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* Department of Pediatrics (Neonatology)
Radiology
CardioPulmonary Research Institute, Winthrop University Hospital, SUNY Stony Brook School of Medicine, Mineola, New York
|| Department of Newborn Medicine, Brigham and Women’s Hospital
¶ Divisions of Newborn Medicine
# Biostatistics, Children’s Hospital
** Harvard Medical School and Harvard School of Public Health, Boston, Massachusetts
Bio-Technology General Corporation, Iselin, New Jersey
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Design. Three hundred two premature infants (600–1200 g birth weight) treated with exogenous surfactant at birth for respiratory distress syndrome were randomized to receive either intratracheal r-h CuZnSOD (5 mg/kg in 2 mL/kg saline) or placebo every 48 hours (as long as intubation was required) for up to 1 month of age. Short-term, as well as longer-term pulmonary outcome was assessed.
Results. There were no differences between groups in the incidence of death or the development of bronchopulmonary dysplasia (oxygen requirement with an Edwards chest radiograph score of 
3) at 28 days of life or 36 weeks’ postmenstrual age. r-h CuZnSOD was well-tolerated and not associated with significant increases in any adverse event. At a median of 1 year corrected age, health assessments and physical examinations were performed on 209 (80%) surviving infants, with complete data available on 189 infants. Thirty-seven percent of placebo-treated infants had repeated episodes of wheezing or other respiratory illness severe enough to require treatment with asthma medications such as bronchodilators and/or corticosteroids compared with 24% of r-h CuZnSOD-treated infants, a 36% reduction. In infants <27 weeks’ gestation, 42% treated with placebo received asthma medications compared with 19% of r-h CuZnSOD-treated infants, a 55% decrease. Infants <27 weeks’ gestation who received r-h CuZnSOD also had a 55% decrease in emergency department visits and a 44% decrease in subsequent hospitalizations. Growth measurements and the results of physical examinations were comparable between groups.
Conclusions. These data indicate that treatment at birth with r-h CuZnSOD may reduce early pulmonary injury, resulting in improved clinical status when measured at 1 year corrected age. r-h CuZnSOD appears to be a safe and effective therapy that improves pulmonary outcome in high-risk premature infants.
Key Words: bronchopulmonary dysplasia • oxygen • antioxidant • superoxide dismutase • asthma • chronic lung disease
Abbreviations: BPD, bronchopulmonary dysplasia • CLD, chronic lung disease • PMA, postmenstrual age • SOD, superoxide dismutase • r-h CuZnSOD, recombinant human CuZnSOD • RDS, respiratory distress syndrome • IT, intratracheal(ly) • DSMC, Data Safety Monitoring Committee • ROS, reactive oxygen species
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The pathogenesis of BPD is multifactorial and associated with a variety of causative factors. Because the lungs of critically ill premature infants are exposed to supraphysiological oxygen concentrations at birth, oxidative insult may be an extremely important component of the injury process. The premature neonate may be particularly vulnerable to oxidant injury because endogenous antioxidant enzyme activity may be deficient at birth.6 A promising intervention that may prevent chronic respiratory morbidity and BPD is prophylactic supplementation with recombinant human antioxidant enzymes. Preliminary animal and human studies have consistently demonstrated that acute and chronic lung injury secondary to hyperoxia may be ameliorated by administration of one of these antioxidants, specifically superoxide dismutase (SOD).7–11
To determine whether recombinant human CuZnSOD (r-h CuZnSOD) could prevent or ameliorate acute and chronic lung injury, premature infants receiving supplemental oxygen, mechanical ventilation and surfactant replacement therapy for the treatment of respiratory distress syndrome (RDS) were enrolled in a randomized, double blind, placebo-controlled trial and their outcome monitored.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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24 weeks’ gestation, were 
24 hours of age, had clinical and radiographic evidence of RDS, and were being treated with supplemental oxygen, mechanical ventilation and exogenous surfactant (Survanta, Ross Laboratories, Columbus, OH). Infants were stratified by birth weight (600–800, 801-1000, 1001–1200 g) and center, and each infant from a multiple birth was randomized separately. The study was approved by the institutional review boards at all hospitals. Parental informed consent was obtained before study entry. Infants were excluded from the study if there was evidence of major congenital abnormalities, overwhelming congenital infection (risk factors in the perinatal history in conjunction with hypotension, leukopenia, neutropenia and/or thrombocytopenia), or severe perinatal asphyxia (10-minute Apgar score <4, significant metabolic acidosis, seizures).
