Inhaled NO for Preterm Infants — Getting to Yes?
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《新英格兰医药杂志》
Preterm birth, especially at an extremely low gestational age, is often perilous. Despite improved survival associated with contemporary neonatal intensive care, more than one third of survivors with a birth weight of less than 1250 g have bronchopulmonary dysplasia (also known as chronic lung disease of prematurity), usually defined as a need for supplemental oxygen at 36 weeks of postmenstrual age. At least 10 to 15 percent of these infants also show ultrasonographic evidence of brain injury in the neonatal period. The two conditions often coexist and are associated with impaired neurodevelopment.
The majority of infants born at an extremely low gestational age require mechanical ventilation during the first week after birth as a result of impaired gas exchange or immature respiratory control; prolonged ventilation is associated with worse outcomes. Although the cause of bronchopulmonary dysplasia is multifactorial, lung inflammation associated with mechanical injury is thought to contribute, suggesting that a minimization of exposure to assisted ventilation by an improvement in gas exchange would improve outcome.
Selective pulmonary vasodilatation with inhaled nitric oxide improves oxygenation and reduces the need for extracorporeal membrane oxygenation in term infants with persistent pulmonary hypertension. Initial reports showed that inhaled nitric oxide improved oxygenation in preterm infants with severe respiratory failure1 and with developing or established bronchopulmonary dysplasia2,3 and suggested that early treatment may decrease the risk of lung injury.1 Subsequent work in animals found that inhaled nitric oxide reduces lung inflammation,4 improves surfactant function,5 attenuates hyperoxic lung injury,6 and promotes lung growth.7,8 These findings offered hope that the use of inhaled nitric oxide in preterm infants might lead to pulmonary benefit, perhaps through mechanisms independent of pulmonary vasodilatation.
Unfortunately, most trials in critically ill preterm infants have not shown that inhaled nitric oxide will prevent bronchopulmonary dysplasia. Among these trials was a large multicenter study by Van Meurs et al.,9 which showed no significant reduction in rates of death or bronchopulmonary dysplasia with inhaled nitric oxide in preterm infants with a birth weight of less than 1500 g. An important exception is a single-center study by Schreiber et al.10 showing a reduction in the combined outcome of death and bronchopulmonary dysplasia in preterm infants treated with inhaled nitric oxide (relative risk, 0.76; 95 percent confidence interval, 0.60 to 0.97), although these infants had less severe respiratory failure than did those in the study by Van Meurs et al. Treated infants also had a reduced incidence of brain injury, as detected on ultrasonography, and at follow-up at two years of age had a better neurodevelopmental outcome than did infants in a control group.11 The control-group infants, however, had rates of bronchopulmonary dysplasia and brain injury that were somewhat higher than expected.
Although the initiation or exacerbation of hemorrhagic or ischemic brain injury by inhaled nitric oxide was not reported by Schreiber et al., it remains a concern in this vulnerable population. Van Meurs et al. showed no overall increase in the risk of severe intracranial hemorrhage among infants treated with inhaled nitric oxide, but in a post hoc analysis, the rates of severe intracranial hemorrhage and death were increased in treated infants with a birth weight of 1000 g or less.
In this issue of the Journal, Kinsella et al.12 and Ballard et al.13 report on two large trials of inhaled nitric oxide in preterm infants. Both studies enrolled infants with birth weights of 500 to 1250 g who were at high risk for lung and brain injury. Although the limit on gestational age differed slightly (34 weeks or less in the study by Kinsella et al. and 32 weeks or less in the study by Ballard et al.), the average gestational age of enrolled infants was nearly the same. In the trial by Kinsella et al., infants who were less than 48 hours of age and receiving mechanical ventilation were randomly assigned to receive inhaled nitric oxide at a dose of 5 ppm or nitrogen placebo for 21 days or until they no longer required mechanical ventilation. Consistent with most other trials,9 the results indicated no overall difference between groups in the combined primary outcome (death or bronchopulmonary dysplasia), which occurred in approximately three quarters of the infants. In prespecified subgroup analyses stratified by birth weight, inhaled nitric oxide treatment reduced the combined primary outcome and bronchopulmonary dysplasia alone in infants with a birth weight of 1000 to 1250 g; however, this group accounted for only 16 percent of the infants who would have had a much lower risk of this outcome than would smaller infants. Overall, a secondary outcome — ultrasonographic evidence of brain injury (severe intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly) — was reduced in the treated group (17.5 percent vs. 23.9 percent; relative risk, 0.73; 95 percent confidence interval, 0.55 to 0.98).
