Clinical Trials of Synthetic Surfactant in the Respiratory Distress Syndrome of Premature Infants

SURFACTANT REPLACEMENT THERAPY

0095-5108/93 $0.00

+ .20

SYNDROME INFANTS Anthony Corbet MB, FRACP

The pulmonary surfactant is a lipoprotein complex that is secreted by specialized lung epithelial cells into the airspaces; it functions to stabilize air expansion and prevent atelectasis of the lungs. 53 Since the pioneering work of Avery and Mead, 2 it has been widely believed that the respiratory distress syndrome (RDS) in premature infants is caused by a deficiency of pulmonary surfactant. In recent years, a major area of research has focused on the realization that the pulmonary surfactant could be reproduced in the laboratory and then used as exogenous surfactant replacement therapy in premature infants with RDS. 49 For this purpose, surfactants of both mammalian and synthetic origin have been prepared.

The composition of the natural pulmonary surfactant is approximately 90% lipid and 10% protein; there is 45% dipalmitoyl phosphatidykholine (DPPC), 25% unsaturated PC, 5% phosphatidylglycerol (PG), 5% other phospholipids, and 10% neutral lipids. The surfactant protein (SP) is composed of three specific proteins: SP-A, SP-B, and SP-C. 53 The most important molecule is DPPC because it alone has the appropriate properties, and From the Department of Pediatrics, Emory University, Atlanta, Georgia

CLINICS IN PERINATOLOGY VOLUME 20 •NUMBER 4 •DECEMBER 1993

737

738

CORBET

is present in sufficient quantities, to function as a pulmonary surfactant. By itself, however, DPPC is a poor surfactant because it adsorbs very slowly to air-liquid interfaces; its adsorbtion is greatly improved by the addition of surfactant proteins or other lipids. 53 EARLY TRIALS WITH SYNTHETIC SURFACTANT

The first clinical trials of exogenous surfactant therapy were conducted in the 1960s with synthetic DPPC alone, aerosolized into the lungs of infants with RDS. 10•43 These trials were not successful because the preparation lacked an appropriate additive to improve the function of DPPC. Later, a 9 : 1 mixture of DPPC : PG was nebulized into the lungs of infants with RDS and small improvements in respiratory gas exchange were documented.27 In 1981, Morley et al3 7 reported results from Cambridge with a 7: 3 mixture of DPPC: PG; a single dose of 25 mg phospholipid was given as a dry powder, by insufflation down an endotracheal tube inserted in premature infants at birth. Although this trial was controlled, it was not blinded and it was certainly not properly randomized. The treated infants appeared to require less ventilatory support, and there were fewer deaths among those who received surfactant. However, subsequent randomized trials with this material in the dry powdered form did not suggest that it would be useful.3 6•57 CONTROLLED TRIALS WITH ARTIFICIAL LUNG EXPANDING COMPOUND

After the relative failure of the 7 : 3 mixture of DPPC : PG given as a dry powder, this same material was administered as a dispersion in 1 mL saline. In addition, the material was administered immediately at birth, the size of each single dose was substantially increased, and repeated doses were given. This material, known as artificial lung expanding compound (ALEC; Pneumactant, Britannia Pharmaceuticals, United Kingdom), was developed by Bangham and associates at Cambridge University. 3 The Two-Center Trial

The two-center trial was conducted in Cambridge and Nottingham; it was controlled and randomized, but possibly not well blinded. 38 Premature infants of 23 to 34 weeks received a pharyngeal instillation of surfactant immediately at birth. Then, if they were intubated, they received subsequent doses of surfactant at 10 minutes, 1 hour, and 24 hours of age, by instillation down the endotracheal tube. Initially, each single dose was 50 mg phospholipid, but later in the trial the dose was increased to 100 mg. Controls were given an instillation of 1 mL saline alone. There were no benefits in larger infants, possibly because the incidence of RDS was low;

CLINICAL TRIALS OF SYNTHETIC SURFACTANT IN THE RDS OF PREMATURE INFANTS

739

......""""''""'" in 136 infants under 30 weeks' gestation, there were substantial benefits for those treated with surfactant. Neonatal was significantly reduced from 36% in controls to 17% in treated infants, a proportionate reduction of 53%, and death attributed to RDS was reduced from 31 % in controls to 9% in treated infants. In addition, the occurrence of intraventricular hemorrhage (IVH) was significantly reduced from 40% to 19% by treatment with surfactant; most of the benefit was apparent in the most severe forms of IVH. There was no change in the incidence of either pneumothorax or patent ductus arteriosus (PDA), but significantly fewer treated infants required supplemental oxygen at the age of 28 days. No adverse events were described and the authors considered the risks of therapy to be very low. The 10-Center Trial

The 10-center trial was conducted at multiple centers throughout Britain. Infants of 25 to 29 weeks' gestation were enrolled and similar infants already enrolled in the two-center trial were induded. 50 The trial protocol was the same as that for the two-center trials and each dose was 100 mg phospholipid. The benefits were again substantial. Among 328 infants, neonatal mortality was significantly reduced from 27% in controls to 14 % in treated infants, a proportionate reduction of 46%, which is very comparable to that of the two-center trial. In treated infants, the incidence of severe IVH was significantly reduced from 24% to 16%. No change in the occurrence of pulmonary air leaks, necrotizing enterocolitis, or acquired infection was apparent. COl\ITR:OLILED TRIALS WITH COLFOSCERIL HEXADECANOL, AND TYLOXAPOL

A second major synthetic surfactant, namely colfosceril palmitate (DPPC), hexadecanol, and tyloxapol (Exosurf Neonatal, Burroughs Wellcome Co., Research Triangle Park, NC), was developed and tested by Clements and associates at the University of California at San Francisco. 19,51 This surfactant (abbreviated hereafter as CPHT) consists of 85% DPPC, 9% hexadecanol, and 6% tyloxapol by weight; DPPC is the major functional component; its activity is greatly accelerated by the addition of hexadecanol, and its dispersion in the aqueous phase is greatly facilitated by tyloxapol. CPHT is prepared as a lyophilized powder stored under vacuum in individual vials. Each vial is reconstituted with sterile water and administered at a dose of 5 mL/kgor67.5 mgDPPC/kgbodyweightbyinstillationdownan endotracheal tube during mechanical ventilation. The controlled trials that have been performed with CPHT may be divided into two broad categories, namely, prophylactic and rescue trials. In prophylactic trials, the infants enrolled are very small and premature, so they are expected to have a very high incidence of RDS, possibly 50% or

740

CORBET

more. The advantage of this approach is that surfactant can be given very soon after birth, either immediately or within 30 minutes, which assists in the distribution of surfactant within the lung 26 and helps prevent the epithelial injury that occurs with ventilation in the absence of adequate surfactant. 39 The disadvantage is that many infants treated may not need to be intubated, and they may not need surfactant. In the rescue strategy, treatment is not given until the infants have actually developed significant RDS, which may be at the age of 2 to 24 hours. The advantage is that only infants who need treatment are actually treated. The disadvantage is that lung injury may occur before treatment; and plasma proteins, which leak into the airspaces, may inactivate surfactant, thus making treatment less effective. 26 Preliminary Trials With CPHT at San Francisco