Drug Administration
After the administration of exogenous surfactant, infants received either r-h CuZnSOD (5 mg/kg in 2 mL/kg of saline) or placebo (2 mL/kg saline) intratracheally (IT) in 2 divided doses with the infant placed in the lateral decubitus (right and left) position in 30° of Trendelenberg to enhance distribution.12 Infants received the study drug within 0.5 to 4 hours of surfactant administration. Infants were eligible to receive additional doses of exogenous surfactant as clinically indicated and were treated with additional doses of study medication IT every 48 hours until 28 days of age as long as intubation and mechanical ventilation were necessary. If an infant was extubated before 28 days of age, the study drug was discontinued. If the infant was subsequently reintubated, the study medication was continued every 48 hours through 28 days of age. The 48-hour dosing interval was based on previous pharmacokinetic data obtained in both animal and human studies.7,10
Laboratory and Radiographic Studies
A number of studies were obtained at baseline and throughout the first month of life to examine safety and efficacy of r-h CuZnSOD including arterial blood gases, complete blood counts, electrolytes and renal and liver function studies. Chest radiographs and cranial sonograms (when possible) were obtained before study drug administration. Initial chest radiographs were required to be consistent with a diagnosis of RDS. Additional chest radiographs and cranial sonograms could be obtained as clinically indicated, but were required at 1 month of life. At that time, a quantitative Edwards score was assigned to the chest radiograph with a value of 3 indicative of BPD.13 All radiographs and sonograms were evaluated by a single pediatric radiologist who was blinded to treatment assignment.
Serum was obtained at baseline and at 60 days of life (or at the time of transfer/discharge) for testing by enzyme-linked immunosorbent assay for anti-r-h CuZnSOD antibodies, as has been previously described.10
Follow-up Studies
At a median of 1 year corrected age (range: 9–25 months), the families of surviving infants were contacted and if possible, brought back to each institution’s Neonatal Follow-up Program. Parents completed health assessment questionnaires that detailed the infant’s clinical course after hospital discharge.14,15 This included general health, episodes of illness, medical treatment (including drug administration), number and type of doctor’s visits, emergency department visits, and hospital admissions. Growth parameters were measured and a comprehensive physical examination was performed. If parents were unable to return with their infant for a study-related visit, available data were obtained via telephone interviews. The infant’s pediatrician then reported growth parameters and any abnormalities on physical examination.
Outcome Variables
The primary outcome variable was death or the development of BPD at 28 days of life. BPD was defined as oxygen dependency at 28 days of life with a chest radiograph with an Edwards score 3. If a chest radiograph was not available for interpretation at 1 month of life and the infant was still receiving supplemental oxygen, then the infant was considered to be a treatment failure (BPD or death). Short-term secondary outcome variables included Edwards scores at 28 days of life, oxygen requirement at 36 weeks’ PMA, number of days in oxygen, number of days of respiratory support, number of days in the hospital, and short-term, adverse neonatal complications. Longer-term secondary outcome variables included number of episodes of significant pulmonary illness (requiring treatment with asthma medications such as bronchodilators and corticosteroids), number and type of doctor’s visits, emergency department visits, and hospital admissions and any abnormalities in growth parameters or physical examination.
Statistical Analyses
The sample size required for 80% power at 
= 0.05 with a continuity correction (assuming a 5% drop out rate) for a combined endpoint of death and/or BPD at 28 days of life was 174 infants in the r-h CuZnSOD and 174 in the placebo group. This calculation assumed an incidence of 40% (10% mortality, 30% BPD) in the control group and 25% in the r-h CuZnSOD treatment group. The intent-to-treat approach was used for all statistical analyses with all infants randomized and treated included in the analysis. The associations between categorical variables that were potential confounders, such as gender, race, and adverse events, and r-h CuZnSOD use and primary and secondary outcomes were evaluated using Fisher’s Exact Test (1-sided) and univariable logistic regression.16,17 These methods were also used to examine relationships between variables that were associated with short-term outcome such as the development of BPD and longer-term outcomes such as respiratory disease requiring pharmacologic intervention at 1 year corrected age. Relationships between growth parameters, laboratory studies, other continuous variables, r-h CuZnSOD use, and outcome measures were evaluated using the Wilcoxon rank sum test.
