PEDIATRICS Vol. 108 No. 3 September 2001, pp. 741-748

Early Postnatal Dexamethasone Therapy for the Prevention of Chronic Lung Disease

The Vermont Oxford Network Steroid Study Group

From the Department of Pediatrics, University of Vermont College of Medicine, Burlington, Vermont.

	ABSTRACT

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Objective.  To test the hypothesis that early postnatal dexamethasone will reduce the incidence of death or chronic lung disease (CLD) in ventilated extremely low birth weight premature infants.

Design.  Multicenter randomized double-blinded controlled clinical trial.

Setting.  A total of 42 neonatal intensive care units in the Vermont Oxford Network.

Participants.  Infants weighing 501 to 1000 g were eligible for enrollment at 12 hours of age if they needed assisted ventilation, had received surfactant replacement therapy, were physiologically stable, had no obvious life-threatening congenital anomaly, and had blood cultures obtained and antibiotic therapy initiated.

Intervention.  Infants were randomly assigned to dexamethasone or saline placebo. Intravenous dexamethasone was administered for 12 days according to the following dosing schedule: 0.5 mg/kg/d for 3 days, 0.25 mg/kg/d for 3 days, 0.10 mg/kg/d for 3 days, 0.05 mg/kg/d for 3 days. Infants in either group could receive treatment with selective late postnatal steroids beginning on day 14 of life if they were on assisted ventilation with supplemental oxygen greater than 30%.

Outcome Measurements.  The primary outcome measure was CLD or death at 36 weeks postmenstrual age.

Results.  The study was stopped before completion of sample size goals because of concern about serious side effects in the early steroid treatment group. A total of 542 infants were enrolled (early treatment N = 273, control N = 269). The 2 groups had similar demographic characteristics. No differences were noted in the primary outcome of CLD or death at 36 weeks postmenstrual age (early treatment 50% vs control: 53%, relative risk: 0.93; 95% confidence interval [CI]: 0.79-1.09). Fewer infants who received early steroid treatment had a patent ductus arteriosus (relative risk: 0.78; 95% CI: 0.63-0.96), and fewer infants in the early steroid group received indomethacin therapy (relative risk: 0.74; 95% CI: 0.64-0.86) or late steroid treatment (relative risk: 0.69; 95% CI: 0.58-0.81). However, more infants who received early steroid treatment had complications associated with therapy including an increase in hyperglycemia (relative risk: 1.29; 95% CI: 1.13-1.46) and an increase in the use of insulin therapy (relative risk: 1.62; 95% CI: 1.36-1.94). A trend toward increased gastrointestinal hemorrhage (relative risk: 1.55; 95% CI: 0.92-2.61), gastrointestinal perforation (relative risk: 1.53; 95% CI: 0.89-2.61), and an increased systolic blood pressure (relative risk: 1.34; 95% CI: 0.97-1.85) was noted. In infants receiving cranial ultrasound examinations, a marginal increase in periventricular leukomalacia was noted in the early steroid treatment group (relative risk: 2.23; 95% CI: 0.99-5.04). Infants who received early steroid therapy had fewer days in supplemental oxygen but experienced poor weight gain.

Conclusions.  A 12-day course of early postnatal steroid therapy given to extremely low birth weight infants did not decrease the risk of CLD or death at 36 weeks postmenstrual age and was associated with an increased risk of complications and poor weight gain.  Key words:  randomized controlled trial, newborn infant, prematurity, chronic lung disease, dexamethasone.

Effective early management of respiratory distress syndrome (RDS) has resulted in the survival of an increasing number of very low birth weight infants.¹ However, chronic lung disease (CLD) remains a significant problem among these low birth weight survivors.² Infants with CLD are at greater risk for pulmonary compromise in childhood, rehospitalization, neurodevelopmental delay, and late mortality.^3-5 The care of infants with CLD is costlier than that of premature infants without pulmonary compromise.⁶

The pathogenesis of CLD involves a cycle of lung injury, repair, and fibrosis.^7,8 Lung injury occurs in susceptible infants exposed to mechanical ventilation and supplemental oxygen. Factors including excess fluid administration, patent ductus arteriosus (PDA), infection, and genetic predisposition may further increase the risk of developing CLD. Conventional therapy to prevent CLD involves decreasing exposure to barotrauma and supplemental oxygen. In cases of established CLD, treatment with bronchodilators and diuretics is common.

