Immediate Changes in Lung Compliance Following Natural Surfactant Administration in Premature Infants with Respiratory Distress Syndrome: a Controlled Trial

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Abstract

OBJECTIVE: To compare immediate changes in lung compliance following the administration of two commercially available natural surfactants.

METHOD: We conducted a prospective, randomized study of 40 preterm infants with respiratory distress syndrome requiring surfactant. Infants received either Infasurf® or Survanta®. The primary outcome measure was the change in compliance assessed by bedside pulmonary monitoring.

RESULTS: There were no significant changes in dynamic lung compliance within or between the two groups 1 hour after surfactant administration. However, infants given Survanta required more doses per patient (4 vs 2, p=0.05) and were more likely to require >2 doses (57 vs 26%, p=0.05). Infants requiring >1 dose of surfactant had a greater change in airway pressure and improved oxygenation just before the second dose when treated with Infasurf.

CONCLUSIONS: We found no significant difference in acute changes in lung compliance. However, treatment with Infasurf seems to be more long lasting than Survanta.

INTRODUCTION

Respiratory distress syndrome (RDS) is a major cause of morbidity and mortality in infants born prematurely. Surfactant replacement therapy for RDS has been studied extensively and has been shown to be both safe and efficacious.1 Animal-derived surfactant preparations include Infasurf® and Survanta®. Both are obtained from bovine lungs and contain phospholipids, neutral lipids, fatty acids, and hydrophobic surfactant apoproteins in different proportions. Survanta and Infasurf differ in their total and specific protein contents. Notter et al.2 showed that surfactant protein (SP)-B contents by weight relative to phospholipid were 0.9% in Infasurf and 0.044% in Survanta.

In premature rabbits, better improvement in dynamic compliance and larger lung volumes on the pressure–volume curve could be demonstrated after treatment with Infasurf and with an SP-B-enriched preparation of Survanta.3 In another study comparing multiple surfactant preparations, premature lambs treated with Infasurf had improved pulmonary compliance demonstrated within 1 hour surfactant administration compared to those treated with Survanta.4 In a controlled trial comparing the efficacy of Infasurf and Survanta in premature infants, the group treated with Infasurf required significantly less oxygen and had significantly lower Paw 1 hour after surfactant administration,5 but measurements for pulmonary compliance were not reported. Extrapolating immediate improvement in compliance from animal studies3, 4 suggests the potential for rapid increase in tidal volume delivery and lung overdistention and injury following surfactant administration if the ventilator is used in a pressure-targeted modality and pressure is not promptly decreased.6

However, such extrapolation from in vitro studies and animal models has to be carried out with caution, since factors other than surface properties are important for the in vivo responses to surfactant treatment.7 We conducted this randomized trial to further define the immediate changes in pulmonary compliance in infants with RDS treated with natural surfactants differing in their SP-B content. Tidal volume and lung compliance were measured by a ventilator-monitoring device, frequently used by clinicians to assist with ventilator management. The null hypothesis was that there would be no differences between the two surfactant preparations in pulmonary mechanics and lung function 1 hour after administration of either preparation.

METHODS

This study was a prospective and randomized (but nonmasked) clinical trial. The investigation was conducted in the Holden Neonatal Intensive Care Unit (HNICU) at the University of Michigan Health System (UMHS) between September 2001 and February 2003. The trial was approved by the University of Michigan Medical School Institutional Review Board for Human Subject Research. Infants were eligible for the study if they were delivered prematurely (less than 37 weeks' gestation), had a chest radiograph compatible with RDS, required intubation, and the medical team at the HNICU determined that treatment with surfactant was needed. Infants were enrolled in the study after obtaining written informed consent from a parent. Patients entered into the study were randomly assigned to receive either Infasurf (Calfactant, Forest Pharmaceuticals, St. Louis, MO) or Survanta (Beractant, Ross Laboratories, Columbus, OH) by sampling without replacement. Patients with major congenital anomalies and those with an Apgar score <5 at 5 minutes were excluded from the study. Patient demographics and the relevant aspects of the clinical course were collected contemporaneously. The incidence of chronic lung disease (CLD), defined as either the need for supplemental oxygen at 36 weeks postmenstrual age for those born ≤32 weeks, or the requirement for an oxygen supplementation at 28 days of life was determined for surviving infants. Infants discharged home with oxygen supplement within 2 weeks of these dates were also considered to have CLD. Early-onset sepsis was defined for infants having a positive blood culture within the first 5 days of life. Clinically significant patent ductus arteriosus (PDA) was noted if it required medical (indomethacin) or surgical intervention. Survival was defined as alive at hospital discharge.

