A Multicenter Randomized Masked Comparison Trial of Synthetic Surfactant Versus Calf Lung Surfactant Extract in the Prevention of Neonatal Respiratory Distress Syndrome
Objective. To compare the efficacy and safety of a synthetic surfactant (Exosurf Neonatal, Burroughs Wellcome Co) and a surfactant extract of calf lung lavage (Infasurf, IND #27,169, ONY, Inc) in the prevention of neonatal respiratory distress syndrome (RDS).
Design and Setting. Ten-center randomized masked comparison trial.
Patients. Premature infants (n = 871) <29 weeks gestational age by best obstetric estimate.
Interventions. Infants were randomly assigned to a course of treatment with Exosurf Neonatal (n = 438) or Infasurf (n = 433) at birth, and if still intubated, at 12 and 24 hours of age. Crossover treatment was allowed within 72 hours of age if severe respiratory failure (defined as two consecutive a/A Po2 ratios ≤.10) persisted after three doses of the randomized surfactant.
Primary Outcome Measures. Three primary outcome measures of efficacy [the incidence of RDS; the incidence of RDS death; and the incidence of survival without bronchopulmonary dysplasia at 28 days after birth] were compared using linear regression techniques.
Results. Of 871 randomized infants, 18 infants did not receive treatment with a study surfactant, and 25 infants did not meet all eligibility criteria. The primary analysis of efficacy was performed in the 846 eligible infants and analysis of safety outcomes in the 853 infants who received study surfactant. Demographic characteristics did not differ between the two treatment groups. Compared with Exosurf, Infasurf treatment resulted in a 62% decrease in the incidence of RDS (Infasurf, 16% vs Exosurf, 42%) and a 70% decrease in RDS death (Infasurf, 1.7% vs Exosurf, 5.4%) but did not increase the incidence of survival without bronchopulmonary dysplasia at 28 days. Treatment with Infasurf resulted in significant improvement in several secondary outcome measures. Infasurf-treated infants had lower average Fio2 (Infasurf, .33 [SEM] vs Exosurf, .42; difference .08; 95% confidence interval [CI], .06 to .11) and average mean airway pressure (Infasurf, 6.0 cm H2O vs Exosurf, 7.1 cm H2O; difference 1.1 cm H2O; 95% CI, .7 to 1.6 cm H2O) for the first 72 hours of life. Crossover surfactant treatment was significantly less frequent in the Infasurf compared with the Exosurf group (Infasurf, 1% vs Exosurf, 6%). Complications (bradycardia, clinical airway obstruction, and transcutaneous arterial desaturation) associated with second and third, but not initial, surfactant treatments were observed more frequently in the Infasurf treatment group. Infasurf-treated infants had significantly less air leak (≤7 days) (Infasurf, 8% vs Exosurf, 14%; adjusted relative risk [ARR] .55; 95% CI, .37 to .81). Severe intraventricular hemorrhage (IVH) (grade 3 and 4) did not differ between the two groups (Infasurf, 11.8% vs Exosurf, 8.3%; ARR 1.41; 95% CI, .94 to 2.09) but total IVH occurred more frequently in Infasurf-treated infants (Infasurf, 39.0% vs Exosurf, 29.9%; ARR, 1.30; 95% CI, 1.08 to 1.57).
Conclusion. Significant reductions in the incidence of RDS, the severity of early respiratory disease, the incidence of pulmonary air leaks associated with RDS, and the mortality attributable to RDS suggest that Infasurf is a more effective surfactant preparation than Exosurf Neonatal in the prophylaxis of RDS. However, Infasurf prophylaxis as used in this study was also associated with a greater risk of total but not severe IVH.
Randomized placebo-controlled trials have convincingly shown that the intratracheal instillation of different surfactant preparations, administered for the prevention or the treatment of neonatal respiratory distress syndrome (RDS), reduces the severity of early respiratory disease and the morbidity and mortality associated with RDS.1-3 Preclinical comparisons have demonstrated substantial differences in physical composition as well as in vitro biophysical and in vivo physiologic activities of commercially available and investigational surfactants.4-9
Infasurf (ONY, Inc, Amherst, NY; IND #27,169) is a natural surfactant containing apoproteins SP-B and SP-C that is extracted from saline lavage fluid of calf lungs.10-12 Compared with Exosurf Neonatal (Burroughs Wellcome Co, Research Triangle Park, NC), a synthetic surfactant preparation without surfactant protein, Infasurf exhibits superior biophysical properties and greater resistance to degradation of biophysical performance by a variety of inhibitors.5,6,8,9 Similarly, Infasurf instillation into surfactant-deficient lungs achieves significantly greater normalization of pulmonary mechanics and physiological function than does instillation of Exosurf.5,7,9
Although debate continues whether it is better to administer surfactant prophylactically to very premature infants (before signs or symptoms of RDS develop) or to treat at the first indication of respiratory distress,13,14 animal studies and two large multicenter clinical trials11,15 have suggested an advantage to a prophylactic strategy. We performed a multicenter, randomized, masked trial designed to compare the efficacy and safety of prophylactic treatment with Exosurf and Infasurf in a population of infants at high-risk for RDS. On the basis of preclinical studies,5-9we hypothesized that compared with Exosurf, Infasurf treatment would decrease the incidence and severity of RDS, reduce the air leak complications associated with RDS, and decrease RDS mortality.