Corticosteroids are widely used to prevent and treat CLD.⁹ Corticosteroid therapy may decrease lung injury through a variety of mechanisms, including stabilization of cellular or lysosomal membranes, decreasing inflammatory response, and decreasing pulmonary edema.^10-13 Investigators have used a variety of corticosteroid regimens in a variety of patient populations. At the time this trial was initiated, a meta-analysis of 5 randomized controlled trials of early corticosteroid treatment (treatment before 72 hours of age) suggested that infants who received early steroid treatment were at less risk of developing bronchopulmonary dysplasia (BPD) at 28 days of age and were perhaps less likely to develop CLD at 36 weeks postmenstrual age.¹⁴ Although investigators were aware of a variety of serious side effects of steroid therapy, none of these side effects were consistently reported.

We conducted a multicenter, randomized, double-blind, controlled clinical trial of early postnatal dexamethasone in premature infants admitted to neonatal intensive care units (NICUs) at 42 centers in the Vermont Oxford Network. Our primary goal was to determine the effect of early dexamethasone therapy in reducing CLD and death at 36 weeks postmenstrual age. Secondary goals included an analysis of the infant's clinical status at 14 and 28 days, duration of assisted ventilation, duration of supplemental oxygen, subsequent need for late postnatal steroids, clinical status at discharge, and other complications of prematurity and steroid therapy.

	METHODS

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The study protocol was developed by the Early Postnatal Corticosteroid Study Steering Committee of the Vermont Oxford Network and approved by the institutional review boards of all participating centers. Informed parental consent was obtained for each infant. A list of participating centers is appended to this report.

Study Population

Infants weighing 501 to 1000 g were eligible for enrollment at 12 hours of age if they were born before 31 completed weeks of gestation, needed assisted ventilation, received surfactant replacement therapy, were physiologically stable, and had no obvious life-threatening congenital anomaly, if blood cultures were obtained and antibiotic therapy initiated, and if the patient had known antenatal steroid exposure status.

Randomization

Parents whose infants met the entry criteria were approached before 12 hours of age for consent. If consent was obtained, infants were stratified based on admission weight (501-750 g, 751-1000 g) and exposure to antenatal steroids (none vs any steroids), then randomly assigned to dexamethasone or saline placebo. Local hospital pharmacies assigned study treatment using opaque sealed envelopes supplied by the Vermont Oxford Network.

Intervention

For infants assigned to receive early steroid treatment, intravenous dexamethasone was administered for 12 days according to the following dosage schedule: 0.5 mg/kg/d for 3 days, 0.25 mg/kg/d for 3 days, 0.10 mg/kg/d for 3 days, 0.05 mg/kg/d for 3 days. Control infants received similar volumes of normal saline. The NICU staff was blinded to treatment assignment.

NICU Care

Investigators were asked to complete appropriate surfactant therapy, continue antibiotics for a minimum of 48 hours, and evaluate infants for selective late postnatal corticosteroid therapy at 14 days of age. Infants in either group were eligible to receive late selective postnatal steroid therapy if the infant needed assisted ventilation and supplemental oxygen >30% at 14 days of age. The selective treatment protocol was modified from the regime of Cummings et al¹⁵ and allowed an 18- or 42-day course of treatment depending on the infant's initial response to treatment. Other aspects of NICU care were at the discretion of the clinical investigators.

Outcomes

Primary Outcome The primary outcome was the rate of CLD and death at 36 weeks postmenstrual age. CLD was defined as any oxygen requirement at 36 weeks postmenstrual age.

Secondary Outcome Secondary outcomes included an analysis of the infant's clinical status at 14 and 28 days of age, duration of assisted ventilation, duration of supplemental oxygen, subsequent need for late postnatal steroids, clinical status at discharge, and other complications of prematurity and steroid therapy.

Complications of Prematurity

Complications related to prematurity were prospectively defined using the Vermont Oxford Network Database definitions.

