Abstract
OBJECTIVE:
To determine the predictors of mortality following early rescue surfactant therapy in preterm babies with respiratory distress syndrome.
STUDY DESIGN:
Prospective cohort study enrolling babies between 28 weeks to 34 weeks with respiratory distress syndrome requiring early rescue surfactant therapy. For statistical analysis babies were further divided into two subgroups: survivors and non-survivors. Maternal and neonatal variables were compared between the two groups to find out the predictors of mortality.
RESULTS:
Out of total 110 babies, 72 (65.45%) survived. The mean birth weight and mean gestational age of the study population was 1614.36 (±487.86) g and 31.40 (±2.0)1 weeks, respectively. Birth weight < 1500 g, gestational age < 32 weeks, primiparity, vaginal delivery, prolonged rupture of membranes, lack of antenatal steroid cover, bag and mask ventilation at birth, sepsis, apneic episodes and mechanical ventilation were significantly associated with death on univariate analysis. On multivariate analysis, very low birth weight, vaginal delivery, lack of antenatal steroid cover, bag and mask ventilation at birth and mechanical ventilation were found to be independent predictors of mortality.
CONCLUSIONS:
Some of the identified predictors of mortality are modifiable and can be used to draw up a screening tool to predict the clinical severity and mortality among these babies.
Abbreviations
Respiratory distress syndrome Surfactant replacement therapy Randomized controlled trials High-income countries Neonatal Intensive Care Unit Continuous positive airway pressure Intermittent positive pressure ventilation Standard deviation Odds ratios Confidence intervals Retinopathy of prematurity Antenatal steroids Low- middle income countries
Introduction
Prematurity is a major cause of neonatal morbidity and mortality. Preterm birth ranges from 5–18% worldwide and the incidence is 9% in developed countries compared with 12% in developing countries [1]. In India among all newborns, 10–15% were born premature [2]. Globally the main causes of neonatal deaths are estimated to be preterm birth (28%), severe infections (26%), and asphyxia (23%) [3]. Respiratory distress syndrome (RDS) is a major cause of morbidity and mortality in premature neonates. Introduction of surfactant replacement therapy (SRT) in the management of RDS is one of the most important advancements in the field of neonatology. SRT has changed the course of disease and outcome of RDS.
Numerous randomized controlled trials (RCTs) and their meta-analyses have established its efficacy in reducing mortality and air leak syndromes in RDS [4, 5]. Almost all the trials evaluating the role of SRT were conducted in high-income countries (HICs). Today, SRT is the standard of care in preterm infants with RDS [6]. There is limited evidence on surfactant use and its outcome from developing countries.6 Also there have been limited data about causes of high mortality rate in infants with RDS from developing countries. Therefore the present study was done to find out the predictors of mortality in premature babies with RDS following early rescue surfactant replacement therapy.
Materials and methods
Study design and setting
This prospective cohort study was carried out in the NICU (Neonatal Intensive Care Unit) of a tertiary care hospital of Northern India with annual delivery rate of 23,000–25,000 per year over a period of one year between January 2016 and December 2016. The study was approved by the Institute Ethics Committee, and written informed consents were taken from the parents before inclusion in the study.
Study population
Inclusion criteria
All preterm neonates between 28–34 weeks of gestational age who had an early onset moderate (Downe’s score 4–6) to severe (Downe’s score ≥ 7) respiratory distress requiring early rescue surfactant replacement therapy (within 2 hours of birth) were included in the study.
Exclusion criteria
Newborns with severe perinatal asphyxia, major congenital malformations, and meconium aspiration syndrome were excluded from the study.
Methodology
The management of newborns with RDS at our centre follows the standard protocol, with emphasis on minimal stimulation, maintenance of thermoneutral environment, continuous positive airway pressure (CPAP) and noninvasive cardiorespiratory monitoring. The study population was initially started on bubble CPAP in NICU with an indigenously made CPAP interface and the clinical course was assessed. Chest radiograph was done to support the diagnosis. In those newborns with persisting or deteriorating respiratory distress even on CPAP pressure of at least 6 cm H2O with FiO2 requirement of > 30% natural bovine surfactant (Survanta) 100 mg/kg/dose (i.e. 4 ml/kg) was administered by INSURE technique. Survanta (Abott laboratories) was instilled endotracheally at 4 ml/kg in four aliquots with manual intermittent positive pressure ventilation (IPPV) in between for 15 to 30 seconds to facilitate surfactant distribution using self-inflating bags. The babies were extubated back to CPAP if having good spontaneous respiratory effort.
Detailed baseline information of maternal, perinatal and neonatal variables, including mortality rate and morbidity profiles during the course of hospital stay were recorded in a pre-designed structured proforma. The enrolled neonates were divided into two subgroups: survivors and non-survivors. Maternal and neonatal variables were compared between the two groups to find out the predictors of mortality.
