A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome

FETAL AND NEONATAL MEDICINE

A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome J e f f r e y D. Horbar, MD, Linda L. Wright, MD, R o g e r F. Soil, MD, Elizabeth C. Wright, PhD, A v r o y A. Fanaroff, MD, Sheldon B. Korones, MD, S e e t h a Shankaran, MD, William Oh, MD, Barry D. Fletcher, MD, Charles R. Bauer, MD, Jon E. Tyson, MD, J a m e s A. Lemons, MD, E d w a r d F. D o n o v a n , MD, Barbara J. Stoll, MD, David D. Stevenson, MD, Lu-Ann Papile, MD, a n d J o s e p h Philips III, MD, for t h e N a t i o n a l Institute of Child Health a n d Human D e v e l o p m e n t N e o n a t a l Research N e t w o r k * From the University of Vermont, Burlington; the National Institute of Child Health and Human Development, Bethe,sda, Maryland; the Biostatistics Center, George Washington University, Washington, D.C.; Case Western Reserve University, Cleveland, Ohio; the University of Tennessee at Memphis, Memphis; Wayne State University, Detroit, Michigan; Brown University, Providence, Rhode Island; St. Jude Children's Research Hospital, Memphis, Tennessee; the University of Miami, Miami, Florida; the University of Texas Southwestern Medical Center, Dallas; Indiana University, Indianapolis; the University of Cincinnati, Cincinnati, Ohio; Emory University, Atlanta, Georgia; Stanford University, Palo Alto, California; the University of New Mexico, Albuquerque; and the University of Alabama at Birmingham

Objective: To compare the efficacy of two surfactants, Exosurf Neonatal (Burroughs WelIcome Co.) and Survanta (Ross Laboratories), for the treatment of neonatal respiratory distress syndrome. Design: Multicenter randomized trial. Setting: Eleven tertiary care university neonatal intensive care units participating in the National Institute of Child Health and Human Development Neonatal Research Network. Patients: Newborn infants (n = 617) weighing 501 to 1500 gm with respiratory distress syndrome who were receiving assisted ventilation with 30% oxygen or more within 6 hours of birth were enrolled between January 1991 and January 1992. Interventions: Infants were randomly assigned to receive up to four intratracheal doses of either Exosurf Neonatal (n = 309) or Survanta (n = 3 0 8 ) . Main outcome measures: The occurrence of death or bronchopulmonary dysplasia 28 days after birth and the a v e r a g e fraction of inspired oxygen (Fio2) and mean airway pressure (MAP) during the first 72 hours after treatment.

Supported by the National Institute of Child Health and Human Development through Cooperative Agreement (U10 HD21466, U01 HD19897, U10 HD21364, U10 HD21415, U10 HD21385, U10 HD27904, U10 HD21397, U10 HD21373, U10 HD27856, U10 HD27853, U10 HD27851, U10 HD27880, U10 HD27881, U10 HD27890). Funds for the purchase of surfactant were provided in part by Ross Laboratories. Presented in part at the Society for Pediatric Research Annual Meeting, Washington, D.C. May 6, 1993.

Submitted for publication April 1, 1993; accepted June 10, 1993. Reprint requests: Jeffrey D Horbar, MD, Department of Pediatrics, University of Vermont College of Medicine, Given Building, Burlington, VT 05405. *For a list of the members of the National Institute of Child Health and Human Development Neonatal Research Network, see the acknowledgment at the end of the text. 9/23/49281

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Results: Death or b r o n c h o p u l m o n a r y dysplasia o c c u r r e d in 67% of the infants in the Exosurf g r o u p a n d 62% of those in the Survanta g r o u p (adjusted relative risk, 1.07; 95% c o n f i d e n c e interval, 0.96 to 1.20). During the 72 hours after the first surf a c t a n t dose, the a v e r a g e FlO2 ( ___SEM) was 0.50 _ 0.01 for Exosurf a n d 0.42 +_ 0.01 for Survanta (difference, 0.08; 95% c o n f i d e n c e interval, 0.05 to 0.14); the a v e r a g e MAP (+_SEM) was 7.64 _+ 0.21 c m H20 for Exosurf a n d 6.93 _+ 0.21 cm H20 for Surv a n t a ( d i f f e r e n c e , 0.71 c m H20; 95% c o n f i d e n c e interval, 0.13 to 1.29 c m H20). There was no d i f f e r e n c e b e t w e e n the groups in the i n c i d e n c e of other n e o n a t a l morbidities or in the duration of hospitalization, assisted ventilation, or supplem e n t a l o x y g e n administration. Conclusion: W e found no d i f f e r e n c e b e t w e e n t r e a t m e n t groups in the i n c i d e n c e of d e a t h or b r o n c h o p u l m o n a r y dysplasia, a l t h o u g h w e did observe a d i f f e r e n c e in the initial response to t r e a t m e n t as m e a s u r e d by Flo2 a n d MAP. (J PEDIATR 1993;123:757-66)

a/A BPD FI02 MAP RDS VEI

Arterial/alveolar [ratio] Bronchopulmonary dysplasia Fraction of inspired oxygen Mean airway pressure Respiratory distress syndrome Ventilator efficiency index