In contrast to this and other trials in which nitric oxide treatment was initiated soon after birth, Ballard et al. enrolled infants who were ventilator-dependent at 7 to 21 days of age; infants in the lowest birth-weight group were also eligible if they were receiving continuous positive airway pressure. Infants were randomly assigned to a 24-day course of nitrogen placebo or inhaled nitric oxide at an initial dose of 20 ppm for 48 to 96 hours, with the dose reduced at weekly intervals to 10, 5, and 2 ppm. Nitric oxide treatment improved survival at 36 weeks of postmenstrual age without bronchopulmonary dysplasia (43.9 percent vs. 36.8 percent) and reduced the duration of oxygen therapy and hospitalization. In a post hoc analysis, the improvement in primary outcome was limited to infants who were 7 to 14 days of age at randomization (approximately 40 percent of the total). No differences were noted in complications of prematurity, including cranial ultrasonographic findings.
Does inhaled nitric oxide have a role in the treatment of preterm infants with respiratory failure? In the most critically ill infants with extremely low birth weights,9 inhaled nitric oxide does not appear to improve survival or bronchopulmonary dysplasia, and since such treatment may be associated with brain injury or increased mortality in some groups, it cannot be recommended. The two reports in this issue of the Journal suggest the possibility of benefit in less critically ill infants, but questions remain. The most effective dose, duration, and time of initiation and the selection of infants most likely to benefit remain uncertain. The finding of no progression13 and perhaps a reduction in the risk of cranial abnormalities on ultrasonography12 is reassuring; yet the pathogenesis of injury in the developing brain is complex,14 and infants with extremely low birth weights who have normal findings on cranial ultrasonography remain at high risk for cerebral palsy and delayed mental development.15 Long-term follow-up is essential, particularly given the experience with postnatal dexamethasone treatment, which conferred short-term benefit but then increased the risk of later neurodevelopmental impairment. Furthermore, inhaled nitric oxide is among the most expensive drugs available for children ($3,000 per day and up to $12,000 for a 30-day period) and is difficult to justify until benefit is proven. For these reasons, getting to yes on inhaled nitric oxide in preterm infants awaits more data, especially longer-term follow-up of children in the studies by Kinsella et al. and Ballard et al. In the meantime, the use of inhaled nitric oxide in this setting should be limited to clinical trials.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Section of Neonatology, the Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston.
References
Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial. Lancet 1999;354:1061-1065.
Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics 1999;103:610-618.
Clark PL, Ekekezie II, Kaftan HA, Castor CA, Truog WE. Safety and efficacy of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2002;86:F41-F45.
Kang JL, Park W, Pack IS, et al. Inhaled nitric oxide attenuates acute lung injury via inhibition of nuclear factor-kappa B and inflammation. J Appl Physiol 2002;92:795-801.
Ballard PL, Gonzales LW, Godinez RI, et al. Surfactant composition and function in a primate model of infant chronic lung disease: effects of inhaled nitric oxide. Pediatr Res 2006;59:157-162.
Cotton RB, Sundell HW, Zeldin DC, et al. Inhaled nitric oxide attenuates hyperoxic lung injury in lambs. Pediatr Res 2006;59:142-146.
McCurnin DC, Pierce RA, Chang LY, et al. Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease. Am J Physiol Lung Cell Mol Physiol 2005;288:L450-L459.
Tang JR, Markham NE, Lin YJ, et al. Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor. Am J Physiol Lung Cell Mol Physiol 2004;287:L344-L351.
Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 2005;353:13-22.
Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 2003;349:2099-2107.
Mestan KKL, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 2005;353:23-32.
Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 2006;355:354-364.
Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 2006;355:343-353.
Haynes RL, Baud O, Kinney HC, Volpe JJ, Folkerth DR. Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol 2005;15:225-233.
