Postnatal Dexamethasone for Lung Disease of Prematurity
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Yeh et al.1 report impairments in neuromotor skills and cognition in school-age children who were treated with dexamethasone as preterm infants, but they do not propose an underlying mechanism. Brain-derived neurotrophic factor is crucial for normal development and for the maintenance of motor function and cognition.2 Lack of brain-derived neurotrophic factor in the prenatal and early postnatal stages of life reduces the survival, differentiation, and synapse formation of central and peripheral neurons.2,3 Expression of brain-derived neurotrophic factor in brain regions critical for cognitive functions (such as the hippocampus) is suppressed by dexamethasone.4 As we can show, dexamethasone also suppresses the release of brain-derived neurotrophic factor from activated human immune cells (Figure 1). Thus, a plausible hypothesis to explain the effects observed by Yeh et al.1 is perinatal, dexamethasone-induced suppression of the release of brain-derived neurotrophic factor, which is vital for neuronal development. Since concentrations of this factor are already lower in preterm infants than in mature infants,5 its further suppression by dexamethasone to prevent chronic lung disease of prematurity is likely to affect neuronal development, leading to long-term deficits in cognitive and neuromotor function, as observed by Yeh and colleagues.1
Figure 1. Suppression by Dexamethasone of the Release of Brain-Derived Neurotrophic Factor (BDNF).
Peripheral-blood mononuclear cells from nine healthy human donors were stimulated with tumor necrosis factor (TNF-) and cultured for 24 hours (2x106 cells per milliliter of culture medium) in the presence of dexamethasone (10–5 M or 10–7 M) or in its absence. The amount of BDNF in the supernatants was determined by enzyme-linked immunosorbent assay (R & D Systems) and was corrected for the percentage of nonviable cells (after 24 hours of culturing) in each group to rule out the presence of artifacts due to dexamethasone-induced apoptosis. The dots denote individual subjects, and the bars arithmetic means.
Marek Lommatzsch, M.D.
Jens Klotz, Dipl.Pharm.
J. Christian Virchow, Jr., M.D.
University Medical Clinic
18057 Rostock, Germany
marek.lommatzsch@med.uni-rostock.de
References
Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350:1304-1313.
Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001;24:677-736.
Lommatzsch M, Braun A, Mannsfeldt A, et al. Abundant production of brain-derived neurotrophic factor by adult visceral epithelia: implications for paracrine and target-derived neurotrophic functions. Am J Pathol 1999;155:1183-1193.
Vellucci SV, Parrott RF, Mimmack ML. Down-regulation of BDNF mRNA, with no effect on trkB or glucocorticoid receptor mRNAs, in the porcine hippocampus after acute dexamethasone treatment. Res Vet Sci 2001;70:157-162.
Chouthai NS, Sampers J, Desai N, Smith GM. Changes in neurotrophin levels in umbilical cord blood from infants with different gastrointestinal ages and clinical conditions. Pediatr Res 2003;53:965-969.
To the Editor: We agree with Yeh and coworkers and with Jobe, who wrote the accompanying editorial,1 that with postnatal corticosteroid treatment regimens, both early exposure (during the first week of life) and protracted exposure in preterm infants should be avoided. In many clinical contexts, corticosteroids are administered as a short-term pulse, with administration repeated periodically if necessary, to accrue the benefits while attenuating the side effects of treatment. Indeed, pulsed dexamethasone treatment in ventilated preterm infants 1 week of age who are at high risk for chronic lung disease has been reported to decrease the incidence of chronic lung disease2 without impairing growth or body composition at 36 weeks' postmenstrual age3 or the short-term (12-month) neurodevelopmental outcome.4 Efforts to refine postnatal corticosteroid-pulse regimens in ventilated preterm infants at high risk for bronchopulmonary dysplasia to enhance pulmonary and neurodevelopmental outcomes are warranted. It is important that neonatologists not "throw the baby out with the bathwater" when it comes to postnatal corticosteroid treatment.
Jon F. Watchko, M.D.
Beverly S. Brozanski, M.D.
University of Pittsburgh School of Medicine
Pittsburgh, PA 15213
jwatchko@mail.magee.edu
References
Jobe AH. Postnatal corticosteroids for preterm infants -- do what we say, not what we do. N Engl J Med 2004;350:1349-1351.