Survanta was administered at 4 ml/kg (100 mg/kg of phospholipids per kg); a dose was repeated every 6 hours if the patient met the criteria for subsequent surfactant treatment, up to a total four doses. Infasurf was administered at 3 ml/kg (100 mg/kg of phospholipids per kg); a dose was repeated every 12 hours if the patient met the criteria for subsequent surfactant treatment, also up to four doses. These doses and intervals followed the recommendations of the respective manufacturers. Both surfactants were administered using the same technique, given in four aliquots using a 5 Fr feeding tube placed within the endotracheal tube. Criteria for subsequent surfactant doses included FiO2≥0.4 to maintain PaO2>50 Torr, or oxygen saturation ≥92%; or dynamic lung compliance <0.8 ml/cmH2O. The V.I.P. BIRD Gold® Infant/Pediatric Ventilator (Viasys Healthcare, Palm Springs, CA) was used for all patients. Flow-cycled, pressure-limited assist-control was used with the initial settings adjusted to deliver a tidal volume of 4 to 7 ml/kg before giving surfactant. For the 1 hour following the surfactant administration, the PIP was adjusted if the tidal volume exceeded 10 ml/kg or fell below 4 ml/kg.

Dynamic compliance (CL) was measured and recorded from the Bird Graphic Monitor (Viasys Healthcare, Palm Springs, CA) as long as the infant remained on mechanical ventilation. The primary outcome measure was dynamic pulmonary compliance 1 hour after the first surfactant dose. Data reflecting pulmonary mechanics and lung function were collected just before and at 1 hour following surfactant administration, and included dynamic compliance (CL), peak inspiratory pressure (PIP), positive end-expiratory pressure (PEEP), mean airway pressure (Paw), FiO2, respiratory rate (RR), tidal volume (Vt), and minute ventilation. Compliance and tidal volume measurements were normalized for infant weights. Percent changes in CL, FiO2, RR, Vt, and Paw measurements from prior to the first and the second treatments were calculated for patients that required a second dose of surfactant as {(predose 2 − predose 1)/ predose 1} × 100. These percent changes were compared between the two study groups.

The sample size required to demonstrate a statistically significant difference of 25% increase in compliance after administering the first dose of surfactant, using an α of 0.05 and 80% power was 40. Analysis of study results was performed using a commercially available statistical software program (SPSS version 11.0, SPSS, Inc., Chicago, IL). Analysis involved both continuous and dichotomous variables. Continuous variables were analyzed using the Students t-test, paired t-test, and nonparametric analysis when appropriate. Dichotomous variables were analyzed using χ2 analysis or Fischer's exact test for small sample sizes. All values are reported as mean±1 SD for continuous variables, and frequency counts for dichotomous variables. A p-value ≤0.05 was used to identify statistically significant differences between the two surfactant treatment groups (Infasurf, Survanta) for each variable of interest.