These two trials were controlled and randomized, but they were open because it was believed that proper blinding would not be possible. 41 One trial with 74 infants was prophylactic, and the other trial with 104 infants was a rescue trial. Only a single dose of surfactant was administered. In both trials, time-average inspired oxygen concentrations and mean airway pressures during the 72 hours after dosing decreased significantly in the treated infants compared with controls. Mortality was not reduced significantly in either trial, but both trials showed an encouraging trend toward reduced mortality in the surfactant-treated group. No change was noted in the incidence of IVH, bronchopulmonary dysplasia (BPD), or PD A. Preliminary results were considered sufficiently good to warrant larger trials. Subsequent North American Trials Conducted With CPHT

A large number of trials were conducted under the sponsorship of Burroughs Welkome Co. as part of the process for obtaining approval from the Food and Drug Administration. These trials all had a similar structure and they will be referred to by their assigned numbers (Table 1). They were all double-blind, controlled, randomized trials. Blinding was achieved by the use of a separate drug administration team, which was responsible for dosing in secret. Parents and hospital staff were not told whether room air or surfactant was administered to the patient. Controls received room air, rather than saline. For each trial the randomization process was stratified by weight and gender so that good comparability between groups was almost invariably obtained. Complications of prematurity were carefully defined in the protocol. Infants were followed through at least the first year of life; both neonatal and infant mortality were important outcome measures. A major outcome measure in the trials was the incidence of BPD, or survival without BPD, so the definition of BPD was carefully detailed in the protocol. The diagnosis of BPD was made by analysis at age 28 days. All the following criteria had to be met: (1) the presence of tachypnea and retrac-

7 41

CLINICAL TRIALS OF SYNTHETIC SURFACTANT IN THE RDS OF PREMATURE INFANTS

Table 1. STUDIES IN THE NORTH AMERICAN EXOSURF CLINICAL TRIALS PROGRAM

No.of

No. of

{g)

Doses

Patients

700-1350 500-699 700-1100 700-1350 ;;::1250 500-749 750-1249 ;;::1250 700-1100 ;;::1250 500-749

1VS0 1VS0 1vs0 2 vsO 2 vs 0 2vs 0 2vs 0 2 3vs1 4vs 2 6vs 3

385 215 446 419 1237 221 342 281 886 000

Birth

04 05 06/09 07 08 12 13

17 19

Prophylaxis Prophylaxis Prophylaxis Rescue Rescue Rescue Rescue Rescue Prophylaxis Rescue Prophylaxis

348

Reference No.

8 48 14 34 32 46 9 5 21 42 33

Studies 10, 11 , 14, and 18 were follow-up studies; study 12 was a dose ranging study: 2.5, 5.0, and 7 .5 ml/kg; and studies 15 and 16 were bridging protocols before the Treatment IND Program.

tions, (2) the need for supplemental oxygen, and (3) chest radiographic abnormalities rating a score of 4 or more on the Edwards' classification. 20 Among infants who died before 28 days and who underwent autopsy, BPD was diagnosed by the histologic criteria of Bonikos and colleagues.7 If an infant died between 10 and 28 days and did not undergo autopsy, BPD was diagnosed if, at the time of death, (1) the infant required more than 60% oxygen and 7 cm H:P mean airway pressure; (2) the infant had a persistently abnormal chest radiograph, and (3) there was no other explanation for respiratory failure. TRIALS Trial With CPHT

Initially, single-center prophylactic trials were started, one in Chapel Hill and one in Houston, enrolling infants of birth weight 700 to 1350 g. 8 The stated primary outcome measure was an increase in the survival of infants without BPD. Both of these trials were terminated early, before enrollment of the targeted number of infants, because a subsequent multicenter prophylactic trial dearly established the efficacy of CPHT .14 Because the combined actual sample size of the two trials approached the originally targeted sample sizes of the individual trials, it was decided to combine the two trials for the purpose of analysis. Altogether, 192 infants received surfactant and 193 received air placebo; surfactant-treated infants required significantly less oxygen and ventilator support during the first 3 days of life, and the incidence of pulmonary interstitial emphysema was significantly reduced. There was a significant increase in the number of surfactant-treated infants who survived without BPD at the age of 28 days. In the Houston trial, there was a large reduction in mortality after treatment with

742

CORBET

surfactant; there was a 78% proportionate reduction of neonatal mortality and a 44% proportionate reduction of infant mortality. 15 03 Trial With CPHT

This trial was a multicenter trial conducted at 23 different hospitals throughout the United States. Two hundred fifteen infants of 500 to 699 g birth weight were enrolled and a single prophylactic dose of surfactant was evaluated. 48 Treated infants required less oxygen and ventilator support during the first 3 days of life; treated infants also experienced fewer pneumothoraces and fewer deaths from RDS than control infants. A significant increase in the incidence of pulmonary hemorrhage in treated infants was noted in this trial. As there was no change in overall mortality, it was concluded that CPHT did not work as well in this group of infants, probably because of marked prematurity. 04 Trial With CPHT

In a multicenter trial conducted at 19 centers in the United States, 446 infants of birth weight 700 to 1100 g were enrolled for the evaluation of a single prophylactic dose at birth. 14 Treated infants required less oxygen and ventilator support during the first 7 days of life, and there were fewer pneumothoraces. Neonatal mortality was significantly reduced from 22% in controls to 13% in those treated with surfactant, a proportionate reduction of 40%. This reduction in mortality was not a transient effect, as infant mortality (through 1 year) was reduced from 32% in controls to 18% in treated infants, a proportionate reduction of 43%. Although the incidence of BPD was slightly higher in treated infants, possibly related to increased survival, the number of infants dying of BPD during the first year of life was significantly reduced in the treated group, suggesting that the severity of BPD was reduced with surfactant treatment. There were no changes in the incidence of complications such as BPD, PDA, necrotizing enterocolitis, or infection. 13 Trial With CPHT

This modified prophylactic trial was conducted at 33 centers in the United States and enrolled 827 infants of 700 to 1100 g birth weight. One dose of surfactant at birth was compared with one dose of surfactant at birth followed by two further doses of surfactant at 12-hour intervals. 21 The second and third doses of surfactant were administered according to schedule if the infant remained on the ventilator, whether or not the infant still had a significant oxygen requirement. Those treated with multiple doses of surfactant required significantly less oxygen and ventilator support during the first 7 days. Neonatal mortality was reduced from 15% in the one-dose

743

CLINICAL TRIALS OF SYNrnETIC SURFACTANT IN THE RDS OF PREMATURE INFANTS

group to 9°/o in the three-dose group, a 42% proportionate reduction. Infant mortality was reduced from 19% in the one-dose group to 14% in the three-dose group, a proportionate reduction. of 26%. There were no important changes in the incidence of prematurity complications; in particular, there was no further reduction in the incidence of pulmonary air leaks.