The trial was conducted at 10 neonatal intensive care units between February 1991 and June 1993. Six centers (hereafter referred to as Infasurf centers) had previously participated in clinical trials of Infasurf. At the four other centers (Exosurf centers), Exosurf had been the most commonly used surfactant. The study protocol and an informed consent form were approved by the institutional review board at each center. The Coordinating Center for the study was located at the Children's Hospital of Buffalo.
Eligibility and Enrollment
Consent for participation in the trial was sought from mothers likely to deliver one or more viable infants at <29 weeks gestation. After birth, an infant born to a mother who had consented to the trial remained eligible for enrollment unless one of the following exclusion criteria was present: 1) a decision not to resuscitate a nonviable infant; 2) a decision not to intubate a viable infant; 3) a failure to stabilize an infant by 15 minutes of age; or 4) a diagnosis of a previously undocumented lethal anomaly. Infants with informed consent were considered to be enrolled in the study at the time of randomization.
Randomization and Masking of Treatment Assignment
Unique randomization codes were generated for each center by applying the Moses-Oakford algorithm to a random sequence of block lengths of 4, 6, 8, and 10.16 Treatment assignments were recorded on index cards sealed within sequentially numbered opaque envelopes.
Surfactant randomization and preparation were performed either by a research assistant (a nurse or respiratory therapist) or by a research pharmacist. Procedures specific for each center were prospectively designed to safeguard masking of the surfactant treatment. Aliquots of surfactant were drawn up into syringes that were covered with cloth tape or a black plastic sheath to insure that the color, consistency, and volume of surfactant were not apparent to other clinical care givers. In the delivery room, the research assistant administered the initial surfactant treatment under the supervision of the usual resuscitation team. In the nursery, surfactant administration was accomplished by the research assistant in the presence of the bedside nurse and either a respiratory therapist or a physician, according to a prospectively written protocol at each study center. The research assistant did not participate in the clinical care of the infant for a minimum of 5 days thereafter.
Exosurf Neonatal is a protein-free synthetic surfactant that contains a single phospholipid (dipalmitoylphosphatidylcholine), hexadecanol, tyloxapol, and sodium chloride. Each vial of lyophilized powder was reconstituted with sterile water in accordance with the instructions on the drug package insert.17 Infasurf is a surfactant preparation purified from a chloroform-methanol extract of a saline lavage of calf lung. Infasurf contains all surfactant lipids and the apoproteins SP-B and SP-C (approximately 2% by weight).18 Each vial of Infasurf suspension was gently agitated by inversion before aliquot preparation.
The initial dose of surfactant (5 mL/kg of Exosurf; 3 mL/kg of Infasurf) was administered as soon as possible after intubation and stabilization. In all cases, the on-site physician responsible for resuscitative efforts was masked to the treatment assignment. Second and third doses were administered 12 and 24 hours after birth if the infant remained intubated and the attending physician approved. Two crossover treatments administered 12 hours apart were permitted after three study treatments if the following criteria were met: 1) the infant had severe respiratory failure, defined by two consecutive arterial to alveolar Po2 (a/A Po2) ratios ≤.10; 2) the infant was ≤72 hours of age; 3) a minimum of 4 hours had passed since the previous surfactant treatment; and 4) the attending physician judged that treatment was of potential benefit.
Both surfactants were administered via the sideport of the endotracheal tube adaptor as recommended on the Exosurf package insert. During the initial prophylactic dose, oxygen and ventilatory support were provided using manual or mechanical ventilation and adjusted as clinically indicated. During subsequent doses, the ventilatory rate was increased to a minimum of 30 breaths/minute. Heart rate, transcutaneous arterial oxygen saturation, and chest excursion were monitored continuously. A decrease in heart rate or arterial saturation, or evidence of airway obstruction, resulted in slowing or cessation of surfactant delivery, an increase in inspired oxygen concentration, ventilator rate, and/or mechanical pressure support, and/or initiation of manual ventilation as judged necessary by the surfactant administration team. Occurrences of bradycardia (heart rate <100 beats/minute), airway obstruction (a requirement for increased ventilatory pressure or rate support or a requirement for manual ventilation), arterial desaturation [an increase in fraction of inspired oxygen (Fio2) requirement ≥.05 to maintain adequate oxygenation], and/or other unusual complications were recorded.
Data Collection and Auditing
Maternal demographics and the obstetric history of the index pregnancy, labor, and delivery were abstracted from the mother's medical record. Information about surfactant administration was transcribed from standardized procedure notes in the infant's medical record. Ventilator and oxygen requirements and results of blood gas analyses for the first 168 hours of life and neonatal outcomes through hospital discharge were abstracted from the infant's medical record. Mean airway pressure (MAP) was calculated, assuming a square respiratory pressure waveform.19 Chest radiographs performed on admission, at days 1, 3, 28, and at 36 weeks postconceptional age, as well as chest radiographs that supported the presence of air leak, were sent to the Coordinating Center and evaluated by a Radiology Reading Committee comprised of three pediatric radiologists. Cranial ultrasound studies were also sent to the Coordinating Center and were evaluated by a single neurosonologist (D.J.M.). Study protocol specified that head ultrasounds were required for all infants at 3 to 7 days and at 4 to 8 weeks of age to screen for intraventricular hemorrhage (IVH) and cystic periventricular leukomalacia (CPVL), respectively.
Causes of death were assigned by the principal investigators using study definitions. For each death, relevant portions of the medical record, including a final autopsy report, were reviewed by the study chairman. When the cause of death assigned by the study chairman and by a principal investigator differed, the final assignment of the cause of death was made by a steering committee comprised of the principal investigators from five of the participating centers. Research assistants, principal investigators, and the study radiologists and neurosonologist were masked to treatment assignment during data collection and outcome determinations.