PDA PDA was diagnosed when there was a heart murmur compatible with a PDA or Doppler evidence of left-to-right ductal shunting plus 2 or more of the following: bounding peripheral arterial pulses, hyperdynamic precordial pulsation, radiographic evidence of cardiomegaly or pulmonary edema, or inability to decrease ventilator settings after 48 hours from the time of birth.

Necrotizing Enterocolitis Necrotizing enterocolitis was diagnosed at surgery, at postmortem examination, or clinically and radiographically using the following criteria: 1 or more of the following signs (bilious gastric aspirate or emesis, abdominal distension, occult or gross blood in stool) and 1 or more of the following radiographic findings (pneumatosis intestinalis, portal venous gas, pneumoperitoneum).

Bacterial Sepsis or Meningitis Bacterial sepsis or meningitis was defined as a predefined bacterial pathogen recovered from blood or cerebral spinal fluid. Early bacterial sepsis or meningitis was defined as occurring on or before day 3 of life; late bacterial sepsis or meningitis was defined as occurring after day 3 of life. Infections with coagulase-negative staphylococcus were coded as an episode of sepsis if the organism was recovered from blood or cerebral spinal fluid culture, signs of generalized infection were noted, and the infant was treated with antibiotics for 5 or more days.

BPD BPD was defined as the need for supplemental oxygen on day 28 of life.

Intraventricular Hemorrhage (IVH) IVH was coded on all infants who had a cranial ultrasound performed on or before day 28 of life based on the grading criteria of Papile et al.¹⁶

Cystic Periventricular Leukomalacia (PVL) PVL was defined as evidence of multiple small periventricular cysts on a cranial ultrasound obtained at any time.

Retinopathy of Prematurity (ROP) If an indirect ophthalmologic examination was performed, the worst stage of ROP in the eye with the most advanced stage was coded based on the International Classification of ROP.¹⁷

Adverse Outcomes

Complications potentially related to steroid treatment were prospectively followed. Assessment of blood glucose greater than 180 mg% and blood pressure (oscillometric measurement) was performed daily during the first 14 days of life. The use of insulin and antihypertensive agents was recorded. Gastrointestinal hemorrhage (defined as frank blood or coffee ground material from gastric secretions) and gastrointestinal perforation (defined as free air on abdominal radiograph or finding of perforation at the time of laparotomy) were noted. Growth parameters (including weight and head circumference) were noted at the time of enrollment, on the day after the initial course of treatment was completed, at 28 days of life, and at 36 weeks postmenstrual age.

Statistical Analysis

Data were analyzed using a Statistical Analysis System (SAS, Cary, NC, Version 6.1). Characteristics of treatment groups were compared using the Student's t test for continuous variables or the Wilcoxon rank sum tests when appropriate. Categorical baseline characteristics, outcomes, and complications were analyzed using Mantel-Haenszel ² analysis. Relative risk and 95% confidence intervals were determined using the Mantel-Haenszel technique for estimating relative risk across strata. All statistical analyses were 2-tailed. All analyses were based on the intention to treat. The Safety Monitoring Committee conducted 2 interim analyses.

Sample size calculation suggested that 411 infants would need to be enrolled in each study group to demonstrate a 10% reduction (55%-45%) in CLD or death at 36 weeks postmenstrual age ( = 0.05;  = 0.2).

	RESULTS

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Patient Population

Forty-two centers in the Vermont Oxford Network participated in the trial. The list of participating centers is appended to this article. Study enrollment began in March 1996. The study was stopped before completion of sample size goals because of concern about serious side effects in the early steroid treatment group and the unlikelihood that additional subject enrollment would yield a significant result regarding the primary outcome measure.

At the time the study was stopped, 2134 infants were admitted to participating centers weighing 501 to 1000 g. Of those infants, 2048 met gestational age criteria. Of these infants, 1142 needed assisted ventilation and 935 had received surfactant treatment. Of the 935 eligible infants, 542 infants were enrolled (early treatment N = 273, control N = 269). The 2 groups had similar demographic characteristics (Table 1). The average gestational age was 25.8 weeks in infants enrolled in the early treatment arm and 25.7 weeks in the control arm. No differences were noted in other demographic characteristics including gender, race, prenatal care, exposure to antenatal steroids, mode of delivery, and multiple birth. No differences were noted in the Apgar scores or the need for resuscitation.