In randomized, controiled trials, the intratracheal administration of exogenous surfactants to infants with or at high risk for respiratory distress syndrome has been shown to reduce the Severity of respiratory distress and the risk of death. 1 Although a variety of both synthetic and natural surfactants have been effective, clinical studies comparing the effects of different surfactant preparations have not been reported. Two surfactants, Exosurf Neonatal (Burroughs Wellcome Co., Research Triangle Park, N.C.) and Survanta (Ross Laboratories, Columbus, Ohio), have been licensed by the U.S. Food and Drug Administration for use in the prevention and treatment of neonatal RDS. a, 3 This report describesthe results of a mulficenter, randomized trial comparing these two surfactants for the treatment of neonatal RDS. METHODS The trial was carried out between January 1991 and January 1992 at 11 neonatal intensive care units participating {n the National Institute of Child Health and Human Development Neonatal Research Network. When the study began, Exosurf Neonatal had already been approved bYthe Food a n d Drug Administration and was commercially available/Survanta was available only under a Treatment Investigational New Drug protocol until it was approved by the U.S. Food and Drug Administration for commercial release in August i991. 4 The protocol, study design, and consent forms were reviewed and approved by the institutional review boards at each institution.

Eligibility. Infants with birth weights of 501 to 1500 gm who were born at a participating center were eligible for the trial if they met the following criteria: (1) postnatal age 6 hours or less, (2) mechanical ventilation via an endotracheal tube, (3) fraction of inspired oxygen 0.30 or more to maintain an arterial or transcutaneous partial pressure of oxygen of 50 mm Hg or more, or to maintain an oxygen saturation measured by pulse oximetry of 90% or more, (4) a chest radiograph consistent with the diagnosis of RDS, (5) respiratory distress not solely attributable to causes other than RDS, (6) the physician's opinion that the infant was likely to benefit from surfactant therapy, and (7) written informed parental consent. Infants were excluded if they had a mature lecithin/sphingomyelin ratio measured On amniotic fluid, had previously received any exogenous surfactant, had a major congenital anomaly or documented chromosomal abnormality considered life threatening, or had persistent physiologic instability including hypotension, bradycardia, hypoglycemia, seizures, persistent pneumothorax, or pneumopericardium. Once physiologic stability had been achieved or air leaks controlled, infants became eligible for enrollment if they met the study criteria. Randomization. Separate randomization lists stratified by birth weight (501 to 750 gin, 751 to 1000 gin, 1001 to 1500 gin) were prepared for each center with the urn method. 5 Treatment assignments were made by research pharmacists. Physicians and nurses werenot unaware of treatment assignment because the appearance, dose, and administration techniques were different for the two surfactants. Snrfaetant treatments. Exosurf Neonatal is a protein-free synthetic surfactant consisting of dipalmitoyl phosphatidylcholine, hexadecanol, and tyloxapol.2 Survanta, which Contains the smaller surfactant proteins B and C, is a modified natural surfactant extracted from bovine lung and Supplemented with dipalmitoyl phosphatidylcholine, palmitic acid, and tripalmitoylglycerol.3 The assigned surfactant