RDS was defined as an Fio2 ≥.30 at 24 hours of life combined with demonstration of reticulogranular opacities on a chest radiograph at 16 to 32 hours of age. If an infant died before 24 hours, RDS was evaluated on the basis of the final chest radiograph and the Fio2 before death. The severity of early respiratory disease was quantitated as the average Fio2 and MAP for the first 72 hours of life. Death was attributed to RDS if death occurred as a result of respiratory failure in the first 14 days of life and causes of respiratory failure other than RDS had been excluded. A diagnosis of pulmonary air leak was assigned if an air leak (pneumothorax, pulmonary interstitial emphysema, pneumomediastinum, pneumopericardium, subcutaneous emphysema) resulting from lung parenchymal disease was verified by the Radiology Reading Committee, or if a clinical diagnosis of air leak resulted in a therapeutic intervention (eg, a positive thoracocentesis or pericardiocentesis and/or thoracostomy or pericardiostomy placement) without preceding radiographic documentation. Right and left lungs were evaluated separately for air leak.
Bronchopulmonary dysplasia (BPD) was defined as a requirement for supplemental oxygen and a chest radiograph with an Edwards score ≥4.20 BPD was assessed both at 28 days after birth and at 36 weeks postconceptional age. Death was attributed to BPD if 1) death occurred primarily as a result of cardiorespiratory failure after 14 days of age; 2) the chest radiograph demonstrated findings consistent with BPD; and 3) another primary etiology of cardiorespiratory failure could not be proven. To broaden the comparison of pulmonary outcomes, the following two different definitions of chronic lung disease (CLD) were evaluated at 28 days after birth and at 36 weeks postconceptional age: 1) the requirement for any supplemental oxygen; and 2) an Fio2 requirement >.30. All definitions were developed and recorded before initiation of the study but were not revealed to masked personnel until termination of the trial.
Pulmonary hemorrhage was defined prospectively as the finding of bright red blood in the endotracheal tube, associated with a deterioration in clinical status, prompting therapeutic intervention. The severity of IVH was graded using the definitions of Papile21 applied to ultrasound examinations or to autopsy findings. A diagnosis of cystic periventricular leukomalacia (CPVL) was made if sonograms demonstrated postnatal development of multiple cystic echolucencies in cerebral white matter. Congenital sepsis was defined as the isolation of a pathogen from blood or cerebrospinal fluid cultured within the first 24 hours of life. All congenital anomalies were screened and are reported as significant if consistent with written definitions developed before study initiation. Causes of respiratory mortality included RDS, pulmonary hemorrhage, pulmonary hypoplasia, BPD, and pneumonia.
The three primary outcome measures of efficacy were: 1) the incidence of RDS; 2) the incidence of death attributable to RDS; and 3) the incidence of survival without BPD at 28 days after birth.
Secondary outcome measures of efficacy included: 1) the severity of initial respiratory disease as quantitated by the average Fio2 and MAP during the first 72 hours of life; 2) crossover surfactant treatment under protocol, or treatment with a nonstudy surfactant after study withdrawal; 3) pneumothorax, pulmonary interstitial emphysema, and any pulmonary air leak; 4) survival at 28 days after birth and to hospital discharge; 5) survival without CLD at 28 days and at 36 weeks postconceptional age; 6) duration of assisted ventilation and supplemental oxygen therapy; and 7) duration of hospitalization. Safety outcome measures included the incidences of acute surfactant administration complications as well as the incidences of serious morbidities of prematurity.
Sample Size Determination
At the time of study design, the outcome of infants treated prophylactically with Exosurf had been reported only in infants with birth weights between 700 and 1100 g. The incidence of RDS for Exosurf-treated infants in this birth weight group was reported to be 68%.17 We calculated that a sample size of 400 infants with birth weights between 700 and 1100 g was required to detect a 20% decrease (from 68% to 55%) in the incidence of RDS associated with Infasurf treatment with a type II error of .20 (power of 80%) and a type I error of .05 (two-tailed). It was expected that the total number of infants recruited into the study would exceed 400 attributable to the enrollment of infants <29 weeks gestational age in two nontarget birth weight subgroups (<700 g; >1100 g).
Statistical Analysis and Data Management
All primary outcome measures of efficacy as well as average Fio2 and MAP during the first 72 hours of life were compared using appropriate linear or logistic regression techniques. By design, statistical models were to include terms for surfactant treatment, birth weight, center, and terms for the interaction of surfactant treatment with birth weight and center, as well as terms for other important baseline variables that might be found to be significantly different between the two treatment groups. Data from centers with fewer than 10 infants in either treatment group were combined and analyzed as a single site. In practice, all interaction terms were not significant and were deleted from the final analysis. The final statistical model (with terms for surfactant treatment, birth weight, and center) identified the independent effect of surfactant treatment.
Groups were compared using the two-tailed Student's t test (normal distributions) or the Wilcoxon rank sum test (nonnormal distributions) for continuous variables and the χ2, Fisher's exact, or Mantel-Haenszel tests for categorical variables. In all cases, P ≤ .05 was considered significant. The point estimate of the relative risk ratio (the ratio of the probability of an outcome among infants treated with Infasurf to the probability of that outcome among infants treated with Exosurf) and the 95% confidence intervals were calculated using the Mantel-Haenszel χ2 test stratified by center and by the three birth weight subgroups.
