Review

Neonatology 2011;99:355366 DOI: 10.1159/000326628

Published online: June 23, 2011

Surfactant Replacement Therapy in Developing Countries

Dharmapuri Vidyasagar a Sithembiso Velaphi b Vishnu B. Bhat c
a

Division of Neonatology, Department of Pediatrics, University of Illinois at Chicago Medical Center, Chicago, Ill., USA; b Metabolic Unit, Department of Pediatrics, Chris Hani Baragwanath Hospital, Johannesburg, South Africa; c Division of Neonatology, Department of Pediatrics, JIPMER, Pondicherry, India

Key Words Developing countries Neonatal and infant mortality rates Prematurity Resource-poor countries Respiratory distress syndrome Surfactant replacement therapy

Abstract Background: Since the first successful report of surfactant replacement therapy (SRT) in infants with respiratory distress syndrome (RDS), numerous randomized clinical trials have shown that SRT reduces mortality and morbidity in RDS. Surfactant is now a standard therapy for RDS. However, the use of SRT in the developing world has been extremely slow. Objective: The objective of this paper is to review the published information regarding the usage and barriers encountered in the use of SRT in developing countries. Methods: We reviewed the available literature and also gathered information from countries with a high burden of prematurity and high infant mortality rate regarding replacement therapy and the barriers to use of SRT. Results: We reviewed the available literature and found that developing countries bear a high burden of prematurity and RDS that contribute to high neonatal and infant mortality rates. Based on the effectiveness of SRT in RDS, surfactant preparations were included in the Essential Drug List of WHO in 2008. However, the use of SRT in devel-

oping countries is still limited because of (1) high cost, (2) lack of skilled personnel to administer SRT, and (3) lack of support systems after the SRT. The cost of SRT may exceed the percapita GNP (300500 USD) in some countries. Data from India and South Africa suggests that SRT is limited to rescue therapy in babies with potential for better survival, usually 128 weeks gestation. Recent studies show that infants with RDS respond well to initial continuous positive airway pressure (CPAP) followed by SRT for those who do not respond. Conclusions: In developing countries, CPAP may be used as the primary mode of management of RDS. SRT may be reserved for non-responders to CPAP. Alternate simpler methods of delivery of surfactant (aerosol technique) are also being explored. There is a need for further studies to develop and assess efficient and less expensive methods of application of CPAP and SRT in developing countries.
Copyright 2011 S. Karger AG, Basel

Introduction

Since the report by Fujiwara et al. [1] in 1980 of the first successful surfactant replacement therapy (SRT) in newborns with respiratory distress syndrome (RDS), numerous randomized clinical trials have established the effiDharmapuri Vidyasagar, MD Division of Neonatology, Department of Pediatrics University of Illinois at Chicago Medical Center 840 South Wood Street, M/C 856, Chicago, IL 60612 (USA) Tel. +1 312 996 4185, E-Mail dvsagarmd@yahoo.com

2011 S. Karger AG, Basel 16617800/11/09940355$38.00/0 Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/neo

cacy of SRT in reducing mortality and morbidity in RDS [24]. Today, SRT is the most effective and standard treatment for RDS in preterm infants in developed countries. In spite of the many publications on the benefits of SRT, only a few developing countries use surfactant routinely. This is understandable, since there is always a lag period for technology diffusion from high-income countries to low-income countries. Papageorgiou et al. [5] studied global diffusion of medical technology from high-income innovative countries to low-income countries. They identified the barriers to technology diffusion to developing countries. They include the trade barriers, high cost of technology, lack of knowledge to use new technology and lack of required support system to implement the new technology. Interestingly they found a significant impact of diffusion of medical technology on infant mortality rate (IMR) in low-income countries even in the presurfactant era. There was an inverse relation between medical technology transfer and IMR in low-income countries. However, the high cost of new technology or a drug remains the main barrier to rapid technology transfer. SRT is no exception. It also requires the availability of basic neonatal care support: incubators/isolettes, pulse oximeters, ventilators, ancillary laboratory support and skilled personnel to provide respiratory care. All these ancillary facilities require additional costs which could drain the meager national budget of low- and middleincome countries (LMICs). However, the benefits of technology diffusion across the globe are being recognized gradually. Considering the universal benefits of SRT in the treatment of RDS and its impact on reduction of neonatal mortality, surfactant preparations were approved and included in the Essential Drug List (EDL) by the World Health Organization (WHO) in 2008 [6]. That paved the way for the health ministries of developing countries to make SRT available in their hospitals albeit in a limited way. The published data on SRT and its impact from LMICs is scant. In this paper we will attempt to discuss the global burden of the disease of prematurity and RDS, and the available information on the current status of SRT in LMICs.