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was prepared and administered in accordance with the manufacturer's drug package insert2, 3 and, in the case of Survanta, with the Treatment Investigational New Drug protocol. 4 Infants treated with Exosurf Neonatal received an initial intratracheal dose of surfactant (5 ml/kg) followed by a second dose (5 ml/kg) 12 hours later if mechanical ventilation continued. Third and fourth doses of Exosurf Neonatal were given at the discretion of the physician at subsequent 12-hour intervals to infants requiring mechanical ventilation and an FIO2 -->0.30 to maintain arterial or transcutaneous partial pressure of oxygen at >--50 mm Hg, or an oxygen saturation by pulse oximeter of 90% or more. Exosurf Neonatal was administered via the sideport of the endotracheal tube adapter without interrupting mechanical ventilation.2 Infants treated with Survanta received an initial intratracheal dose of surfactant (4 ml/kg) and could receive up to three additional doses (4 ml/kg each) at least 6 hours apart if they required mechanical ventilation with an Fio2 >-0.30 to maintain arterial or transcutaneous partial pressure of oxygen at ->50 mm Hg, or an oxygen saturation measured by pulse oximetry of 90% or more. Survanta was administered through a catheter inserted into the endotracheal tube while the infant was disconnected from the ventilator.3, 4 Study end points. The primary study end points were the frequency of death or bronchopulmonary dysplasia 28 days after birth, and the average FIo2 and mean airway pressure during the 72 hours after the initial surfactant dose. Bronchopulmonary dysplasia was defined as a requirement for supplemental oxygen on day 28 and for at least 21 of the first 28 days, plus a chest radiograph compatible with a diagnosis of BPD obtained between days 21 and 28. 6 The condition was diagnosed if the chest radiograph showed diffuse bilateral pulmonary abnormalities, of any severity, that could not he attributed to other disorders. The chest radiographs were interpreted by a single central radiologist (B.D.F.) who was unaware of the treatment assignment. In the case of missing films that had been interpreted previously by a radiologist at the local center, the local readings were used. Ventilator settings and Fro2 were recorded every 6 hours for 72 hours after the first dose Of surfactant and before and 2 hours after each dose of surfactant. Mean airway pressure was calculated with a square respiratory pressure waveform assumed. 7 Secondary measures of outcome included (1) survival to hospital discharge, (2) requirement for supplemental oxygen at 36 weeks after conception,8 (3) duration of hospitalization, assisted ventilation, and supplemental oxygen administration, (4) survival, arterial/alveolar oxygen ratio, 9 and ventilator efficiency index 1~3 days after treatment was started, (5) death before or on day 21, or assisted ventila-

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tion with an Flo2 >--0.40 on day 21, and (6) the following concurrent diagnoses: pneumothorax, patent ductus arteriosus treated with indomethacin or surgical ligation, necrotizing enterocolitis (stage II or greaterH), acquired sepsis, apnea treated with xanthines, severe intraventricular hemorrhage (grade 3 or 4),t2 retinopathy of prematurity,13 and pulmonary hemorrhage. Pulmonary hemorrhage was defined as the finding of bright red blood in the endotracheal tube in association with a clinical deterioration of the infant. The VEI was calculated as VEI = 3800/(VP x rate • Paco2) where VP is the difference between peak inspiratory pressure and end-expiratory pressure in millimeters of mercury, and Paco2 is the arterial partial pressure of carbon dioxide, l~ Infants were monitored during surfactant administration for an increase in oxygen saturation to >95% or a decrease to <85% (measured by pulse oximetry), for bradycardia (heart rate, <60 beats/min for more than 20 seconds), and for reflux of surfactant into the endotracheal tube. Statistical methods. A total sample size of 600 was sufficient to detect a difference between rates of death or BPD of 38.5% and 50%, respectively, in the two treatment groups with a power of 0.80 and a type I error of 0.05 (two sided). The frequencies of the primary outcome, death or BPD, and of the categorical outcomes were compared with the Mantel-Haenszel chi-square test, with stratification by center and birth weight group. The point estimate of the risk ratio (the ratio of the risk of an outcome event among infants assigned to the Exosurf group to the risk of an outcome event among infants assigned to the Survanta group) and corresponding 95% confidence intervals were used to indicate the magnitude of the difference between the groups. The average FIO2 and MAP for 72 hours were determined for each infant by computation of the area under the time curve for each measure and division of the result by the number of hours up to the last available measurement within 72 hours. An MAP value of 2 cm H20 was assigned to infants whose endotracheal tube had been removed; the continuous positive airway pressure was assigned as the MAP value for infants receiving positive airway pressure. The effects of Exosurf and Survanta on F~O2, MAP, a / A oxygen ratio, and VEI were compared by analysis of variance with terms for treatment, center, and birth weight group as main effects, and with terms for the interactions between treatment and birth weight and between treatment and center. The durations of hospitalization, ventilation, and supplemental oxygen administration were compared between groups by the Wilcoxon Rank Sum Test. Statistical analyses were performed by the George Washington University Biostatistics Center (SAS program, version 6.07). 14 The data safety and monitoring committee in December 1991 made one interim look at the data after 422 infants had

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T a b l e I. Mother and infant characteristics

Birth weight (gm)* Gestationa| age (wk)* Small for gestational age (%) Male sex (%) Black race (%) Multiple birth (%) Prenatal care (%) Antenatal steroids (%) Cesarean section (%) Apgar scores at 1 and 5 min (median)

Exosurf (n = 308)

Survanta (n = 306)