Primary Outcome Measure

Results regarding the primary outcome measure and the relative risk and 95% confidence interval are reported in Table 2. No difference was noted in the primary outcome of CLD or death at 36 weeks postmenstrual age: 50% of the infants given early treatment had CLD or had died, compared with 53% of control infants (relative risk: 0.93; 95% confidence interval [CI]: 0.79-1.09). Significantly fewer infants who received early steroids needed supplemental oxygen at 36 weeks postmenstrual age: 23% in the early treatment group, compared with 31% in the control group (relative risk 0.73; 95% CI, 0.55-0.96). However, 5% more infants receiving early steroids died (relative risk: 1.22; 95% CI: 0.90-1.64).

Similar results were seen in the subgroup analysis of the 2 birth weight strata. No significant difference in the combined outcome of CLD or death at 36 weeks postmenstrual age was noted in either weight group. In infants weighing 501 to 750 g, 66% of the early treatment group had CLD or death, compared with 69% of the control group (relative risk: 0.96; 95% CI: 0.82-1.13). In infants weighing 751 to 1000 g, 32% of the early treatment group had CLD or death, compared with 35% in the control group (relative risk: 0.90; 95% CI: 0.64-1.28). The lower birth weight group had significantly less CLD (relative risk 0.68; 95% CI, 0.48-0.98), but as seen in the analysis of all birth weight groups, they had a concerning trend toward increased mortality (relative risk: 1.28; 95% CI: 0.94-1.74).

Secondary Outcome Measures

The incidence and relative risk of common complications of prematurity are presented in Table 3. No differences were seen in the risk of pneumothorax, necrotizing enterocolitis, or IVH. Nine percent fewer infants who received early steroid treatment had a hemodynamically significant PDA (relative risk: 0.78; 95% CI, 0.63-0.96), and 17% fewer infants in the early steroid group received indomethacin therapy (relative risk: 0.74; 95% CI: 0.64-0.86). Significantly fewer infants in the early steroid treatment group received late selective steroid therapy: 42% in the early treatment group, compared with 61% in the control group (relative risk: 0.69; 95% CI: 0.58-0.81). Of infants who had a cranial ultrasound examination, 7% of infants in the early steroid treatment group had evidence of PVL, compared with 3% in the control group (relative risk: 2.23; 95% CI: 0.99-5.04).

Complications Associated With Steroid Therapy

More infants who received early steroid treatment experienced complications associated with steroid therapy (Table 4). Infants who received early steroid therapy had a significant increase in hyperglycemia: 74% of infants in the early treatment group had blood glucose >180 mg%, compared with 57% in the control group (relative risk: 1.29; 95% CI: 1.13-1.46). Early steroid treatment was also associated with an increase in the use of insulin therapy: 62% of infants in the early treatment group received insulin, compared with 38% of the control group (relative risk: 1.62; 95% CI: 1.36-1.94). More infants who received early steroid therapy had clinical evidence of gastrointestinal hemorrhage: 12% in the early treatment group compared with 8% in the control group (relative risk: 1.55; 95% CI: 0.92-2.61). In addition, a trend toward increased gastrointestinal perforation was noted in association with early steroid therapy: 11% of infants receiving early steroid treatment had gastrointestinal perforation, compared with 7% of control infants (relative risk: 1.53; 95% CI: 0.89-2.61). A trend toward increased systolic blood pressure was also noted. No significant difference in nosocomial infection (defined as any bloodstream infection with a known pathogen or coagulase-negative staphylococcus) was noted (Table 3).

A more detailed look at infection demonstrates that 5% more infants who received early steroids acquired an infection with a known pathogen other than coagulase-negative staphylococcus (relative risk: 1.27; 95% CI: 0.91-1.78). Similar numbers of infants in both groups had infections with coagulase-negative staphylococcus (relative risk: 0.96; 95% CI: 0.74-1.25) or fungal organisms (relative risk: 0.83; 95% CI: 0.51-1.35).