Table 1. Distribution of estimated number of preterm babies born annually and the rate of prematurity by region [modified from 33]
Region Preterm births rounded to millions Preterm birth rate, %

More developed regions Less developed regions Least developed regions Africa Asia Europe Latin America and the Caribbean North America World total

1 8 4 4 7 0.5 1 0.5 13

7.5 8.8 12.5 11.9 9.1 6.2 8.1 10.6 9.6

global and regional prematurity in the world (table1). The global rate of prematurity is estimated to be 9.6% accounting for 13 million preterm births every year. Of these, 1 million are born in developed countries, 8 million in less developed countries and 4 million in least developed countries. Asia and Africa contribute to 11 of the 13 million (80%) global preterm births. Overall, prematurity contributes to 27% of global neonatal deaths. Although there are no data on global occurrence of RDS, it is encouraging to see that data regarding RDS are emerging from centers in developing countries. Status in South Asia The National Neonatal Forum of India, NNF [8], published data on 145,623 consecutively born newborns at 15 centers [9]. These data show a prematurity (!37 weeks gestation) rate of 14.5%. Among the 21,125 preterm infants, there were 1,674 with the diagnosis of RDS (8% of preterm infants) accounting for 1.2% of all births. There was no information regarding use of surfactant. Based on these data from India with annual births of 27 million, the number of preterm births can be estimated to be over 4 million/year and the annual number of infants with RDS over 300,000. The very large number of preterm births and cases of RDS pose a great challenge to clinicians and the national health planners in India. The number of neonatal intensive care units (NICU) providing care for infants with RDS in India has increased substantially during the past three decades. The outcome of low birth weight babies has improved steadily [1012]. The survival rates are comparable to pubNeonatology 2011;99:355366

Global Burden of Prematurity and Respiratory Distress Syndrome

Although the global burden of RDS is difficult to assess, the data on prematurity provides the basis for estimates of global RDS since it is the major cause of death among preterm babies. Beck et al. [7] made estimates of
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Table 2. Patient profile of babies admitted with RDS to NICU (October 2009 to October 2010)
Preterm babies <28 weeks with RDS Number of patients with RDS Number who received surfactant Number survived Number who did not receive surfactant Total deaths 54 none, but all were treated with nasal CPAP 11 (20%) with nasal CPAP only 54 (100% of all RDS) 43 (80% of all RDS) Preterm babies with RDS 28 to <37 weeks 81 62 received surfactant in addition to ventilator support 42/62 (68%) 19/81 (23% of all RDS; 100% died) 38/81 (47% of all RDS)

The table shows the number of babies with RDS and their treatment with surfactant, admitted to NICU at Jawaharlal Nehru Institute of Post Graduate Institute of Medical Education and Research (JIPMER), Pondicherry, India. Note that in the <28-week group none received surfactant.

Of these infants only 20% survived. Among the 28- to <37-week group, 62/81 received surfactant. 68% of infants receiving surfactant survived. All 19 infants who did not receive surfactant died. Overall survival was 53% (43/81) infants. See text for further details.