927 + 261 26.8 _+ 2.3 16

924 + 249 26.8 + 2.2 17

53 59 23 85 17 49 4, 6

52 58 26 84 17 55 3, 6

There were no statistically significantdifferencesbetweengroups for any of the characteristics. *Values are expressed as mean _+ SD.

been evaluated. Adjustment for this interim look was made by the method of Lan and DeMets 15; a p value of 0.045 was therefore used to determine statistical significance in the final analysis for the primary study end point. RESULTS A total of 1703 infants were screened for entry into the study: Of these, 796 (47%) met the clinical and radiographic criteria for a diagnosis of RDS. This group represented 65% of infants weighing 501 to 1000 gm at birth but only 34% of infants weighing 1001 to 1500 gm. O f the 796 infants, 76 (t0%) were excluded for the following reasons: 8 had congenital anomalies, 23 were physiologically unstable, 24 were thought to be unlikely to benefit from surfactant therapy, 9 could not be examined within 6 hours of birth, and 12 had already received either Exosurf or Survanta. Of the 720 eligible infants, 103 (14%) were not enrolled, 40 because the mother was too ill to give consent, 40 because the parents refused, and 23 for other reasons (transferred, clinical improvement, study staff unavailable, treated off protocol). Six hundred seventeen infants were randomly assigned to receive surfactant: 309 to receive Exosurf and 308 to receive Survanta. Three infants (1 Exosurf, 2 Survanta) were excluded from all analyses because they weighed less than 501 gm or more than 1500 gm. An additional 12 infants (9 Exosurf, 3 Survanta) were later found to have not met the eligibility criteria: 2 were outborn, 1 had an FIn2 <0.30, 2 did not have a chest radiograph consistent with R D S , and 8 (including one of the outborn infants) were more than 6 hours of age at the time of assignment. One of these infants did not receive the assigned treatment (Exosurf). Twentytwo of the eligible infants (12 Exosurf, 10 Survanta) were randomly assigned to receive surfactant but not treated with

T a b l e II. Ventilator settings at treatment assignment and before first surfactant dose

At randomization Age (hr) FIn2 Rate PIP (cm H20) MAP (cm H20) At first dose Age (hr) FIn2 Rate PIP (cm H20) MAP (cm H20) VEI (ml/mm Hg/kg) a/A Po2 ratio a/A Po2 ratio <0.22 (%)

Exosurf (n = 308)

Survanta (n = 306)

3.2 +_ 1.6 0.75 _+ 0.23 42 + 15 22 + 4 10 + 3 (n = 294) 4.5 +_ 2.0 0.75 + 0.23 42 _ 15 22 + 5 10 + 3 0.12 _+ 0.07 0.18 + 0.13 78

3.3 + 1.8 0.73 + 0.24 42 +_ 15 22 _+ 4 10 _+ 3 (n = 296) 4.5 _+ 1.9 0.73 _ 0.24 43 _+ 15 22 + 5 10 + 3 0.12 +__0.08 0.19 +_ 0.14 75

Values (except a/A Po2 ratio) are expressedas Mean + SD. There were no statistically significantdifferences between the groups for any of the ventilator settings. PIP, Peak inspiratory pressure; Poe, partial pressure of oxygen. it. As a result of pharmacy errors, two infants assigned to Exosurf were given Survanta and 7 infants assigned to Survanta were given Exosurf. The primary analysis is an intent-to-treat analysis based on data from 614 infants. This group included 181 infants weighing 501 to 750 gin, 220 infants weighing 751 to 1000 gm, and 213 infants weighing 1001 to 1500 gm. All analyses were repeated after exclusion of the 12 ineligible infants and the 31 infants who either were not treated or who were given the wrong treatment (571 infants: 285 Exosurf and 286 Survanta). Infants in the Exosurf and Survanta groups were comparable with regard to both maternal and infant characteristics (Table I). Ventilator settings were also similar both at treatment assignment and before the first dose of surfactant (Table II). In the Exosurf group, 72 infants (23%) received a single dose, 95 (31%) received 2 doses, 48 (16%) received 3 doses, and 79 (26%) received 4 doses. The corresponding numbers in the Survanta group were 110 (36%), 62 (20%), 35 (11%), and 89 (29%). The mean ( + S D ) number of surfactant doses was 2.5 +_ 1.1 in the Exosurf group and 2.3 + 1.3 in the Survanta group (p = 0.12). The median ages at each dose were 4, 17, 30, and 44 hours for the Exosurf group and 4, 12, 20, and 28 hours for the Survanta group. Eleven infants in the Exosurf group had a dosing interval of less than 12 hours between doses, and 2 infants in the Survanta group had an interval of less than 6 hours. Three infants received a dose of Survanta after 48 hours of age. Two infants in each group met the oxygen criteria for bronchoputmonary dysplasia but did not have chest radio-