Brozanski BS, Jones JG, Gilmour CH, et al. Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant. J Pediatr 1995;126:769-776.
Gilmour CH, Sentipal-Walerius JM, Jones JG, et al. Pulse dexamethasone does not impair growth and body composition of very low birth weight infants. J Am Coll Nutr 1995;14:455-462.
Hofkosh D, Brozanski BS, Edwards MD, Williams LA, Jones JG, Cheng KP. One-year outcome of infants treated with pulse dexamethasone for prevention of BPD. Pediatr Res 1995;37:259A-259A. abstract.
To the Editor: Jobe's editorial is appropriately sobering but fails to address the aspect of corticosteroid use in modern neonatology that is of greatest concern — namely, the risks associated with combining prophylactic therapies in the growing population of second-trimester survivors. We have known for some time that dexamethasone increases the incidence of intestinal perforations in the tiniest infants.1,2 However, the combination of dexamethasone and indomethacin significantly increases the risk of these perforations.3 Worse still, antenatal corticosteroid exposure has been linked with gut disease in a national data set and may also cause harmful synergism in the extremely premature gut.4
The effects of corticosteroids on neurologic development are a matter of serious concern, but intestinal perforations are lethal and, unlike neurologic development, do not appear to correlate with the duration or potency of the dosage.2,5 It is not sufficient to condone future corticosteroid trials that will do the least harm. For now, because we do not fully understand these harmful synergies, we should abandon prospective trials of corticosteroids in infants who weigh less than 1000 g.
Phillip V. Gordon, M.D., Ph.D.
University of Virginia
Charlottesville, VA 22908
pvg4n@virginia.edu
References
Gordon P, Rutledge J, Sawin R, Thomas S, Woodrum D. Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants. J Perinatol 1999;19:573-577.
Gordon PV, Young ML, Marshall DD. Focal small bowel perforation: an adverse effect of early postnatal dexamethasone therapy in extremely low birth weight infants. J Perinatol 2001;21:156-160.
Stark AR, Carlo WA, Tyson JE, et al. Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. N Engl J Med 2001;344:95-101.
Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J, Clark RH. Necrotizing enterocolitis among neonates in the United States. J Perinatol 2003;23:278-285.
Watterberg KL, PROPHET Study Group. Prophylaxis of early adrenal insufficiency (AI) to prevent BPD: multicenter trial. Pediatr Res 2004;55:Suppl:465a-465a. abstract.
The authors reply: Corticosteroids have been used for the past two decades in the treatment of preterm infants with the respiratory distress syndrome, for various reasons: for the prevention or treatment of chronic lung disease, for facilitating the process of weaning a patient from mechanical ventilation, and for resuscitation. Although the mechanisms responsible for the clinical improvement are not completely understood, the short-term beneficial effects are quite clear. The main controversy over the use of postnatal corticosteroids is the risk–benefit ratio and the potential for long-term complications. The pharmacokinetics of dexamethasone in this age group have not been well studied. We do not know the effective dosage for specific clinical conditions. According to our previous study,1 a dose of 0.125 mg per kilogram of body weight every 12 hours may be needed to suppress lung inflammation, as indicated by tracheal-aspirate cell counts, protein content, and leukotriene B4 in dexamethasone-treated infants as compared with controls.
As clinicians, we are pleased to see the reports by Brozanski et al.,2 who show that pulsed-dexamethasone therapy was effective in reducing the incidence and severity of chronic lung disease, and by Hofkosh et al.,3 who show that it had not impaired growth or the neurodevelopmental outcome at one year of age. However, longer follow-up is needed before this regimen can be recommended.
The developing brain is very sensitive to perinatal "programming" by agents that are known to affect brain development permanently; among such agents are stress and corticosteroids. Lommatzsch et al. propose that dexamethasone-induced suppression of brain-derived neurotrophic factor released from human immune cells could be a plausible mechanism for the long-lasting adverse effect of dexamethasone on neuroplasticity. It is an interesting hypothesis. However, it remains to be documented.
Tsu F. Yeh, M.D.
Hung C. Lin, M.D.