lished reports from other developing countries [1315]. However, although SRT became available three decades ago, surfactant usage is minimal. Data from India and nearby countries regarding the use of Survanta [16] revealed that during the first 10 months of 2010, only 7,700 doses were consumed in India. An additional 690 doses were used in nearby countries: Sri Lanka (400), Mauritius (100), Maldives (100), Nepal (50) and Bangladesh (40). Although there are few other surfactant preparations available in the region, we do not have access to information on market share of other surfactants and their usage to estimate total surfactant use in the region. However, Survanta remains the major product in use. It may be speculated that SRT usage in India is manifold higher than the numbers given here. Deorari [17] estimates total usage of surfactant of all available brands may be in the range of 30,00040,000 doses. These numbers indicate only a small fraction of babies are getting the benefit of SRT. There are other interesting findings: SRT was used more commonly in states with existing lower IMR, than states with higher IMR; SRT was more prevalent in major metro cities than urban towns where the diffusion of technology (albeit establishment of NICUs) is lagging behind. Since the cost of the drug is borne by parents, SRT in India and other developing countries is a function of affordability and regional affluence. The cost of surfactant product ranges from 200500 USD which exceeds the per-capita GNP of many developing countries including India, Pakistan and Bangladesh [18]. Review of Reports from India During the last two decades ventilator care in NICUs across India has improved significantly [1017]. The experience with SRT in India varies among institutions. A
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few major teaching institutions with established level III NICUs have been using SRT for over 15 years with extremely good results. SRT is available to infants with indications in a few major teaching institutions. Survival rates of babies with RDS in these institutions are comparable to published reports from developed countries [13 17]. However, the majority of institutions and hospitals in the country, especially public hospitals, face far more limitations in use of SRT. Prophylactic SRT is usually not practised because of the high cost of the drug and other considerations. Rescue therapy is the major approach practised in most units in India. The experience of one of the authors (V.B.) from a major public teaching hospital is summarized in table2. During a 12-month period from October 2009, 135 babies with RDS were admitted to the NICU: 54 were ! 28 weeks and 81 were 2836 weeks gestation. All had an increasing requirement of oxygen or continuous positive airway pressure (CPAP) support, or worsening clinical condition qualifying for surfactant therapy. All of them received nasal CPAP or ventilation. None of the babies ! 28 weeks received surfactant therapy. Survival in the ! 28-week group was only 20%. Of the 28- to 36week gestation group, only 62/81 babies received natural surfactant (Survanta 4 ml/kg) followed by positive pressure ventilation (IMV or SIMV pressure-controlled). In the 28- to 36-week group, 19 of the 81 babies who did not receive SRT died, whereas 42/62 (68%) receiving SRT survived. The majority of infants receiving SRT were late preterm infants. Of those who received surfactant, 13 (21%) were !30 weeks, and 49 (79%) were 130 weeks. 46% of those !30 weeks gestation died as against 26% of newborns 130 weeks gestation. The odds ratio for death for !30 weeks maturity at birth was 2.37. Major barriers for the use of SRT included: cost of surVidyasagar /Velaphi /Bhat

factant, lack of availability of ventilators and lack of experience in use of the technique. It is worth mentioning that the recent effective use of CPAP has changed the situation significantly. Indigenous methods of providing continuous distending pressure with intercostal tube drainage bags were used until the commercial devices became available in the unit. After introduction of bubble CPAP devices with bi-nasal short prongs, the need for surfactant therapy was avoided in a number of babies in the unit. Review of Reports from Pakistan Experience with management of RDS from a teaching institution from Pakistan was reported in 1996 [19]. This report was in the pre-surfactant era. It is important in that it provides the prevalence of RDS in Pakistan. Among 2,003 consecutive admissions to the NICU over a 6-year period, RDS was diagnosed in 200 infants, 79% of whom required assisted ventilation. The overall mortality of RDS was 39% and mortality in infants !1,000 g was 68%. Ghafoor et al. [20] from a different hospital in Pakistan reported a little higher rate in their unit in 2003: 1.7% of all live births developed RDS (37.3% of preterm and 0.11% of term neonates) born at their hospital. The incidence of RDS was 100% at or below 26 weeks gestation, 57.1% at 32 weeks, and 3.7% at 36 weeks. The mortality with RDS was 43.6%. In a more recent communication, Qadir [21] noted that SRT in Pakistan has been available in major teaching hospitals since the 1990s, but not in public hospitals. He also noted that SRT is used in small hospitals in the private sector. It costs about 411 USD at todays exchange rate of Pakistan rupee to US dollar. In general, cost remains the major barrier use of SRT. With time and experience, SRT is becoming a routine practice but is limited to infants with greater potential for survival. Qadir noted that the incidence and mortality rate in his institution was more than that documented in the literature from developed countries. In Malaysia, SRT became available in the mid-1990s [22]. Haksari [23] from Indonesia reported that SRT became readily available around 2005. The drug costs about 500 USD. SRT is mainly used in major NICUs in the country. High cost, lack of skilled healthcare professionals and availability of ventilator support are the major constraints in the use of SRT in her unit and in Indonesia in general. Status in Africa Africa as a continent has the second highest number of preterm births [7]. There is wide variation in rates of
Surfactant Replacement Therapy in Developing Countries