Multivariable logistic regression was used to evaluate the relationship between r-h CuZnSOD use and various outcomes while controlling for potential confounders as previously described.16 All variables associated with r-hCuZnSOD use and outcome, either of presumed biological importance or based on significance in univariable analysis, were considered as confounders in the multivariable models. An independent Data Safety Monitoring Committee (DSMC) comprised of 3 neonatologists and a biostatistician reviewed all data for safety and efficacy during the study.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Demographic information and background characteristics of the 302 infants enrolled in the trial are presented in Table 1. The groups were comparable on birth weight, gestational age, gender, ethnic composition, maternal complications, use of antenatal steroids, and mode of delivery. There were no significant differences in these characteristics between infants from both experimental groups who were seen in long-term follow-up compared with those who were lost to longer-term follow-up (data not shown).
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3. There were 14 deaths in each group during the first month of the study. The incidence of BPD (34%) at 28 days of life in the r-h CuZnSOD group was slightly higher than that in the placebo group (26%; P = .08). As expected, the highest incidence of BPD occurred in the most immature infants <27 weeks’ gestation. There was significant variability in the incidence of BPD among participating centers, ranging from 10% to 61%. Representative variables evaluated as possible confounders are shown in Table 2.17 In an optimized logistic regression model adjusting for antenatal steroid therapy, high early fluid rates, early acidosis, use of dexamethasone in the first 2 weeks of life, and hospital of enrollment, the odds ratio for BPD in r-h CuZnSOD-treated infants was 0.69, 95% confidence interval (0.09–5.1; P = .72).
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25% in the first 2 weeks of life). There were no significant differences between groups in the incidence of adverse events (Table 4). Although the incidence of severe interventricular hemorrhage (grades III, IV) tended to be lower in the r-h CuZnSOD group compared with the placebo group, the difference did not reach statistical significance (P = .2). The incidence of late-onset sepsis (positive bacterial cultures in blood, urine, or cerebrospinal fluid at 3 days of age) was not significantly different between groups (8% in the r-h CuZnSOD group and 7% in placebo controls). The incidence of pneumonia was increased in the r-h CuZnSOD group, but the difference was not significant and varied among centers with 1 center reporting 45% of all cases of pneumonia for the entire r-h CuZnSOD group. There were also no differences between groups in the incidence of necrotizing enterocolitis, retinopathy of prematurity or any other laboratory abnormality.
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Longer-Term Outcomes
Of 274 infants surviving until initial hospital discharge, 13 infants were known to have died during the first 2 years of life (no difference between groups). Sixty-five infants were lost to follow-up. Long-term follow-up was performed at a median of 1 year corrected age in 209 (80%) surviving infants, 103 of whom received r-h CuZnSOD and 106 of whom received placebo. Complete data were available for 189 infants. Infants were examined for pulmonary abnormalities such as asthma or pulmonary infections severe enough to be treated with asthma medications such as bronchodilators or corticosteroids (inhaled, systemic) as well as growth characteristics.14,15 In infants who had received r-h CuZnSOD, 23% had respiratory illness severe enough to require treatment with asthma medications compared with 36% of placebo controls (P = .05; see Fig 1), a 36% reduction. The effect was most significant in the most immature infants <27 weeks’ gestation (n = 88), with 19% of infants who had received r-h CuZnSOD receiving asthma medications compared with 42% in placebo controls, a 55% reduction (P = .01). The improved pulmonary outcome seen in r-h CuZnSOD-treated infants occurred despite significantly fewer r-h CuZnSOD-treated infants receiving prophylactic treatment with Respigam (Medimmune, Gaithersburg, MD) (16%) compared with placebo controls (35%; P = .03). These data strongly suggest that r-h CuZnSOD prevented the development of chronic respiratory morbidity, despite the absence of any measurable differences in short-term pulmonary outcome (Table 5).