RESULTS

In all, 40 patients were enrolled in the study. A Total of 21 infants received treatment with Survanta and 19 infants received Infasurf. A summary of the demographic characteristics is presented in Table 1. Changes in CL, FiO2, RR, and Paw, and Vt around the first two doses of surfactant are summarized in Table 2. There were no significant differences in CL, FiO2, or RR between the two groups before surfactant administration. No significant changes in CL 1 hour after the surfactant administration could be demonstrated between the Infasurf and Survanta groups or within each group (Table 2). There was a significant decrease in FiO2 and Paw within the Infasurf group, but not in the Survanta group, 1 hour after administration. The number of doses of surfactant required for the treatment of RDS is displayed in Table 3. Infants treated with Infasurf required fewer doses per patient than those treated with Survanta (2 vs 4, p=0.05). The number of infants requiring more than two doses was 5 (26%) in the Infasurf group, and 12 (57%) in the Survanta group (p=0.05). The comparison of percent changes in CL, FiO2, RR, Vt and Paw measurement before administering the first dose of surfactant and before administering the second dose in infants who required it is shown in (Table 2). The percent changes data are also shown in a box-plot presentation (Figure 1) to give a better idea about the degree of change and the distribution of the measurements. Data from 16 of 17 infants in the Survanta group and from 12 of 13 infants in the Infasurf group who were treated with a second dose were available for comparison. Greater changes in FiO2 and Paw were observed following Infasurf treatment (Mann–Whitney test). No statistically significant differences in survival, the incidence of CLD, pulmonary interstitial emphysema, pneumothorax, sepsis, pneumonia, or PDA were found between the two groups (Table 4). The two infants who died were in the Survanta group. The first infant born at 24 weeks, weighed 630 g at birth, and lived 23 days. She had pulmonary and renal failure at the time of her death. The second infant born at 31 weeks, weighed 744 g at birth, and lived 8 days. She had cerebral hemorrhage, refractory hypotension and respiratory failure at the time of her death.

Table 1 Demographic Data
Table 2 Respiratory Data
Table 3 Surfactant Dosing
Figure 1
figure1

Comparing percent changes in respiratory measurements from predose 1 to predose 2. Box plot representation of percent changes in pulmonary parameters from prior to the first and prior to the second treatments calculated for patients requiring a second dose of surfactant. Circles represent outliers. *p≤0.05 between groups.

Table 4 Results

DISCUSSION

In this prospective, randomized trial, dynamic compliance changes were similar 1 hour after the initial administration of either Infasurf or Survanta in premature infants with RDS. The present study demonstrates that for infants that needed treatment with more than one dose of Infasurf, a better response was shown over a longer period of time rather than immediately. Differences in pulmonary mechanics were more obvious when we compared percent changes in FiO2 and Paw following the first dose in the infants who required subsequent dosing. The detection of significant difference in percent changes but no difference in the group means prior to administering the second surfactant doses could result from the degree of variability in the measurements between patients. Our results support those reported by other investigators who did not demonstrate improvement in compliance immediately after surfactant administration but showed a longer-lasting effect that persists for days.8, 9, 10 However, our study was not powered to evaluate outcome measures for the sub-group of infants receiving more than one dose of surfactant.

Infants in the Infasurf group required fewer doses of surfactant and were less frequently treated with more than two doses. These findings suggest better efficacy of Infasurf in the treatment of RDS. Owing to the small sample size, differences detected in the secondary outcome measures are subject to type II error and need to be considered with caution. However, our results are similar to those of Bloom et al.5

The method we chose to measure dynamic compliance is readily available to the clinician caring for infants with RDS, can be used to guide ventilator management, and is a good trending device. The method may not be sensitive enough in infants with uncuffed endotracheal tubes who move spontaneously11 and may partially explain the inability to demonstrate differences in immediate change in lung mechanics following surfactant administration. The higher proportion of male infants in the Infasurf group is a limitation imposed by a small sample size. However, this might have resulted in a higher vulnerability of developing RDS and a higher morbidity and mortality than in the Survanta group.12, 13 In our study population, there was no statistical difference in average lung compliance before surfactant administration between the two groups, which suggests comparability of disease severity.

The incidence of CLD in our study was high.14 The frequent use of oxygen at discharge in this study reflects the institutional practice of using supplemental oxygen rather than being an a indicator of true lung pathology.15

In summary, this is the first controlled study evaluating the immediate change in pulmonary compliance following the administration of these two surfactant preparations. Although a significant difference in dynamic compliance was not detected acutely in our study, the findings suggest better improvement in lung function in the group treated with Infasurf, which could also be demonstrated over a longer period of time. The results also suggest that premature infants with RDS may require fewer doses of Infasurf compared to Survanta, potentially reducing the cost of care related to surfactant treatment. The demonstrated changes in lung mechanics support previous studies comparing the efficacy of these two surfactant preparations.

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Correspondence to Mohammad A Attar MD.

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