The average Fio2 and MAP between 1 and 72 hours of life were calculated as the area under the curve using the trapezoidal approximation. In cases of death or discharge before 72 hours, the last value of Fio2 or MAP at death or discharge was used through 72 hours.
The primary analysis of all outcome measures of efficacy was performed in randomized infants who met all study eligibility criteria. Outcome measures of safety were analyzed using all treated infants. Secondary analyses of outcome measures of efficacy were performed for all randomized infants (an intent-to-treat analysis) as well as for infants who received an initial treatment with a study surfactant (an as-treated analysis). All analyses were performed by surfactant received.
Weekly monitoring of all enrolled infants was performed by the Coordinating Center. Coordinating Center staff conducted periodic data audits at participating centers during the trial. Design, customization, and management of the electronic database (Paradox for Windows, Borland, Inc, Scotts Valley, CA) and statistical analysis (SAS Institute, Inc, Cary, NC) were performed by the Coordinating Center. At the conclusion of the study, sponsor personnel conducted a 100% audit of the case report forms of infants in the target birth weight group.
A Data Monitoring and Advisory Committee comprised of two epidemiologists/statisticians, two neonatologists, and one lay person met before the study and at 6-month intervals during the study to determine its rules of operations and to review safety, efficacy, and center performance data. At its initial meeting, the Committee decided not to set any preordained stopping rules, as it felt it could not anticipate all possible outcomes. The Committee also decided to recommend study closure before accrual of the target sample size if it became evident that continued enrollment posed safety risks to infants in one or the other treatment groups. In practice, no differences in mortality at discharge or in major safety outcomes emerged during the study and the Committee allowed the trial to continue to its predetermined sample size. For this reason, no correction for the multiple looks performed by the Committee was necessary. In April 1993, the Committee made a recommendation to close enrollment on June 30, 1993; this recommendation was finalized in June and was conveyed to the study sponsors.
A total of 1177 infants who were born at or before 29 weeks by best obstetric estimate were screened for eligibility (Table1). Thirty-five infants met prenatal exclusion criteria. Of the remaining 1142 infants, informed consent was obtained for 894 (78%). Twenty-three infants for whom consent had been obtained were not randomized for the reasons detailed in Table 1. Treatment assignment was randomized to Exosurf in 438 infants and to Infasurf in 433 infants.
Twenty-five of the 871 randomized infants (13 Exosurf, 12 Infasurf) did not meet eligibility criteria and were prospectively excluded from the primary analysis of efficacy. In 15 infants, the best obstetric estimate of gestational age was ≥29 weeks, and all except one of these infants were treated with a study surfactant. Ten infants were randomized, in violation of protocol, before appropriate assessment and stabilization was accomplished. Of these, 9 infants did not receive treatment with a study surfactant (1 stillborn; 8 previable and/or could not be stabilized). One infant had not been stabilized at the time of initial surfactant treatment.
Eight of the 846 eligible randomized infants (6 Exosurf, 2 Infasurf) did not receive an initial treatment with a study surfactant. For 7 infants, the senior physician did not administer surfactant because in his clinical judgment, no respiratory distress was present. The eighth infant required more extensive stabilization and could later have been treated with study surfactant but was not. Two eligible infants who were erroneously treated with Infasurf were analyzed with the Infasurf group. The analysis of safety outcome measures and a secondary analysis of efficacy outcome measures were performed in all 853 infants who were treated with a study surfactant.
Maternal and Neonatal Demographics
The treatment groups were comparable in terms of maternal and neonatal demographic, physical, and clinical characteristics (Table2). Distribution within the three birth weight subgroups was equivalent for each treatment group (P = .7). The treatment groups did not differ with respect to the incidence of maternal preeclampsia, abruptio placentae, placenta praevia, gestational or insulin-dependent diabetes mellitus, or prolonged oligohydramnios.
Surfactant administration was initiated by 30 minutes of age in 93% and 96% of infants in the Exosurf and Infasurf treatment groups, respectively. The mean number of treatments with the randomized surfactant was 2.6 for infants in each treatment group. The distribution of the number of doses of randomized surfactant did not differ between the two treatment groups (Table 3). Early extubation, death, or transfer to another hospital accounted for 77% and study withdrawal for 10% of missed second and third surfactant treatments. The remaining 13% of missed second and third surfactant treatments (representing 2.3% of total potential treatments) were withheld by the attending physician either because the infant was judged not to have respiratory distress (n = 34) or because the infant was judged too unstable to treat (n = 5).
Acute Complications of Surfactant Administration
Surfactant administration complications occurred rarely during the initial dose and more frequently in association with the second and third surfactant retreatments (Fig 1). The incidences of bradycardia, clinical airway obstruction, arterial desaturation, and any complication during the second and third doses were significantly higher in the Infasurf treatment group. Reintubation was required during or shortly after surfactant treatment in 2 Exosurf-treated and 12 Infasurf-treated infants (P = .01).
