关于Inhaled Nitric Oxide的原因,关于Inhaled Nitric Oxide的相关知识。 To the Editor: In the article by Van Meurs et al. (July 7 issue)1 on the use of inhaled nitric oxide for preterm infants with severe respiratory failure, the authors suggest that inhaled nitric oxide is ineffective in infants weighing less than 1500 g. Other studies of the effects of treatment with inhaled nitric oxide in preterm infants have shown contradictory results.2,3,4,5 These differences might be due to an inability to select patients who are especially likely to respond to this therapy. We suggest that it is essential to compare the clinical characteristics of infants who do not respond to therapy with inhaled nitric oxide with the characteristics of infants who do respond (instead of comparing only the clinical characteristics of treated and untreated infants) to identify possible predictive factors for the response to inhaled nitric oxide.
The results of a randomized, controlled trial performed in our center (unpublished data) showed that, in partial agreement with Van Meurs et al., a birth weight lower than 750 g had a significant predictive value for the failure to respond to therapy with inhaled nitric oxide. This suggests that the exclusion of infants weighing less than 750 g or 1000 g from randomized, controlled trials might be crucial for demonstrating the effectiveness of inhaled nitric oxide in the treatment of preterm infants with respiratory failure.
Carlo Dani, M.D.
Giovanna Bertini, M.D.
Firmino F. Rubaltelli, M.D.
University of Florence
50134 Florence, Italy
cdani@unifi.it
References
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.
Subhedar NV, Shaw NJ. Changes in oxygenation and pulmonary haemodynamics in preterm infants treated with inhaled nitric oxide. Arch Dis Child Fetal Neonatal Ed 1997;77:F191-F197.
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.
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.
Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants. J Pediatr 2005;146:318-323.
To the Editor: The two studies reported in the July 7 issue — by Van Meurs et al. and Mestan et al.1 — on the effects of inhaled nitric oxide in very-low-birth-weight infants have discrepant results. An accompanying editorial2 points out a number of differences between the two studies. However, the studies have little in common, and a comparison could invoke misleading conclusions. In contrast to the study by Van Meurs et al., that of Mestan et al. (initially reported by Schreiber et al.3) used inhaled nitric oxide at a higher dose at an earlier age and continued with a smaller dose for a longer period. These infants also received prophylactic indomethacin. Furthermore, the weaning protocols were dissimilar. Therefore, the question arises of whether the inhaled nitric oxide treatment in the study by Van Meurs et al. was too little, too late, or both to prevent pulmonary injury and subsequent effects,2 or whether a positive synergistic effect exists between indomethacin and inhaled nitric oxide. Also, it is not clear whether significant differences in outcome existed between the infants who had a complete response to inhaled nitric oxide and infants who had a partial response or no response.
Shabih U. Hasan, M.D.
University of Calgary
Calgary, AB T2N 4N1, Canada
hasans@ucalgary.ca
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.
Martin RJ, Walsh MC. Inhaled nitric oxide for preterm infants -- who benefits? N Engl J Med 2005;353:82-84.
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.
To the Editor: In their editorial, Martin and Walsh note that the discrepancies in results between the articles by Mestan et al. and Van Meurs et al. might be considered to be due, in part, to the racial composition of the two studies, since 70 percent of the infants in the trial by Mestan et al. and 35 percent in the trial by Van Meurs et al. were black. They discount this explanation, however, stating that there are no previous data to suggest differential responsiveness to nitric oxide between black infants and white infants. Although there may be no data among infants, there are a number of reports that indicate that there may be a relative dearth of endogenous nitric oxide in blacks.1,2,3 Given this, and until the level of endogenous nitric oxide in infants is shown to be different from that in adults, it would appear to be credible to assign greater significance to the racial composition of the two studies.
Elliott C. Lasser, M.D.
8081 Calle Del Cielo
La Jolla, CA 92037
elasser@ucsd.edu
References
Stein CM, Lang CC, Nelson R, Brown M, Wood AJ. Vasodilation in black Americans: attenuated nitric oxide-mediated responses. Clin Pharmacol Ther 1997;62:436-443.