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Table III. Incidence of death or bronchopulmonary dysplasia 28 days after birth Exosurf (n = 3 0 8 )

All infants BPD (02 criteria)]. BPD (02 and radiograph)~ Death before day 28 Death or BPDw Infants weighing 501-750 gm BPD (02 criteria)]" BPD (Oz and radiograph):~ Death before day 28 Death or BPD[[ Infants weighing 751-1000 gm BPD (02 criteria)]" BPD (02 and radiograph):~ Death before day 28 Death or BPD 82 Infants weighing 1001-1500 gm BPD (02 criteria)]" BPD (Oa and radiograph):~ Death before day 28 Death or BPD#

Survanta (n = 306)

n

(%)

n

(%)

Risk ratio*

9 5 % Cl

147 132 72 204

(48) (43) (23) (67)

147 131 57 188

(48) (43) (19) (62)

1.07

(0.96, 1.20)

42 41 46 87

(47) (46) (51) (97)

50 47 33 80

(55) (52) (36) (89)

1.11

(1.00, 1.23)

68 62 20 82

(60) (55) (18) (73)

60 53 17 70

(57) (50) (16) (67)

1.10

(0.92, 1.31)

37 29 6 35

(36) (28) (6) (34)

37 31 7 38

(34) (28) (6) (35)

0.96

(0.67, 1.39)

cI, Confidenceinterval. *Adjusting for center and birth weight strata. ~'On supplementary 02 on day 28 and for 21 out of first 28 days. $02 criteria plus chest radiograph consistent with BPD. w = 306 for Exosurf and 304 for Survanta. IIn= 90 for Exosurf and 90 for Survanta. 82 = 112 for Exosurf and 105 for Survanta. #n = 104 for Exosurf and 109 for Survanta.

graphs. The radiographic diagnosis was based on the central reader for 360 infants; the local reading was used for 92 infants. On the twenty-eighth day, 234 infants in the Exosurf group and 247 in the Survanta group were alive and had complete O2 and radiographic information. There were no differences between the two groups in the percentage of infants who met the oxygen criteria for BPD (48% in both groups) or in the percentage of infants who met all the criteria for a diagnosis of BPD (43% in both groups). Twenty-three percent of-infants in the Exosurf group and 19% of infants in the Survanta group died before day 28, resulting in an incidence of death or BPD of 67% in the Exosurf group and 62% in the Survanta group (p = 0.20; Table III). Because there was a lack of agreement between some local radiologic interpretations and those of the central radiologist with respect to the diagnosis of BPD, the primary analysis was repeated with the definition of BPD based on the local readings. The incidence of BPD or death was then 61% in the Exosurf group and 57% in the Survanta group (p = 0.25). The mean (_+ S E M ) FI02 and M A P at each scheduled sampling time for the first 72 hours of age are shown in Fig.

1. Survanta-treated infants required lower FIO2 and M A P during the 72 hours after the first surfactant dose than did Exosurf-treated infants. The 72-hour averages (area under the curve) for the Exosurf and Survanta groups were 0.50 _+ 0.01 and 0.42 _+ 0.01, respectiveIy, for Fro2 and 7.64 + 0.21 cm H 2 0 and 6.93 _+ 0.21 cm H20, respectively, for M A P (p = 0.0001 for FJo2 and 0.0078 for M A P ; Table IV). There were significant differences in these measurements among the clinical centers (p = 0.0001) and birth weight strata (p = 0.0001), but there were no significant interactions between treatment and clinical center or between treatment and birth weight strata. There was no difference between the two groups in mean VEI at 72 hours (0.26 _+ 0.21 for Exosurf; 0.27 _+ 0.18 for Survanta), but the mean a / A oxygen ratio at 72 hours was significantly higher in the Survanta group (0.43 + 0.24 and 0.49 + 0.27; p = 0.016). There were no differences between the two groups in the frequencies of death before discharge from the hospital, patent ductus arteriosus, intraventricular hemorrhage, sepsis, pulmonary hemorrhage, or any of the other concurrent diagnoses listed in Table V. There were no differences between the Exosurf and Sur-

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30 ,36 42 48 54 60 66 72 Hours

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Fig. t. Mean (_+ SEM) FI02 (upper graph) and MAP (lowergraph) for study infants during the 72 hours after the initial surfactant dose.