Primary Efficacy Outcome Measures
Infasurf treatment was associated with a 62% reduction in the incidence of RDS, compared with treatment with Exosurf (42% in Exosurf-treated vs 16% in Infasurf-treated infants, P< .0001). A reduction in RDS with Infasurf treatment occurred at each center (range, 36% to 90%) and within each of the three birth weight groups. Infasurf treatment was associated with a 71% reduction (from 62% to 18%) in the incidence of RDS at the four Exosurf centers (P < .0001) and a 59% reduction (from 38% to 16%) at the six Infasurf centers (P < .0001). The regression model found that in addition to the type of surfactant treatment, birth weight and treatment center also had strong independent effects on the incidence of RDS (Table 4). Infasurf treatment also resulted in a significant decrease in the RDS mortality rate in all infants (from 5.4% to 1.7%, P = .001) and in the target birth weight group (from 3.4% to .0%,P = .005), but the most important risk factor for RDS mortality in the regression model was birth weight. Birth weight and treatment center, but not the type of surfactant treatment, were important determinants of survival without BPD at 28 days.
Severity of RDS
Compared with Exosurf-treated infants, infants treated with Infasurf required significantly lower Fio2and MAP support and demonstrated significantly greater a/A Po2 ratios from 1 hour through 60 hours of age (Figs 2 and 3). Infasurf treatment was associated with a lower average Fio2 (0.42 ± 0.01 vs .33 ± .01, mean ± SEM, P < .0001) and MAP (7.1 ± 0.2 vs 6.0 ± .1 cm H2O,P < .0001) from 1 to 72 hours of age. Infasurf treatment produced significant increases in Po2and decreases in Pco2 compared with treatment with Exosurf. Although the differences in Po2resolved by 6 hours, differences in Pco2persisted through 48 hours of age (Fig 3). Radiographic findings consistent with RDS were noted significantly less frequently in the Infasurf compared with the Exosurf treatment group (Table5).
Crossover surfactant treatment under protocol or withdrawal of an infant from the study attributable to severe respiratory failure occurred significantly less frequently in the Infasurf group (Table 3). The incidence of early (≤7 days) RDS-related pulmonary air leak was decreased by 45%, from 14% to 8% (P = .006), in the Infasurf treatment compared with the Exosurf treatment group (Table 6). High-frequency ventilation was initiated for severe respiratory failure and/or pulmonary air leak in 12.6% of Exosurf-treated and in 7.2% of Infasurf-treated infants (P = .01).
Mortality, BPD, and Survival Without CLD (Table 7)
A significant decrease in total respiratory deaths through hospital discharge associated with Infasurf treatment (from 9.5% to 5.2%, P = .008) paralleled the decrease in RDS mortality (from 5.4% to 1.7%, P = .001). However, mortality before hospital discharge was not different (19.4% in Exosurf-treated vs 17.7% in Infasurf-treated infants,P = .53) attributable to a slight although not significant excess of nonrespiratory deaths in the Infasurf treatment group. Initial surfactant treatment had no effect on the incidence of BPD among evaluable survivors at 28 days or at 36 weeks postconceptional age or on the incidence of survival without CLD (Table7). Similarly, surfactant treatment assignment did not influence the severity of CLD, as determined by days on supplemental oxygen or by days of assisted ventilation, for all infants or for infants surviving to discharge. Pharmacologic therapies commonly used in the treatment of CLD (diuretics, systemic or aerosolized bronchodilators, and corticosteroids) were employed with equal frequency in the two treatment groups.
Total IVH was significantly increased in the Infasurf compared with the Exosurf treatment group (39.0% vs 29.9%, P = .005), but severe (grade 3 or 4) IVH was not (11.8% vs 8.3%,P = .09). CPVL was identified in 6.5% of Infasurf-treated and in 3.3% of Exosurf-treated infants (P = .03). There were no significant differences identified in the incidences of pulmonary hemorrhage, patent ductus arteriosus, apnea of prematurity treated with methylxanthines, retinopathy of prematurity, necrotizing enterocolitis, sepsis, or nosocomial pneumonia between the two treatment groups.
Secondary Efficacy Analyses
An as-treated analysis of the 853 infants who received study surfactant did not alter the statistical significance of any of the primary or secondary outcome measures of efficacy. In an intent-to-treat analysis, neonatal mortality was significantly less in infants randomized to Infasurf treatment (Exosurf, 17.0% vs Infasurf, 12.4% adjusted relative risk, .73; 95% confidence interval, .53 to .99).
Randomized controlled trials have demonstrated that the administration of surfactant within the first minutes of life to very premature infants at high-risk for RDS reduces the severity of early respiratory disease, decreases the incidence of pulmonary air leak, lessens RDS mortality, and improves survival and/or survival to 28 days without BPD.1-3 At the onset of this study, no multicenter clinical trials had compared the efficacy and safety of different surfactant preparations in the prevention of RDS. However, comparative data that evaluated the in vitro biophysical properties of different surfactants as well as their effects on pulmonary mechanics, gas exchange, and survival in animal models of surfactant deficiency suggested a potential clinical advantage for protein-containing natural surfactants.4-9 This trial was designed to compare the efficacy and safety of the investigational surfactant Infasurf (an extract of natural surfactant containing surfactant proteins B and C) and Exosurf (a synthetic protein-free surfactant) in the prophylactic treatment of RDS.
