Respiratory distress syndrome (RDS) is a disease of inadequate endogenous surfactant production and immature lung anatomy, typically affecting premature neonates.1 Advances in neonatal critical care, especially the introduction of surfactant replacement therapy (SRT), have led to a mortality reduction of 85% in the United States.2 For the 10 million children born prematurely in low-income countries (LICs), however, RDS remains a leading cause of death, with published mortality rates roughly 10-fold higher than wealthy nations at 40%–60%.1–6 This stark contrast is largely due to resource availability. A large percentage of births occur at home, and babies often die without receiving any care.2 Even if care is sought, regional clinics in many locations can provide little more than oxygen to neonates in distress.2 , 7 A lack of skilled personnel, especially in rural areas, remains a constant problem.2 , 8 , 9
As LICs attempt to develop their critical care capacity, tertiary centers have begun to open neonatal intensive care units. Such facilities may be able to provide advanced respiratory support modalities, including continuous positive airway pressure (CPAP), mechanical ventilation, and SRT.6 , 9 However, availability rarely meets demand, and equipment may be out of date and prone to breakdown.2 , 10 Importantly, the cost of advanced treatments often falls on poor families, and care may be withheld if payment is not forthcoming.6
Previous research in this field has focused on the impact of introducing new treatment modalities for RDS into LICs, or on the incidence or natural progression of this disease in such settings.3–7 , 10 This study seeks instead to describe practice patterns in the care of RDS-afflicted neonates in a resource-limited setting, to isolate predictors of mortality in this environment, and to identify care modalities that may improve outcomes.
Approval for this retrospective, observational study was obtained from the institutional review boards of Bangladesh Institute of Research and Rehabilitation for Diabetes, Endocrine, and Metabolic Disorders General Hospital (Bangladesh) and The University of Pittsburgh (United States). Written informed consent was waived by both institutions. This manuscript adheres to the applicable The Strengthening of Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The study site was an academic, semiprivate referral center in Dhaka, the capital and largest city of Bangladesh. This institution’s neonatal intensive care unit consists of 27 beds and is staffed in daylight hours by neonatologists, with trainee and nonspecialized physicians in-house overnight. Nursing-to-patient ratios vary from 1:3 in daylight hours to 1:7 overnight. A total of 4 CPAP machines and 5 mechanical ventilators are stocked on-site. Management of these devices is left solely to the physicians, as no respiratory therapists are on staff. Surfactant is available in multiple centers in Bangladesh (including the study site), but its use is limited to those patients whose families are able to pay its cost ($250 per dose compared to an average annual income of $1331).11
All neonates diagnosed with RDS at the host institution between July 1, 2015, and June 31, 2016, were included. Diagnosis was made via clinical features (respiratory distress within 4 hours of birth, grunting on expiration, intercostal retractions, cyanosis, and apnea) and radiographic findings on chest x-ray (diffuse granular opacification, air bronchograms). Of note, this institution has no protocols to guide the management of patients with RDS, with clinical decisions left to the neonatologist and limited to those treatments the families can afford.
For each neonate diagnosed with RDS in the study period, specific health and general information (including sex, gestational age and weight, and mode of delivery) were recorded via retrospective chart review. Evidence of sepsis was recorded, based on positive blood cultures, or elevated blood concentrations of either calcitonin or C-reactive protein. Finally, the highest level of respiratory support provided during admission was recorded, with those in the “invasive” group requiring endotracheal intubation and mechanical ventilation and those in the “noninvasive” group receiving either CPAP or supplemental oxygen.
Multivariable logistic regression analysis was used to investigate the associations between several potential risk factors and the primary outcome of death before discharge. Those factors included birth site (born at the study site or elsewhere), level of respiratory support (invasive versus noninvasive), sex, diagnosis of sepsis (defined as above), mode of delivery (vaginal or cesarean), and gestational age and weight at birth. The analysis was not designed to determine a specific exposure versus outcome relationship of any individual factor, but rather to analyze the association of all the factors with the primary outcome, adjusting for each other. Univariable logistic regression identified factors associated with the primary outcome of death. Adjusted odd ratios for mortality were obtained by multivariable logistic regression analysis. Confounding was assessed by comparing unadjusted and variable-adjusted log odds of the outcome for a 10% change. The independent variables considered were respiratory support, birth location, mode of delivery, sex, septicemia, gestational age, and birth weight. Variable screening was also performed using a backward elimination procedure and the likelihood ratio test, using a P value cutoff of .1 to retain variables in the model. Final model selection was made based on considerations of clinical judgment, weighed together with the results of these analyses. All reported P values were 2-sided, and an α of .05 was required to reject the null hypothesis. Sample size was determined by the available data within the time parameters of the study, as agreed on by the researchers and the host institution. The number of variables included in the analysis was limited by the sample size available for analysis. Univariable and multivariable logistic regression analyses were performed using The SAS System (SAS Institute, Inc, Cary, NC) and Stata SE 14.1 (Stata Corp, College Station, TX).
Of 107 neonates diagnosed with RDS in the study period, 3 neonates were excluded due to incomplete medical records. Overall, 38 neonatal deaths were reported, a mortality rate of 36.5%. Seventy-nine patients were treated with noninvasive ventilation as a primary treatment modality. Thirty-four (43.0%) of these eventually required invasive ventilation. Of 59 total patients requiring invasive ventilation, the mortality rate was 62.7% (N = 37), compared to just 2.2% (N = 1) of the 46 patients managed noninvasively.