If the results of the 04 and 13 trials are examined together, it can be seen that infant mortality was reduced from 32% in controls to 19% in those treated with one dose of surfactant at birth, and to 14 % in those treated with the multidose prophylactic regimen (Fig. 1). If control and three-dose groups are compared, it would appear that the modified prophylactic threedose regimen can be expected to proportionately reduce infant mortality by 56%.13 19 Trial With CPHT

This trial examined infants of 500 to 749 g birth weight; it compared the modified prophylactic three-dose regimen with a four- to six-dose strategy, the first four doses given. at 12-hour intervals according to schedule, and two other doses added at 6- to 24-hour intervals if the infants had a significant oxygen requirement. There were no further improvements in clinical response or in overall mortality with the additional doses of surfactant. 33

o.9

''S·-.. ·

I:-.. ,_,

Cl

1

c: :~ 0.8

·--·----

-- . -- . -- . -- . -, . -- . - . -- . -- . -- . -- . -- -- . - . -- . -- . -- . -- . -- . -- . --

·----- ------~-~-~~---····································---········-········

~ :::l

----~---------------------

en c:

-~ 0.7 0

ea..

Treatment Group -- · -- Exosurl® (Study 13) - 3 Doses -· · · · · Exosurl® (Study 13) - 1 Dose - - - Exosurl® (Study 04) · 1 Dose Air (Study 04)

0.6

...... 50

0.5'--~

0

~--'~~_.._~___..~~~~~~~~~~~~~~~

100

150

200

250

300

350

400

450

500

Study Day Figure 1. Combined Kaplan Meier curves for the 04 trial (1 versus 0 dose) and the 13 trial (3 versus 1 dose). The proportionate reduction of infant mortality with 3 doses was 56%.

744

CORBET

OXYGEN

90 >R. c:

~

80 70 60

CD Cl

50

0

40

>x

30 20

0

2

A

0 :i:::"' E

-8.

a.. <(

:;

15 14 13 12 11 10 9 8 7 6 5 4

5

6

7

MAP

0

2

B ~

3 4 Study Day

460

4 3 Study Day

5

6

7

6

7

A-a P02 GRADIENT

g 420

::::- 380 ~ 340

~ ~~~

(.!)

"'220 180 '\l 140 <( 1000

~

c

2

4 3 Study Day

5

Figure 2. Reduction of oxygen and ventilator support in infants of birth weight 700 to 1350 g treated with Exosurf, two rescue doses 12 hours apart. Mean oxygen concentrations measured in percentage (A), mean airway pressures {MAP) measured in centimeters of water (B), and mean alveolar arterial {A-a) P02 gradients measured in millimeters of mercury (C) {all ± SEM), are shown for the first 7 days after the initial dose, in infants randomly assigned to receive air placebo (closed circles) or Exosurf (open circles). Note that improvements lasted at least 3 days and up to 1 week. (From Long W, Thompson T, Sundell H, et al: Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 7001350 g infants with respiratory distress syndrome. J Pediatr 118:595-605, 1991; with permission).

RESCUE TRIALS

05 Trial With CPHT

In a trial conducted at 21 American hospitals, two doses of surfactant or air placebo were administered to 419 infants weighing 700 to 1350 g; they had RDS with an arterial alveolar oxygen pressure ratio of less than 0.22, which corresponds to an oxygen requirement of approximately 50%. 34 The first dose was given between 2 and 24 hours of age; the second dose was given 12 hours later if the infant remained on mechanical ventilation. Oxygen and ventilator requirements were significantly reduced in those treated with surfactant (Fig. 2). Statistically significant reductions of inspired oxygen were manifested before the age of 2 hours and significant reductions of mean airway pressure were observed before the age of 6 hours (Fig. 3). The incidence of pneumothorax was reduced by one third and the incidence of pulmonary interstitial emphysema was reduced by one half in those treated

Hours Poot-Dose

Hours Poot-Dose

2

2

6

o-.--.-~..,..,..,..,....--.---~-

P=(l.0001

0.2

i

00\j

~

Cl)

<

0

j

-0.2

350

:!l 411 c

.5

·10

E

g

'E

.!!! 'C

~ -0.4 I.

I!

300

~""

250

~

IV

I.I.

..@::

-0.6 -0.8

-20

A

P=(l.0010

0.4

~

;,!!. e...

J

6

P=(l.0001

B

P=(l.003

c

Fig11re 3. Onset of action. Mean changes of 0 2 (A), mean airway pressure (B), and alveolar arterial (A-a) Po2 gradient (C) at 2 and 6 hours after dosing (first and second time points at which data were collected), for infants of birth weight 700-1350 g who were randomly assigned to receive air placebo (open bars) or rescue Exosurf (hatched bars). Significant improvements in oxygenation were present by 2 hours, and significant improvements in MAP were present by 6 hours after dosing. (From long W, Thompson T, Sundell H, et al: Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700-1350 g infants with respiratory distress syndrome. J Pediatr 118:595-605, 1991; with permission).

~

y,

746

CORBET

1.0

0.9

.\.

0.8

...

Proportion Surviving

··--···································................................................................... 0.7 Treatment Group

0.6

Exosurl® =

Air o.5-1--~~~~~~~~...-~~,.---.--,~-.---.~..---.

0

50 100 150 200 250 300 350 400 450 500 550 600 650 700 Study Day

Figure 4. Kaplan-Meier survival curves through 1 year adjusted age in infants of birth weight

700-1350 g treated in the rescue mode for established RDS. They were randomly allocated to receive air placebo (broken line) or Exosurf (solid line). Note that early gains in survival in the Exosurf group were maintained. Survival through 1 year adjusted age was significantly better in the Exosurf group (P < 0.001). (From Long W, Thompson T, Sundell H, et al: Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700-1350 g infants with respiratory distress syndrome. J Pediatr 118:595-605, 1991; with permission).

with surfactant. Neonatal mortality was reduced from 23% in controls to 11 % in treated infants, a proportionate reduction of 52 % with surfactant. Infant mortality was reduced from 29 % in controls to 16 %in treated infants, a proportionate reduction of 46% with surfactant (Fig. 4). Complications of prematurity, including BPD and IVH, were unchanged by treatment. 06/09 Trial With CPHT

In a trial conducted at 36 American and Canadian hospitals, two doses of surfactant or air placebo were administered to 1237 infants weighing at least 1250 g; they had RDS with an arterial alveolar oxygen pressure ratio of less than 0.22. 32 The first dose was given between 2 and 24 hours of age; the second dose was given 12 hours later if the infant remained on mechanical ventilation. Oxygen and ventilator requirements were significantly reduced in those treated with surfactant. The incidence of pneumothorax, pulmonary interstitial emphysema, BPD, IVH, and PDA was significantly reduced in the surfactant-treated group. Neonatal mortality was reduced from 5% in controls to 3% in treated infants; infant mortality was reduced from 8% in controls to 5% in treated infants. The proportionate reductions in mortality were similar to those seen in other trials.