China Medical University
Taichung 40421, Taiwan
master@mail.cmu.edu.tw
Chao C. Huang, M.D.
National Cheng-Kung University
Tainan 704, Taiwan
References
Yeh TF, Lin YJ, Hsieh WS, et al. Early postnatal dexamethasone therapy for the prevention of chronic lung disease in preterm infants with respiratory distress syndrome: a multicenter clinical trial. Pediatrics 1997;100:e3-e3. abstract.
Brozanski BS, Jones JG, Gilmour CH, et al. Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant. J Pediatr 1995;126:769-776.
Hofkosh D, Brozanski BS, Edwards MD, Williams LA, Jones JG, Cheng KP. One-year outcome of infants treated with pulse dexamethasone for prevention of BPD. Pediatr Res 1995;37:259A-259A. abstract.
The editorialist replies: The primary conclusion of my editorial is that high-dose dexamethasone given soon after the birth of a very-low-birth-weight infant to prevent bronchopulmonary dysplasia is a bad idea because of adverse effects on neurologic development. Watchko and Brozanski refer to their small, single-center trial of repeated pulses of dexamethasone for 3 days every 10 days as a safe alternative.1 They used a higher dose of dexamethasone than is likely to be necessary. Furthermore, their limited one-year follow-up included just 67 percent of the surviving infants — an inadequate follow-up for reliable assessments of outcomes.
Watchko and Brozanski's point about "not throwing the baby out with the bathwater" suggests an appropriate response to the letter from Dr. Gordon, who points out the increased risks of isolated intestinal perforation and necrotizing enterocolitis with the use of corticosteroid treatments soon after the birth of very preterm infants, especially when corticosteroids are given with indomethacin. These adverse associations of gastrointestinal injury occur with the early use of corticosteroids but do not seem to occur when corticosteroids are used to treat bronchopulmonary dysplasia, beginning after perhaps two weeks of age. Corticosteroid treatments soon after birth should be avoided. However, less toxic approaches to the treatment of bronchopulmonary dysplasia need to be evaluated, since they are likely to be effective.2 I would be cautious in overinterpreting an association between antenatal glucocorticoid treatments and an increased risk of necrotizing enterocolitis on the basis of an administrative data set, because in randomized, controlled trials, antenatal corticosteroid treatment decreased the rate of necrotizing enterocolitis.3
Alan H. Jobe, Ph.D.
Cincinnati Children's Hospital Medical Center
Cincinnati, OH 45229-3039
References
Brozanski BS, Jones JG, Gilmour CH, et al. Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant. J Pediatr 1995;126:769-776.
Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;1:CD001144-CD001144.
Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane review). In: The Cochrane library. Oxford, England: Update Software, 2001.
Figure 1. Suppression by Dexamethasone of the Release of Brain-Derived Neurotrophic Factor (BDNF).
Peripheral-blood mononuclear cells from nine healthy human donors were stimulated with tumor necrosis factor (TNF-) and cultured for 24 hours (2x106 cells per milliliter of culture medium) in the presence of dexamethasone (10–5 M or 10–7 M) or in its absence. The amount of BDNF in the supernatants was determined by enzyme-linked immunosorbent assay (R & D Systems) and was corrected for the percentage of nonviable cells (after 24 hours of culturing) in each group to rule out the presence of artifacts due to dexamethasone-induced apoptosis. The dots denote individual subjects, and the bars arithmetic means.
Marek Lommatzsch, M.D.
Jens Klotz, Dipl.Pharm.
J. Christian Virchow, Jr., M.D.
University Medical Clinic
18057 Rostock, Germany
marek.lommatzsch@med.uni-rostock.de
References
Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 2004;350:1304-1313.
Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001;24:677-736.
Lommatzsch M, Braun A, Mannsfeldt A, et al. Abundant production of brain-derived neurotrophic factor by adult visceral epithelia: implications for paracrine and target-derived neurotrophic functions. Am J Pathol 1999;155:1183-1193.
Vellucci SV, Parrott RF, Mimmack ML. Down-regulation of BDNF mRNA, with no effect on trkB or glucocorticoid receptor mRNAs, in the porcine hippocampus after acute dexamethasone treatment. Res Vet Sci 2001;70:157-162.