Statistical analysis
Statistical analysis was done using the SPSS statistical package (version 23.0). Data were expressed as mean±standard deviation (SD) for continuous variables and as number or percentages for categorical variables. The two groups (survivors and non-survivors) were compared for various parameters using univariate and multivariate logistic regression analysis to find out the predictors of mortality. Odds ratios (OR) and 95% Confidence intervals (C.I.) were calculated for significant variables. A value of p < 0.05 was considered statistically significant.
Results
Patient characteristics
During the study period, a total of 350 babies were admitted with a diagnosis of neonatal RDS. In majority of the cases respiratory distress got settled on CPAP. A total of 110 (31.4%) babies with RDS requiring early rescue surfactant replacement therapy met the eligibility criteria and were enrolled in the study. Mean weight of the enrolled newborns was 1614.36 (±487.86) g and mean gestational age was 31.4 (±2.01) weeks. Twice as many male (n = 73) newborns received surfactant as compared to females (n = 37). Table 1 shows the baseline characteristics of study population.
Baseline characteristics of study population
Baseline characteristics of study population
Abbreviations: SD, standard deviation; PROM, prolonged rupture of membranes; APH, antepartum hemorrhage; DM, diabetes mellitus; RD, respiratory distress. *: defined as ≥3 antenatal visits, ζ: includes both partial as well as full course of dexamethasone/betamethasone.
Among 110 neonates with RDS requiring early rescue surfactant replacement therapy, 72 (65.45%) survived. Mean duration of hospital stay was 210 (±254.89) hours. Among the survivors, mean duration of respiratory support requirement was 103.88 (±89.90) hours and mean time to reach full feeds was 87.78 (±51.28) hours. Duration of respiratory support requirement and time to reach full feeds was significantly less in higher gestational ages (> 32 weeks vs≤32 weeks) and higher birth weight (< 1500 g vs≥1500 g). Out of 110 newborns, 35 (31.8%) developed sepsis. Retinopathy of prematurity (ROP) occurred in 9 (12.5%) of survivors, 7 had stage 1 ROP and 2 had stage 2 ROP. Out of 110 babies, 2 (1.81%) developed pneumothorax. Table 2 shows morbidity profile of the study population.
Mortality and morbidity profile of study population (n = 110)
Mortality and morbidity profile of study population (n = 110)
Abbreviations: SD, standard deviation; ROP, retinopathy of prematurity.
Various maternal and neonatal variables of the two groups (survivors and non-survivors) are compared in Table 3. The odds ratio was also calculated to identify risk factors associated with mortality using univariate analysis (Table 3). Birth weight below 1500g (OR 9.333; 95% CI 2,707–36.754; P = 0.001) and gestational age 28–30 weeks (OR 10.2; 95% CI 3.482, 30.003; P = <0.005) and gestational age 30–32 weeks (OR 3.529; 95% CI 1.086, 11.469; P = 0.036) significantly affected the survival of babies. Babies born to primigravida mothers were found to be at a significantly increased risk of death as compared to multigravida mothers (OR 3.724; 95% CI 1.631, 8.501; P = 0.002). Neonates born with risk factors for early onset sepsis had significantly higher mortality as compared to those who did not had sepsis setting (OR 14.328; 95% CI 5.355, 38.333; P < 0.005). It was found that antenatal steroids (ANS) increased the survival significantly. Babies born to mothers who had received complete course of antenatal steroids showed significantly better outcome in terms of survival (OR 0.111; 95% CI 0.036, 0.346; P < 0.005). There was significantly higher mortality among babies who required resuscitation at birth (OR 8.353; 95% CI 0.898, 77.612; P = 0.048). Babies with sepsis and apneic episodes had significantly higher mortality as compared to those without sepsis (OR 5.118; 95% CI 2.153, 12.163; P < 0.005) and apneic episodes (OR 17.360; 95% CI 6.492, 46.421; P < 0.005). Significantly higher number of patients required mechanical ventilation among non-survivors as compared to survivors (OR 38.577; 95% CI 11.648, 127.757; P < 0.005). Variables found to be significant on univariate analysis were tested on multivariate analysis (Table 4). Among these variables, birth weight less than 1500 g, vaginal delivery, lack of antenatal steroid coverage, bag and mask ventilation at birth and need for mechanical ventilation were found to be significant independent predictors of mortality among babies with RDS requiring early rescue surfactant replacement therapy.
Comparison of the survivors and deaths among preterm babies requiring early rescue surfactant therapy
Comparison of the survivors and deaths among preterm babies requiring early rescue surfactant therapy
Abbreviations: SD, standard deviation; CI, confidence interval; RD, respiratory distress; PROM, prolonged rupture of membranes; ANS, antenatal steroids; APH, antepartum hemorrhage; DM, diabetes mellitus; BMV, bag and mask ventilation; MV, mechanical ventilation. *P value statistically significant at < 0.05.
