Effect of surfactant in respiratory distress syndrome as early rescue therapy verses delayed selective therapy in 28 to 32 weeks of gestation

Background: This prospective interventional study is designed to compare effect of giving surfactant in Respiratory Distress Syndrome (RDS), stabilized on CPAP, as Early Rescue Therapy verses Delayed Selective therapy in Early Preterms 28 to 32 weeks, using INSURE method. The main objectives if the studies are to study survival rate and mortality rate in the two groups and to compare the various complications of RDS and surfactant therapy in two groups. Methods: Cases were selected from the Preterm newborn, 28-30 weeks of gestation, confirmed cases of RDS on the basis of Chest X-ray findings and shake test, admitted. Total 96 cases were enrolled, out of which 51 randomly allotted to Early Rescue therapy and 45 to Delayed Selective treatment. Surfactants were administered using INSURE technique. Observations, clinical findings, course of treatment, vitals and outcomes were noted. Data was analyzed using appropriate statistical methods. Efforts were made to study maximum parameters to find out, which treatment strategy provides better outcomes and feasible in our settings. Results: In Early group more cases (68.6%) are discharged than in Delayed group (66.7%). Survival rate is more in Early group. In Early group less mortality is seen 16(31.4%), than in Delayed group 15(33.3%). Mean total duration of stay in NICU is decreased in Early group (7.08±6.209 days) as compared to Delayed group (8.896.±793 days). Conclusion: Early Rescue Therapy increases the survival rate of preterm than the Delayed selective Treatment. Survival rate is increased when surfactant is administered earlier, less than two hours of life, during the course of RDS. Mortality is reduced in Early administration of surfactant but pulmonary causes of mortality is more in them as compared to Delayed administration, where pulmonary as well as non-pulmonary causes of death both affect the mortality.


Introduction
Respiratory Distress Syndrome (RDS) or Hyaline Membrane Disease (HMD) is a disease primarily of premature infants, accounting for most of mortality and morbidity, as well as its long term sequelae are responsible for most hospital visits. Its incidence is inversely related to gestational age and birthweight.
RDS has been recognized as the most common complication of prematurity, with more than half of those with birth weight of between 501 grams and 1500 grams, showing signs of RDS. Surfactant deficiency or decreased secretion is the main cause, and hence the cornerstone of treatment of RDS. Clinical trials have confirmed that surfactant therapy is effective in improving the immediate need for respiratory distress syndrome. Since the discovery of surfactant, various synthetic and natural surfactants have been used to either prevent RDS as Prophylactic therapy or treat RDS as Early or Delayed selective treatment [1].
Prophylactic therapy is found to be superior over selective therapy. While Early administration of surfactant should is preferred in all settings, in settings where its use within the first two hours of life is not be possible, use of surfactant in respiratory distress syndrome requiring mechanical ventilation should be encouraged irrespective of timing.

Materials and Methods
The present study was conducted in Department of were also noted.