prematurity among countries with the highest rates being in Sub-Saharan countries. However, information regarding the occurrence of RDS among African countries is difficult to obtain. In a perinatal care survey conducted in more than 140 healthcare facilities in South Africa for the years 20032005, prematurity was reported to account for 51% of deaths among newborn infants weighing 6500 g and 32% among those weighing 61,000 g [24]. In a similar survey conducted in 20062007, prematurity accounted for 46% of deaths in babies weighing 6500 g [25]. The diagnosis among those who died from prematurity was hyaline membrane disease or RDS in 35.6% of cases. A significant number of the deaths in South Africa occur in district (level 1) hospitals. These hospitals often do not have adequate resources and the health workers do not have the necessary skills and support to look after sick preterm infants. Therefore, one of the major contributors to deaths of preterm infants is inadequate resources. This is unlikely to be different from other developing countries in Africa. In a prospective unmatched case-control study conducted in Muhimbili Medical Centre in Tanzania, RDS accounted for 6% of all neonatal admissions and 52% of neonates with RDS died [26]. Woldehanna and Idejene [27] reported that the highest case-related mortality was seen in hyaline membrane disease with 91% of patients dying. Similarly in a study from Egypt, hyaline membrane disease was reported to be the number one cause of neonatal deaths [28]. These reports highlight the need for improving the care of preterm infants, especially those with RDS, and implementing interventions that have been shown to reduce mortality in these infants. SRT has been shown to reduce mortality, incidence of pulmonary air leaks and duration of mechanical ventilation. Most of the large randomized clinical trials using SRT have been conducted in developed countries [2]. There are a few reports of SRT from developing countries. The results of these studies are discussed later in this review. In one of the largest hospitals in South Africa, Cooper et al. [29] compared the survival rate in very low birth weight (VLBW, 1,0001,499 g) infants between 1981 1982 and 19951996 when SRT was introduced and reported that the survival rate improved from 64 to 79%. Survival in this group of infants in the same hospital has continued to improve and was reported to be 84% in 20012002. In public hospitals that provide level II and III neonatal care in South Africa, SRT is available for most cases in which surfactant is indicated according to the local protocols [30]. Wide availability of surfactant,
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CPAP and healthcare workers with the necessary skills to provide all levels of care would have a major impact in improving survival rates of preterm infants.

Table 3. Clinical respiratory distress scoring system [31] (see text for details)

Score Resp. rate/min Cyanosis Retractions Grunting Air entry (auscultation)

0 <60 none none none clear

1 6080 in air mild audible with stethoscope delayed or decreased

2 >80 or apnea in 40% O2 moderate-severe audible without stethoscope barely audible

Management of Infants with RDS in Resource-Poor Situations

Clinical Diagnosis Successful management of infants with RDS depends on early diagnosis and early initiation of treatment. Management depends on the availability of facilities properly equipped to provide respiratory care. Other support systems include availability of nursing support, equipment, x-rays and laboratory support. The basic principles of management of all preterm infants include providing warmth and nutritional support. Infants in RDS require oxygen to overcome hypoxemia. Since the majority of resource-poor countries lack laboratory facilities at most hospitals the diagnosis of RDS depends on clinical assessment. Downes et al. [31] had previously described a RDS score based on clinical principles of observation and auscultation to assess respiratory status and degree of clinical hypoxemia. The score consists of hourly assessment of five clinical signs: respiratory rate, grunting, color, retractions and breath sounds on auscultation (table3). The score is simple and can be learned by almost any health professional; it requires no electronic or biochemical monitoring and provides a trend of changing clinical status to initiate interventions when required. The score correlates well with blood oxygenation and was found to be helpful in assessing prognosis when serially recorded. Healthcare personnel working at primary health centers can use the RDS score to identify infants who require referral to a NICU. In a study in Indonesia, investigators found that the RDS score was good at predicting hypoxemia using pulse oximetry [32]. In this study, the score showed a sensitivity of 88% (CI 95% 7999) and specificity of 88% (CI 85% 7091), positive predictive value of 92% (CI 95% 5896) and negative predictive value of 92% (CI 95% 84100%). The investigators concluded that the RDS score could be used to clinically evaluate hypoxemia in neonates with RDS in resource-poor countries where pulse oximetry and blood gas analysis might not be available. Treatment of Preterm Babies with RDS Barros et al. [33] evaluated over 2,000 published interventions during pregnancy and the postnatal period. Among the 82 most relevant interventions, 49 were rele359 58
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vant to LIMCs according to the authors. Each intervention was assessed by the quality of its evidence and its potential to prevent or treat preterm babies. Of the 49 interventions, 11 were found to improve survival of preterm infants. Among these, antenatal steroid administration to mothers in preterm labor, CPAP and SRT were found to be the most effective treatments relevant to LMICs. These are indeed very important observations. The findings were based on strong evidence-based data from developed countries; however, they were strongly recommended for LMICs. The authors found a few articles reporting experience from LMICs providing evidence in support of these recommended interventions. Prevention of RDS As stated earlier, prematurity is the major cause of neonatal mortality at global level. While prevention of prematurity is a major goal, we should attempt to improve survival of preterm infants. Antenatal steroids have been shown to reduce RDS by 36% (RR 0.64, 95% CI 0.560.72) and neonatal mortality among preterm infants (!36 weeks) by 31% [34]. In a review by Barros et al. [33], 4 of 21 studies were from LMICs. The benefits of antenatal steroids on neonatal outcome were reported by Mwansa-Kambafwile et al. [35]. When they divided randomized clinical trials according to the economic status of the country in which the studies were conducted there was a reduction of 53% in mortality and 37% in morbidity in middle-income countries. They therefore concluded that if antenatal steroids are used as indicated in developing countries, they may have an even greater impact and could save up to 500,000 newborn lives annually. In addition to reducing mortality, antenatal steroids also decrease other morbidities such as intraventricular hemorrhage and necrotizing enterocolitis that are associated
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Table 4. Published reports of use of surfactant and CPAP usage from developing countries (see text for details)