CLINICAL TRIALS OF SYNTHETIC SURFACTANT IN THE RDS OF PREMATURE INFANTS

747

07 Trial With

In a trial conducted at 12 Canadian hospitals, two doses of surfactant or air placebo were administered to 221 infants weighing between 500 and 749 g; they had RDS with an arterial alveolar oxygen pressure ratio of less than 0.22. 47 The first dose was administered between 2 and 24 hours of age; the second dose was administered 12 hours later if the infant remained on mechanical ventilation. Oxygen and ventilator requirements were significantly reduced in those treated with surfactant. However, there were no significant changes in the mortality or morbidity of infants in the treatment group.

08 Trial With CPHT

In a preliminary report from a trial conducted at 12 Canadian hospitals, two doses of surfactant or air placebo were administered to 342 infants weighing 750 to 1249 g. The infants had RDS with an arterial alveolar oxygen pressure ratio of less than 0.22.9 The first dose was administered between 2 and 24 hours of age; the second dose was administered 12 hours later if the infant remained on mechanical ventilation. The trial was terminated short of the targeted sample size because of reduced mortality in other trials. Oxygen and ventilator requirements were significantly reduced in those treated with surfactant. The incidence of pneumothorax and pulmonary interstitial emphysema was significantly reduced in the surfactant group. Although mortality was not reduced significantly, death from RDS was decreased in the treated infants. The incidence of BPD was significantly decreased in the treated group, and survival without BPD was significantly increased in those treated with surfactant.

17 Trial With CPHT

This trial compared two rescue doses at 12-hour intervals, with up to four rescue doses administered as frequently as every 6 hours, if criteria for requirement of oxygen were met in infants weighing at least 1250 g. 42 It was not designed to be large enough to show differences in mortality, but there were no differences in oxygen or ventilator support between the two groups. It was concluded that there is no advantage to the use of more than two doses of CPHT for the rescue strategy.

12 Trial With

This trial compared two rescue doses of 2.5, 5.0, or 7.5 mL/kg in 281 infants weighing at least 1250 g, comparing improvements in oxygenation.5 During the first 72 hours, improvement in the alveolar arterial oxygen

748

CORBET

pressure difference (A-a.Po2) was equivalent for the 5.0 and 7.5 mL/kg doses but not as good for the 2.5 mL/kg dose. After 72 hours, improvement in the A-a.Po2 appeared to be greater with the 7.5 mL/kg dose than with the 5.0 mL/kg dose, but more infants appeared to be off the ventilator with the 5 .0 mL/kg dose. It was concluded thatthe 5.0 mL/kg dose used throughout the controlled trials was appropriate.

TREATMENT INVESTIGATIONAL NEW DRUG PROGRAM WITH CPHT

After the efficacy and safety of CPHT were established, the material was used in over 11,000 patients without controls while the results were monitored. 44 Physicians were given a choice between using the prophylactic or the rescue strategy: 85% of patients were treated in the rescue mode and 15% were treated in the prophylactic mode. The results for mortality and morbidity were almost the same as in the controlled trials, except the incidence of pulmonary hemorrhage was increased to 4% and the risk of BPD was higher. This last observation may have resulted because a much larger number of hospitals were involved, and criteria for the diagnosis of BPD were not specified.

OTHER TRIALS OUTSIDE NORTH AMERICA The OSIRIS Trial With CPHT (Wellcome Foundation)

OSIRIS stands for Open Study of Infants at high risk of, or with, Respiratory Insufficiency-the role of Surfactant. 40 This study was a very large, unblinded, international trial designed to answer two questions: (1) Is prophylactic treatment* better than rescue treatment? and (2) Do additional doses beyond two doses provide an advantage? This was not a placebocontrolled trial: all infants could receive surfactant if they met certain criteria. A total of 2690 infants were enrolled before the age of 2 hours. They were considered by their individual clinicians to be at high risk for the development of RDS, and they were intubated because it was believed they needed respiratory assistance. Intubated infants were randomized to either prophylactic surfactant treatment as soon as possible, or they were assigned

•In this context, the term prophylactic treatment means the administration of surfactant because the infant was intubated and at risk for RDS. In many other trials, the term indicates delivery room administration, which was not performed in the OSIRIS trial.

CLINICAL TRIALS OF SYNTHETIC SURFACTANT IN THE RDS OF PREMATURE INFANTS

749

to later rescue treatment the specific oxygen criterion of an 0.22. Another 4067 infants with arterial alveolar oxygen ratio of less RDS were enrolled after 2 hours of age, when the diagnosis of RDS was better established, although they were not used in the comparison of prophylactic versus rescue treatment. All 6757 infants were further randomized to receive either a total of 2 doses of CPHT at an interval of 12 hours, or up to four doses if they continued to meet the oxygen criterion. Infants in the prophylactic versus rescue comparison were first treated at median ages of 2 and 3 hours, respectively. The risk of either death or dependence on oxygen at the expected date of delivery (BPD) was 16% lower in those allocated prophylactic treatment, which was a significant improvement. Earlier administration was also associated with a 32 % lower risk of pneumothorax. In the dosing comparison of two versus four doses, there were no improvements with additional doses of surfactant. The conclusion from the trial was that there is a distinct advantage to prophylactic treatment and that a difference as small as 1 hour could change the outcome.

This trial enrolled 420 infants with a gestational age of 26 to 29 weeks, who required intubation in the first 2 hours of life. 20a Infants were randomized to receive either two prophylactic doses of CPHT or two doses of air at an interval of 18 hours. This part of the trial was blinded. If the infant developed RDS at any time between 2 and 18 hours after the first blinded dose, as manifested by an arterial alveolar oxygen ratio of less than 0.22, then two unblinded rescue doses of surfactant 12 hours apart were given. Thus, this trial was a test of early prophylactic treatment compared with later rescue treatment, but with a "rescue" safety net for any infant in either group who developed moderate RDS. Neonatal mortality in the prophylactically treated group was reduced proportionately by 19%, but this change was not statistically significant. Also, in the prophylactically treated group, there was an important reduction in the incidence of pulmonary air leaks compared with the rescue-treated infants.

Synthetic surfactants produced impressive reductions of mortality, except in very small infants of birth weight under 700 g. The proportionate reduction of infant mortality with the modified three-dose prophylactic regimen of CPHT was estimated at 56%. Significant improvements in the gas exchange of treated infants occurred and lasted for at least 3 days after a

750

CORBET

single dose. A reduction of pulmonary air leak events was uniformly observed with CPHT. Death attributed to RDS was consistently reduced by treatment with CPHT. In individual trials of CPHT, there were no consistent statistically significant reductions in other complications of prematurity, but in meta-analysis of rescue trials the incidence of BPD and IVH was significantly reduced26a, 3o (see below).