Multivariate analysis of risk factors for mortality among Preterm babies with RDS requiring early rescue surfactant therapy
Abbreviations: RDS, respiratory distress syndrome *P value statistically significant at < 0.05.
In spite of the evidence supporting the role of SRT in RDS, only few developing countries are routinely using surfactant therapy for RDS [6, 7]. The major barriers of surfactant use in developing countries are high cost, lack of required support system and lack of experience in use of the technique. However, the most important barrier is the cost of SRT, which varies from USD 100 to 500 in different countries [6].
Antenatal steroids (ANS) significantly reduces mortality and surfactant use in preterm infants [8]. Animal studies and clinical trials have clearly demonstrated the synergistic effect of antenatal steroids and surfactant in improving the pulmonary mechanics and hence, reducing the severity of disease, air leaks and mortality in babies with RDS [9]. The antenatal steroid coverage rate in our study was only 37.3%. This poor ANS coverage is largely attributed to poor antenatal care, maternal chorioamnionitis, seeking medical care late just before impending delivery.
Prophylactic surfactant administration is defined as a strategy that mandated intubation and bolus administration of surfactant immediately after birth (either prior to the first breath or after a brief period of resuscitation) in extreme preterm neonates [10]. Recent randomized clinical trials do not support the routine use of prophylactic SRT in extremely preterm neonates as the benefit of prophylactic surfactant therapy are no longer evident when early CPAP is used routinely in the delivery room [10–13]. However, all of these trials were conducted in HICs where the antenatal steroid coverage rate was more than 90% [11, 15]. We do not practice prophylactic surfactant replacement at our centre because of cost factor and other considerations.
With the recent effective use of bubble CPAP with short bi-nasal prongs, the need for surfactant therapy was avoided in a number of babies in our unit. In the present study, 110 (31.4%) babies with RDS received early rescue SRT. Among babies receiving early rescue SRT, survival was 65.45%. Although our gestational age specific survival rates after SRT is comparable to previous studies from India, however, it is lower than that reported from the developed countries [16–18]. In a longitudinal study from Korea, mortality was 14.3% for a period of 2007.19 High mortality rate seen in our study can be attributed to lack of adequate number of healthcare staff and overcrowding as our centre is the largest referral hospital in northern India.
Comparison of morbidity profiles revealed higher rates of sepsis (31.8%) in the present study, which was lower than the previous Indian reports, comparable to Korean experience but more than double of a study from a Greece [16–19]. The patients in present study are from low socioeconomic status, although, majority of pregnant mothers (91.8%) were booked prior to the delivery but most of them usually have imminent delivery due to poor educational as well as socioeconomic status, and hence, the rate of use of intrapartum antibiotics was also less, in addition inappropriate nurse: patient ratio and overcrowding also contributed to high sepsis rate. Mean duration of hospital stay in our study is 210.25 (±254.89) hours which was shorter as compared to the study by Narang et al. [17]. This can be explained by the fact that newborns in our study had higher mean gestational age and mean birth weight. 12.5% newborns had ROP in our study as compared to 15% in study from Korea and 10% in study from Denmark [19, 20]. It was also observed that out of all babies, 42.7% required mechanical ventilation. 72.34% of these newborns died, Verder et al. showed a mortality of 40.2% among the ventilated babies [20]. A higher mortality rate in the present study is attributed to the sickness profile of the patients admitted as it is the referral centre as well as higher sepsis rate in our NICU as compared to that in developed countries. Different variables were found to contribute to increased mortality rate in the present study. Birth weight < 1500 g, gestational age < 32 weeks, primiparity, vaginal delivery, prolonged rupture of membranes, lack of antenatal steroid cover, bag and mask ventilation at birth, early onset sepsis, apneic episodes and mechanical ventilation were significantly associated with death on univariate analysis. Factors which were independently found to predict death and survival in this study were very low birth weight (< 1500 g), vaginal delivery, lack of antenatal steroid cover, bag and mask ventilation at birth and mechanical ventilation. The literature review till date have not shown any study predicting the risk of mortality in babies receiving early rescue surfactant therapy in low- middle income countries (LMICs). Similar to the study from Korea, the survival rates of those given SRT improved with increasing gestational age and birth weight in the present study.19 Birth weight below 1500 g and gestational age below 32 weeks significantly affected the survival of newborns.
Conclusions
Very low birth weight (< 1500 g), vaginal delivery, lack of antenatal steroid cover, bag and mask ventilation at birth and mechanical ventilation were found to be independent predictors of mortality. The survival of those given surfactant replacement therapy (SRT) improved with increasing gestational maturity and birth weight. Sepsis is an important complication. Antenatal steroids reduced the mortality in preterm newborns with RDS. These predictors can be used to draw up a screening tool to predict the clinical severity and mortality among these babies.
Footnotes
Acknowledgments
None
Funding
None