Caffeine for Apnea of Prematurity
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Schmidt et al. (May 18 issue)1 appear to misconstrue the effect of caffeine on growth. Figure 2 of the article identifies a difference in growth appearing at one week of age and reflecting a greater weight loss in babies treated with caffeine. The difference in weight gradually vanishes during the next three weeks, indicating greater weight gain in babies receiving caffeine.
Premature infants with very low birth weight rarely receive adequate growth calories in the first days of life. However, most of the 5 to 10 percent of birth weight they lose reflects a loss of water from a reservoir that is established in utero and that is mobilized and excreted in response to falling levels of prolactin.2 Caffeine does not affect the secretion of prolactin,3 but it is a diuretic.4 In a baboon model of the respiratory distress syndrome associated with prematurity, caffeine treatment doubled the output of urine during the first day of treatment.5 These data appear to show that caffeine augments the loss of fluid in the first week of life and that the resulting water deficit resolves during the next three weeks. Caffeine does not appear to affect somatic growth.
David M. Coulter, M.D.
University of Utah School of Medicine
Salt Lake City, UT 84158
david.coulter@hsc.utah.edu
References
Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112-2121.
Coulter DM. Prolactin: a hormonal regulator of the neonatal tissue water reservoir. Pediatr Res 1983;17:665-668.
Spindel E. Action of the methylxanthines on the pituitary and pituitary-dependent hormones. Prog Clin Biol Res 1984;158:355-363.
Williams M, Jarvis MF. Adenosine antagonists as potential therapeutic agents. Pharmacol Biochem Behav 1988;29:433-441.
Yoder B, Thomson M, Coalson J. Lung function in immature baboons with respiratory distress syndrome receiving caffeine therapy: a pilot study. Acta Paediatr 2005;94:92-98.
To the Editor: Schmidt et al. report decreased rates of bronchopulmonary dysplasia and a decreased need for closure of patent ductus arteriosus among infants with very low birth weight who were given caffeine for apnea of prematurity. We believe these findings may relate not to the physiological effects of caffeine but to current neonatal practice. The study's definition of bronchopulmonary dysplasia was the need for oxygen at 36 weeks. Although this is an accepted clinical definition,1 it is not a physiological one2 and is more a reflection of the clinical staff's perception of which infants require oxygen. Thus, the maintenance of an infant on oxygen or the treatment of patent ductus arteriosus was presumably related to the need to "do something" for apnea, often with little evidence. This conclusion is also evident from the cited cointerventions, since the use of doxapram, postnatal corticosteroids, and transfusions of red cells were all increased in the placebo group. For these reasons, we urge caution in the interpretation of the results of this study and await the primary outcomes of neurodevelopment.
Ivan L. Hand, M.D.
Lawrence M. Noble, M.D.
Jacobi Medical Center
Bronx, NY 10461
hand@aecom.yu.edu
References
Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirements in the neonatal period. Pediatrics 1988;82:527-532.
Walsh MC, Yao Q, Gettner PA, et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics 2004;114:1305-1311.
The authors reply: Coulter suggests that the diuretic effect of caffeine may explain the difference in weight gain between the caffeine group and the placebo group. We agree that this is a plausible hypothesis. We wish to stress, however, that Figure 2 of our article shows the weeks since randomization, not the weeks since birth. Moreover, published data also support the alternative hypothesis that caffeine impairs somatic growth. For example, Bauer et al.1 reported that oxygen consumption and metabolic rate among infants with very low birth weight who received caffeine were significantly greater than those among infants in a control group who were matched for age and weight. Despite similar caloric intake during the four-week study period, caffeine therapy was associated with a significantly reduced weight gain in this observational study.
Hand and Noble are correct in questioning the physiological significance of defining bronchopulmonary dysplasia solely with respect to the need for supplemental oxygen at a postmenstrual age of 36 weeks. On the basis of this clinical definition, bronchopulmonary dysplasia alone is only a modest predictor of poor pulmonary and neurosensory outcomes in early childhood.2,3 Therefore, we have suggested that investigators directly measure the long-term disabilities for which bronchopulmonary dysplasia is a short-term surrogate.2 However, it would not be prudent to dismiss entirely the prognostic value of bronchopulmonary dysplasia as defined in our study. When bronchopulmonary dysplasia is combined with brain injury and severe retinopathy of prematurity, a count of these three common neonatal illnesses strongly predicts the risk of death or survival with neurosensory impairment.3 Nevertheless, we concur with the cautious recommendation of Hand and Noble to await the long-term outcomes of our study, as stated at the end of our first study report. Follow-up to the corrected ages of 18 to 21 months and 5 years is under way. We look forward to sharing these long-term outcomes with those who care for very preterm infants.
Barbara Schmidt, M.D.
Robin S. Roberts, M.Sc.
McMaster University
Hamilton, ON L8N 3Z5, Canada
schmidt@mcmaster.ca
Peter Davis, M.D.
University of Melbourne
Melbourne 3053, Australia
for the Caffeine for Apnea of Prematurity Trial Investigators
References
Bauer J, Maier K, Linderkamp O, Hentschel R. Effect of caffeine on oxygen consumption and metabolic rate in very low birth weight infants with idiopathic apnea. Pediatrics 2001;107:660-663.
