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PEDIATRICS Vol. 106 No. 2 August 2000, pp. 282-288
,,
,
From the * University of Virginia, Charlottesville,
Virginia; Wesley Medical Center, Wichita, Kansas; § University of
Mississippi, Jackson, Mississippi; Newark Beth Israel Medical Center,
Newark, New Jersey; ¶ University of Texas Medical Branch, Galveston,
Texas; # University of Nebraska, Omaha, Nebraska; and ** State University
of New York, Buffalo, New York.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Surfactant therapy has become an effective standard therapy for infants with respiratory distress syndrome (RDS). The first dose may be given either as prophylaxis immediately after delivery, or as rescue after an infant has developed RDS. Second and subsequent doses are currently recommended by the manufacturers to be administered at minimal levels of respiratory support.
Purpose. This study compared the relative efficacy of administering second and subsequent doses of Infasurf surfactant at a low threshold (FIO2 >30%, still requiring endotracheal intubation) versus a high threshold (FIO2 >40%, mean airway pressure >7 cm H2O) of respiratory support.
Methods. A total of 2484 neonates received a first dose of surfactant; 1267 reached conventional retreatment criteria and were randomized to be retreated according to low- or high-threshold criteria. They were then retreated at a minimum of 6-hour intervals each time they reached their assigned threshold until receiving a maximum of 4 total doses. Subjects were stratified by whether they received their first dose by prophylaxis or rescue and by whether their lung disease was considered complicated (evidence of perinatal compromise or sepsis) or uncomplicated.
Results. Among the patients randomized, 33% of prophylaxis and 23% of rescue subjects met criteria for the complicated stratum. Although infants allocated to the high-threshold strategy were receiving slightly more oxygen at 72 hours, there was no difference in the number receiving mechanical ventilation at 72 hours or in the secondary respiratory outcomes (requirement for supplemental oxygen or mechanical ventilation at 28 days, supplemental oxygen at 36 weeks' postconceptional age, inspired oxygen concentration >60% at any time). However, there was a significantly higher mortality for infants with complicated RDS who had received retreatment according to the high-threshold strategy.
Conclusions. We conclude that equal efficacy can be realized by delaying surfactant retreatment of infants with uncomplicated RDS until they have reached a higher level of respiratory support than is the current standard. We speculate that this would result in a substantial cost-saving from less utilization of drug. Conversely, we believe that infants with complicated RDS should continue to be treated by the low-threshold retreatment strategy, which is currently recommended by the manufacturers of the commercially available surfactants.
Key words: surfactant, respiratory distress syndrome, surfactant therapy.
Respiratory distress syndrome (RDS)
results, in part, from an insufficiency of functioning pulmonary
surfactant. Although surfactant deficiency is most commonly a
reflection of immature type II alveolar cells in the infant born
prematurely, there is increasing evidence that existing surfactant can
also be deactivated by serum proteins and inflammation mediators that
have leaked into damaged or atelectatic alveoli.1-3
Ventilation of surfactant deficient lungs produces leakage of protein,
inactivation of surfactant, and bronchoepithelial
damage.4,5 Lung injury also impairs surfactant synthesis
in type II cells.6 Patients with clinical RDS that has
been complicated by asphyxia, sepsis, or pneumonitis secondary to
chorioamnionitis are likely to have more type II cell injury, more
leakage of protein, and more surfactant inactivation and therefore
worse disease.
Efficacy studies of natural or synthetic surfactants have utilized
various strategies for retreatment The current study was designed to test the hypothesis that the higher
retreatment criteria are as effective as the standard (low) retreatment
criteria when considering a variety of outcomes from RDS. Reducing the
number of unnecessary doses would represent a significant cost-saving
as well as decreasing the number of complications associated with
surfactant administration. We also planned to examine the possibility
that infants with RDS resulting from surfactant inactivation may
require more redosing because of their tendency to continue to
leak inactivating proteins.
The study was conducted at the intensive nurseries of 6 medical
centers. A seventh center initially agreed to participate, but was
dropped from the study after having randomized only 1 subject after
more than 1 year of participation. Enrollment began in October 1993, and continued through February 1998.
