Inhaled Nitric Oxide for Preterm Infants — Who Benefits?
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《新英格兰医药杂志》
Endogenously released nitric oxide is widely recognized to play a key role in multiple vertebrate organ systems, and its deficiency disrupts pulmonary parenchymal and vascular development. These observations have suggested that exogenously inhaled nitric oxide might protect the respiratory and the central nervous systems during a critical phase of development and thus improve outcomes in preterm infants.
In this issue of the Journal, Mestan et al.1 and Van Meurs et al.2 assess the utility of inhaled nitric oxide in preterm neonates with respiratory failure, with contrasting results. Mestan and colleagues report improved cognitive neurodevelopmental outcome in two-year-olds who had been treated with inhaled nitric oxide as neonates.1 This is a very reassuring follow-up to their previous report in the Journal that showed a reduced rate of death or bronchopulmonary dysplasia in premature infants treated with inhaled nitric oxide (relative risk, 0.76; 95 percent confidence interval, 0.60 to 0.97).3 In contrast, Van Meurs and colleagues report that treatment with inhaled nitric oxide as compared with placebo resulted in no overall improvement in survival to hospital discharge and suggests worse outcomes in a subgroup of neonates with birth weights of 1000 g or less.2
How can these discrepant results be explained? Although the studies investigate the same drug, few other aspects of the studies are similar. Mestan and colleagues studied premature infants with an average birth weight of 992 g and a gestational age of 27.4 weeks. In contrast, the infants in the study by Van Meurs et al. were considerably smaller (mean weight, 839 g) and less mature (average gestational age, 26 weeks); 47 percent had a birth weight of less than 750 g.
In addition, the infants enrolled in the study by Mestan et al. had a median oxygenation index (a measure of the severity of respiratory distress, calculated as 100 x the fraction of inspired oxygen x the mean airway pressure [in centimeters of water] ÷ the partial pressure of arterial oxygen [in millimeters of mercury]) of approximately 7, indicating that they were substantially less ill than the infants in the study by Van Meurs et al., who had a mean oxygenation index in excess of 20. (Oxygenation indexes that are less than 10 reflect mild disease, 10 to 20 moderate disease, and greater than 20 critical respiratory distress.) The mortality in the placebo group studied by Van Meurs et al. as compared with that in the placebo group studied by Mestan et al. (44 percent vs. 22.5 percent) is additional evidence that the participants in the study by Van Meurs et al. were more ill.
Plausible explanations for the discrepant results are that effects of inhaled nitric oxide may differ depending on the severity of illness and that administration of inhaled nitric oxide to critically ill preterm infants with respiratory failure does not improve outcome. In the study by Van Meurs et al., a post hoc analysis of the subgroup of infants with birth weights of 1000 g or less revealed a higher incidence of severe hemorrhagic or ischemic brain injury in the group treated with nitric oxide. However, it is uncertain whether these very ill infants had an intraventricular hemorrhage before their exposure to inhaled nitric oxide; platelet inactivation induced by inhaled nitric oxide may have exacerbated a preexisting complication. Post hoc analysis of the subgroup with birth weights greater than 1000 g actually revealed a significantly reduced rate of the combined outcome of death or bronchopulmonary dysplasia (P=0.03) with inhaled nitric oxide therapy.
There is also a striking difference in the racial composition of the two studies. Seventy percent of the infants in the trial by Mestan et al. and 35 percent in the trial by Van Meurs et al. were black. Race or ethnic group is a very crude marker of potential biologic differences in drug response, known as pharmacogenomics.4 However, there are no previous data in infants to suggest differential responsiveness to nitric oxide between blacks and whites.
Whereas the trial by Mestan et al. was a single-center study, the study by Van Meurs et al. was larger and involved many centers. Drug delivery was performed by blinded personnel, and outcomes were evaluated by observers blinded to therapy, minimizing the chance of bias in the outcome assessments. Even with these precautions, however, small trials have been shown to overestimate the effects of treatment, as compared with multicenter studies.5 It is likely that this is caused in part by the variations in concomitant processes of care that occur among centers as opposed to the processes within a single center.