Houghton JL, Philbin EF, Strogatz DS, et al. The presence of African American race predicts improvement in coronary endothelial function after supplementary L-arginine. J Am Coll Cardiol 2002;39:1314-1322.
Cardillo C, Kilcoyne CM, Cannon RO III, Panza JA. Racial differences in nitric oxide-mediated vasodilator response to mental stress in the forearm circulation. Hypertension 1998;31:1235-1239.
Dr. Van Meurs and a colleague reply: We were interested to note that the randomized, clinical trial performed at the University of Florence showed that infants weighing less than 750 g did not benefit from inhaled nitric oxide, which is in agreement with the subgroup analysis in our trial. We agree with Dr. Dani and colleagues regarding the importance of determining which clinical factors are predictive of a response to inhaled nitric oxide. Identification of factors associated with adverse outcomes such as intracranial hemorrhage is also critical. At present, we are beginning a further analysis of the trial data. The methods used for these analyses will include standard multivariable regression models, as well as categorization classification-and-regression-tree analyses. The goals are to identify the very-low-birth-weight infants who are likely to respond and are therefore good candidates on the basis of their clinical characteristics, to identify the infants who have an adequate response and can be continued on inhaled nitric oxide, and to identify new clinical variables that are associated with outcomes, leading to the generation of hypotheses and new clinical trials. We will attempt to determine whether birth weight, race and ethnic group, and other variables are determinants of the response to inhaled nitric oxide. It will be interesting to determine whether a differential responsiveness to nitric oxide between blacks and whites is present, as suggested by Dr. Lasser and recent reports.1 Some of the questions raised by Dr. Hasan may also be answered by our planned analysis, such as the differences in outcome among those infants with a complete response, a partial response, or no response and the timing of treatment with inhaled nitric oxide. The potential for a positive synergistic effect between indomethacin and inhaled nitric oxide seems unlikely, since indomethacin is known to decrease prostaglandin synthesis.2
Krisa Van Meurs, M.D.
David Stevenson, M.D.
Stanford University School of Medicine
Palo Alto, CA 94304
vanmeurs@stanford.edu
References
Kalinowski L, Dobrucki IT, Malinski T. Race-specific differences in endothelial function: predisposition of African Americans to vascular diseases. Circulation 2004;109:2511-2517.
Barnard JW, Wilson PS, Moore TM, Thompson WJ, Taylor AE. Effect of nitric oxide and cyclooxygenase products on vascular resistance in dog and rat lungs. J Appl Physiol 1993;74:2940-2948.
Dr. Schreiber and colleagues reply: We agree with Dr. Lasser that racial differences in nitric oxide metabolism could contribute to our findings. We had performed an ad hoc analysis comparing our black patients with nonblack patients. Unfortunately, because of space constraints, we were unable to include this in the original report.1 Either chronic lung disease developed or death occurred in 81 of the black premature infants enrolled (49.3 percent of those given inhaled nitric oxide and 62.2 percent of the placebo group; odds ratio, 0.79; 95 percent confidence interval, 0.59 to 1.07; P=0.13). Either chronic lung disease developed or death occurred in 35 of the nonblack premature infants enrolled (47.1 percent of those given inhaled nitric oxide and 67.9 percent of the placebo group; odds ratio, 0.69; 95 percent confidence interval, 0.45 to 1.07; P=0.13). The P value for the interaction was 0.62. Because the sample size is too small for meaningful interpretations to be made, these results cannot support the concept that race significantly influences the response of premature infants to inhaled nitric oxide.
Dr. Hasan correctly points out that the duration of therapy with inhaled nitric oxide was significantly different in the two studies. Premature infants in our original study were treated for seven full days or until extubation. As pointed out by Martin and Walsh in the accompanying editorial, nitric oxide may have positive effects on the developing lung other than pulmonary vasodilation. These beneficial effects may be enhanced with longer exposure to inhaled nitric oxide. Accordingly, a longer course of therapy with inhaled nitric oxide in the infants in our study, perhaps until they no longer required supplemental oxygen, might have further reduced the risk of chronic lung disease and death and might also have further improved two-year neurodevelopmental outcomes.