Chouthai NS, Sampers J, Desai N, Smith GM. Changes in neurotrophin levels in umbilical cord blood from infants with different gastrointestinal ages and clinical conditions. Pediatr Res 2003;53:965-969.
To the Editor: We agree with Yeh and coworkers and with Jobe, who wrote the accompanying editorial,1 that with postnatal corticosteroid treatment regimens, both early exposure (during the first week of life) and protracted exposure in preterm infants should be avoided. In many clinical contexts, corticosteroids are administered as a short-term pulse, with administration repeated periodically if necessary, to accrue the benefits while attenuating the side effects of treatment. Indeed, pulsed dexamethasone treatment in ventilated preterm infants 1 week of age who are at high risk for chronic lung disease has been reported to decrease the incidence of chronic lung disease2 without impairing growth or body composition at 36 weeks' postmenstrual age3 or the short-term (12-month) neurodevelopmental outcome.4 Efforts to refine postnatal corticosteroid-pulse regimens in ventilated preterm infants at high risk for bronchopulmonary dysplasia to enhance pulmonary and neurodevelopmental outcomes are warranted. It is important that neonatologists not "throw the baby out with the bathwater" when it comes to postnatal corticosteroid treatment.
Jon F. Watchko, M.D.
Beverly S. Brozanski, M.D.
University of Pittsburgh School of Medicine
Pittsburgh, PA 15213
jwatchko@mail.magee.edu
References
Jobe AH. Postnatal corticosteroids for preterm infants -- do what we say, not what we do. N Engl J Med 2004;350:1349-1351.
Brozanski BS, Jones JG, Gilmour CH, et al. Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant. J Pediatr 1995;126:769-776.
Gilmour CH, Sentipal-Walerius JM, Jones JG, et al. Pulse dexamethasone does not impair growth and body composition of very low birth weight infants. J Am Coll Nutr 1995;14:455-462.
Hofkosh D, Brozanski BS, Edwards MD, Williams LA, Jones JG, Cheng KP. One-year outcome of infants treated with pulse dexamethasone for prevention of BPD. Pediatr Res 1995;37:259A-259A. abstract.
To the Editor: Jobe's editorial is appropriately sobering but fails to address the aspect of corticosteroid use in modern neonatology that is of greatest concern — namely, the risks associated with combining prophylactic therapies in the growing population of second-trimester survivors. We have known for some time that dexamethasone increases the incidence of intestinal perforations in the tiniest infants.1,2 However, the combination of dexamethasone and indomethacin significantly increases the risk of these perforations.3 Worse still, antenatal corticosteroid exposure has been linked with gut disease in a national data set and may also cause harmful synergism in the extremely premature gut.4
The effects of corticosteroids on neurologic development are a matter of serious concern, but intestinal perforations are lethal and, unlike neurologic development, do not appear to correlate with the duration or potency of the dosage.2,5 It is not sufficient to condone future corticosteroid trials that will do the least harm. For now, because we do not fully understand these harmful synergies, we should abandon prospective trials of corticosteroids in infants who weigh less than 1000 g.
Phillip V. Gordon, M.D., Ph.D.
University of Virginia
Charlottesville, VA 22908
pvg4n@virginia.edu
References
Gordon P, Rutledge J, Sawin R, Thomas S, Woodrum D. Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants. J Perinatol 1999;19:573-577.
Gordon PV, Young ML, Marshall DD. Focal small bowel perforation: an adverse effect of early postnatal dexamethasone therapy in extremely low birth weight infants. J Perinatol 2001;21:156-160.
Stark AR, Carlo WA, Tyson JE, et al. Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. N Engl J Med 2001;344:95-101.
Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J, Clark RH. Necrotizing enterocolitis among neonates in the United States. J Perinatol 2003;23:278-285.
Watterberg KL, PROPHET Study Group. Prophylaxis of early adrenal insufficiency (AI) to prevent BPD: multicenter trial. Pediatr Res 2004;55:Suppl:465a-465a. abstract.