Respiratory Support

The duration of ventilator support and supplemental oxygen is summarized in Table 4. Surviving infants who received early steroid therapy demonstrated no significant reduction in the number of days on ventilator support (29 days compared with 33 days). Surviving infants who received early steroid therapy had fewer days on supplemental oxygen (45 days compared with 50 days; P < .05).

Growth Parameters

Growth parameters are represented in Table 4. Weight and head circumference was followed after treatment (14 days of age), at 28 days of age, and at 36 weeks postmenstrual age. Infants who received early steroid treatment experienced poor weight gain after treatment and at 28 days of life but had no evidence of poor head growth at any time during the study.

	DISCUSSION

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Corticosteroids are widely used to treat CLD. In 1997, 50% of all extremely low birth weight infants in the Vermont Oxford Network received postnatal corticosteroids to treat or prevent CLD.⁹ Trials have evaluated a variety of strategies in treating and preventing bronchopulmonary dysplasia (respiratory insufficiency at 28 days of age) and CLD (respiratory insufficiency at 36 weeks postmenstrual age). Postnatal steroid treatment has been tested in infants with established bronchopulmonary dysplasia, using courses ranging from 1 to 6 weeks of dexamethasone therapy.^1518-23 Dexamethasone therapy in infants with established CLD has been shown to improve pulmonary function and decrease duration of assisted ventilation. However, the efficacy of dexamethasone on important clinical parameters such as CLD at 36 weeks postmenstrual age and mortality is unproven. Meta-analysis of these trials suggests a limited effect on mortality.²⁴ In addition, concern had been expressed about possible side effects of dexamethasone therapy including hyperglycemia, hypertension, cardiomyopathy, gastrointestinal bleeding, ROP, and sepsis.^1325-30

At the time this trial was initiated, 5 randomized controlled clinical trials had been conducted evaluating the efficacy of early steroid therapy in preventing bronchopulmonary dysplasia or CLD.^31-36 These 5 trials included a total of 353 infants. These initial trials studied a variety of patient populations, used a variety of dosage regimens, and treated for variable periods of time. Meta-analysis of these trials suggests that early steroid therapy led to a significant decrease in the risk of bronchopulmonary dysplasia at 28 days and a trend toward decreased risk of CLD at 36 weeks postmenstrual age.¹⁴ Studies using longer courses of high-dose steroids early in the course of RDS reported the greatest improvement in bronchopulmonary dysplasia at 28 days of age.^32-34 Fewer infants given early postnatal steroid therapy received later corticosteroid treatment for established CLD. No overall increase in sepsis, PDA, or mortality was noted. Although investigators were aware of a variety of serious side effects of steroid therapy, none of these side effects were consistently reported.

In this trial, extremely low birth weight infants on assisted ventilation were eligible for enrollment. In previous studies, this group of infants demonstrated a 55% risk of death or CLD at 36 weeks postmenstrual age.³⁷ This risk was judged sufficiently high to warrant enrollment in the study. In this trial, a 12-day course of early postnatal steroid therapy given to ventilated extremely low birth weight infants did not decrease the risk of CLD or death at 36 weeks postmenstrual age. Although improvements in the early respiratory course were noted, early postnatal steroid therapy was associated with serious complications including hyperglycemia, hypertension, and poor weight gain. Trends toward increased risk of gastrointestinal bleeding, gastrointestinal perforation, and hypertension also were noted.

To date, including this trial, 19 randomized controlled trials have evaluated the effect of early corticosteroids in the prevention of CLD.^{31-34,3638-50} As noted in the earlier meta-analysis, a variety of dosage regimes and patient populations were studied. The results of these trials (including the results of this study) have been summarized in a meta-analysis.⁵¹ In this analysis, early corticosteroids are noted to lead to earlier extubation, a decreased risk of CLD at 28 days and at 36 weeks gestation, and a decreased risk of PDA. No differences in the risk of neonatal mortality, IVH, or infection were noted. Of concern, the risk of gastrointestinal bleeding, gastrointestinal perforation, hypertension, and hyperglycemia were all significantly increased.