Michael D. Schreiber, M.D.
Jeremy D. Marks, Ph.D., M.D.
Karen K.L. Mestan, M.D.
University of Chicago
Chicago, IL 60637
mschreiber@peds.bsd.uchicago.edu
References
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.
Drs. Martin and Walsh reply: Hasan expands on an issue that we sought to highlight in our editorial, the markedly different populations enrolled in the Chicago and National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trials of inhaled nitric oxide for preterm infants. The beneficial effect in the former study may well relate to the lower severity of respiratory distress, the longer duration of nitric oxide therapy, or both. Exposure to nitric oxide lasted at least seven days in the Chicago study, whereas in the NICHD Neonatal Research Network trial, nitric oxide could have been discontinued within hours in the absence of improving oxygenation, thus negating any potential benefit of prolonged exposure on lung development. Hasan notes that nearly 80 percent of the Chicago cohort received prophylactic indomethacin for closure of patent ductus arteriosus and speculates on possible drug synergy between indomethacin and nitric oxide. Important interactions may occur between the nitric oxide synthase and cyclooxygenase systems, although inhibition of prostaglandin synthesis with indomethacin would probably attenuate prostaglandin-induced vasorelaxation, and therefore, mechanisms other than synergistic vasodilatation would need to be implicated.
We are particularly intrigued by the comment of Lasser reminding us that blacks and whites may have differential responsiveness to nitric oxide, on the basis of the observed attenuation of nitric oxide–mediated vasodilatation in black Americans. It would be premature to attribute the beneficial effect of nitric oxide in the Chicago study to the preponderance of black infants in that cohort. However, there is no doubt that the two large, multicenter trials of prolonged inhaled nitric oxide exposure for preterm infants, which have just completed enrollment and begun data analysis, will attempt to address this question of differential racial responsiveness in post hoc analyses. This, in turn, might lead to more meaningful genotypic and phenotypic markers of a predisposition to neonatal lung injury and resultant therapeutic advances.
Richard J. Martin, M.B., F.R.A.C.P.
Michele C. Walsh, M.D.
Rainbow Babies and Children's Hospital
Cleveland, OH 44106-6010 (文章出处：《新英格兰医药杂志》)
The results of a randomized, controlled trial performed in our center (unpublished data) showed that, in partial agreement with Van Meurs et al., a birth weight lower than 750 g had a significant predictive value for the failure to respond to therapy with inhaled nitric oxide. This suggests that the exclusion of infants weighing less than 750 g or 1000 g from randomized, controlled trials might be crucial for demonstrating the effectiveness of inhaled nitric oxide in the treatment of preterm infants with respiratory failure.
Carlo Dani, M.D.
Giovanna Bertini, M.D.
Firmino F. Rubaltelli, M.D.
University of Florence
50134 Florence, Italy
cdani@unifi.it
References
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.
Subhedar NV, Shaw NJ. Changes in oxygenation and pulmonary haemodynamics in preterm infants treated with inhaled nitric oxide. Arch Dis Child Fetal Neonatal Ed 1997;77:F191-F197.
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.
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.
Hascoet JM, Fresson J, Claris O, et al. The safety and efficacy of nitric oxide therapy in premature infants. J Pediatr 2005;146:318-323.
To the Editor: The two studies reported in the July 7 issue — by Van Meurs et al. and Mestan et al.1 — on the effects of inhaled nitric oxide in very-low-birth-weight infants have discrepant results. An accompanying editorial2 points out a number of differences between the two studies. However, the studies have little in common, and a comparison could invoke misleading conclusions. In contrast to the study by Van Meurs et al., that of Mestan et al. (initially reported by Schreiber et al.3) used inhaled nitric oxide at a higher dose at an earlier age and continued with a smaller dose for a longer period. These infants also received prophylactic indomethacin. Furthermore, the weaning protocols were dissimilar. Therefore, the question arises of whether the inhaled nitric oxide treatment in the study by Van Meurs et al. was too little, too late, or both to prevent pulmonary injury and subsequent effects,2 or whether a positive synergistic effect exists between indomethacin and inhaled nitric oxide. Also, it is not clear whether significant differences in outcome existed between the infants who had a complete response to inhaled nitric oxide and infants who had a partial response or no response.