The authors reply: Corticosteroids have been used for the past two decades in the treatment of preterm infants with the respiratory distress syndrome, for various reasons: for the prevention or treatment of chronic lung disease, for facilitating the process of weaning a patient from mechanical ventilation, and for resuscitation. Although the mechanisms responsible for the clinical improvement are not completely understood, the short-term beneficial effects are quite clear. The main controversy over the use of postnatal corticosteroids is the risk–benefit ratio and the potential for long-term complications. The pharmacokinetics of dexamethasone in this age group have not been well studied. We do not know the effective dosage for specific clinical conditions. According to our previous study,1 a dose of 0.125 mg per kilogram of body weight every 12 hours may be needed to suppress lung inflammation, as indicated by tracheal-aspirate cell counts, protein content, and leukotriene B4 in dexamethasone-treated infants as compared with controls.
As clinicians, we are pleased to see the reports by Brozanski et al.,2 who show that pulsed-dexamethasone therapy was effective in reducing the incidence and severity of chronic lung disease, and by Hofkosh et al.,3 who show that it had not impaired growth or the neurodevelopmental outcome at one year of age. However, longer follow-up is needed before this regimen can be recommended.
The developing brain is very sensitive to perinatal "programming" by agents that are known to affect brain development permanently; among such agents are stress and corticosteroids. Lommatzsch et al. propose that dexamethasone-induced suppression of brain-derived neurotrophic factor released from human immune cells could be a plausible mechanism for the long-lasting adverse effect of dexamethasone on neuroplasticity. It is an interesting hypothesis. However, it remains to be documented.
Tsu F. Yeh, M.D.
Hung C. Lin, M.D.
China Medical University
Taichung 40421, Taiwan
master@mail.cmu.edu.tw
Chao C. Huang, M.D.
National Cheng-Kung University
Tainan 704, Taiwan
References
Yeh TF, Lin YJ, Hsieh WS, et al. Early postnatal dexamethasone therapy for the prevention of chronic lung disease in preterm infants with respiratory distress syndrome: a multicenter clinical trial. Pediatrics 1997;100:e3-e3. abstract.
Brozanski BS, Jones JG, Gilmour CH, et al. Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant. J Pediatr 1995;126:769-776.
Hofkosh D, Brozanski BS, Edwards MD, Williams LA, Jones JG, Cheng KP. One-year outcome of infants treated with pulse dexamethasone for prevention of BPD. Pediatr Res 1995;37:259A-259A. abstract.
The editorialist replies: The primary conclusion of my editorial is that high-dose dexamethasone given soon after the birth of a very-low-birth-weight infant to prevent bronchopulmonary dysplasia is a bad idea because of adverse effects on neurologic development. Watchko and Brozanski refer to their small, single-center trial of repeated pulses of dexamethasone for 3 days every 10 days as a safe alternative.1 They used a higher dose of dexamethasone than is likely to be necessary. Furthermore, their limited one-year follow-up included just 67 percent of the surviving infants — an inadequate follow-up for reliable assessments of outcomes.
Watchko and Brozanski's point about "not throwing the baby out with the bathwater" suggests an appropriate response to the letter from Dr. Gordon, who points out the increased risks of isolated intestinal perforation and necrotizing enterocolitis with the use of corticosteroid treatments soon after the birth of very preterm infants, especially when corticosteroids are given with indomethacin. These adverse associations of gastrointestinal injury occur with the early use of corticosteroids but do not seem to occur when corticosteroids are used to treat bronchopulmonary dysplasia, beginning after perhaps two weeks of age. Corticosteroid treatments soon after birth should be avoided. However, less toxic approaches to the treatment of bronchopulmonary dysplasia need to be evaluated, since they are likely to be effective.2 I would be cautious in overinterpreting an association between antenatal glucocorticoid treatments and an increased risk of necrotizing enterocolitis on the basis of an administrative data set, because in randomized, controlled trials, antenatal corticosteroid treatment decreased the rate of necrotizing enterocolitis.3
Alan H. Jobe, Ph.D.
Cincinnati Children's Hospital Medical Center
Cincinnati, OH 45229-3039
References
Brozanski BS, Jones JG, Gilmour CH, et al. Effect of pulse dexamethasone therapy on the incidence and severity of chronic lung disease in the very low birth weight infant. J Pediatr 1995;126:769-776.
Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;1:CD001144-CD001144.
Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane review). In: The Cochrane library. Oxford, England: Update Software, 2001.