PEDIATRICS Vol. 123 No. 1 January 2009, pp. 89-96 (doi:10.1542/peds.2007-2680)
ARTICLE |
A Pilot Randomized, Controlled Trial of Later Treatment With a Peptide-Containing, Synthetic Surfactant for the Prevention of Bronchopulmonary Dysplasia
a School of Medicine, University of North Carolina, Chapel Hill, North Carolina
b Department of Neonatology, New Hanover Regional Medical Center, Wilmington, North Carolina
c Division of Neonatology, Department of Pediatrics, and Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee
d Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Michigan Health System, C.S. Mott Children's Hospital, Ann Arbor, Michigan
e Division of Neonatology, Lehigh Valley Hospital, Allentown, Pennsylvania
f Brody School of Medicine, East Carolina University, Greenville, North Carolina
g Discovery Laboratories, Inc, Warrington, Pennsylvania
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Oxidant injury and lung inflammation in extremely premature infants are associated with the development of bronchopulmonary dysplasia. Surfactant dysfunction resulting from these events may contribute to the pathogenesis of bronchopulmonary dysplasia. Treatment with exogenous surfactant may decrease the incidence or severity of bronchopulmonary dysplasia. We conducted a masked, multicenter, multinational, randomized, controlled, pilot study to estimate the effects of treating infants at high risk for developing bronchopulmonary dysplasia with lucinactant, a synthetic, peptide-containing surfactant, on safety during dosing and the incidence of death or bronchopulmonary dysplasia.
METHODS. Preterm infants between 600 and 900 g requiring mechanical ventilation and a fraction of inspired oxygen of 
0.30 between 3 and 10 days of age were randomly assigned to receive either sham air (placebo) or 1 of 2 doses of lucinactant (90 or 175 mg/kg total phospholipid) every 48 hours to a maximum of 5 doses, if they remained on mechanical ventilation.
RESULTS. Of 136 infants enrolled at 34 sites, 44 received placebo, 47 received 90 mg/kg total phospholipid, and 45 received 175 mg/kg total phospholipid. The 90 mg/kg group had a significantly higher percentage of boys (64%) compared with the placebo group (39%); no other significant differences in baseline characteristics among groups were present. Compared with placebo, both the 90 mg/kg and 175 mg/kg groups experienced a significantly higher incidence of desaturation and bradycardia during dosing. Twenty-four hours after dosing, the mean fraction of inspired oxygen was lower in both lucinactant groups (33%) compared with the placebo group (39%). The incidence of mortality or bronchopulmonary dysplasia was 66% in the placebo group, 79% in the 90 mg/kg group, and 58% in the 175 mg/kg group. These differences were not statistically significant. There were no statistical differences among groups for pneumothorax, pulmonary interstitial emphysema, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, or mortality.
CONCLUSIONS. There were trends toward lower oxygen requirements and toward a lower incidence of mortality or bronchopulmonary dysplasia at 36 weeks' postmenstrual age in infants who received the higher dose of lucinactant, and this warrants further investigation.
Key Words: premature infant • surfactant • bronchopulmonary dysplasia
Abbreviations: BPD—bronchopulmonary dysplasia • FIO2—fraction of inspired oxygen • DOL—day of life • S-90—90 mg/kg lucinactant • S-175—175 mg/kg lucinactant • PMA—postmenstrual age • CI—confidence interval • OR—odds ratio
Bronchopulmonary dysplasia (BPD) is the most frequent serious complication of extremely premature birth.1,2 The pathogenesis of BPD is multifactorial and includes features related to immaturity of the lung, such as underdeveloped parenchyma, altered alveolarization, and deficient surfactant production, as well as lung inflammation.3 The early administration of surfactant improves pulmonary function and survival, but it has not been shown to consistently reduce the incidence of BPD.4–6 Evaluation of ventilated preterm infants with evolving BPD has demonstrated several abnormalities of the surfactant system, such as a quantitative deficiency of surfactant components (particularly surfactant proteins), a decreased ability of endogenous surfactant to lower surface tension, and increased surfactant turnover.7–9 Temporary improvement in pulmonary function after surfactant administration has been reported in preterm infants requiring prolonged mechanical ventilation.10–12 Therefore, it is plausible that administration of surfactant therapy beyond the first few days of life may be beneficial in preventing BPD.