Davis PG, Thorpe K, Roberts R, Schmidt B, Doyle LW, Kirpalani H. Evaluating "old" definitions for the "new" bronchopulmonary dysplasia. J Pediatr 2002;140:555-560.
Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124-1129.
Premature infants with very low birth weight rarely receive adequate growth calories in the first days of life. However, most of the 5 to 10 percent of birth weight they lose reflects a loss of water from a reservoir that is established in utero and that is mobilized and excreted in response to falling levels of prolactin.2 Caffeine does not affect the secretion of prolactin,3 but it is a diuretic.4 In a baboon model of the respiratory distress syndrome associated with prematurity, caffeine treatment doubled the output of urine during the first day of treatment.5 These data appear to show that caffeine augments the loss of fluid in the first week of life and that the resulting water deficit resolves during the next three weeks. Caffeine does not appear to affect somatic growth.
David M. Coulter, M.D.
University of Utah School of Medicine
Salt Lake City, UT 84158
david.coulter@hsc.utah.edu
References
Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112-2121.
Coulter DM. Prolactin: a hormonal regulator of the neonatal tissue water reservoir. Pediatr Res 1983;17:665-668.
Spindel E. Action of the methylxanthines on the pituitary and pituitary-dependent hormones. Prog Clin Biol Res 1984;158:355-363.
Williams M, Jarvis MF. Adenosine antagonists as potential therapeutic agents. Pharmacol Biochem Behav 1988;29:433-441.
Yoder B, Thomson M, Coalson J. Lung function in immature baboons with respiratory distress syndrome receiving caffeine therapy: a pilot study. Acta Paediatr 2005;94:92-98.
To the Editor: Schmidt et al. report decreased rates of bronchopulmonary dysplasia and a decreased need for closure of patent ductus arteriosus among infants with very low birth weight who were given caffeine for apnea of prematurity. We believe these findings may relate not to the physiological effects of caffeine but to current neonatal practice. The study's definition of bronchopulmonary dysplasia was the need for oxygen at 36 weeks. Although this is an accepted clinical definition,1 it is not a physiological one2 and is more a reflection of the clinical staff's perception of which infants require oxygen. Thus, the maintenance of an infant on oxygen or the treatment of patent ductus arteriosus was presumably related to the need to "do something" for apnea, often with little evidence. This conclusion is also evident from the cited cointerventions, since the use of doxapram, postnatal corticosteroids, and transfusions of red cells were all increased in the placebo group. For these reasons, we urge caution in the interpretation of the results of this study and await the primary outcomes of neurodevelopment.
Ivan L. Hand, M.D.
Lawrence M. Noble, M.D.
Jacobi Medical Center
Bronx, NY 10461
hand@aecom.yu.edu
References
Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirements in the neonatal period. Pediatrics 1988;82:527-532.
Walsh MC, Yao Q, Gettner PA, et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics 2004;114:1305-1311.
The authors reply: Coulter suggests that the diuretic effect of caffeine may explain the difference in weight gain between the caffeine group and the placebo group. We agree that this is a plausible hypothesis. We wish to stress, however, that Figure 2 of our article shows the weeks since randomization, not the weeks since birth. Moreover, published data also support the alternative hypothesis that caffeine impairs somatic growth. For example, Bauer et al.1 reported that oxygen consumption and metabolic rate among infants with very low birth weight who received caffeine were significantly greater than those among infants in a control group who were matched for age and weight. Despite similar caloric intake during the four-week study period, caffeine therapy was associated with a significantly reduced weight gain in this observational study.
Hand and Noble are correct in questioning the physiological significance of defining bronchopulmonary dysplasia solely with respect to the need for supplemental oxygen at a postmenstrual age of 36 weeks. On the basis of this clinical definition, bronchopulmonary dysplasia alone is only a modest predictor of poor pulmonary and neurosensory outcomes in early childhood.2,3 Therefore, we have suggested that investigators directly measure the long-term disabilities for which bronchopulmonary dysplasia is a short-term surrogate.2 However, it would not be prudent to dismiss entirely the prognostic value of bronchopulmonary dysplasia as defined in our study. When bronchopulmonary dysplasia is combined with brain injury and severe retinopathy of prematurity, a count of these three common neonatal illnesses strongly predicts the risk of death or survival with neurosensory impairment.3 Nevertheless, we concur with the cautious recommendation of Hand and Noble to await the long-term outcomes of our study, as stated at the end of our first study report. Follow-up to the corrected ages of 18 to 21 months and 5 years is under way. We look forward to sharing these long-term outcomes with those who care for very preterm infants.
Barbara Schmidt, M.D.
Robin S. Roberts, M.Sc.
McMaster University
Hamilton, ON L8N 3Z5, Canada
schmidt@mcmaster.ca
Peter Davis, M.D.
University of Melbourne
Melbourne 3053, Australia
for the Caffeine for Apnea of Prematurity Trial Investigators
References
Bauer J, Maier K, Linderkamp O, Hentschel R. Effect of caffeine on oxygen consumption and metabolic rate in very low birth weight infants with idiopathic apnea. Pediatrics 2001;107:660-663.
Davis PG, Thorpe K, Roberts R, Schmidt B, Doyle LW, Kirpalani H. Evaluating "old" definitions for the "new" bronchopulmonary dysplasia. J Pediatr 2002;140:555-560.
Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289:1124-1129.