In the study by Mestan et al., the finding of a decrease in the rate of neurodevelopmental impairment at two years of age in patients who had been treated with inhaled nitric oxide as infants, as compared with those who had been treated with placebo (24 percent vs. 46 percent, respectively), is impressive. The mechanism for this beneficial result is not immediately obvious. The improved outcome was associated with significantly less severe hemorrhagic and ischemic brain injury and a trend toward less bronchopulmonary dysplasia, although other factors, such as better growth, may also contribute. Infants with bronchopulmonary dysplasia have a number of related coexisting conditions, including poor growth, congestive heart failure, reactive airway disease, intermittent hypoxemic episodes, and exposure to postnatal steroids.6 It is therefore not surprising that numerous studies have shown a persistent link between bronchopulmonary dysplasia and adverse neurodevelopmental outcomes. Endogenous nitric oxide directly influences neural function, and inhaled nitric oxide may have more potent protective systemic effects than previously believed.7 However, there is currently no clear evidence that inhaled nitric oxide or active circulating nitrosylated proteins directly affect the developing brain.8
Inhaled nitric oxide was introduced to the therapeutic armamentarium as a means of rapidly improving oxygenation in term infants with primary pulmonary hypertension. Oxygenation improves in many preterm infants with respiratory failure within minutes after exposure to inhaled nitric oxide, presumably as a consequence of improved ventilation–perfusion matching. However, as shown by Van Meurs et al. as well as others,9,10 the administration of inhaled nitric oxide for one to three days does not necessarily translate into lower mortality or morbidity. Meanwhile, there is increasing interest in the effect of inhaled nitric oxide given for several weeks at low doses to modulate development of the respiratory system (Figure 1), including effects on angiogenesis and the maturation of lung parenchyma and airway smooth muscle.11,12,13
Figure 1. Proposed Effects of Nitric Oxide on the Development of the Respiratory System.
Endogenously released and exogenously inhaled nitric oxide (NO) may influence many facets of perinatal lung development, including lung parenchyma, bronchi, and vascular structures. This schematic figure depicts a fetal or preterm lung during the transition from a saccular to an alveolar stage, corresponding to 25 to 28 weeks of gestation. Endogenous nitric oxide is released primarily from epithelial and endothelial cells that contain nitric oxide synthase, and it is implicated in the structural and functional aspects of the development of pulmonary vasculature and airway smooth muscle. Nitric oxide also contributes to growth of the lung parenchyma and to extracellular matrix deposition and may modulate surfactant and inflammation in the developing lung. Animal models of bronchopulmonary dysplasia that have deficient levels of nitric oxide synthase show that inhaled nitric oxide can preserve lung growth. The implications of supplementation with inhaled nitric oxide in preterm infants are currently uncertain. The upward arrows indicate increased and the downward arrows decreased.
Meanwhile, what should the clinician conclude from these two studies? The sobering finding of increased mortality and increased hemorrhagic or ischemic brain injury with inhaled nitric oxide therapy in the subgroup of severely ill infants with birth weights of 1000 g or less, although a post hoc finding, must not be ignored. It may reflect the production of biologically toxic byproducts, such as peroxynitrite, from the combination of nitric oxide with the high oxygen concentration to which these very sick infants are exposed. Therefore, short-term use of inhaled nitric oxide cannot be considered an effective rescue therapy for very preterm infants with profound respiratory failure.2,9,10 In contrast, less ill preterm infants may benefit from this therapy, both in the short term and over the long term, as suggested by the study by Mestan et al.
Another recent report suggests that in less ill infants, inhaled nitric oxide may permit aggressive weaning from inspired oxygen and improve biomarkers of oxidative stress.14 Currently, at least two large, multicenter, randomized trials of prolonged inhaled nitric oxide exposure beginning shortly after birth are completing enrollment; we are participating in one of them. Pending the results, it is prudent to avoid the use of inhaled nitric oxide in preterm infants in the first week of life. The benefits and risks of inhaled nitric oxide need further scrutiny before its use becomes widespread.
Source Information
From the Division of Neonatology, Rainbow Babies and Children's Hospital, Cleveland.
References
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.
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.
Bloche MG. Race-based therapeutics. N Engl J Med 2004;351:2035-2037.
Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small trials in meta-analyses. Ann Intern Med 2001;135:982-989.
Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-1729.
Cannon RO, Schecter AN, Panza JA, et al. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest 2001;108:279-287.
Hess DT, Matsumoto A, Kim S-O, Marshall HE, Stamler JS. Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 2005;6:150-166.
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.
Field D, Elbourne D, Truesdale A, et al. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005;115:926-936.
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.
Martin RJ, Mhanna MJ, Haxhiu MA. The role of endogenous and exogenous nitric oxide on airway function. Semin Perinatol 2002;26:432-438.
Tang J-R, Markham NE, Lin Y-J, 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.