Many infants who develop BPD have early, severe lung disease characterized by a need for substantial supplemental oxygen and mechanical ventilation. In contrast, approximately one third of infants who develop BPD experience a period of minimal lung disease during the first week of life, during which little or no supplemental oxygen or mechanical ventilation is required. This period of minimal support is followed by pulmonary deterioration during the second week of life.13 Therapies for the prevention of BPD should target both of these at-risk populations.
We hypothesized that later additional administration of surfactant to infants at risk for developing BPD, defined by either persistent early moderate lung disease or pulmonary deterioration after a period of relative stability, would reduce the incidence of BPD. Therefore, we conducted a masked, multicenter, multinational, randomized, controlled, pilot study to estimate the effects of treating infants at high risk for developing BPD with a peptide-containing synthetic surfactant, lucinactant. Lucinactant was selected as the surfactant of choice because of evidence showing resistance to inactivation by plasma proteins and oxidant species14–16 and inherent anti-inflammatory properties.17 In our study, we examined the tolerability of lucinactant by infants at risk for developing BPD and the effect on the incidence of death or BPD.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Population
Infants were enrolled at 34 sites, 19 in the United States, 5 in Chile, 7 in Poland, and 3 in Hungary. All of the US and international sites were selected based on their capabilities to conduct rigorous clinical trials. In addition, all of the non-US centers and some US centers had participated in previous randomized, controlled trials with lucinactant.18,19 All provided care comparable to tertiary care centers in the United States (eg, use and management of mechanical ventilation, access to intravenous nutrition and management of nutrition, surfactant therapy, and general management of the extremely low birth weight infant). Infants were eligible for the study if they were mechanically ventilated, required fraction of inspired oxygen (FIO2) >0.30, and were treated with surfactant during the first 2 days of life when clinically indicated. The original protocol enrolled infants on day of life (DOL) 3 only. Subsequently, we amended the protocol to include infants who met entry criteria any time between DOL 3 and 10.13 Exclusion criteria included delivery after prolonged (
2 weeks) rupture of membranes, culture-proven sepsis, severe intraventricular hemorrhage (determined by profoundly abnormal neurologic examination or a cranial sonogram demonstrating a grade IV intraventricular hemorrhage20), congenital heart disease other than a patent ductus arteriosus, congenital anomalies inconsistent with life or likely to confound efficacy or safety end points, or previous treatment with inhaled nitric oxide or steroids (with the exception of hydrocortisone for blood pressure support). In addition, infants with severe lung disease, defined as treatment with FIO2 0.80 and mean airway pressure 12 cmH2O were excluded. Infants were also excluded if the FIO2 fell below 0.25 at any time between eligibility and random assignment. The study was approved by each center's institutional review board, and written, informed parental consent was obtained before enrollment. A data, safety, and monitoring board reviewed masked safety data at the time point when one third of patients completed the study. The data, safety, and monitoring board recommended the study to continue as planned after this interim analysis.
Study Surfactant and Preparation
Lucinactant (Surfaxin [Discovery Laboratories, Inc, Warrington, PA]) is a sterile, white suspension supplied in 10-mL (30 mg of phospholipids per mL) single-use vials consisting of a phospholipid combination of dipalmitoyl-phosphatidylcholine (22.5 mg/mL), palmitoyl-oleyl phosphatidylglycerol (7.5 mg/mL), and palmitic acid (4 mg/mL), as well as a 21-residue synthetic peptide, sinapultide, which mimics the functions of surfactant-associated protein B.18,19,21 Lucinactant was warmed for 15 minutes at 44°C using a specially designed heating block, followed by vigorous shaking until a uniform, free-flowing suspension was obtained. The appropriate volume of lucinactant (or sham air for masking purposes) was drawn into syringes marked with the patient's name and identification number that were partially covered with opaque labels designed to make the contents not readily visible.
Study Design
Infants were stratified only by center, using only sealed envelopes, and were randomly assigned to 1 of 3 treatment groups: sham air (placebo), 90 mg/kg lucinactant (S-90), or 175 mg/kg lucinactant (S-175), a dose used in previous clinical trials and demonstrated to be efficacious.18,19 Because there was no established surfactant dosing data for the treatment of infants at risk for BPD, we designed a dose-ranging study, which included 2 lucinactant doses, and sought to determine whether there was a dose response in this population. Treatment allocations were assigned in randomized blocks of 3 per site. Randomization occurred as soon as possible after determination of eligibility but no later than 8 hours after meeting entry criteria. In the case where both members of a twin set were eligible for and enrolled in the study, each twin was treated as a randomly assigned event. Treatment was administered every 48 hours for a maximum of 5 doses, as long as the infant was still receiving mechanical ventilation. For infants extubated before receiving all 5 doses of the study treatment but who were subsequently reintubated, dosing was resumed and continued at 48-hour intervals, up to the maximum of 5 total doses, or until DOL 18, whichever occurred first.