Results
The present study had been carried out in the Department of Pediatrics, Shyam Shah Medical College and Gandhi Memorial Hospital, Rewa, M.P. from November 2014 to November 2015.
Cases were selected from newborn patients admitted to Neonatal intensive Care unit after informed consent from attendants.
All the neonates were randomly divided into the two groups, Early and Delayed group.  Majority of cases are appropriate for gestational age (92.7%) as compared to small for gestational age (7.3%).     Among all patients pulmonary haemorrhage is the most common complication (25%) followed by collapse (12.5%) and pneumo-thorax (6.3%). Emphysema and BPD is developed only in 1% patient each.
Statistical Analysis-Statistical analysis was done using computer software (SPSS version 20). The qualitative data were expressed in proportion and percentages and the quantitative data expressed as mean and standard deviations. The difference in proportion was analysed by using chi square test and the difference in means were analysed by using student T Test [unpaired] and one way ANOVA.
Significance level for tests was determined as 95%, p value is significant if P< 0.05). The critical values for the significance of the results were considered at 0.05 levels. In these studies surfactant is administered in infants intubated for respiratory distress, not specifically for surfactant dosage. The meta-analyses demonstrate significant reductions in the risk of neonatal mortality, chronic lung disease and chronic lung disease of death at 36 weeks associated with Early treatment of intubated infants with RDS.
Intubated infants randomized to Early selective surfactant administration also demonstrated a decreased risk of acute lung injury including a decreased risk of pneumothorax, pulmonary interstitial emphysema, and overall air leak syndromes.
A trend toward risk reduction for bronchopulmonary dysplasia (BPD) or death at 28 days was also evident. No differences in other complications of RDS or prematurity were noted [7]. Similarly, study population in the studies referred to, include <30 weeks of gestation. All studies evaluated a population at high risk for RDS, but differed slightly in their inclusion criteria.
Most of these clinical trials are done in preterm babies who were intubated for respiratory distress, not specifically for surfactant dosage, and surfactant administration is done within first 2/3 hours of life.
In the present study, we have taken diagnosed cases of RDS who are spontaneously breathing, stabilized on nasal bubble CPAP since admission.
As due to lack of technical staff and equipment it in not possible to intubate and provide mechanical ventilation to all preterm with RDS.
Studies have shown nasal CPAP application and Early selective surfactant treatment is better than prophylactic therapy and early intubation in spontaneously breathing neonates [7].
CURPAP trial concluded that prophylactic surfactant therapy was not superior to nCPAP and Early selective surfactant in decreasing the need for mechanical ventilation and other morbidities of prematurity in spontaneously breathing very preterm infants on nCPAP. Of 208 inborn infants, 25 to 28 weeks of Death and type of survival at 28 days of life and at corrected 36 weeks of gestational age, and incidence of main morbidities of prematurity (secondary outcomes) were similar between groups.
A total of 78.1% of infants in the prophylactic surfactant group and 78.6% in the nCPAP group survived in room air at corrected 36 weeks of gestational age [7].
The Surfactant Positive Pressure and Pulse Oximetry Randomized Trial (SUPPORT) by the NICHD Neonatal Research Network, infants between 24 and 27 week of gestational age were assigned to intubation and surfactant treatment within 1 hour after birth or to CPAP treatment, including the possibility of surfactant administration if intubation criteria were met, demonstrated that CPAP with subsequent surfactant therapy (if needed) is an equivalent alternative to intubation and primary surfactant treatment.
Overall, death or BPD was not significantly different between the study groups.
A significantly lower mortality rate was found in infants who were born between 24 and 25 weeks and treated with CPAP compared to the same age group treated with intubation and surfactant therapy (death during hospitalization: 23.9% vs. 32.1%, P=0.03; death at 36 weeks: 20.0% vs. 29.3%, P=.01) [11]. given immediately after intubation, with an eligibility criteria for the study as intubation and assisted ventilation needed within 3 hours after delivery for significant RDS with a mean time of 5 minutes to surfactant administration in the Early group [4,7,9,10].
Overall maximum mortality is seen among cases where surfactant is given at 2-6 hours of age. Probable reason being majority of the cases in Delayed group given surfactant during this period.
Total duration of stay in NICU in Early group 7.08±6.209 days is significantly less than Delayed group 8.89±6.793 days (p-0.176). Similarly among the discharged patients mean duration of stay was less in early group (8.51± 6.84 days) than delayed group (11.00 ±7.25).
Therefore cases in early group discharged earlier. In the study 60.8% (n=31) cases in Early group and 64.4% (n=29) cases in Delayed group do not develop any pulmonary complications.
Pulmonary haemorrhage is the most common complication in both groups, 29.4% (n=15) in Early group verses 20% (n=9) in Delayed group, but more in Early group. Surfactant used in the study is Neosurf, extract of natural bovine surfactant, studies have proved benefit of natural surfactant over synthetic [6], we are using this preparation, as it is under government supply in our settings.
Primary outcomes of this study are discharge or death. 68.6% (n=35) cases in Early group are successfully discharged as compared to 66.7% (n=30) in Delayed group. In European Exosurf Study out of 212 babies randomized to Early group 105 babiesand out of 208 to And in Delayed group also survival rate in AGA babies (60%) is significantly more than SGA babies (6.6%), with p-value 0.35.
Konishi M1, Fujiwara T et al in their study found that the rate of intubation, severity of RDS, rate of surfactant administration, pulmonary air leaks, and days on the ventilator did not differ between AGA and SGA babies.
However, the requirement for prolonged nasal continuous positive airway pressure (p < 0.001), supplemental oxygen therapy (p < 0.01), and the incidence of bronchopulmonary dysplasia at 28 days and 36 weeks (both p < 0.01) was greater in SGAinfants [8].In this study overall significantly more survival is seen (p-0.002) LBW babies when compared with VLBW babies. 84.1% LBW patients survived compared to 53.8% VLBW patients.

Conclusion
 Early Rescue Therapy increases the survival rate of preterm than the Delayed selective Treatment.
 For spontaneously breathing preterm neonates, having RDS, but not intubated during first 2 hours of life for RDS, and stabilized on bubble nasal CPAP, Early surfactant administration does not provide significant benefit in reducing mortality over Delayed therapy.
 Survival rate is increased when surfactant is administered earlier, less than two hours of life, during the course of RDS.
 Preventive measure for associated co-morbidities and their Early diagnosis and prompt treatment should be done as, they are significantly related to mortality and seen more patients having Delayed administration of surfactant.
 VLBW and Gestation age <30 weeks are significant independent risk factors for mortality.
 Pulmonary haemorrhage and pneumothorax have significant relation with poor outcome, therefore must be prevented, timely diagnosed and promptly treated.

What this study addsto existing knowledge?
For spontaneously breathing preterm neonates, having RDS, but not intubated during first 2 hours of life for RDS, and stabilized on bubble nasal CPAP, Early Rescue Therapy increases the survival rate than the Delayed selective Treatment.

Contribution by authors:
PB: design of the study, data acquisition, data analysis, writing of manuscript; VT: contributed to the design and planning of the study, intellectual contribution; JS: contributed to study design, revision of the manuscript for important intellectual content.