Two elements of the study protocol warrant additional emphasis. First, the methodology of administration, the number of doses, and the dosing interval for both surfactants adhered to the recommendations on the Exosurf package insert.17 From a practical standpoint, this feature of the study design both facilitated masking of surfactant treatment and obviated potential confounding effects of different administration techniques and treatment regimens on efficacy endpoints.22,23 It might be argued that compliance with each manufacturer's dosage recommendations (resulting in total phospholipid doses of approximately 67.5 mg/kg and 105 mg/kg for Exosurf and Infasurf, respectively) biased the study in favor of Infasurf. However, an increase in Exosurf dose from 67.5 mg phospholipid/kg to 100 mg/kg has been shown not to confer additional efficacy.24 On the other hand, there is some evidence to suggest that the administration of the first dose of Infasurf after lung aeration (at an average of 13 minutes after birth) as a slow infusion might have diminished its efficacy compared with previous studies in which Infasurf instillation was delivered as a single preventilatory bolus.25 Moreover, an infusion of Infasurf during the second and third doses may have resulted in a less uniform distribution of Infasurf through the lung compared with the aliquot delivery method previously in use.22,23 Finally, the substantial modifications of Infasurf administration and prescription practices adopted specifically for this study may have had unanticipated consequences. A second protocol element that merits explanation is the provision for crossover treatment. The intent of this provision was to afford infants with severe respiratory failure (eg, Pao2 < 70 at Fio2= 1.00) access to both surfactants in case critical differences in efficacy did exist between Exosurf and Infasurf.
Certain results of this trial that pertain both to efficacy and to safety endpoints were unexpected and merit careful consideration. Beginning with the efficacy outcomes, this trial has shown that compared with Exosurf administration, Infasurf prophylaxis of very premature infants at substantial risk for RDS reduced the severity of early respiratory disease. Yet, this study identified no differences in the incidence of BPD, in survival without BPD, or in survival to discharge.
In this trial, Infasurf prophylaxis reduced RDS mortality, for all infants as well as for infants in the target birth weight group. Of course, difficulties in distinguishing other causes of early respiratory mortality (eg, pulmonary hypoplasia, pneumonia) from RDS might make this conclusion suspect if not for two other observations. First, the absolute difference in RDS mortality was equivalent to the absolute difference in total respiratory mortality. This would likely not have occurred had actual RDS deaths in Infasurf infants been erroneously assigned to another cause of respiratory mortality. Second, Kaplan-Meier survival curves showed that a clear difference in mortality between the two groups had evolved by 24 hours, consistent with an inference that RDS was the cause of the early excess mortality. In retrospect, the decrease in RDS mortality is not as surprising as it first seemed. Large placebo-controlled surfactant trials have repeatedly linked a reduction in the severity of early respiratory disease to a reduction in early respiratory mortality.26-32 Also, the provision for crossover treatment might not have averted excess RDS mortality, given the relatively late age (28 hours) at which an infant could first qualify for this option under the study protocol.
Although lower, overall mortality before discharge in the Infasurf treatment group was not significantly different from the Exosurf group, attributable to a greater rate of nonrespiratory mortality after 28 days among Infasurf-treated infants. It might be argued that failure to define a difference in mortality before discharge negates the significance of the differences in RDS and respiratory mortality. On the other hand, future development of effective strategies to prevent or treat the neonatal morbidities responsible for postRDS mortality (eg, sepsis, necrotizing enterocolitis, IVH) can only be meaningful if infants do not succumb early to RDS.
Although the regression model identified a significant influence of treatment center on the incidence of RDS, the finding of similar rates of RDS reduction at Exosurf (71%) and Infasurf (59%) centers excludes the possibility that the overall reduction in RDS in Infasurf-treated infants was systematically influenced by center differences in familiarity with the two surfactants. Indeed, the incidence of RDS after Exosurf treatment was substantially higher at Exosurf (62%) compared with Infasurf (44%) centers, yet equal at the two groups of centers (18% vs 16%) after Infasurf treatment.
A significant reduction in pulmonary air leak in the Infasurf treatment group occurred even though it is likely that these infants were ventilated with greater tidal volumes, as may be inferred from the consistently lower Pco2 values and ventilator rates observed in this group through 60 hours of life. One explanation of this finding could be that Infasurf treatment produces a narrower range of alveolar time constants throughout the lung than Exosurf and thus lowers the risk of alveolar rupture. Our findings also substantiate the hypothesis, generated by meta-analysis, that protein-containing surfactants prevent RDS-associated air leak complications more effectively than synthetic surfactants.1-3
Both this trial, as well as a similar but larger study that compared Exosurf and Infasurf treatment of infants with established RDS, failed to find significant differences between the two surfactant treatment groups in BPD or in survival without BPD.33 For reasons detailed previously we had considered such results likely.
Two study observations support a contention that the observed differences in the incidence and severity of RDS are attributable to differences in the mechanisms of action of the two surfactants. First, in contrast to Exosurf, the physiologic effects of Infasurf were immediate. Exosurf prophylaxis, compared with placebo treatment, failed to produce significant reductions in Fio2 and MAP until 6 to 12 hours of life.26 In contrast, Infasurf prophylaxis, compared with Exosurf treatment, achieved significant reductions in Fio2 and MAP by 1 hour of life. Second, significantly fewer Infasurf-treated compared with Exosurf-treated infants (25% vs 54%) had radiographic evidence of RDS (reticulogranular densities and air bronchograms) at 24 hours. This difference is even more striking because MAP was greater in the Exosurf treatment group. These observations agree with the premise that the reduced efficacy and the slower onset of action of Exosurf is attributable to an inability of exogenous phospholipid to compensate fully for a deficiency of endogenous surfactant protein, to a delay in the adsorption of dipalmitoylphosphatidylcholine into the surface film, and/or to a need for exogenous dipalmitoylphosphatidylcholine to undergo cellular reprocessing to attain optimal physiologic activity.4,34 In contrast, the balanced mixture of phospholipid to surfactant proteins in Infasurf might be expected to disperse more quickly into a surface film and to mimic more effectively the activity of mature endogenous surfactant without any requirement for endogenous surfactant components.