The surfactant administered in this protocol (Infasurf) was
provided by ONY, Inc (Amherst, NY) and Forest Pharmaceuticals (St
Louis, MO) and prepared as previously described.7 Centers
were required to keep track of all surfactant given, regardless of
whether or not the patient was entered into the study. Subjects were
considered eligible for study enrollment if they had received Infasurf
surfactant under either a prophylaxis or a rescue strategy. Under the
prophylaxis strategy, the first dose could be given as prophylaxis if
the delivering fetus had been judged to be 30 weeks gestational age or
less and the birth weight in the delivery room was documented as Patients were excluded if they had a respiratory disorder related to a
congenital malformation or were thought not to have RDS.
Consent was obtained before administration of the first dose, although
subjects were not randomized until qualifying to receive a second dose
(Fig 1).
ie, indications for second and
subsequent doses, after an infant has received his initial surfactant
dose. Protocols used during development of Survanta (Abbott
Laboratories, Abbott Park, IL) and Exosurf (Glaxo Wellcome,
Inc, Research Triangle Park, NC) required minimal
indications for retreatment (FIO2
>21%-30%, any ongoing requirement for endotracheal intubation, and 6-12 hours from the previous dose). The original calf
lung surfactant extract (Infasurf, ONY, Inc, Amherst, NY) prophylaxis and rescue protocols allowed retreatment only after a
previously treated infant required a higher degree of respiratory support (mean airway pressure 7-10 cm H2O;
FIO2 40%-60%, minimum of 8 hours
from previous dose). The lower threshold has been incorporated into the
package insert recommendations for commercially available surfactants.
METHODS
Top
Abstract
Methods
Results
Discussion
Conclusion
References
1500
g. Under the rescue strategy, the first dose could be given if
the patient had been intubated and ventilated for RDS and was requiring
an FIO2 >40% to achieve a
PaO2 80 mm Hg.
View larger version (22K):
[in a new window]
Fig. 1.
Study protocol. Subjects could enter after receiving initial dose by
either prophylaxis or rescue. Determination of strata (complicated or
uncomplicated) and randomization to low or high threshold did not occur
until subjects reached low-threshold criteria. Second and subsequent
doses, to a maximum of 4 total doses, were required as soon as subjects
reached their assigned criteria and a minimum of 6 hours had elapsed
since the previous dose. No doses were permitted after 96 hours of age.
Low threshold was defined as still intubated for RDS and requiring
>30% FIO2 to maintain
PaO2 80 mm Hg. High threshold was defined as
requiring >40% FIO2 plus a mean airway
pressure >7 cm H2O. Protocol required that
FIO2 and/or ventilator settings be adjusted to
maintain PaO2 80 mm Hg.
For all doses, 100 mg/kg of Infasurf was given as a 33-mg/mL solution (3.0 mL/kg). The surfactant was administered in 1/4-dose aliquots as a bolus down the endotracheal tube, with hand-bagging or mechanical ventilation between each aliquot and 90° rotation of the patient between each aliquot.
The entry criteria for randomization were chosen as the current
published recommended criteria for Survanta retreatment (30% FIO2 plus continued requirement for
intubation and ventilation and at least 6 hours from previous dose).
These were also the criteria for defining low-threshold retreatment.
Once subjects reached low-threshold criteria for a second dose, a
sealed envelope was opened and subjects were randomized to be treated
according to either low-threshold or high-threshold criteria. High
threshold was defined as requiring >40%
FIO2 plus a mean airway pressure of
>7 cm H2O. The protocol required that ventilator
and/or FIO2 changes be made to
maintain PaO2 80 mm Hg. Once
assigned to low or high threshold, subjects remained in that category
until they had received a total of 4 doses or had reached 96 hours of
age.
Randomization sequences were stratified by whether a subject entered via the prophylaxis or rescue strategies and whether a subject was considered to have complicated or uncomplicated RDS. Complicated RDS was defined as: 1) culture-positive sepsis or meningitis or 2) any 2 of the following:
1500, or
5 at 5 minutes or greater or
15 mEq/L
or base deficit >10 mEq/L.
Subjects were first analyzed according to an intent-to-treat grouping, ie, based on data available at the time of randomization. Some subjects subsequently moved from the uncomplicated to the complicated group after randomization when blood or cerebrospinal fluid cultures, drawn before randomization, later became positive. A repeat analysis was conducted after this regrouping occurred. Because there were no significant differences in outcomes, the intent-to-treat analysis is reported here.