ADVERSE EVENTS

Use of CPHT appears to be remarkably free of problems, but a number of adverse events were recognized during the trials. 1. The most important safety problem identified was pulmonary hemorrhage in the 03 trial, examining infants of 500 to 699 grams. The incidence of pulmonary hemorrhage was 2% in controls and 12% in treated infants. 48 Although it was not an important finding in any of the other trials, an examination of all North American trials of CPHT indicated that the incidence of pulmonary hemorrhage was 1% in controls and 2% in treated infants. 54 No evidence was found that surfactant therapy was associated with a general bleeding diathesis. 31 Pulmonary hemorrhage was rarely considered the primary cause of death; in an autopsy review, pulmonary hemorrhage was not more common in those treated with CPHT than in controls. 54 The prevailing theory is that pulmonary hemorrhage is related to the presence of a PDA. 54 Surfactant administration is associated with improved ventilation, decreased pulmonary vascular resistance, increased left-to-right shunt across the ductus, increased pulmonary blood flow, raised microvascular pressures, and hemorrhagic pulmonary edema. 11 Some evidence suggests that the problem may be averted by early closure of the ductus with indomethacin; others have suggested that the problem is due to early weaning of positive airway pressure. 2. There have been a number of reports of mucous plugs, which cause obstruction of the endotracheal tube. When examined, these plugs have the appearance and consistency of CPHT. This complication is comparatively rare, the reported incidence being 3 per 1000 infants. 44 3. Several of the trials of CPHT reported an increase in the incidence of recurrent apnea, requiring xanthine treatment, among the treated infants. 14, 32, 34 This observation was believed to be due to earlier weaning of ventilator support in the surfactant-treated group, so that apnea could be more easily manifested. For both treated and control infants, apnea proved to be a marker for survival, 14, 32,34 so it should not be considered an adverse event.

CLINICAL TRIALS OF SYNTHETIC SURFACTANT IN THE RDS OF PREMATURE INFANTS

751

UNMET

There were a number of things that synthetic surfactant was expected to cause but were not evident in these trials. 1. The incidence of RDS, as defined in the protocols, was reduced by

the prophylactic administration of synthetic surfactant in only two 11, 20a of five 8•14•20a· 41 •48 placebo-controlled trials of prophylaxis of CPHT. The major change was a reduction in the severity of RDS. 2. The incidence of PDA or of symptomatic PDA was not increased by CPHT. At least in the trials of CPHT this may have resulted from a policy of early treatment of this complication with indomethacin in both experimental groups. 3. Because oxygen and ventilator support could be reduced in the treated infants, it was expected that a substantial reduction in the incidence of BPD would be observed. However, reductions in the incidence of BPD were not documented in most of the placebo-controlled trials with two important exceptions. 9•32 The explanation may be that the risk of BPD was higher among the large number of additional survivors in the surfactant-treated group. One exception was the 08 trial, a rescue trial of infants weighing 750 to 1250 g, in which mortality was not reduced, but treated infants had a lower risk for BPD. 9 The other exception was the large 06 /09 trial, involving more mature infants, in which the incidence of BPD was quite low in the control group but nevertheless significantly reduced in those treated with surfactant. 32 When the relative risk of BPD is examined across the placebo-controlled trials of CPHT conducted in infants weighing more than 700 g, it is dear that in rescue use of CPHT reduces BPD (Fig. 5 ). The conclusion that rescue use of CPHT reduces the incidence of BPD has been confirmed in a meta-analysis recently published by Jobe 26". It remains unclear why the incidence of BPD is reduced after rescue but not prophylactic administration of CPHT. If prophylactic administration of surfactant saves the lives of infants who cannot be saved by rescue treatment (see below) and these extra survivors are at increased risk of BPD, then it would not be unexpected that reductions in the incidence of BPD have only been observed in rescue trials. In any case, the severity of BPD was reduced in both prophylactic and rescue trials of CPHT, as judged by fewer infants on oxygen or mechanical ventilation at 1 year follow-up in both types of trials. This conclusion is also supported by the occurrence of fewer deaths after the neonatal period from BPD in the largest placebo-controlled trial of prophylaxis, 14 and by the fact that in the rescue trials the Edwards' scores of the radiographic severity of BPD were consistently lower in the synthetic surfactant group in both middle-sized babies (Fig. 6) and large babies (Fig. 7). 4. Because the severity of RDS is decreased by surfactant and the

752

CORBET

3.0 2.8 2.6 2.4 2.2 .:.:: 2.0 I/) 1.8 ~ 1.6 ~ 1.4 Qi 1.2 a: 1.0 0.8 0.6 0.4 0.2 0.0 ~.------.----.-----,...------.-Prophylactic Prophylactic Rescue Trial Rescue Trial Rescue Trial

a:

l--------l------··r··------·r··----·rTrial

(combined)

Trial (multicenter)

(middle-size) (U.S.)

(middle-size) (Canada)

(large infants)

Figure 5. Graphic display of the relative risk for BPD in infants treated with Exosurf compared with controls. Relative risks are shown with 95% confidence intervals; a relative risk of less than 1.0 means the risk is reduced. From left to right, the values represent the 01 /02, 04, 05, 08, and 06/09 trials, respectively (see Table 1 for references). It can be seen that in rescue trials (05, 08, 06/09), the risk of BPD is reduced. This conclusion has recently been confirmed in a metaanalysis published by Jobe. 26•

incidence of pulmonary air leaks is reduced, a substantial reduction in the incidence of IVH would also be expected. It would appear that after administration of CPHT, there is an increase in cerebral blood flow velocity, which may offset any expected decrease in the incidence of IVH.52 There was no reduction in the risk of IVH in small premature infants, although in the larger infants enrolled in the 06/09 trial, a significant reduction was observed in this complication.32 Again, meta-analysis indicates that rescue use of synthetic surfactant does reduce the incidence of IVH significantly26•; the same was not true for prophylactic use. The explanation for this difference remains unclear, but it may lie in enhanced survival of sicker infants with prophylaxis.

PHYSIOLOGIC ISSUES

Improvements in oxygenation with synthetic surfactant are relatively slow in comparison with mammalian surfactants. In a direct comparison of CPHT and bovine surfactant, Cotton and associates 16 found that the arterial alveolar oxygen ratio and lung volume were both increased to the same extent by 6 hours after dose administration. Significant improvement was

CLINICAL TRIALS OF SYNTHETIC SURFACTANT IN THE RDS OF PREMATURE INFANTS

753

0 .5 hour after the case of bovine the case of was not seen until 2 hours after there was an excellent beWith both tween the arterial alveolar oxygen ratio and lung volume, suggesting that improved oxygenation is associated with a progressive increase in lung volume. This observation confirms predictions that surfactant therapy would be associated with decreased atelectasis in treated infants. Bhutani et al6 found that dynamic lung compliance was not changed 2 hours after a dose of CPHT, but significant improvements were apparent from 1to14 days following treatment. There is no evidence from the clinical trials that CPHT decreased endogenous surfactant secretion. Gerdes and coworkers22 analyzed tracheal aspirates following treatment with CPHT and found that the appearance of SP-A was increased in the treatment group, when compared with controls.