That Exosurf demonstrates clinical efficacy in very premature neonates most likely depends on the ability of these infants to release components into the alveoli at or shortly after birth, which combine with the phospholipids in Exosurf. This can be inferred from animal studies in which Exosurf instillation into completely surfactant-deficient lungs does not improve pulmonary mechanics or gas exchange or prolong survival.7,9 Bubble surfactometer studies have shown that the minimum surface tensions of surfactant suspensions with minute concentrations of surfactant apoproteins SP-B and SP-C can be substantially reduced by supplementation with phospholipid.35 In other words, a greater deficiency of surfactant phospholipid relative to surfactant protein in premature infants with RDS would be consistent with the observed efficacy of Exosurf.
Physiologic instability (bradycardia, clinical evidence of airway obstruction, and arterial desaturation) occurred at a low rate with either surfactant during the initial dose; however, administration complications occurred more frequently in the Infasurf treatment group during the second and third doses. We believe that these findings were related to substantial differences in the degree of obstruction of the endotracheal tube and airways that occurred during dosing. Similar administration complications have been rarely reported in other Infasurf trials. In those trials, Infasurf instillation was performed by delivery of several aliquots through a catheter that had been advanced to the distal tip of the endotracheal tube. Between aliquots, surfactant dispersion was accomplished by manual ventilation that allowed the rapid adjustments in pressure, rate, and inspired oxygen concentration that were necessary to maintain adequate chest excursion and oxygenation. Furthermore, infants received Infasurf retreatment only with recurrence or persistence of significant respiratory disease. In contrast, to facilitate the masking of surfactant treatment, Infasurf administration methodology and retreatment indications in this study were substantially altered to conform to the recommendations on the Exosurf package insert. During the second and third doses, Infasurf infants had less severe RDS and may have been more susceptible to treatment complications. In retrospect, the Infasurf treatment protocol in use before this study would seem to be better suited for preventing ventilatory obstruction with resultant bradycardia and arterial desaturation.
In this study, the incidence of total (but not severe) IVH was unexpectedly greater in the Infasurf treatment group. This finding cannot be explained by the occurrence of intergroup differences in prenatal (eg, white maternal race, male gender), perinatal (eg, lower gestational age and birth weight, lower use of antenatal steroids, higher incidence of vaginal delivery) or postnatal (increased incidences of pneumothorax or patent ductus arteriosus) factors that have previously been associated with an increased risk of IVH. Furthermore, there is no evidence to suggest that this difference could have been caused by some direct central or peripheral cardiovascular drug effect(s) specific to Infasurf.
Several surfactant treatment-induced differences between the groups were observed and were considered as potential etiologic factors for IVH. Neither the improved respiratory status nor the decreased incidence of air leak in the Infasurf treatment group is a credible cause of the difference in IVH. Lower mean Pco2and higher mean Po2 in Infasurf-treated infants in the first hours of life might be expected to mediate an increase in IVH through a decrease in cerebral perfusion,36-38 but we could find no association between the initial Pco2 or Po2 levels and IVH or severe IVH within each surfactant treatment group or for the population as a whole.
The increased incidence of acute complications associated with surfactant retreatment in the Infasurf treatment group could have induced changes in cerebral perfusion and/or oxygenation that might be important in the pathogenesis of IVH.39-42 The number of episodes of bradycardia, airway obstruction, and arterial desaturation during the second and third surfactant retreatments correlated with both IVH and severe IVH by Mantel-Haenszel χ2 analysis. Hence, we examined the independent effects of birth weight, gestational age, surfactant treatment, and surfactant treatment complications on IVH and severe IVH using regression techniques. Gestational age (P = .0001), the number of bradycardias (P = .0013), and surfactant treatment (P = .03) were independent risk factors for IVH, whereas gestational age (P = .0001) and the number of bradycardias (P = .0002) but not surfactant treatment (P = .32) were associated with severe IVH. We have tested this association in a companion study of Exosurf and Infasurf for the treatment of RDS. In that study, acute complications with surfactant retreatment were also increased in the Infasurf treatment group, but the same regression analysis showed no significant relationship between IVH or severe IVH and administration complications.33 A follow-up study designed to compare the safety of different Infasurf administration methodologies and retreatment indications is in progress.
A statistically significant increase in the incidence of IVH associated with surfactant treatment has been found in only one other placebo-controlled study of a natural surfactant.43 An analysis of placebo-controlled surfactant trials by Gunkel44 failed to demonstrate an increased risk of IVH associated with natural surfactant treatment. More recently, three large comparison trials of Exosurf versus a natural surfactant for the treatment of established RDS failed to identify any differences in the incidence of total or severe IVH.33,45,46
This study identified significantly more cases of CPVL in Infasurf-treated than in Exosurf-treated infants. These findings can be used to provide only lower boundary estimates of the actual incidence of CPVL for three reasons. First, 278 infants (including 118 neonatal deaths) without a diagnosis of CPVL, or nearly one-third of all study patients, had no cranial ultrasound study performed after 28 days. Second, it is possible that some infants may have developed CPVL as a result of late postnatal events (eg, sepsis). In such cases, CPVL may not have been present at the time of the 4- to 8-week ultrasound study obtained under study protocol. Third, infants with small or transient CPVL lesions may not have been identified by a single late ultrasound study. However, we can identify no obvious bias in ultrasound screening that would have increased the identification of CPVL in the Infasurf treatment group. In contrast to IVH, CPVL was not associated with the acute complications of surfactant administration.