vanta groups in the number of days in the hospital, days of ventilatory support, or days of oxygen supplementation for all infants or for survivors. For the Exosurf and Survanta groups, respectively, the median days in the hospital were 64 and 71 for all infants (p = 0.08) and 76 and 80 for survivors (,p = 0.19); the median days of ventilatory support were 11 and 15 for all infants (p = 0.19) and 16 and 20 for survivors (p = 0.63); and the median days of oxygen supplementation were 26 and 29 for all infants (p = 0.40) and 41 and 39 for survivors (p = 0.87). The percentages of infants with oxygen saturation more than 95% or less than 85%, with bradycardia, or with reflux of surfactant during administration of any surfactant dose are shown in Fig. 2. There was a significant difference in the percentage of infants whose oxygen saturation was more than 95% during dosing (59% in the Exosurf group and 72% in the Survanta group; p = 0.0001). There was also a significant difference in the percentage of infants whose oxy-

gen saturation was less than 85% (46% in the Exosurf group and 35% in the Survanta group; p = 0.0017). There were no significant differences between the groups in the percentage of infants with bradycardia or with reflux of surfactant. The analysis based on the 571 infants who met the eligibility criteria and received the surfactant to which they were assigned gave results almost identical to the results of the intent-to-treat analysis. For example, the incidence of BPD or death was 67% in the Exosurf group and 60% in the Survanta group (p = 0.11). The average FIO2 was 0.51 for Exosurf and 0.42 for Survanta (p = 0.0001), and the average M A P was 7.80 cm H 2 0 for Exosurf and 6.89 cm H 2 0 for Survanta (p = 0.0033). DISCUSSION Synthetic surfactants 1621 and natural surfactants extracted from bovine 2~3a and porcine lung 33 and from human amniotic fluid 34, 35 have all been shown to be effective in the

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T a b l e IV. Average fraction of inspired oxygen and mean airway pressure for 72 hours after treatment Exosurf n

All infants FIo2 305 MAP (cm H20) 305 Infants weighing 501-750 gm Fio2 88 MAP (cm H20) 88 Infants weighing 751-1000 grn Flo; 1,I4 MAP (cm H20) 114 Infants weighing 1001-1500 gm FIo2 103 MAP (cm H20) 103

Survanta

M e a n _+ SEM

n

M e a n _+ SEM

Difference

95% CI

0.50 _+ 0.01 7.64 + 0.21

303 302

0.42 _+ 0.01 6.93 + 0.21

0.08 0.71

(0.05, 0.11) (0.13, 1.29)

0.62 ___0.03 9.00 _+ 0.41

88 88

0.51 _+ 0.02 7.97 _+ 0.38

0.11 1.03

(0.04, 0.18) (-0.06, 2.12)

0.49 _+ 0.02 7.72 + 0.35

106 106

0.42 _+ 0.02 6.81 _+ 0.34

0.08 0.91

(0.02, 0.13) (-0.06, 1.87)

0.41 _+ 0.02 6.41 _+ 0.28

109 108

0.36 _+ 0.02 6.21 _+ 0.36

0.05 0.20

(-0.70, 1.09)

(o.o1, o,o9)

Table V. Mortality rate and concurrent diagnoses Survanta (n = 306)

Exosurf (n = 3 0 8 )

Death before discharge Assisted ventilation or death before 21 dayst Pneumothorax Patent ductus arteriosus Necrotizing enterocolitis Sepsis Apnea treated with xanthines Intraventricular hemorrhage Grades I-IV:l: Grades III-IV:~ Pulmonary hemorrhage Retinopathy of prematurityw Supplemental 02 at 36 wk after conceptionl[

n

(%))

n

(%)

Risk ratio"

9 5 % Cl

81 54

(26) (23)

70 6I

(23) (25)

1.17 0.99

(0.90, 1.51) (0.73, 1.34)

39 119 14 103 194

(13) (39) (5) (34) (63)

27 116 19 122 212

(9) (38) (6) (40) (69)

1.51 1.01 0.76 0.86 0.90

(0.95, (0.83, (0.40, (0.70, (0.81,

2.39) 1.22) 1.46) 1.06) 1.01)

121 53 28 li9 75

(44) (19) (9) (56) (37)

136 66 32 127 72

(48) (23) (10) (54) (34)

0.91 0.83 0.85 0.99 1.f6

(0.76, (0.60, (0.52, (0.87, (0.89,

1.09) 1.14) 1.38) 1.14) 1.51)

C1, Confidenceinterval. *Adjusting for center and birth weight strata. ]'Death before or on day 21, or assisted ventilation with F1o2 _>0.40 on day 21. :~Based on 276 in the Exosurf group and 283 in the Survanta group. w on 213 in the Exosurf group and 234 in the Survanta group. []Based on 204 in fhe Exosarf group and 210 in the Survanta group.