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3 in the neonatal period were independent predictors of respiratory illness requiring treatment at 1 year corrected age, especially in infants <27 weeks’ gestation at birth (P = .03 and P = .05, respectively). A diagnosis of BPD at 28 days of life or at 36 weeks’ PMA was not associated with an increased risk of significant respiratory illness requiring treatment later in life. In the group of infants at highest risk for BPD (those <27 weeks’ gestation), 19% of r-h CuZnSOD-treated infants had emergency department visits by the second year of life compared with 42% of placebo controls (P = .01), a decrease of 55% (Fig 2). There was also a 44% decrease in the number of hospitalizations among infants <27 weeks’ gestation who had received r-h CuZnSOD compared with placebo controls (30% vs 54%; P = .05). No significant differences in the number of outpatient physician visits of any type were identified between r-h CuZnSOD-treated and placebo groups. Finally, there were no differences between groups in any growth measurement or abnormality on physical examination.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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The pathogenesis of BPD is complex, with several adverse contributors such as hyperoxia, mechanical ventilation, and infection acting simultaneously to generate excessive, toxic reactive oxygen species (ROS) and injure the developing lung.22 The premature infant appears to be especially vulnerable to ROS-induced damage because of the relative lack of antioxidant defenses at birth.6 The ability to increase synthesis of antioxidant enzymes in response to ROS is decreased in preterm animals, resulting in an imbalance between oxidants and antioxidants and an increased risk for the development of BPD.23
Several studies have found indirect evidence of ROS (oxidation of lipids and proteins) in serum and in the lung soon after birth in premature infants who subsequently developed BPD.24–26 The multicenter STOP-ROP trial examined whether exposing premature infants to higher inspired oxygen concentrations would prevent the development of severe retinopathy of prematurity.27 Although the effects of the increased oxygen were minimal on the eyes, exposed infants had dramatic increases (55%) in the incidence of BPD and pulmonary infections. BPD is believed to begin as ROS-induced cell injury leading to acute inflammatory changes and lung injury followed by the development of CLD.
Oxygen, bronchodilators, diuretics, inhaled or systemic steroids, and nutritional supplements (ie, vitamin A) have been used for the prevention and treatment of BPD with variable results. Although initial studies suggested that early postnatal steroids (dexamethasone) may reduce the incidence and severity of BPD, significant adverse effects have recently been found, including increased mortality, cerebral palsy, bowel perforation and infection.18,19 New treatments for the prevention of chronic respiratory morbidity related to RDS and BPD are urgently needed.
Multiple studies have demonstrated that overexpression or supplementation of SOD mitigates cell damage, prevents inflammatory changes and reduces the development of acute and chronic lung injury.7–9,28–32 Two small clinical trials have been performed comparing IT administration of single or multiple doses of r-h CuZnSOD to placebo in premature infants with RDS at risk for the development of BPD.10,11 In both of these studies, r-h CuZnSOD was detected in serum, urine, and tracheal aspirate fluid for up to 48 hours after IT administration. Acute inflammatory changes in the lung (which are seen early in infants developing BPD) were significantly reduced in the lungs of infants treated with r-h CuZnSOD, although the number of infants studied was too small to determine if there was an effect on the incidence or severity of BPD in the immediate newborn period. Long-term follow-up studies suggested that the development of chronic pulmonary dysfunction (ie, asthma) was ameliorated in infants treated with r-h CuZnSOD.34 Although all of these studies support a critical role of SOD in the prevention of ROS-induced lung injury, caution should be exercised with the use of antioxidants such as SOD, especially in high-risk premature infants.33 ROS may potentially be toxic, but may also have important cellular functions in many organ systems.
The present study did not demonstrate any effect of r-h CuZnSOD on the incidence of BPD (either 28 days or at 36 weeks’ PMA) or any other short-term outcome variable. However, improvements in clinical status were found at 1 year corrected age with significant decreases in the incidence of pulmonary disease severe enough to require treatment with asthma medications such as bronchodilators or corticosteroids, especially in infants <27 weeks’ gestation at birth. Although the use of these medications to treat significant pulmonary disease could vary among different health care professionals, there was a strong correlation with significant reductions in the number of emergency department visits and hospitalizations. This occurred despite a significant increase in the use of Respigam in infants in the placebo group. Respigam was approved by the Food and Drug Administration for use in high-risk infants for the prevention of respiratory syncytial virus infection, an important cause of severe pulmonary morbidity in premature infants.35 However, standardized guidelines for the use of Respigam did not exist at the time this trial was performed. This suggests that Respigam was administered because of more worrisome respiratory symptoms in the placebo group at the time of hospital discharge. Despite this, infants treated with r-h CuZnSOD were still less likely to develop significant respiratory illness. These data strongly suggest that r-hCuZnSOD administration at birth ameliorated acute lung injury and prevented long-term pulmonary damage, decreasing the incidence of asthma and severe pulmonary infections.