Laptook AR, O'Shea TM, Shankaran SS, Bhaskar B. Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents. Pediatrics 2005;115:673-680.(Ann R. Stark, M.D.)
The majority of infants born at an extremely low gestational age require mechanical ventilation during the first week after birth as a result of impaired gas exchange or immature respiratory control; prolonged ventilation is associated with worse outcomes. Although the cause of bronchopulmonary dysplasia is multifactorial, lung inflammation associated with mechanical injury is thought to contribute, suggesting that a minimization of exposure to assisted ventilation by an improvement in gas exchange would improve outcome.
Selective pulmonary vasodilatation with inhaled nitric oxide improves oxygenation and reduces the need for extracorporeal membrane oxygenation in term infants with persistent pulmonary hypertension. Initial reports showed that inhaled nitric oxide improved oxygenation in preterm infants with severe respiratory failure1 and with developing or established bronchopulmonary dysplasia2,3 and suggested that early treatment may decrease the risk of lung injury.1 Subsequent work in animals found that inhaled nitric oxide reduces lung inflammation,4 improves surfactant function,5 attenuates hyperoxic lung injury,6 and promotes lung growth.7,8 These findings offered hope that the use of inhaled nitric oxide in preterm infants might lead to pulmonary benefit, perhaps through mechanisms independent of pulmonary vasodilatation.
Unfortunately, most trials in critically ill preterm infants have not shown that inhaled nitric oxide will prevent bronchopulmonary dysplasia. Among these trials was a large multicenter study by Van Meurs et al.,9 which showed no significant reduction in rates of death or bronchopulmonary dysplasia with inhaled nitric oxide in preterm infants with a birth weight of less than 1500 g. An important exception is a single-center study by Schreiber et al.10 showing a reduction in the combined outcome of death and bronchopulmonary dysplasia in preterm infants treated with inhaled nitric oxide (relative risk, 0.76; 95 percent confidence interval, 0.60 to 0.97), although these infants had less severe respiratory failure than did those in the study by Van Meurs et al. Treated infants also had a reduced incidence of brain injury, as detected on ultrasonography, and at follow-up at two years of age had a better neurodevelopmental outcome than did infants in a control group.11 The control-group infants, however, had rates of bronchopulmonary dysplasia and brain injury that were somewhat higher than expected.
Although the initiation or exacerbation of hemorrhagic or ischemic brain injury by inhaled nitric oxide was not reported by Schreiber et al., it remains a concern in this vulnerable population. Van Meurs et al. showed no overall increase in the risk of severe intracranial hemorrhage among infants treated with inhaled nitric oxide, but in a post hoc analysis, the rates of severe intracranial hemorrhage and death were increased in treated infants with a birth weight of 1000 g or less.
In this issue of the Journal, Kinsella et al.12 and Ballard et al.13 report on two large trials of inhaled nitric oxide in preterm infants. Both studies enrolled infants with birth weights of 500 to 1250 g who were at high risk for lung and brain injury. Although the limit on gestational age differed slightly (34 weeks or less in the study by Kinsella et al. and 32 weeks or less in the study by Ballard et al.), the average gestational age of enrolled infants was nearly the same. In the trial by Kinsella et al., infants who were less than 48 hours of age and receiving mechanical ventilation were randomly assigned to receive inhaled nitric oxide at a dose of 5 ppm or nitrogen placebo for 21 days or until they no longer required mechanical ventilation. Consistent with most other trials,9 the results indicated no overall difference between groups in the combined primary outcome (death or bronchopulmonary dysplasia), which occurred in approximately three quarters of the infants. In prespecified subgroup analyses stratified by birth weight, inhaled nitric oxide treatment reduced the combined primary outcome and bronchopulmonary dysplasia alone in infants with a birth weight of 1000 to 1250 g; however, this group accounted for only 16 percent of the infants who would have had a much lower risk of this outcome than would smaller infants. Overall, a secondary outcome — ultrasonographic evidence of brain injury (severe intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly) — was reduced in the treated group (17.5 percent vs. 23.9 percent; relative risk, 0.73; 95 percent confidence interval, 0.55 to 0.98).