prevention and treatment of neonatal RDS. 1 Because current d a t a are inadequate to guide clinicians faced with choosing among surfactants, this study was designed to Compare two widely available surfactants with very different formulations. Both Exosurf Neonatal and Survanta have been shown to improve the i m m e d i a t e respiratory course and long-term clinical outcome of infants with established R D S ) ' 17-2t, 28-30 The drug dosages, methods of administration, and dosing intervals used in this study were based on the recommendations of the manufacturers. The Exosurf Neonatal package insert gives no specific recommendation regarding more

than two doses, and only preliminary data from a trial using three doses o f Exosurf Neonatal were available when this study began. 36 Because investigators at the participating centers wanted the option to give more than two doses of Exosurf to infants with persistent respiratory distress, third and fourth doses were allowed at subsequent t 2-hour intervals for infants receiving mechanical ventilation and supplemental oxygen. We believe that the treatment regimens used in this study reflect those used in clinical practice at the time the trial was conducted. The O S I R I S trial subsequently showed t h a t giving more than two doses of Exosurf confers no advantage. 37

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Horbar et al.

Percent

The Journal of Pediatrics November 1993

100.

•

90.

80'

[-7 Survanta

70'

60

50.

fJJ fi/ /JJ fj-j

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(p=0.0017)

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Fig. 2. Events occurring in associationwith surfactant administration. Oxygen saturation (Sao2) was measured by pulse oximetry. Bradycardia was defined as a heart rate of less than 60 beats/rain lasting more than 20 seconds. The study found no difference between the two surfactant treatment groups in the combined incidence of death or BPD. Although there was lack of agreement between the radiographic interpretations of the central reader and those of the local readers at some of the centers, the results concerning BPD were the same regardless of whether central or local radiographic readings were used. A study is in progress to evaluate the concordance among radiologists with respect to the radiologic identification of BPD. During the 72 hours after the initial dose of surfactant, infants treated with Survanta received less supplemental oxygen and lower ventilator pressures than infants treated with Exosurf Neonatal. These findings are consistent with data from animal models of RDS showing that natural surfacrant extracts result in greater improvement in oxygenation and lung compliance than do synthetic surfactants. 384~ These models also suggest that there may be differences in the physiologic responses to various natural surfactant preparations. 38 The VE! is an empiric analog of dynamic compliance that relates arterial partial pressure of arterial carbon dioxide to

ventilator pressures and rate. 1~ The lower limit of normal has been considered to be 0.3 m l / m m Hg per kilogram.41 Seventy-two hours after treatment, infants in both groups had values just below this level. There are several possible interpretations for our findings that infants with RDS had similar rates of death or BPD 28 days after birth but responded differently to the two surfacrants during the first 3 days of treatment. The risk of death or BPD may be unrelated to early supplemental oxygen administration and ventilator pressures. Alternatively, the 8% difference in supplemental oxygen and the 0.7 cm H20 difference in MAP may be associated with a change in the risk of death or BPD that is too small to be detected by a trial of this size, which was designed to detect an absolute difference in the frequencies of death or BPD between groups of 11.5%. Oxygen saturations greater than 95% were seen more frequently in infants during administration of Survanta, whereas saturations of less than 85% were seen more frequently in infants treated with Exosurf Neonatal. These alterations in oxygen saturation may be related to the spe-