Shabih U. Hasan, M.D.
University of Calgary
Calgary, AB T2N 4N1, Canada
hasans@ucalgary.ca
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.
Martin RJ, Walsh MC. Inhaled nitric oxide for preterm infants -- who benefits? N Engl J Med 2005;353:82-84.
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.
To the Editor: In their editorial, Martin and Walsh note that the discrepancies in results between the articles by Mestan et al. and Van Meurs et al. might be considered to be due, in part, to the racial composition of the two studies, since 70 percent of the infants in the trial by Mestan et al. and 35 percent in the trial by Van Meurs et al. were black. They discount this explanation, however, stating that there are no previous data to suggest differential responsiveness to nitric oxide between black infants and white infants. Although there may be no data among infants, there are a number of reports that indicate that there may be a relative dearth of endogenous nitric oxide in blacks.1,2,3 Given this, and until the level of endogenous nitric oxide in infants is shown to be different from that in adults, it would appear to be credible to assign greater significance to the racial composition of the two studies.
Elliott C. Lasser, M.D.
8081 Calle Del Cielo
La Jolla, CA 92037
elasser@ucsd.edu
References
Stein CM, Lang CC, Nelson R, Brown M, Wood AJ. Vasodilation in black Americans: attenuated nitric oxide-mediated responses. Clin Pharmacol Ther 1997;62:436-443.
Houghton JL, Philbin EF, Strogatz DS, et al. The presence of African American race predicts improvement in coronary endothelial function after supplementary L-arginine. J Am Coll Cardiol 2002;39:1314-1322.
Cardillo C, Kilcoyne CM, Cannon RO III, Panza JA. Racial differences in nitric oxide-mediated vasodilator response to mental stress in the forearm circulation. Hypertension 1998;31:1235-1239.
Dr. Van Meurs and a colleague reply: We were interested to note that the randomized, clinical trial performed at the University of Florence showed that infants weighing less than 750 g did not benefit from inhaled nitric oxide, which is in agreement with the subgroup analysis in our trial. We agree with Dr. Dani and colleagues regarding the importance of determining which clinical factors are predictive of a response to inhaled nitric oxide. Identification of factors associated with adverse outcomes such as intracranial hemorrhage is also critical. At present, we are beginning a further analysis of the trial data. The methods used for these analyses will include standard multivariable regression models, as well as categorization classification-and-regression-tree analyses. The goals are to identify the very-low-birth-weight infants who are likely to respond and are therefore good candidates on the basis of their clinical characteristics, to identify the infants who have an adequate response and can be continued on inhaled nitric oxide, and to identify new clinical variables that are associated with outcomes, leading to the generation of hypotheses and new clinical trials. We will attempt to determine whether birth weight, race and ethnic group, and other variables are determinants of the response to inhaled nitric oxide. It will be interesting to determine whether a differential responsiveness to nitric oxide between blacks and whites is present, as suggested by Dr. Lasser and recent reports.1 Some of the questions raised by Dr. Hasan may also be answered by our planned analysis, such as the differences in outcome among those infants with a complete response, a partial response, or no response and the timing of treatment with inhaled nitric oxide. The potential for a positive synergistic effect between indomethacin and inhaled nitric oxide seems unlikely, since indomethacin is known to decrease prostaglandin synthesis.2
Krisa Van Meurs, M.D.
David Stevenson, M.D.
Stanford University School of Medicine
Palo Alto, CA 94304
vanmeurs@stanford.edu
References
Kalinowski L, Dobrucki IT, Malinski T. Race-specific differences in endothelial function: predisposition of African Americans to vascular diseases. Circulation 2004;109:2511-2517.