Sample size estimates were based on data from a previous study
comparing Survanta and Infasurf.8 That study reported a
4.7% absolute difference in the proportion of subjects requiring
>30% supplemental oxygen at 72 hours. The sample size was selected to
detect a similar difference (
= .05; 2 tails; 
= .20)
between low- and high-threshold-treated patients in either or both of
2 primary outcomes:
Calculations projected that we would require 488 subjects in each of the 2 retreatment categories. We then allowed enrollment of an extra 10% to allow for exclusions, assignment errors, and unequal matching.
Secondary outcome measures included requirement for supplemental oxygen or mechanical ventilation at 28 days, supplemental oxygen at 36 weeks' postconceptional age, inspired oxygen concentration >60% at any time, and death.
Statistical methods of analysis were as follows: within each stratum,
Kaplan-Meier curves were used to estimate the survival distributions in
the low- and high-threshold groups; the log-rank test was used to
compare these survival distributions. For the binary outcomes, such as
whether or not a patient had an oxygen measurement >30% at 72 hours,
analyses were done to account for the differences in survival between
the low- and high-threshold groups. In these analyses, the low- and
high-threshold groups were compared in 3 possible outcome categories:
1) the proportion of patients who died before 72 hours, 2) the
proportion of patients with oxygen requirements >30% at 72 hours,
among patients surviving at least 72 hours, and 3) the proportion of
patients who survived at least 72 hours and had oxygen requirements
30% at 72 hours. The method of continuation ratios9
allows the comparison among the 3 categories to be made by considering 2 separate comparisons: 1) the proportion of all patients randomized who died before 72 hours relative to the proportion who survived at
least 72 hours and 2) among those who survived at least 72 hours, the
proportion of patients who had oxygen requirements >30% at 72 hours
relative to the proportion who had oxygen requirements 30% at 72 hours. The advantage of using continuation ratios is that each of the 2 separate comparisons can be made based on a 2 × 2 table, allowing
for simpler statistical tests, graphical displays, and interpretations.
Similar analyses were done for other binary outcome variables measured
at 72 hours', 28 days', and 36 weeks' postconceptional age.
For outcome variables such as the number of days on oxygen, or the number of days on mechanical ventilation, standard 2-sample t tests and confidence intervals were used to estimate the differences in the mean outcomes between the low- and high-threshold groups. The results were similar to those found using the assumption of a Poisson distribution for the outcome variable. Poisson regression models were used to estimate the difference in the mean outcomes for the low and high threshold, adjusting for differences in survival time between the groups.
Comparisons between the low- and high-threshold groups were made separately for each stratum; Bonferroni adjustments were used for these comparisons. Overall comparisons were also made, as planned in the protocol. These comparisons are based on the assumption made in the protocol that the difference between the low- and high-threshold groups is constant across the strata. Statistical tests were undertaken to examine the validity of the assumption of a constant treatment effect across strata. Strata-specific analyses were undertaken when the statistical tests cast doubt on the validity of the assumption.
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RESULTS |
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Abstract
Methods
Results
Discussion
Conclusion
References
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A total of 2484 patients received a first dose of surfactant, 1598 as prophylaxis and 886 as rescue (Table 1). Of the 2426 who remained after exclusions, 47% of the prophylaxis group and 61% of the rescue group had persistent RDS, reached low-threshold criteria, and were randomized to low- or high-threshold criteria. One third (33%) of the prophylaxis group and about one quarter (23%) of the rescue subjects met criteria for the complicated strata. Fifty patients were later found to be ineligible after randomization, although they were included in the intent to treat analysis. The 50 patients and the reasons for exclusion had a reasonably random distribution across strata.
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There were no significant differences in birth weight, gestational age, gender, inborn versus outborn, proportion receiving antenatal steroids, or age at first dose between the high- and low-threshold groups, when observed as a total population, or separately by prophylaxis or rescue strategies, or by complicated or uncomplicated designations (Table 2). As expected, there were more males in all groups and the infants in the complicated arms tended to be smaller and more immature and had lower Apgar scores than those categorized as uncomplicated. Similarly, the prophylaxis infants were smaller, more immature, and more had received antenatal steroids when compared with those receiving their first dose as rescue.