Hamon I, Fresson J, Nicolas M-B, Buchweiller M-C, Franck P, Hascoet J-M. Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res 2005;57:637-643.(Richard J. Martin, M.B., )
In this issue of the Journal, Mestan et al.1 and Van Meurs et al.2 assess the utility of inhaled nitric oxide in preterm neonates with respiratory failure, with contrasting results. Mestan and colleagues report improved cognitive neurodevelopmental outcome in two-year-olds who had been treated with inhaled nitric oxide as neonates.1 This is a very reassuring follow-up to their previous report in the Journal that showed a reduced rate of death or bronchopulmonary dysplasia in premature infants treated with inhaled nitric oxide (relative risk, 0.76; 95 percent confidence interval, 0.60 to 0.97).3 In contrast, Van Meurs and colleagues report that treatment with inhaled nitric oxide as compared with placebo resulted in no overall improvement in survival to hospital discharge and suggests worse outcomes in a subgroup of neonates with birth weights of 1000 g or less.2
How can these discrepant results be explained? Although the studies investigate the same drug, few other aspects of the studies are similar. Mestan and colleagues studied premature infants with an average birth weight of 992 g and a gestational age of 27.4 weeks. In contrast, the infants in the study by Van Meurs et al. were considerably smaller (mean weight, 839 g) and less mature (average gestational age, 26 weeks); 47 percent had a birth weight of less than 750 g.
In addition, the infants enrolled in the study by Mestan et al. had a median oxygenation index (a measure of the severity of respiratory distress, calculated as 100 x the fraction of inspired oxygen x the mean airway pressure [in centimeters of water] ÷ the partial pressure of arterial oxygen [in millimeters of mercury]) of approximately 7, indicating that they were substantially less ill than the infants in the study by Van Meurs et al., who had a mean oxygenation index in excess of 20. (Oxygenation indexes that are less than 10 reflect mild disease, 10 to 20 moderate disease, and greater than 20 critical respiratory distress.) The mortality in the placebo group studied by Van Meurs et al. as compared with that in the placebo group studied by Mestan et al. (44 percent vs. 22.5 percent) is additional evidence that the participants in the study by Van Meurs et al. were more ill.
Plausible explanations for the discrepant results are that effects of inhaled nitric oxide may differ depending on the severity of illness and that administration of inhaled nitric oxide to critically ill preterm infants with respiratory failure does not improve outcome. In the study by Van Meurs et al., a post hoc analysis of the subgroup of infants with birth weights of 1000 g or less revealed a higher incidence of severe hemorrhagic or ischemic brain injury in the group treated with nitric oxide. However, it is uncertain whether these very ill infants had an intraventricular hemorrhage before their exposure to inhaled nitric oxide; platelet inactivation induced by inhaled nitric oxide may have exacerbated a preexisting complication. Post hoc analysis of the subgroup with birth weights greater than 1000 g actually revealed a significantly reduced rate of the combined outcome of death or bronchopulmonary dysplasia (P=0.03) with inhaled nitric oxide therapy.
There is also a striking difference in the racial composition of the two studies. Seventy percent of the infants in the trial by Mestan et al. and 35 percent in the trial by Van Meurs et al. were black. Race or ethnic group is a very crude marker of potential biologic differences in drug response, known as pharmacogenomics.4 However, there are no previous data in infants to suggest differential responsiveness to nitric oxide between blacks and whites.
Whereas the trial by Mestan et al. was a single-center study, the study by Van Meurs et al. was larger and involved many centers. Drug delivery was performed by blinded personnel, and outcomes were evaluated by observers blinded to therapy, minimizing the chance of bias in the outcome assessments. Even with these precautions, however, small trials have been shown to overestimate the effects of treatment, as compared with multicenter studies.5 It is likely that this is caused in part by the variations in concomitant processes of care that occur among centers as opposed to the processes within a single center.