Univariable analysis suggested a significant link between the primary outcome of death and several hypothesized associated factors, specifically birth outside the study facility, vaginal delivery, birth weight <1500 g, gestational age <32 weeks, and need for invasive ventilation (Table). Both gestational age and birth weight were confounders in the relationship between respiratory support and the outcome of death (change in log odds >10%). Although statistically significant in univariable analysis, respiratory support was not included in the final model due to the rarity of the event in the noninvasive group (n = 1). After backward elimination with likelihood ratio testing, birth location and birth weight emerged as variables to be retained in the model, whereas mode of delivery, gestational age, sepsis, and sex were not retained. Based on clinical judgment coupled with these results, the final model included birth location, mode of delivery, gestational age, and birth weight. Adjusted odds ratios demonstrated significance only for birth weight <1500 g. Trends toward increased mortality were seen with birth outside the study facility and evidence of sepsis, but statistical significance was not reached.
While all intubated children were candidates for SRT, the decision to give the therapy was based solely on the families’ ability to pay. Of 59 neonates requiring invasive ventilation, 12 (20.3%) were treated with SRT. Of those, 7 (58.3%) survived. Simultaneously, only 14 of 46 (30.4%) untreated neonates survived.
The results of this study elucidate a number of key issues in the management of RDS in low-resource settings. First, in contrast to practice in the United States, where many centers intubate and mechanically ventilate neonates early in the disease process, providers adopted a practice of care escalation, reserving invasive treatments for the most critically ill patients. This conclusion is supported by the fact that the use of such therapy was associated with mortality. Conversely, the alarmingly high mortality rate in invasively ventilated patients suggests that the introduction of such modalities in isolation may be futile. Indeed, despite the availability of a number of advanced respiratory support modalities at the study institution, overall mortality was only modestly reduced when compared to previously published reports. The known effectiveness of SRT in high-resource settings, and the clear trend in mortality improvement in those few neonates receiving SRT in this study, suggests that appropriate introduction of this therapy in conjunction with invasive ventilation may reduce the overall mortality in this population. However, the costs of this strategy must be weighed against other areas of need, such as improving the nursing ratios, hiring skilled respiratory therapists, or increasing the complement of CPAP machines. Ongoing and future research will be powered to demonstrate the impact of universal SRT in neonates requiring invasive ventilation and to determine the cost–effectiveness of such modalities in low-resource settings.
The authors thank Sohan Rahman (founder, Center for International Development and Research, Dhaka, Bangladesh), who served as a local advisor on the project; Dr Tetsuro Sakai, MD, PHD (professor, University of Pittsburgh Medical Center [UPMC] Department of Anesthesiology, Pittsburgh, PA), for his guidance and advice through all stages of the study design and implementation; and Dr Joseph Tobias, MD (chief, Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, OH), for his review and encouragement in the latter stages of the writing process.
Name: Richard M. Hubbard, MD.
Contribution: This author helped design the study, analyze the results, and write the body of the text.
Name: Kamal M. Choudhury, MBBS, MS.
Contribution: This author helped design the study, gather the data, and review the draft.
Name: Grace Lim, MD, MS.
Contribution: This author served as a senior advisor in study design, data analysis, and draft review.
This manuscript was handled by: Angela Enright, MB, FRCPC.
1. Howson CP, Kinney MV, Lawn JE. Born Too Soon: The Global Action Report on Preterm Birth. 2012.Geneva: World Health Organization.
2. Kamath BD, Macguire ER, McClure EM, Goldenberg RL, Jobe AH. Neonatal mortality from respiratory distress syndrome: lessons for low-resource countries. Pediatrics. 2011;127:1139–1146.
3. Ghafoor T, Mahmud S, Ali S, Dogar SA. Incidence of respiratory distress syndrome. J Coll Physicians Surg Pak. 2003;13:271–273.
4. Mlay GS, Manji KP. Respiratory distress syndrome among neonates admitted at Muhimbili Medical Centre, Dar es Salaam, Tanzania. J Trop Pediatr. 2000;46:303–307.
5. Kumar A, Bhat BV. Epidemiology of respiratory distress of newborns. Indian J Pediatr. 1996;63:93–98.
6. Narang A, Kumar P, Dutta S, Kumar R. Surfactant therapy for hyaline membrane disease: the Chandigarh experience. Indian Pediatr. 2001;38:640–646.
7. Chen A, Deshmukh AA, Richards-Kortum R, Molyneux E, Kawaza K, Cantor SB. Cost-effectiveness analysis of a low-cost bubble CPAP device in providing ventilatory support for neonates in Malawi—a preliminary report. BMC Pediatr. 2014;14:288.
8. Darmstadt GL, Bhutta ZA, Cousens S, Adam T, Walker N, de Bernis L; Lancet Neonatal Survival Steering Team. Evidence-based, cost-effective interventions: how many newborn babies can we save? Lancet. 2005;365:977–988.
9. Vidyasagar D, Velaphi S, Bhat VB. Surfactant replacement therapy in developing countries. Neonatology. 2011;99:355–366.
10. Thukral A, Sankar MJ, Chandrasekaran A, Agarwal R, Paul VK. Efficacy and safety of CPAP in low- and middle-income countries. J Perinatol. 2016;36(suppl 1):S21–S28.