There are a number of reasons why significant long-term improvement in pulmonary status did not correspond to a reduction in the incidence of BPD. As demonstrated by Palta and associates,21 analysis of criteria used to predict the development of BPD (ie, oxygen requirements, BPD scores) had a relatively weak correlation with neonatal outcome. The use of asthma medications to treat illness in the first 1 to 2 years of life and the number of hospitalizations could be predicted with a sensitivity ranging from 38% to 56% and a specificity of 68% to 82%. The present study again demonstrates that acute symptoms in small, premature infants are not necessarily associated with abnormal long-term outcome. Our failure to demonstrate short-term benefits of r-hCuZnSOD could have been influenced by the absence of uniformly accepted guidelines for the clinical use of oxygen, which is intimately involved in the pathogenesis, definition, and treatment of BPD. Ellsbury and colleagues20 recently reported the results of a survey that demonstrated wide variability in pulse oximetry thresholds for oxygen use in different institutions, suggesting that a definition of BPD that includes a need for oxygen may not be completely accurate.
The use of r-h CuZnSOD was well-tolerated and not associated with a significant increase in any adverse outcome. Although administration of r-h CuZnSOD could potentially interfere with superoxide generation and bacterial killing by neutrophils and macrophages, the incidence of late-onset sepsis (8% r-h CuZnSOD vs 7% placebo; P = .45) and pneumonia (7% in the r-h CuZnSOD group vs 3% in the placebo group; P = .11) were comparable between groups.36 These findings are consistent with previous studies that indicate that hyperoxia injures monocytes and alveolar macrophages, reducing bacterial clearance and killing.37,38 The administration of r-h CuZnSOD to these mononuclear cells exposed to hyperoxia has been shown to actually improve mononuclear cell function, including bacterial clearance and killing.37,38 Preventing damage to the pulmonary epithelium and alveolar macrophages would be expected to decrease the development of invasive pulmonary and systemic infections, as was seen in the long-term segment of the present study.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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ACKNOWLEDGMENTS |
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We wish to thank Susan Richter, MD, Lisa Salerno, Nadim Kassem, MD, William Huang, Norman Barton and Hschi-Chi Koo for their valuable contributions to this study. We would also wish to acknowledge the critical involvement of the DSMC: Drs T. Allen Merritt, Jacob V. Aranda, Ivan D. Frantz III, and Sylvan Wallenstein. The study centers and principal investigator at each center are as follows: Stephen Baumgart, MD, Thomas Jefferson Medical Center, Philadelphia, PA; Wally Carlo, MD, University of Alabama at Birmingham School of Medicine, Birmingham, AL; Robert Couser, MD, Minneapolis Children’s Medical Center, Minneapolis, MN; Dennis Davidson, MD, Schneider Children’s Hospital, New Hyde Park, NY; Jonathan M. Davis, MD, Winthrop University Hospital, Mineola, NY; Steven Donn, MD, University of Michigan Medical Center, Ann Arbor, MI; Ira Gewolb, MD, University of Maryland, Mercy Medical Centers, Baltimore, MD; Mark Hudak, MD, University of Florida Medical Center, Jacksonville, FL; John Kinsella, MD, Children’s Hospital of Denver, Denver, CO; Mark Mammel, MD, Children’s Health Care, St Paul, St Paul, MN; Stephen Minton, MD, Utah Valley Regional Medical Center, Provo, UT; Richard Parad, MD, Brigham and Women’s Hospital, Boston
, Boston, MA; Douglas Richardson, MD, Beth Israel-Deaconess Medical Center, Boston, Boston, MA; Ann Stark, MD, Children’s Hospital, Boston, Boston, MA; Lance Parton, MD, Children’s Medical Center at Stony Brook, Stony Brook, NY; Tonse Raju, MD, University of Illinois at Chicago Medical Center, Chicago, IL; Rangasamy Ramanathan, MD, Women’s and Children’s, Good Samaritan Hospitals, Los Angeles, CA.
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FOOTNOTES |
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Reprint requests to (J.M.D.) Department of Pediatrics, Winthrop University Hospital, SUNY Stony Brook School of Medicine, 259 First St, Mineola, NY 11501. E-mail: jdavis{at}winthrop.org
The authors acknowledge the untimely death of Dr Richardson after submission of this manuscript. 
Counted as a single center for reporting purposes.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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