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We initially intended to examine outcome variables by comparing high- versus low-threshold outcomes for the entire group, subdivided only by complicated and uncomplicated designation. Our original study design included stratification only to ensure equality of randomization within each subgroup. However, after finding significant differences in mortality for the complicated patients, we report here both the overall analyses and the subgroup analyses.
Overall, there were 1835 doses of surfactant given to those assigned to low threshold and 1443 doses given to those assigned to high threshold, for a mean of 2.95 and 2.29 doses per patient, respectively (Table 2). Significantly more surfactant was given to the low-threshold subjects at each stratum.
The quantitative outcome data for all of the primary and secondary outcome variables are shown in Table 3. Figures 2 and 3 display the natural-log (ln) odds ratios and associated 95% confidence limits for both the overall group as well as for the various complicated and uncomplicated subgroups. If the 95% odds ratio line crosses the 0 vertical, the difference between the low- and high-threshold strategies is not statistically significant for that particular outcome. If the line lies to the left of the vertical, the low-threshold strategy is favored (ie, fewer subjects treated with the low strategy had that particular complication). If the line lies to the right of the vertical, the high-threshold strategy is favored. Because subjects who die would be eliminated from the analysis of respiratory variables, we have reported the deaths analysis with the corresponding analysis of each variable.
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Significantly more infants in the high-threshold stratum required >30% supplemental oxygen at 72 hours of age, although there was no difference in the number receiving positive-pressure ventilation or in the number of deaths at 72 hours (Fig 2).
There were no significant differences for the secondary outcome measures: requirement for supplemental oxygen or for mechanical ventilation at 28 days, requirement for supplemental oxygen at 36 weeks' postconceptional age, or requirement for FIO2 >60% at any time during hospitalization (Fig 3). However, this lack of difference may have been influenced somewhat by the fact that there were more deaths in the infants treated by the high-threshold strategy in the prophylaxis/complicated stratum.
A further analysis of deaths is shown by the Kaplan-Meier survival curves in Fig 4. Although there was essentially no difference in deaths for infants in the uncomplicated strata, those classified as complicated experienced a trend toward a greater survival rate if treated by the low-threshold strategy (P = .058). A subgroup analysis of the complicated strata revealed that the difference was coming primarily from the infants in the prophylaxis stratum.
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Numerous studies have established the efficacy of administering exogenous surfactant for prophylaxis and/or treatment of RDS.10 Surfactant administered immediately after birth (prophylaxis) appears to result in less respiratory failure and less need for retreatment than surfactant administered after an infant develops RDS (rescue).11-16 There is also evidence that surfactant administered within approximately 2 hours after birth is more effective than waiting until severe RDS develops somewhat later,17 although a recent controlled trial involving a smaller number of infants who had had a high rate of prenatal steroid exposure failed to find such a difference.18
Despite the fact that administered surfactant is phagocotized, repackaged, and resecreted by the lung,19 experience and controlled trials have found some amount of retreatment to be beneficial,20 as the treatment effect deteriorates over time.21 Numerous in vitro and animal studies have shown that both endogenous and administered surfactant are cleared from the alveoli in a few hours in the adult lung and over longer time periods in the immature, surfactant-deficient lung.19,22,23 In addition, surfactant is inactivated by serum proteins that leak into alveoli over time24 and it is likely that the extent of protein leak worsens with hypoxia/ischemia and/or infection. Therefore, one can speculate that the requirements for retreatment may vary, depending on the clinical situation. However, to our knowledge, there are no previous controlled trials comparing different strategies for retreatment, controlled for various clinical conditions that may influence the degree of protein leak.
The results of the current study confirm our original hypothesis that infants with uncomplicated RDS treated with natural surfactant can be treated with a less aggressive retreatment strategy than is currently recommended in the package insert. Although there was a slightly higher use of oxygen by the high-threshold group at 72 hours, there was no difference in the requirement for positive-pressure ventilation at 72 hours and no long-term differences in respiratory outcomes. It is likely that the observed 72-hour difference in oxygen use reflected the well-described immediate effect of natural surfactant on oxygenation25-28 and the protocol mandate that patients assigned to the high-threshold strata not be retreated until they reached a higher level of oxygen. Because most infants requiring surfactant therapy will have uncomplicated RDS, a decrease in the number of retreatment doses could represent a substantial cost-savings. For this study alone, using low-threshold criteria resulted in 331 additional doses for the 453 subjects in the low-threshold uncomplicated groups, or the equivalent of >$165 000 worth of unnecessary drug (based on a hospital cost of $500 per vial of drug, exclusive of pharmacy overhead and preparation charges and administration costs).