Multiple prenatal and perinatal conditions have been associated with an increased risk of CPVL.47-52 Of these, only early Pco2 levels differed significantly between the two treatment groups (Fig 3). Hypocarbia decreases cerebral blood flow in fetal and newborn animals and in newborn infants36,37,53,54 and is a plausible risk factor for CPVL, which is believed to occur as a result of hypoxic-ischemic injury.39 Vannucci has shown that moderate hypercarbia in a rat model of hypoxia-ischemia protects the brain from pathologic changes analogous to CPVL.55 In this study, infants with CPVL had significantly lower initial Pco2levels compared with infants without CPVL (30.9 Torr vs 36.7 Torr). Clearly, clinical studies specifically designed to ascertain the actual incidence of CPVL and to determine the influence of respiratory management on CPVL are needed.
In summary, we conclude that Infasurf prophylaxis offers premature infants at high-risk for RDS several important advantages compared with Exosurf. Consistent with preclinical data, Infasurf reduced the incidence, severity, and air leak morbidities of RDS. Infasurf treatment also reduced RDS as well as respiratory mortality. The increased incidence of IVH in the Infasurf treatment group may have been causally related to greater physiologic instability associated with using the Exosurf treatment protocol for Infasurf administration. The possible association of consistently lower early Pco2 levels and a higher identification rate of the rare complication CPVL in Infasurf-treated infants cautions for more meticulous respiratory management immediately after birth even as the role of hypocarbia in the pathogenesis of CPVL undergoes further investigation.
This study was supported by a research grant from ONY, Inc and from Forest Laboratories.
We thank the parents of the enrolled infants, the nursing staffs, respiratory therapists, house officers, and attending physicians at the participating centers, the research associates, and the members of the Data Monitoring and Advisory Committee. Special thanks are due to Lindy Canavan, Elizabeth Matteson, RN NNP, Jessica Baus, RN, and Karen Middleton for their work in coordinating the study; to Kathleen Hughes for manuscript preparation; and to Bonnie Hudak, MD, Frederick C. Morin, III MD, and Bruce Holm, PhD for reviewing the manuscript.
The research associates who participated in this trial were as follows: Donna Curtis, RN, Children's Hospital of Buffalo, Buffalo, NY; Jeanette M. Asselin, MS RRT, Oakland Children's Hospital, Oakland, CA; Katherine E. O'Brien, RN and Paul C. Fitzgerald, RN, MSN, Northwestern Memorial Hospital, Chicago, IL; Lois V. Kimberlin, RNC, Evanston Hospital, Evanston, IL; Sharon E. Strobel, BSN, MSN, Johns Hopkins Hospital, Baltimore, MD; Kathy J. Auten, BA, Duke University Medical Center, Durham, NC; Sue Mackey, RRT, Miami Valley Hospital, Dayton, OH; Shawna Baker, RN and Karen Osborne, RN, Primary Children's Hospital and University of Utah Medical Center, Salt Lake City, UT; Shirley MacKenzie, RN, MSN, Faith McNabb, RN, and Kathy Hale, BSN, University of Colorado Medical Center, Denver, CO; Kathleen M. Laskay, MSN, University of South Alabama, Mobile, AL; and Margaret Wen, RRT, Alta Bates Hospital, Berkeley, CA.
The members of the Data Monitoring and Advisory Committee were: Curtis Meinert, PhD (Chairman) and Richard Royall, PhD, Department of Biostatistics and Epidemiology, Johns Hopkins School of Public Health and Hygiene, Baltimore, MD; Lillian R. Blackmon, MD, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD; Billie Lou Short, MD, Department of Pediatrics, George Washington University School of Medicine, Washington DC; and Fr Frank Tuchols, Department of Pastoral Care, Children's Hospital of Buffalo, Buffalo, NY.
The members of the Steering Committee were: James J. Cummings, MD, Department of Pediatrics, Childrens Hospital of Buffalo, Buffalo, NY; Elaine E. Farrell, MD, Department of Pediatrics, Evanston Hospital, Evanston, IL; Richard L. Auten, MD, Department of Pediatrics, Duke University Medical Center, Durham, NC; August L. Jung, MD, Department of Pediatrics, University of Utah Medical Center, Salt Lake City, UT; and Adam A. Rosenberg, MD, Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO.
The members of the Radiology Reading Committee were: Alan S. Brody, MD, Paul Montgomery, MD, and Merchline M. Riddlesberger, MD, Department of Pediatric Radiology, Children's Hospital of Buffalo, Buffalo, NY.
- Received November 6, 1995.
- Accepted June 24, 1996.
Reprint requests to (M.L.H.) Department of Pediatrics, University of Florida Health Science Center, 653–1 West 8th St, Jacksonville, FL 32209.
Presented in part at the annual meeting of the Society for Pediatric Research, Seattle, Washington, May 1994.
- RDS =
- respiratory distress syndrome •
- a/A Po2 =
- arterial to alveolar partial pressure of oxygen •
- Fio2 =
- fraction of inspired oxygen •
- MAP =
- mean airway pressure •
- IVH =
- intraventricular hemorrhage •
- CPVL =
- cystic periventricular leukomalacia •
- BPD =
- bronchopulmonary dysplasia •
- CLD =
- chronic lung disease
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- Copyright © 1997 American Academy of Pediatrics