The Journal o f Pediatrics Volume 123, Number 5

cific approaches to oxygen and ventilator management used during administration of the two surfactants. The dosing recommendations for Survanta mandate increases in both the Fto2 and the ventilator rate before surfactant administration, whereas the recommendations for Exosurf do not. Modifications in the recommended dosing procedures that might reduce fluctuations in oxygen saturation should be investigated in the future. Complications of prematurity have been associated with surfactant treatment in individual studies. Increased incidences of apnea 19, 20 and pulmonary hemorrhage have been reported in association with Exosurf treatment, and increased incidences of intraventricular hemorrhage 29 and sepsis 3 have been reported in association with Survanta treatment. An increased incidence of patent ductus arteriosus has been reported in studies of Surfactant-TA (Tokyo Tanabe), a modified bovine surfactant extract similar to Survanta. 26 In this direct comparison of Exosurf and Survanta, no differences were seen in any of these common complications of prematurity. This study is one of the first surfaetant studies to evaluate infants for pulmonary hemorrhage prospectively, The cause of these pulmonary hemorrhages is unknown, but it has been speculated that the blood observed in the endotracheal tube may represent hemorrhagic edema fluid caused by patent ductus arterioSUS.2 In conclusion, we found no difference between the treatment groups in the incidence of death or BPD, although a difference was observed in the initial response to treatment as measured by FIOe and M A P during the 72 hours after the first surfactant dose. Therefore we regard both surfactants as reasonable choices for the treatment of neonatal R D S . Members of the National Institute of Child Health and Human Development Neonatal Research Network are as follows (asterisk indicates current member: Milton S. Hershey Medical Center: Ronald L. Poland, MD, Chairman*; University of Alabama at Birmingham: Joseph B. Philips III, MD; Case Western Reserve University: Avroy A. Fanaroff, MD,* and Maureen Hack, MD*; University of Cincinnati: Edward F. Donovan, MD,* and Reginald C. Tsang, MD*; Dartmouth Hitchcock Medical Center: William Edwards, MD, and George Little, MD; Emory University: Barbara J. Stoll, MD,* and George W. Brumley, MD*; George Washington University Biostatistics Center: Raymond P. Bain, PhD,* Naji Younes, MS,* and Kathleen A. Foley; Indiana University: James A. Lemons, MD,* and Scott C. Denne, MD*; Miami University: Charles Bauer, MD,* and Emmalee Bandstra, MD*; National Institute of Child Health and Human Development: Sumner J. Yaffe, MD,* Linda L. Wright, MD,* and Michael Malloy, MD; University of New Mexico: Lu-Ann Papile, MD*; Stanford University: David K. Stevenson, MD*; University of Tennessee at Memphis: Sheldon B. Korones, MD,* and Henrietta Bada, MD*; University of Texas Southwestern Medical Center: Jon E. Tyson, MD,* and Kathleen Kennedy, MD*; University of Vermont: Jerold F. Lucey,

H o r b a r et al.

765

MD, and Jeffrey D. Horbar, MD; Wayne State University: Seetha Shankaran, MD,* and Enrique Ostrea, MD*; Women and Infants Hospital: William Oh, MD,* and Barbara Stonestreet, MD; and Yale University: Richard Ehrenkranz, MD,* and Ian Gross, MD. REFERENCES

1. Soll RF, McQueen MC. Respiratory distress syndrome. In: Sinclair JC, Bracken MB, eds. Effective care of the newborn infant. Oxford: Oxford University Press, 1992. 2. Exosurf Neonatal (colfosceril palmitate, cetyl alcohol, tyloxapol) for intratracheal suspension package insert. Research Triangle Park, North Carolina: Burroughs Wellcome, August 1990. 3. Survanta (Beractant) intratracheal suspension package insert. Columbus, Ohio: Ross Laboratories, June 1991. 4. Survanta (Surfactant TA, Beractant) investigational drug brochure. Columbus, Ohio: Ross Laboratories, 1989. 5. Wei L J, Lachin JM. Properties of the urn randomization in clinical trials [published erratum appears in Controlled Clinical Trials 1989;10:following 126]. Controlled Clin Trials 1988;9:345-64. 6. HIFI Study Group. High-frequency oscillatory ventilation compared with conventional mechanical ventilation in the treatment of respiratory failure in preterm infants, N Engl J Med 1989;320:88-93. 7. Glenski JA, Marsh HM, Hall RT. Calculation of mean airway pressure during mechanical ventilation in neonates. Crit Care Med 1984;12:642-4. 8. Shennan AT, Dunn MS, Ohlsson A, et al. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988;82:527-32. 9. Gilbert R, Keighly JF. The arterial/alveolar oxygen tension ratio: an index of gas exchange applicable to varying oxygen concentrations. Am Rev Respir Dis 1974;109:142-5. 10. Notter RH, Egan EA, Kwong MS, et al. Lung surfactant replacement in premature lambs with extracted lipids from bo9vine lung lavage: effects of dose, dispersion technique and gestational age. Pediatr Res 1985;19:569-77. 11. Bell M J, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Ann Surg 1978;187:1-7. 12. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birthweights less than 1500 gin. J PEDIATR 1978;92:529-34. 13. An international classification of retinopathy of prematurity. Pediatrics 1984;74:127-33. 14. SAS/STAT user's guide; vols 1 and 2. Version 6; 4th ed. Cary, North Carolina: SAS Institute, 1985. 15. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659-63. 16. Ten Centre Study Group. Ten centre trial of artificial surfactant (artificial lung expanding compound) in very premature babies. BMJ 1987;294:991-6. 17. Bose C, Corbet A, Bose G, et al. Improved outcome at 28 days of age for very low birth weight infants treated with a single dose of a synthetic surfactant. J PEDIATR 1990;117:947-53. 18. Canadian Exosurf Pediatric Study Group. Effects of two rescue doses of Exosurf, Pediatric in 342 750-1249 gram infants [Abstract]. Pediatr Res 1990;27:200A. 19. Long W, Thompson T, Sundell H, et al. Effects of two rescue

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The Journal o f Pediatrics November 1993

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