The current study noted an increase in the risk of PVL. PVL was diagnosed on any cranial ultrasound that demonstrated evidence of multiple small periventricular cysts. Cranial ultrasounds were not standardized in the protocol, so this secondary finding should not be overinterpreted. However, there is concern about developmental follow-up of infants exposed to postnatal steroid therapy. Animal models support a deleterious effect of dexamethasone exposure after experimentally induced ischemic damage.⁵² In the few studies that have reported developmental follow-up, infants who receive early corticosteroid therapy have significantly worse outcomes.^33,53 Of particular concern, these follow-up studies support an increase in cerebral palsy, the likely consequence of PVL.

The results of this and other studies leave many questions unanswered. Corticosteroid therapy appears to confer both significant clinical improvements and significant clinical risks. Improved identification of the infant who will most benefit from therapy may be important in optimizing benefit. Garland et al³⁸ demonstrated significant benefit from a 3-day course of early dexamethasone in infants weighing 500 to 1500 g. Infants were eligible if they were at significant risk for CLD or death, using a model to predict CLD or death at 24 hours of age.⁵⁴ Other steroid treatment protocols including the use of pulse steroids or inhaled steroids may prove to be of equal benefit but of less risk.⁵⁵ Steroid preparations other than dexamethasone may also hold promise.⁵⁰ A variety of issues might affect the success or failure of steroid therapy. Additional study of the timing, dosage and route of corticosteroid therapy as well as improved criteria for patient selection is warranted. Future studies will have to address the impact of steroid therapy not only on respiratory condition, but on neurodevelopmental outcome as well.

	APPENDIX

Participating Investigators

Centers are listed in alphabetical order as follows: Aultman Hospital, Canton, OH: Martha W. Magoon, MD, Louis J. Heck, MD; Baylor University Medical Center, Dallas, TX: Jonathan M. Whitfield; Brooklyn Hospital Center, Brooklyn, NY: Meena LaCorte, MD, Kimon M. Violaris, MD; Children's Hospital of Illinois at St Francis, Peoria, IL: James R. Hocker, MD, Constance M. McConnell, RN; Children's Hospital Medical Center of Akron, OH: Anand D. Kantak, MD, JoAnn Lindeman, RN, CNNP; Children's Hospital at Providence, Anchorage, AL: Roy F. Davis, PhD, MD, MHA, Sharon J. Hulman, RN, MPH; Children's of Orange County, Orange, CA: Sudeep Kukreja, MD, Carrie Worcester, MD; Children's Regional Hospital at Cooper UMC, Camden, NJ: Paresh B. Pandit, MD, Sherry E. Courtney, MD; Christiana Care, Newark, DE: Stephen A. Pearlman, MD, Kathleen H. Leef, RN; Columbia Hospital for Women, Washington, DC: Chowdhry Parveen K, MD; Deaconess Medical Center, Spokane, WA: Ronald Shapiro, MD, Ann Seaburg, RNC; Devos Children's Hospital, Grand Rapids, MI: Ed Beaumont, MD, Dinah Sutton, RN; Eastern Maine Medical Center, Bangor, ME: Mary Connolly, MD; Fletcher-Allen Health Care, Burlington, VT: Roger F. Soll, MD; Good Samaritan Hospital, Cincinnati, OH: Horacio S. Falciglia, MD, Kimberly A. Hasselfeld, BS; Henrico Doctors' Hospital, Richmond, VA: Charles R. Frakes, MD, Cheryl Carlson, RNC, MSN, NNP; Henry Ford Hospital, Detroit, MI: Savitri P. Kumar, MD; Sudhakar G. Ezhuthachan, MD, Chris Newman, MS, RNC, CNNP; Huntsville Hospital, Huntsville, AL: Meyer E. Dworsky, MD, Janet Price, RN; Kosair Children's Hospital, Louisville, KY: Tonya W. Robinson, MD, Tony R. Hilbert, RRT; Legacy Emanuel Children's Hospital, Portland, OR: Patrick K. Lewallen, MD, Karen Waske, RN, MN; Lenox Hill Hospital, New York, NY: Michael A. Giuliano, MD, Kathleen A. Green, RNC, MSN, NNP; Marshfield Clinic, Marshfield, WI: George J. Hoehn, MD; McKay-Dee Hospital Center, Ogden, UT: Michael Clark, MD; Methodist Hospitals, Gary, IN: Bangalore R. Suresh, Cholemari V. Sridhar; Miami Children's Hospital, Miami, FL: Ian P. Jeffries, MB, Mary E. Schwartz, ARNP; Northside Hospital, Atlanta, GA: Wendy A. Troyer, MD; Ottawa Hospital-CHEO, Ottawa, Ontario, Canada: Marc Blayney, MB, FRCPI, FRCPC, Elaine Whalen, RN; Parkview Memorial Hospital, Fort Wayne, IN: Joel W. Secrest, MD, Lois Ambrosini, RN; Rogue Valley Medical Center, Medford, OR: Patricia L. Jett, MD, Tracy Ritchie, RNC, NNP; Sacred Heart Medical Center, Spokane, WA: Barry Halpern, MD; Saint Agnes Health Care, Baltimore, MD: Howard J. Birenbaum, MD, Barbara A. Long, RN; Saint Barnabas Medical Center, Livingston, NJ: Shyan C. Sun, MD, Kamtorn Vangvanichyakorn, MD; Saint Cloud Hospital, St Cloud, MN: Norm Virnig, MD, Gregory A. Franklin, MD, FAAP; Saint Elizabeth's Medical Center, Boston, MA: James I. Hagadorn, MD, Silvia Z. Testa, MD; Saint John's Mercy Medical Center, St Louis, MO: Michael Maurer Jr, MD; Saint Joseph's Children's Hospital, Paterson, NJ: Adel Zauk, MD, Denis DiLallo, MD; Saint Joseph's Hospital & Medical Center, Phoenix, AZ: Montgomery Hart, MD; Saint Luke's Hospital, Bethlehem, PA: Lloyd Tinianow, MD, Andrew Unger, MD; Saint Vincent Hospital, Indianapolis, IN: Deborah Franzek, MD, Niceta C. Bradburn, MD; Scott & White Memorial Hospital, Temple, TX: Cheryl Cipriani, MD, Madhava Beeram, MD; Sparrow Hospital, Lansing, MI: P. Karna; Ann Hunt-Fugate, PharmD; Tulane Hospital for Children, New Orleans, LA: Jane Reynolds, MD, Maria Pierce, MD; University of Louisville Hospital, Louisville, KY: Linda Smith.