There are a number of frequent questions asked by physicians using surfactant, the answers to which can often be suggested by examining trials with other kinds of exogenous surfactant, as well as those with synthetic surfactant. 1. How many doses are necessary? For the prophylactic approach, it would appear that the optimal number of doses is either two or three. The evidence for this lies in the 13 trial, in which the superiority of three doses over one dose was dearly established; however, this trial cannot discern between two and three doses. 21 At least in infants of 500 to 749 g, there is no advantage to increasing the number of doses further, as seen in the 19 trial. 33 For the rescue approach, it would appear that the optimal number of doses is two. Several trials with mammalian surfactants have established that multiple doses are better than only one dose. 17•47 The 17 trial, 42 and especially the OSIRIS trial, 40 established that more than two doses provides no further advantage. 2. At what interval should doses of surfactant be administered? There is no evidence to suggest any better interval than 12 hours for the use of CPHT. The 17 and 19 trials provided no evidence for improvement with a 6-hour interval.33, 42 3. Should the surfactant be administered according to schedule or only if the infant appears to need a further dose? It is frequently suggested that a second or third dose should only be administered if the infant requires at least 30% oxygen, as was the practice in the trials of beractant. 24•29 However, in successful trials with CPHT, 32•34 porcine surfactant47 and ALEC,311•50 the doses were repeated according to schedule if the infants remained on the ventilator. The objection

754

CORBET

40

~

z

~

30

z ~20 fz w

a?w 10 CL

0

0

2

3 4 5 6 EDWARDS' SCORE

7

8

Figure 6. Edwards' scores of the radiographic severity of bronchopulmonary dysplasia on 28-day chest radiographs in neonatal survivors of a cohort of 415 infants with birth weights of 700-1350 g requiring mechanical ventilation for RDS; they were randomized 1 : 1 in a doubleblind study to either two doses of synthetic surfactant (hatched columns) or air placebo (black columns) 12 hours apart. 34 A score of 4 or more was considered diagnostic of BPD in infants requiring oxygen at day 28; the maximum possible score was 10. Note that scores of infants treated with synthetic surfactant were shifted to the left (toward lower scores) (P = 0.057, Wilcoxon's rank sum test).

to scheduled redosing is that dose administration may be difficult if ventilator rates and pressures have been reduced to low levels; the surfactant may obstruct the airways and cause a temporary deterioration in gas exchange. Ventilation parameters must be temporarily increased in order to accomplish dose administration. It would appear that this matter has not been resolved. 4. Is the prophylactic approach better than the rescue approach? The 04 and 13 trials suggest that the prophylactic strategy can reduce neonatal mortality by 56% in the whole po;JUlation of infants weighing 700 to 1100 g, 13 whereas in the 05 trial, the rescue approach reduced mortality by 52% in only that proportion of infants with RDS. 34 In the multidose trials of beractant, the proportionate mortality reductions were far more impressive in the prophylactic than in the rescue strategy. In the prophylactic trial, for infants of 750 to 1250 g, the proportiona ;e reduction was 53 %, whereas in the rescue trial, for infants of 750 to 1250 g, the proportionate reduction was only 23%. 23•29 In a head-to-head comparison of the two strategies, Kendig and associates28 have provided clear evidence that prophylaxis gives better results than comparatively late rescue in infants under 30 weeks' gestation (Fig. 8), and these results have been confirmed by Kattwinkel and coworkers. 27 However, there is a trend for rescue treatment to be commenced earlier, so in several recent trials rescue treatment was begun at age 2 to 3 hours, instead of 6 to 12 hours; in these, there was little difference between the two strat-

CLINICAL TRIALS OF SYNTHETIC SURFACTANT IN THE RDS OF PREMATURE INFANTS

755

40 (j)

I-

~ 30

LL

~

l:5 20 I-

z w

iiw 10 I)_

0

0

2

3 4 5 EDWARDS' SCORE

6

7

8

Figure 1. Edwards' scores of the radiographic severity of bronchopulmonary dysplasia on 28-day chest radiographs in neonatal survivors of a cohort of 1237 infants with birth weights ~ 1250 g requiring mechanical ventilation for RDS; they were randomized 1 : 1 in a double-blind study to either two doses of synthetic surfactant (hatched columns) or air placebo (black columns) 12 hours apart. 32 A score of 4 or more was considered diagnostic of BPD in infants requiring oxygen at day 28; the maximal possible score was 10. Note that scores of infants treated with synthetic surfactant were shifted to the left (toward lower scores) (P = 0.049, Wilcoxon's rank sum test).

egies. 18•35 On the other hand, the European multicenter trial of CPHT showed that prophylactic treatment reduced air leaks further .20" The OSIRIS trial also documented the advantages of prophylactic treatment; a difference of only 1 hour, between prophylactic and rescue treatment (2 versus 3 hours) resulted in significantly increased mortality and more BPD among survivors:"0 The prophylactic strategy should be reserved for less-mature infants with a high risk of RDS, and should only be used in hospitals having a large experience with such infants. Otherwise, the early rescue approach is to be preferred. 5. Should surfactant be administered to tiny infants of 500 to 700 g birth weight? The 03 trial failed to show an improvement in neonatal and infant mortality, but there were a number of other improvements.48 It is anticipated that with further advances in the management of this group, the effects of surfactant will be more noticeable. 6. If surfactant is available, is antenatal steroid prophylaxis still necessary in the mother? In the Treatment IND Program in which all infants received CPHT, mortality was significantly reduced in the population that received antenatal steroids compared with the group that did not. 1 It is very important that obstetricians both continue and expand the use of antenatal steroids fqr the prevention of RDS. 7. Are mammalian surfactants better than synthetic surfactants?

'I U1 Q'I

100\

90j·-~ ~

g> :~

••.~!'~.•.t!i•rapy

80

::J

I

~

:~2: (/)

70

J!J c

~

60

501n=~~~~~~~~~~

0

10

20

30

40

50

60

70

~--- ......... fl~~tll~r"!'~ ......................

90

90

~ 80

Prophylactic therapy

::J

(/)

I

1001~

100

'

g> :~

80

::J

10j

(/)

...... '-Lil"""'.'" therapy

60

--1_ -L __

50\.cn~~"""'~~.,_,,-.~~~P"""'=I 0 10 20 30 40 50 60 70

I

70

60

50,_~~"'F'~~~~~~omno/

0

10

20

30

40

50

Days after Delivery

Days after Delivery

Days after Delivery

A

B

c

60

70

Figure 8. Survival over time among infants under 30 weeks' gestation, subjected to the rescue versus prophylaxis strategy for surfactant administration. The solid lines represent the prophylaxis group, and the dotted lines the rescue group. Kaplan-Meier survival plots are shown for all infants (A); infants delivered at 26 weeks' gestation or earlier (B); and those delivered after 26 weeks' gestation (C). The proportionate reduction of mortality in the prophylaxis group was 35% to 40% in all groups, even in the more mature infants. (From Kendig KW, Notter RH, Cox C, et al: A comparison of surfactant as immediate prophylaxis and as rescue therapy in newborns of less than 30 weeks' gestation. N Engl J Med 324:865-871, 1991; with permission).

CLINICAL TRIALS OF SYNTHETIC SURFACTANT IN THE RDS OF PREMATURE INFANTS

757

Mammalian surfactants may more but there is no evidence that gas response the later overall rate are in any way correlated. The reductions of mortality seen with synthetic surfactant have been impressive. Direct comparisons of synthetic and mammalian surfactant have been performed, but the results are not yet published in full. It is anticipated that any differences in mortality will be so small that such studies will have to be very large to detect a difference.