Clinical providers were masked to study treatment. Management of mechanical ventilation, including weaning and extubation, was left to the clinical provider. The preparation of lucinactant/sham air was restricted to a location not visible to patient caregivers. The individuals responsible for preparing lucinactant/sham air were either a pharmacist or another professional not involved in the clinical management of any study infant. Infants were screened from view during treatments, and individuals administering study treatments did not participate in subsequent clinical decision-making.
During dosing, the drug administrator placed the infant in a head-up, left lateral decubitus position and slowly (over 1–2 minutes) administered one quarter of the syringe volume. After allowing a brief recovery period, the infant was placed in the right lateral decubitus position for administration of another quarter of study drug. Administration of the remaining dose was repeated while the infant was in the left and right lateral decubitus position, respectively. Infants assigned to receive sham air for masking purposes were given 3.0 mL/kg. For the lucinactant groups, the drug administrator gave either 3.0 mL/kg (S-90) or 5.8 mL/kg (S-175). All of the doses were administered through catheters introduced into the distal end of the endotracheal tube via a side port or Bodai Neo2-Safe valve (B&B Medical Technologies, Orangevale, CA) without disconnecting the infant from mechanical ventilation. After dosing, the head of the infant was raised slightly to reduce the likelihood of reflux of surfactant. Endotracheal suctioning was avoided for 1 hour after dosing, unless there were obvious signs of endotracheal tube obstruction. We defined desaturation during dosing as pulse oxygen saturation <75% for >30 seconds and bradycardia during dosing as a heart rate <100 beats per minute for >30 seconds.
Outcomes and Statistical Methods
This was a pilot randomized, controlled trial to estimate the treatment effects of administering lucinactant beginning on DOL 3 in infants at high risk for BPD. The treatment effect of primary interest was the incidence of mortality or BPD at 36 weeks' postmenstrual age (PMA). Gestational age was determined by best obstetrical measurement. We also examined the effect of treatment on other complications of prematurity and evaluated safety and tolerability during dosing.
A sample size estimate could not be calculated in the absence of preliminary data describing the effect of surfactant treatment for this indication. Therefore, the sample size was selected based on practical issues but was of sufficient size to detect a large treatment effect, if present. Analysis of data from 2 clinical studies of lucinactant indicated that the estimated incidence of death or BPD at 36 weeks' PMA in the patient population selected for this study was 
70% to 75%.18,19 With a planned sample size of 70 infants per group, if the observed incidence of mortality and/or BPD at 36 weeks' PMA was comparable to the data derived from the previous lucinactant trials (70% in the placebo group), the 90% confidence intervals (CIs) of a 14% absolute risk reduction of the treatment difference (from 70% to 56%) would be –27.3% to –0.72%.
Statistical analyses included all of the randomly assigned patients using an intention-to-treat approach. Categorical demographic variables were compared using the Cochrane-Mantel-Haenszel test for general association. Continuous variables were assessed by treatment group using either analysis of variance or the Wilcoxon rank-sum test if the data were not normally distributed. Comparisons for the death or BPD efficacy end points were performed using the logistic regression model. Proportional hazard models were used to compare the proportions of infants requiring mechanical ventilation or supplemental oxygen over time. The Cochrane-Mantel-Haenszel or 
2 tests were used to assess categorical variables of safety and tolerability. All of the tests were 2 sided. We did not adjust for the distribution of twin pairs among treatment groups.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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From December 2004 to May 2006, 809 infants with a birth weight of 600 to 900 g were screened, and 136 were enrolled (17%; Fig 1). Of these, 56 (41%) were enrolled in US centers. There were 6 twin pairs enrolled in the study; all of these pairs were randomly assigned to different treatment groups. The study was electively terminated after two thirds of the planned subject enrollment was achieved because of both slow accrual of patients and issues regarding availability of lucinactant product. The lucinactant used in the study patients met all of the product specifications throughout the study period. However, other lucinactant batches manufactured during the same period failed to meet certain stability criteria. Considering this circumstance, the sponsor, in consultation with the steering committee, decided that it was in the best interest of patients to discontinue further enrollment while an investigation into the stability failure was conducted and resolved.