In the study by Mestan et al., the finding of a decrease in the rate of neurodevelopmental impairment at two years of age in patients who had been treated with inhaled nitric oxide as infants, as compared with those who had been treated with placebo (24 percent vs. 46 percent, respectively), is impressive. The mechanism for this beneficial result is not immediately obvious. The improved outcome was associated with significantly less severe hemorrhagic and ischemic brain injury and a trend toward less bronchopulmonary dysplasia, although other factors, such as better growth, may also contribute. Infants with bronchopulmonary dysplasia have a number of related coexisting conditions, including poor growth, congestive heart failure, reactive airway disease, intermittent hypoxemic episodes, and exposure to postnatal steroids.6 It is therefore not surprising that numerous studies have shown a persistent link between bronchopulmonary dysplasia and adverse neurodevelopmental outcomes. Endogenous nitric oxide directly influences neural function, and inhaled nitric oxide may have more potent protective systemic effects than previously believed.7 However, there is currently no clear evidence that inhaled nitric oxide or active circulating nitrosylated proteins directly affect the developing brain.8
Inhaled nitric oxide was introduced to the therapeutic armamentarium as a means of rapidly improving oxygenation in term infants with primary pulmonary hypertension. Oxygenation improves in many preterm infants with respiratory failure within minutes after exposure to inhaled nitric oxide, presumably as a consequence of improved ventilation–perfusion matching. However, as shown by Van Meurs et al. as well as others,9,10 the administration of inhaled nitric oxide for one to three days does not necessarily translate into lower mortality or morbidity. Meanwhile, there is increasing interest in the effect of inhaled nitric oxide given for several weeks at low doses to modulate development of the respiratory system (Figure 1), including effects on angiogenesis and the maturation of lung parenchyma and airway smooth muscle.11,12,13
Figure 1. Proposed Effects of Nitric Oxide on the Development of the Respiratory System.
Endogenously released and exogenously inhaled nitric oxide (NO) may influence many facets of perinatal lung development, including lung parenchyma, bronchi, and vascular structures. This schematic figure depicts a fetal or preterm lung during the transition from a saccular to an alveolar stage, corresponding to 25 to 28 weeks of gestation. Endogenous nitric oxide is released primarily from epithelial and endothelial cells that contain nitric oxide synthase, and it is implicated in the structural and functional aspects of the development of pulmonary vasculature and airway smooth muscle. Nitric oxide also contributes to growth of the lung parenchyma and to extracellular matrix deposition and may modulate surfactant and inflammation in the developing lung. Animal models of bronchopulmonary dysplasia that have deficient levels of nitric oxide synthase show that inhaled nitric oxide can preserve lung growth. The implications of supplementation with inhaled nitric oxide in preterm infants are currently uncertain. The upward arrows indicate increased and the downward arrows decreased.
Meanwhile, what should the clinician conclude from these two studies? The sobering finding of increased mortality and increased hemorrhagic or ischemic brain injury with inhaled nitric oxide therapy in the subgroup of severely ill infants with birth weights of 1000 g or less, although a post hoc finding, must not be ignored. It may reflect the production of biologically toxic byproducts, such as peroxynitrite, from the combination of nitric oxide with the high oxygen concentration to which these very sick infants are exposed. Therefore, short-term use of inhaled nitric oxide cannot be considered an effective rescue therapy for very preterm infants with profound respiratory failure.2,9,10 In contrast, less ill preterm infants may benefit from this therapy, both in the short term and over the long term, as suggested by the study by Mestan et al.
Another recent report suggests that in less ill infants, inhaled nitric oxide may permit aggressive weaning from inspired oxygen and improve biomarkers of oxidative stress.14 Currently, at least two large, multicenter, randomized trials of prolonged inhaled nitric oxide exposure beginning shortly after birth are completing enrollment; we are participating in one of them. Pending the results, it is prudent to avoid the use of inhaled nitric oxide in preterm infants in the first week of life. The benefits and risks of inhaled nitric oxide need further scrutiny before its use becomes widespread.
Source Information
From the Division of Neonatology, Rainbow Babies and Children's Hospital, Cleveland.
References
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.
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.
Bloche MG. Race-based therapeutics. N Engl J Med 2004;351:2035-2037.
Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small trials in meta-analyses. Ann Intern Med 2001;135:982-989.
Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001;163:1723-1729.
Cannon RO, Schecter AN, Panza JA, et al. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest 2001;108:279-287.
Hess DT, Matsumoto A, Kim S-O, Marshall HE, Stamler JS. Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 2005;6:150-166.
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.
Field D, Elbourne D, Truesdale A, et al. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339). Pediatrics 2005;115:926-936.
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.
Martin RJ, Mhanna MJ, Haxhiu MA. The role of endogenous and exogenous nitric oxide on airway function. Semin Perinatol 2002;26:432-438.
Tang J-R, Markham NE, Lin Y-J, 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.
Hamon I, Fresson J, Nicolas M-B, Buchweiller M-C, Franck P, Hascoet J-M. Early inhaled nitric oxide improves oxidative balance in very preterm infants. Pediatr Res 2005;57:637-643.(Richard J. Martin, M.B., )