Although there may be little difference in the efficacy of synthetic and mammalian surfactant preparations, some feel that it may be safer to use a synthetic surfactant. It has been argued that a rapid response, as seen with mammalian surfactant, may be associated with an increased incidence of IVH. 12 At least one trial of beractant reported an increase in the incidence of IVH,24 although most trials of beractant have not shown this result. With all mammalian preparations, there is at least a theoretical risk of infection, which is not the case with synthetic surfactants because CPHT has been shown to have antibacterial properties. 45 When results for all clinical studies of beractant were analyzed, there was a significant increase in the risk of sepsis following treatment, 16% in controls and 21 % in the surfactant group. 29 A further possible problem is that in surfactants containing surfactant proteins, there is a risk of antibody production and the possibility of later hypersensitivity reactions. In one study, 5% of infants 30 to 34 weeks' gestation, treated with mammalian surfactant, produced antibodies against surfactant proteins. 4 However, most evidence so far suggests that less-mature premature infants do not produce such antibodies. 56

OF INFANTS IN TRIALS OF CPHT

Examination of infants at the age of 1 and 2 years has suggested that, despite increased numbers of survivors, the treated group is functioning as well as the control group. 55 The incidence of retinopathy of prematurity was unchanged by surfactant treatment. Growth parameters were equivalent in the two groups. Bayley scores were also similar in the two groups, except that in infants under 750 g birth weight, there was a significant, but small, improvement among those treated with surfactant. Similarly, functional impairments were not changed, except that moderate impairments in infants under 750 g birth weight were reduced among treated infants. The absolute number of impaired children was not increased by treatment with surfactant. At the age of 1 year, twice as many controls were still dependent

758

CORBET

on either oxygen or ventilator support. These differences at 1 year tended to disappear with time, so that at 2 years the differences were minimal. The major conclusion is that increased survival with surfactant treatment is not obtained at the price of increased numbers of functionally impaired children.

References 1. Andrews EB, White AD, Weinberg JM, et al: Antenatal steroids and neonatal outcomes in

infants receiving surfactants in the EXOSURF Treatment IND. Pediatr Res 31 :24 lA, 1992 2. Avery ME, Mead J: Surface properties in relation to atelectasis and hyaline membrane disease. Am J Dis Child 97:517-523, 1959 3. Bangham AD, Morley CJ, Phillips MC: The physical properties of an effective lung surfactant. Biochim Biophys Acta 573:552-556, 1979 4. Bartmann P, Jorch G, Pohlandt F, et al: Antibody response to bovine surfactant in preterm infants. Pediatr Res 29:203A, 1991 5. Berry D, Philips J, Puri A, et al: Effects of 50% increment/decrement in rescue dose of EXOSURF NEONATAL in 244 1250 gram or more infants [abstract]. Pediatr Res 29:204A, 1991 6. Bhutani VK, Abbasi S, Long W, et al: Pulmonary mechanics and energetics in preterm infants who had respiratory distress syndrome treated with synthetic surfactant. J Pediatr 120:S18-S24, 1992 7. Bonikos DS, Bensch KG, Northway WH, et al: Bronchopulmonary dysplasia: The pulmonary sequel of necrotizing bronchiolitis and pulmonary fibrosis. Hum Pathol 7:643-666, 1976 8. Bose C, Corbet A, Bose G, et al: Improved outcome at 28 days of age for very low birthweight infants treated with a single dose of a synthetic surfactant. J Pediatr 117:947953, 1990 9. Canadian EXOSURF PEDIATRIC Study Group: Effects of 2 rescue doses of EXOSURF PEDIATRIC in 342 750-1249 gram infants [abstract]. Pediatr Res 27:200A, 1990 10. Chu J, Clements JA, Cotton EK, et al: Neonatal pulmonary ischemia: Clinical and physiological studies. Pediatrics 40:709-782, 1967 11. Clyman RI, Jobe A, Heymann M, et al: Increased shunt through the patent ductus arteriosus after surfactant replacement therapy. J Pediatr 100:101-107, 1982 12. Collaborative European Multicenter Study Group: Factors influencing the clinical response to surfactant replacement therapy in babies with severe respiratory distress syndrome. Eur J Pediatr 150:433-439, 1991 13. Corbet A: Prophylaxis versus rescue surfactant: how many doses and at what interval? In Long WA, Tilson HH (eds): Proceedings of the EXOSURF NEONATAL Treatment IND Investigators Meeting. Langhorne, PA, Adis International, 1992, pp 45-51 14. Corbet A, Bucciarelli R, Goldman S, et al: Decreased mortality rate among small premature infants treated at birth with a single dose of synthetic surfactant: A multicenter controlled trial. J Pediatr 118:277-284, 1991 15. Corbet AJ, Long WA, Murphy JA, et al: Reduced mortality in small premature infants treated at birth with a single dose of synthetic surfactant. J Paediatr Child Health 27:245249, 1991 16. Cotton RB, Law AB, Lindstrom DP, et al: Differential effects of synthetic and bovine surfactants on lung volume and oxygenation in premature infants with RDS [abstract]. Pediatr Res 31:304A, 1992 17. Dunn MS, Sherman AT, Possmayer F, et al: Single versus multiple dose surfactant replacement therapy in neonates of 30 to 36 weeks gestation with respiratory distress syndrome. Pediatrics 86:564-571, 1990