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Table 1 displays the baseline demographic and clinical characteristics of each group. Compared with the placebo group, a statistically significant larger percentage of infants in the S-90 group were boys (64% vs 39%), and there was a trend toward more infants with a 5-minute Apgar score
3 (11% vs 0%). Otherwise, the 3 groups had similar characteristics. Four infants (2.9%) enrolled were outside of the eligible weight range but were included in the analyses.
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Figure 2 demonstrates the mean FIO2 of infants 15 minutes before the first dose of study medication and 2, 6, 24, and 48 hours after the first dose. The baseline FIO2 was highest in the placebo group. The mean FIO2 transiently increased after dosing in the S-175 and S-90 lucinactant groups (peaking at 49% and 44%, respectively) and then decreased thereafter. Twenty-four hours after dosing, the mean FIO2 was lower in both lucinactant groups (33%) compared with the placebo group (39%). At 48 hours after dosing, the mean FIO2 was lower in the S-175 group (31%) compared with the S-90 group (33%) and the placebo group (38%). Because this analysis was not planned a priori, we did not subject these numbers to statistical testing. The use of multiple modalities of ventilation (ie, volume targeted ventilation) precluded determination of the mean airway pressure after lucinactant or placebo.
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Table 2 shows the primary outcomes of each group. Infants in the S-90 group had a higher incidence of death or BPD at 36 weeks' PMA (79%), and infants in the S-175 group had a lower incidence (58%) compared with the placebo group (66%). These differences did not reach statistical significance. Within each treatment group, there was no difference in overall mortality or any of the key outcomes between US and foreign sites. An analysis of covariance was conducted to determine whether imbalances of risk factors among groups explained the differences in the incidence of death or BPD. Gender, gestational age, and birth weight, factors that have been shown to influence the risk of death or BPD, were included in this analysis. (Fig 3A and B) After adjustment, the odds ratio (OR) and 95% confidence interval (CI) of death or BPD for the S-90 group compared with the placebo group decreased from 1.9 (CI: 0.8–4.9) to 1.5 (CI: 0.5–4.3). After adjustment, the OR of death or BPD in the S-175 group compared with the placebo group remained unchanged (0.7 [CI: 0.3–1.7] to 0.7 [CI: 0.3–1.8]).
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Table 3 lists the incidence of complications of prematurity. All were in the range expected for a high-risk population such as the one included in this study. Except for a statistically significant lower incidence of pulmonary hemorrhage in the S-90 lucinactant group, there were no significant differences among groups. The duration of mechanical ventilation and oxygen therapy tended to be lower in the S-175 group, although this was not statistically significant. Table 4 displays the safety and tolerability of dosing in each group. Compared with placebo, both the S-90 and S-175 groups experienced a significantly higher incidence of desaturation and bradycardia during and immediately after dosing. These events were transient in nature.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This pilot study was designed to explore the potential risks and benefits of administering a synthetic peptide-containing surfactant to infants at high risk for developing BPD. The use of surfactant for this indication has not been systematically investigated. Within 2 hours of treatment with lucinactant, we observed improvements in lung function, as evidenced by a reduction in the need for supplemental oxygen. This improvement persisted for 48 hours, the interval chosen for redosing. We examined whether these improvements in lung function translated into long-term benefits by determining the incidence of death or BPD in treated infants compared with infants receiving sham air. We observed an apparent differential effect between infants receiving 175 mg/kg, the standard dose of lucinactant for respiratory distress syndrome, and 90 mg/kg, a lower dose containing an amount of phospholipids below that contained in the standard dose of any commercially available surfactant preparation in the United States. The incidence of death or BPD was lower among infants receiving 175 mg/kg and higher among infants receiving 90 mg/kg. In both cases, the effect size did not reach statistical significance. Of note, the absolute risk difference (8%) seen in the 175 mg/kg group compared with placebo is similar to that of inhaled nitric oxide22 (7%) and intramuscular vitamin A23 (7%), prophylactic therapies for the reduction of BPD, suggesting that if this effect is real, then a larger study may demonstrate statistical significance. However, the sample size of this pilot study limits our ability to explore further the differential treatment effect observed between the lower lucinactant dose and the standard dose versus placebo.