However, analysis of the survival data suggests that if RDS has been complicated by infection or perinatal hypoxia/ischemia, the lower threshold retreatment strategy may be preferable. Although we were unable to demonstrate a clinically significant difference in primary and secondary outcome variables for this complicated group, this lack of difference may have been partly a reflection of the higher mortality exhibited by the high-threshold subjects in this stratum (ie, infants who had died would not contribute to the variables chosen for the morbidity outcome factors). It is quite likely that infants with complicated RDS are more likely to leak serum proteins into their alveoli, thus inactivating exogenous surfactant. The additional stress imposed by functional surfactant deficiency in an infant with numerous other life-threatening factors might prove to be lethal. Therefore, it appears as if earlier retreatment may be indicated specifically for these extremely high-risk neonates.
It should be noted that the ability of surfactant to resist inactivation by serum proteins appears to be quite different for various surfactant preparations, perhaps because of differences in the apoprotein composition in the surfactants. The current study was performed with Infasurf. While Alveofact (Boehringer, Germany) appears to have similar properties to Infasurf, other preparations, such as Survanta and Curosurf (Chiesi Pharmaceuticals, Parma, Italy) have been shown to have less resistance to protein inactivation29 and thus patients treated with these preparations may benefit from lower threshold retreatment strategies.
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CONCLUSION |
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Abstract
Methods
Results
Discussion
Conclusion
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In summary, this large, multicenter, randomized, controlled trial demonstrates that substantially less surfactant use and thus presumably a significant cost-savings can be realized by delaying surfactant retreatment of infants with uncomplicated RDS until they have reached a higher level of respiratory support than is currently recommended by the manufacturers of the commercially-available surfactants. Although the optimum level for retreatment has not been defined precisely, when using Infasurf the high- threshold used in this protocol (ie, a requirement for endotracheal intubation, 40% inspired oxygen concentration, and a mean airway pressure of >7 cm H2O) appears to be as effective as the current, more conservative, threshold. Conversely, in view of the mortality differences encountered in the current study, and until a larger study of infants with complicated RDS can be conducted, it would appear advisable that infants who have had perinatal compromise or are thought to have sepsis or pneumonitis from infected amniotic fluid, continue to be retreated according to the manufacturer's low-threshold criteria (still intubated after 6 hours and requiring a FIO2 >30%).
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ACKNOWLEDGMENTS |
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We are appreciative of the support contributed by Bob Matuszewski (ONY, Inc), and by Forest Pharmaceuticals, which provided funding and surfactant.
We express sincere thanks to the many clinicians and data coordinators who assisted in conducting this protocol at each of the participating institutions. In particular, we would like to thank Melinda Robinson and Becky Holloway at the University of Virginia, and Patricia M. Leuschen at the University of Nebraska.
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FOOTNOTES |
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a Edmund A. Egan, MD, is the president of ONY, Inc, maufacturer of Infasurf.
Received for publication Dec 7, 1999; accepted Dec 7, 1999.
Reprint requests to (J.K.) Department of Pediatrics, University of Virginia Health Science Center, Charlottesville, VA 22908. E-mail: jk3f{at}virginia.edu
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ABBREVIATIONS |
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RDS, respiratory distress syndrome; ln, natural-log odds ratio.
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REFERENCES |
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the judgement of OSIRIS.
Lancet.
1992;
340:1363-1369 [CrossRef][Medline]This article has been cited by other articles:
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  M. Ghodrat Lung surfactants. Am. J. Health Syst. Pharm., August 15, 2006; 63(16): 1504 - 1521. [Abstract] [Full Text] [PDF]
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 P. D Reiter, C. Sims, L. Harmes, J. Paisley, A. A Rosenberg, and R. J Valuck Calfactant Sterility in Multiple Doses from Single-Use Vials Ann. Pharmacother., September 1, 2003; 37(9): 1219 - 1223. [Abstract] [Full Text] [PDF]
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