In contrast to this and other trials in which nitric oxide treatment was initiated soon after birth, Ballard et al. enrolled infants who were ventilator-dependent at 7 to 21 days of age; infants in the lowest birth-weight group were also eligible if they were receiving continuous positive airway pressure. Infants were randomly assigned to a 24-day course of nitrogen placebo or inhaled nitric oxide at an initial dose of 20 ppm for 48 to 96 hours, with the dose reduced at weekly intervals to 10, 5, and 2 ppm. Nitric oxide treatment improved survival at 36 weeks of postmenstrual age without bronchopulmonary dysplasia (43.9 percent vs. 36.8 percent) and reduced the duration of oxygen therapy and hospitalization. In a post hoc analysis, the improvement in primary outcome was limited to infants who were 7 to 14 days of age at randomization (approximately 40 percent of the total). No differences were noted in complications of prematurity, including cranial ultrasonographic findings.
Does inhaled nitric oxide have a role in the treatment of preterm infants with respiratory failure? In the most critically ill infants with extremely low birth weights,9 inhaled nitric oxide does not appear to improve survival or bronchopulmonary dysplasia, and since such treatment may be associated with brain injury or increased mortality in some groups, it cannot be recommended. The two reports in this issue of the Journal suggest the possibility of benefit in less critically ill infants, but questions remain. The most effective dose, duration, and time of initiation and the selection of infants most likely to benefit remain uncertain. The finding of no progression13 and perhaps a reduction in the risk of cranial abnormalities on ultrasonography12 is reassuring; yet the pathogenesis of injury in the developing brain is complex,14 and infants with extremely low birth weights who have normal findings on cranial ultrasonography remain at high risk for cerebral palsy and delayed mental development.15 Long-term follow-up is essential, particularly given the experience with postnatal dexamethasone treatment, which conferred short-term benefit but then increased the risk of later neurodevelopmental impairment. Furthermore, inhaled nitric oxide is among the most expensive drugs available for children ($3,000 per day and up to $12,000 for a 30-day period) and is difficult to justify until benefit is proven. For these reasons, getting to yes on inhaled nitric oxide in preterm infants awaits more data, especially longer-term follow-up of children in the studies by Kinsella et al. and Ballard et al. In the meantime, the use of inhaled nitric oxide in this setting should be limited to clinical trials.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Section of Neonatology, the Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston.
References
Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial. Lancet 1999;354:1061-1065.
Banks BA, Seri I, Ischiropoulos H, Merrill J, Rychik J, Ballard RA. Changes in oxygenation with inhaled nitric oxide in severe bronchopulmonary dysplasia. Pediatrics 1999;103:610-618.
Clark PL, Ekekezie II, Kaftan HA, Castor CA, Truog WE. Safety and efficacy of nitric oxide in chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2002;86:F41-F45.
Kang JL, Park W, Pack IS, et al. Inhaled nitric oxide attenuates acute lung injury via inhibition of nuclear factor-kappa B and inflammation. J Appl Physiol 2002;92:795-801.
Ballard PL, Gonzales LW, Godinez RI, et al. Surfactant composition and function in a primate model of infant chronic lung disease: effects of inhaled nitric oxide. Pediatr Res 2006;59:157-162.
Cotton RB, Sundell HW, Zeldin DC, et al. Inhaled nitric oxide attenuates hyperoxic lung injury in lambs. Pediatr Res 2006;59:142-146.
McCurnin DC, Pierce RA, Chang LY, et al. Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease. Am J Physiol Lung Cell Mol Physiol 2005;288:L450-L459.
Tang JR, Markham NE, Lin YJ, et al. Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor. Am J Physiol Lung Cell Mol Physiol 2004;287:L344-L351.
Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 2005;353:13-22.
Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med 2003;349:2099-2107.
Mestan KKL, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 2005;353:23-32.
Kinsella JP, Cutter GR, Walsh WF, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 2006;355:354-364.
Ballard RA, Truog WE, Cnaan A, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 2006;355:343-353.
Haynes RL, Baud O, Kinney HC, Volpe JJ, Folkerth DR. Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol 2005;15:225-233.
Laptook AR, O'Shea TM, Shankaran SS, Bhaskar B. Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents. Pediatrics 2005;115:673-680.(Ann R. Stark, M.D.)