 114 in the nitric oxide group had similar base-line clinical characteristics. Sixty-four percent of the control group and 46 percent of the nitric oxide group died within 120 days or were treated with extracorporeal membrane oxygenation (P=0.006). Seventeen percent of the control group and 14 percent of the nitric oxide group died (P not significant), but significantly fewer in the nitric oxide group received extracorporeal membrane oxygenation (39 percent vs. 54 percent, P=0.014). The nitric oxide group had significantly greater improvement in PaO2 (mean [+SD) increase, 58.2 +/-85.2 mm Hg, vs. 9.7+/-51.7 mm Hg in the controls; P<0.001) and in the oxygenation index (a decrease of 14.1+/-21.1, vs. an increase of 0.8+/-21.1 in the controls; P<0.001). The study gas was not discontinued in any infant because of toxicity.
Conclusions: Nitric oxide therapy reduced the use of extracorporeal membrane oxygenation, but had no apparent effect on mortality, in critically ill infants with hypoxic respiratory failure.
ABSTRACT: Roberts JD et al
Background: Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension.
Methods: In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used.
Results: Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P=0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase in methemoglobin levels.
Conclusions: Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatment.
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