CLINICAL TRIALS OF SYNTHETIC SURFACTANT IN THE RDS OF PREMATURE INFANTS

759

18. Dunn MS, Sherman AT, D, et al: Bovine surfactant repfacement therapy in neotrial of prophylaxis versus nates of less than 30 weeks gestation: treatment. Pediatrics 87:377-386, 1991 19. Durand DJ, Clyman RI, Heymann MA, et al: Effects of a protein free synthetic surfactant on survival and pulmonary function in preterm lambs. J Pediatr 107:775-780, 1985 20. Edwards DK: Radiology of hyaline membrane disease, transient tachypnea of the newborn, and bronchopulmonary dysplasia. In Farrell PM (ed): Lung development: Biological and clinical perspectives, vol 2. New York, Academic Press, 1982, pp 47-89 20a. European Exosurf Study Group: Early or selective surfactant (colfosceril palmitate Exosurf) for intubated babies at 26-29 weeks' gestation: a European double blind trial with sequential analysis. On line J. Curr Clin Trials 1992: Doc #28 21. Gerdes J, Cook L, Beaumont E, et al: Effects of three versus one prophylactic doses of EXOSURF NEONATAL in 700-1100 gram infants [abstract]. Pediatr Res 29:214A, 1991 22. Gerdes J, Whitsett J, Long W, et al: Elastase activity and surfactant protein concentration in tracheal aspirates from neonates receiving synthetic surfactant. J Pediatr 120:534-539, 1992 23. Hoekstra RE, Jackson JC, Myers TF, et al: Improved neonatal survival following multiple doses of bovine surfactant in very premature neonates at risk for respiratory distress syndrome. Pediatrics 88:10-18, 1991 24. Horbar JD, Soll RF, Schachinger H, et al: A European multicenter randomized controlled trial of single dose surfactant therapy for idiopathic respiratory distress syndrome. Eur J Pediatr 149:416-423, 1990 25. Ivey HH, Roth S, KattwinkelJ: Use of nebulized surfactants in treatment of the Respiratory Distress Syndrome of infancy. Pediatr Res 10:462, 1976 26. Jobe A, Ikegami M: Surfactant for the treatment of respiratory distress syndrome. Am Rev Respir Dis 136:1256-1275, 1987 26a. Jobe A: Pulmonary surfactant therapy. N Engl J Med 328:861-868, 1993 27. Kattwinkel J, Bloom BT, Delmore P, et al: Prophylactic administration of calf lung surfactant extract is more effective than early treatment of respiratory distress syndrome in neonates of 29 through 32 weeks' gestation. Pediatrics 92:90-98, 1993 28. Kendig KW, Notter RH, Cox C, et al: A comparison of surfactant as immediate prophylaxis and as rescue therapy in newborns ofless than 30 weeks gestation. N Eng!J Med 324:865871, 1991 29. Liechty EA, Donovan E, Purohit D, et al: Reduction of neonatal mortality after multiple doses of bovine surfactant in low birth weight neonates with respiratory distress syndrome. Pediatrics 88:19-28, 1991 30. Long W: Product monograph: Synthetic lung surfactant for the treatment of neonatal respiratory distress syndrome. Burroughs Wellcome Co., 1990 31. Long W, Corbet A, Allen A, et al: Retrospective search for bleeding diathesis among premature newborn infants with pulmonary hemorrhage after synthetic surfactant treatment. J Pediatr 120:S45-S48, 1992 32. Long W, Corbet A, Cotton R, et al: A controlled trial of synthetic surfactant in infants weighing 1250 grams or more with respiratory distress syndrome. N Engl J Med 325:1696-1703, 1991 33. Long W, Merritt TA, Muetzel S, et al: Randomized comparison of three versus six doses of synthetic surfactant in 348 infants weighing less than 750 grams [abstract]. Pediatr Res 31:314A, 1992 34. Long W, Thompson T, Sundell H, et al: Effects of two rescue doses of a synthetic surfactant on mortality rate and survival without bronchopulmonary dysplasia in 700-1350 gram infants with respiratory distress syndrome. J Pediatr 118:595-605, 1991 35. Merritt TA, Hallman M, Berry C, et al: Randomized placebo controlled trial of human surfactant given at birth versus rescue administration in very low birth weight infants with lung immaturity. J Pediatr 118:581-594, 1991 36. Milner AD, Vyas H, Hopkin IE: Effects of artificial surfactant on lung function and blood gases in idiopathic respiratory distress syndrome. Arch Dis Child 58:458-460, 1983 3 7. Morley CJ, Bangham AD, Miller N, et al: Dry artificial lung surfactant and its effect on very premature babies. Lancet 1:64-68, 1981

760

CORBET

38. Morley CJ, Greenough A, Miller NG, et al: Randomized trial of artificial surfactant (ALEC) given at birth to babies from 23-34 weeks gestation. Early Hum Dev 17:41-54, 1988 39. Nilsson R, Grossman G, Robertson B: Lung surfactant and the pathogenesis of neonatal bronchiolar lesions induced by artificial ventilation. Pediatr Res 12:249-255, 1978 40. OSIRIS Collaborative Group: Early versus delayed neonatal administration of a synthetic surfactant-the judgement of OSIRIS. Lancet 340:1363-1369, 1992 41. Phibbs RH, Ballard RA, Clements JA, et al: Initial clinical trial of EXOSURF, a protein free synthetic surfactant, for the prophylaxis and early treatment of hyaline membrane disease. Pediatrics 88:1-9, 1991 42. Pramanik A, Dhanireddy R, Hallman M, et al: Randomized comparison of two versus four doses of synthetic surfactant in 548 infants with RDS weighing at least 1250 grams [abstracts]. Pediatr Res 31:217A, 1992 43. Robillard E, Alarie Y, Dagenais-Perusse P, et al: Microaerosol administration of synthetic dipalmitoyl-L-lecithin in the respiratory distress syndrome: A preliminary report. Can Med Assoc J 90:55-57, 1964 44. Russell L, White A, Andrews E, et al: Observational study of synthetic surfactant in 11455 infants [abstracts]. Pediatr Res 31:100A, 1992 45. Sherman MP, Campbell LA, Merritt TA, et al: The infected preterm rabbit lung: A model to test the effect of surfactant replacement on lung host defenses. Prog Respir Res 25:204208, 1990 46. Smyth J, Allen A, Sankaran K, et al: Effects of 2 rescue doses of EXOSURF NEONATAL in 221 500-749 infants [abstracts]. Pediatr Res 29:330A, 1991 47. Speer CP, Robertson B, Curstedt T, et al: Randomized European multicenter trial of surfactant replacement therapy for severe neonatal respiratory distress syndrome: Single versus multiple doses of CUROSURF. Pediatrics 89:13-20, 1992 48. Stevenson D, Walther F, Long WA, et al: Controlled trial of a single dose of synthetic surfactant at birth in premature infants weighing 500-699 grams. J Pediatr 120:S3-Sl2, 1992 49. Taeusch HW, Clements J, Benson B: Exogenous surfactant for human lung disease: Current status. Am Rev Respir Dis 128:791-794, 1983 50. Ten Center Study Group: Ten center trial of artificial surfactant (artificial lung expanding compound) in very premature babies. Br Med J 294:991-996, 1987 51. Tooley WH, Clements JA, Muramatsu K, et al: Lung function in prematurely delivered rabbits treated with a synthetic surfactant. Am Rev Respir Dis 136:651-656, 1987 52. Van de Bor M, Ma EJ, Walther FJ: Cerebral blood flow velocity after surfactant instillation in preterm infants. J Pediatr 118:285-287, 1991 53. Van Golde LMG, Batenburg JJ, Robertson B: The pulmonary surfactant system: Biochemical aspects and functional significance. Physiol Rev 68:374-455, 1988 54. Van Houten J, Long W, Mullett M, et al: Pulmonary hemorrhage in premature infants after treatment with synthetic surfactant: An autopsy evaluation. J Pediatr 120:S40-S44, 1992 55. Walter D, McGuinness G, Bose C, et al: Double blind one year follow up in 1450 infants randomized to EXOSURF NEONATAL or air [abstract]. Pediatr Res 29:270A, 1991 56. Whitsett JA, Hull WM, Luse S, et al: Failure to detect surfactant protein specific antibodies in sera of premature infants treated with SURVANTA, a modified bovine surfactant. Pediatrics 87:505-510, 1991 57. Wilkinson A, Jenkins PA, Jeffrey JA: Two controlled trials of dry artificial surfactant: Early effects and later outcome in babies with surfactant deficiency. Lancet 2:287-291, 1985

Address reprint requests to Anthony Corbet, MB, FRACP Department of Pediatrics Emory University 2040 Ridgewood Drive Atlanta, GA 30322