Steering Committee Members

Mark E. Anderson, MD, University of Tennessee Medical Center at Knoxville; Francis J. Bednarek, MD, University of Massachusetts Memorial Health; Gary Dreyer, MD, St John's Mercy Medical Center; Martha W. Magoon, MD, Aultman Hospital; Charles E. Mercier, MD, University of Vermont College of Medicine; Roger F. Soll, MD (Chair), University of Vermont College of Medicine.

Safety Committee Members

Jeffrey Garland, MD, SM (Chair), Medical College of Wisconsin; Peter Havens, MD, SM, Medical College of Wisconsin; Timothy McAuliffe, PhD, Medical College of Wisconsin; Robert Nelson, MD, PhD, Medical College of Wisconsin.

Statistician

Diantha Howard, MS, University of Vermont.

Study Coordinators

Mary Lou Butterfield, RN, Fletcher Allen Health Care; Jeanette M. Conner, PhD, MS, ARNP, Vermont Oxford Network.

Study Administration

Susan Dyer, Vermont Oxford Network; Daniel Morris, Vermont Oxford Network.

	ACKNOWLEDGMENTS

This work was supported in part by a grant from the Children's Miracle Network and the University of Vermont General Clinical Research Center Grant MO1 RR00109.

	FOOTNOTES

Received for publication Aug 30, 2000; accepted May 7, 2001.

Reprint requests to Roger F. Soll, MD, Department of Pediatrics, Medical Alumni Building A-121, University of Vermont College of Medicine, Burlington, VT 05405. E-mail: rsoll{at}salus.med.uvm.edu

	ABBREVIATIONS

RDS, respiratory distress syndrome; CLD, chronic lung disease; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; NICU, neonatal intensive care unit; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity; CI, 95% confidence interval.

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