There are strong reasons to believe that treatment with surfactant after day 2 of life may be beneficial. In chronically ventilated preterm infants, endogenous surfactant often fails to retain its physiologic effect and may be rendered dysfunctional.7–9 Additional surfactant replacement therapy with lucinactant might overcome inactivation or dysfunction and lead to improved lung function, reduced ventilatory requirements, and less ventilator-induced lung injury. Although not statistically significant, the trend toward decreased oxygen therapy and mechanical ventilation days in the S-175 group lends some support to this possibility. This observation, along with a reduction in death or BPD in the S-175 group supports this hypothesis. These findings are consistent with observations from previous retrospective or uncontrolled studies of late surfactant therapy.10–12 The small sample size in this pilot trial precludes a definitive conclusion but raises the possibility that this effect is real.
We investigated whether the apparent increase in the incidence of death or BPD in the S-90 group resulted from imbalances in baseline risk factors between groups. After adjusting for known risk factors, the OR for this outcome in the S-90 group compared with the placebo group approached unity, raising the possibility that that an imbalance in risk factors in this group may have influenced outcomes. Adjustment in the S-175 group had little effect on the OR. It is possible that the S-90 therapy exposed infants only to the adverse effects of dosing (desaturation and bradycardia) but did not impart the benefit of the higher phospholipid concentration used in the S-175 group. An alternative explanation is that there is no true effect, and the variability among groups resulted from chance alone. The sample size of this pilot study does not permit resolution of this question.
As expected, we observed a higher incidence of desaturation and bradycardia during administration of lucinactant in both groups compared with placebo, effects of late surfactant therapy that have not been reported previously. These results are consistent with previously reported studies of the use of surfactant for respiratory distress syndrome in which bradycardia and desaturation during dosing were observed in 19% to 42% and 40% to 75% of infants, respectively.24,25 In the present study, the increased incidence of adverse events during dosing did not correlate with statistically significant increases in adverse outcomes (eg, periventricular leukomalacia or retinopathy of prematurity). However, the incidence of periventricular leukomalacia in the S-175 group will need to be closely evaluated in future studies.
There were several limitations to this study, most importantly the small sample size. However, this was an estimation study by design. Other limitations of the study include the lack of mechanical ventilation guidelines and weaning criteria. Presumably, random assignment should have balanced these issues. Finally, we did not use a room air challenge to assign the diagnosis of BPD using a physiologic definition.26 This would have made the diagnosis of BPD more precise.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Administration of S-175 of the synthetic protein-containing surfactant, lucinactant, to high-risk preterm infants after the first 48 hours of life may reduce the incidence of death or BPD. A larger, more definitive study that is adequately powered, based on the estimated treatment effect (8%) observed in this pilot study, is warranted to establish whether late treatment with lucinactant might be an effective therapy to prevent the development of BPD.
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ACKNOWLEDGMENTS |
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This trial was supported by Discovery Laboratories, Inc.
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FOOTNOTES |
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Accepted Apr 2, 2008.
Address correspondence to Matthew Laughon, MD, MPH, UNC Hospital, Division of Neonatal-Perinatal Medicine, CB 7596, 4th Floor, Chapel Hill, NC 27599-7596. E-mail: matt_laughon{at}med.unc.edu
Financial Disclosure: Drs Laughon, Bose, Moya, Aschner, and Donn were compensated by Discovery Laboratories, Inc, for their time and effort as members of the scientific advisory board for this study; Drs Laughon, Cummings, and Morabito were site investigators; and Drs Segal, Guardia, and Liu are employees of Discovery Laboratories, Inc.
This trial has been registered at www.clinicaltrials.gov (identifier NCT00215540).
| What's Known on This Subject Surfactant therapy in the first 48 to 72 postnatal hours reduces the incidence of pneumothorax and mortality. It is unclear if later surfactant therapy, after 72 postnatal hours, might reduce the incidence of BPD.
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| What This Study Adds This randomized, controlled trial adds information regarding the risks and benefits of later surfactant therapy. Infants assigned to later surfactant therapy with 175 mg/kg lucinactant had non–statistically significant trends towards a lower incidence of mortality or BPD.
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PEDIATRICS (ISSN 1098-4275). ©2009 by the American Academy of Pediatrics
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