Barnard JW, Wilson PS, Moore TM, Thompson WJ, Taylor AE. Effect of nitric oxide and cyclooxygenase products on vascular resistance in dog and rat lungs. J Appl Physiol 1993;74:2940-2948.
Dr. Schreiber and colleagues reply: We agree with Dr. Lasser that racial differences in nitric oxide metabolism could contribute to our findings. We had performed an ad hoc analysis comparing our black patients with nonblack patients. Unfortunately, because of space constraints, we were unable to include this in the original report.1 Either chronic lung disease developed or death occurred in 81 of the black premature infants enrolled (49.3 percent of those given inhaled nitric oxide and 62.2 percent of the placebo group; odds ratio, 0.79; 95 percent confidence interval, 0.59 to 1.07; P=0.13). Either chronic lung disease developed or death occurred in 35 of the nonblack premature infants enrolled (47.1 percent of those given inhaled nitric oxide and 67.9 percent of the placebo group; odds ratio, 0.69; 95 percent confidence interval, 0.45 to 1.07; P=0.13). The P value for the interaction was 0.62. Because the sample size is too small for meaningful interpretations to be made, these results cannot support the concept that race significantly influences the response of premature infants to inhaled nitric oxide.
Dr. Hasan correctly points out that the duration of therapy with inhaled nitric oxide was significantly different in the two studies. Premature infants in our original study were treated for seven full days or until extubation. As pointed out by Martin and Walsh in the accompanying editorial, nitric oxide may have positive effects on the developing lung other than pulmonary vasodilation. These beneficial effects may be enhanced with longer exposure to inhaled nitric oxide. Accordingly, a longer course of therapy with inhaled nitric oxide in the infants in our study, perhaps until they no longer required supplemental oxygen, might have further reduced the risk of chronic lung disease and death and might also have further improved two-year neurodevelopmental outcomes.
Michael D. Schreiber, M.D.
Jeremy D. Marks, Ph.D., M.D.
Karen K.L. Mestan, M.D.
University of Chicago
Chicago, IL 60637
mschreiber@peds.bsd.uchicago.edu
References
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.
Drs. Martin and Walsh reply: Hasan expands on an issue that we sought to highlight in our editorial, the markedly different populations enrolled in the Chicago and National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trials of inhaled nitric oxide for preterm infants. The beneficial effect in the former study may well relate to the lower severity of respiratory distress, the longer duration of nitric oxide therapy, or both. Exposure to nitric oxide lasted at least seven days in the Chicago study, whereas in the NICHD Neonatal Research Network trial, nitric oxide could have been discontinued within hours in the absence of improving oxygenation, thus negating any potential benefit of prolonged exposure on lung development. Hasan notes that nearly 80 percent of the Chicago cohort received prophylactic indomethacin for closure of patent ductus arteriosus and speculates on possible drug synergy between indomethacin and nitric oxide. Important interactions may occur between the nitric oxide synthase and cyclooxygenase systems, although inhibition of prostaglandin synthesis with indomethacin would probably attenuate prostaglandin-induced vasorelaxation, and therefore, mechanisms other than synergistic vasodilatation would need to be implicated.
We are particularly intrigued by the comment of Lasser reminding us that blacks and whites may have differential responsiveness to nitric oxide, on the basis of the observed attenuation of nitric oxide–mediated vasodilatation in black Americans. It would be premature to attribute the beneficial effect of nitric oxide in the Chicago study to the preponderance of black infants in that cohort. However, there is no doubt that the two large, multicenter trials of prolonged inhaled nitric oxide exposure for preterm infants, which have just completed enrollment and begun data analysis, will attempt to address this question of differential racial responsiveness in post hoc analyses. This, in turn, might lead to more meaningful genotypic and phenotypic markers of a predisposition to neonatal lung injury and resultant therapeutic advances.
Richard J. Martin, M.B., F.R.A.C.P.
Michele C. Walsh, M.D.
Rainbow Babies and Children's Hospital
Cleveland, OH 44106-6010 (文章出处：《新英格兰医药杂志》)
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