No. 1 2 3 4 5 6 7 8

Reference (first author) Victorin [42] Narang [14] Sai [47] Koyamaibole [40] Pieper [41] Zaharie [44] Cooper [29] Gharebaghi [46]

Country Kuwait India India Fiji South Africa Romania South Africa Iran

Year 1990 2001 2009 2006 2003 2008 1999 2010

Strategy administration of surfactant by ET without ventilation surfactant NIPPV vs. CPAP bubble CPAP nCPAP preventive vs. curative CPAP compared survival before and after surfactant therapy compared two surfactants used in rescue therapy

Results improved oxygenation and survival improved survival NIPPV reduced need for intubation and surfactant treatment 50% reduction in need for mechanical ventilation improved survival 45 vs. 20% in control decreased need for surfactant and need for ventilation in preventive strategy survival improved 79 vs. 64% before surfactant and 84% in 2002 first study from Iran. Overall 80% survival

with high mortality and poor neurodevelopmental outcomes. In spite of these observations, most preterm babies in developing countries are born without the benefit of antenatal steroid treatment. Therefore, use of antenatal steroid treatment should be given a high priority to be implemented in developing countries.

Management of Infants with RDS Using CPAP

Once the diagnosis of RDS is established the infant should be admitted to a level II hospital with facilities to provide intravenous nutritional therapy, warmth, oxygen and other respiratory support. Respiratory care should include provision of oxygen, CPAP and ventilator care where possible. CPAP by itself may be adequate in many infants with RDS. There are numerous clinical trials of use of CPAP in RDS from the developed countries: COIN [36], CURPAP [37], SUPPORT [38] and INSURE [39] studies. When these studies are analysed as a group, although there is no difference for the primary outcome of death or bronchopulmonary dysplasia (BPD), more infants in the CPAP groups survived and were off mechanical ventilation by day 7 than in the early surfactant-treated groups. The CPAP groups required less ventilation days (p ! 0.03), and less postnatal steroid for BPD (p ! 0.001). Infants of 2425 weeks gestation had significantly lower mortality while in hospital. These data, though limited to extremely low birth weight
Surfactant Replacement Therapy in Developing Countries

(ELBW, !1,000 g) infants, indicate that early CPAP with a limited ventilator strategy has potential for improved survival. There are limited published data from developing countries regarding use of CPAP and CPAP in conjunction with SRT. A recent review of many interventional therapies shows clear benefits of CPAP in RDS [33]. The authors reviewed 29 studies using CPAP as treatment for RDS, 2 of which were from low-income countries: Fiji [40] and South Africa [41]. In addition, we found a few other studies from LMICs and the results are summarized in table4. Victorin et al. [42] were the first to report successful treatment of RDS by instilling surfactant by endotracheal tube followed by CPAP in a series of preterm infants in Kuwait. The authors from Fiji [40] reported a retrospective analysis of their experience with bubble CPAP in RDS. Nurses were given training over 12 months to enable them to independently and safely apply bubble CPAP. Outcome data were analyzed 18 months before and 18 months after the introduction of bubble CPAP in their unit. This was associated with a 50% reduction (10.1% before vs. 5.1% after CPAP) in the need for mechanical ventilation with no difference in mortality. The cost of bubble CPAP was only 15% of that of the cheapest mechanical ventilator in the country. In a prospective study from South Africa, Pieper et al. [41] studied the efficacy of nasal CPAP in infants !1,200 g with RDS who were either treated with nasal CPAP or oxygen hood. Infants treated with the oxygen
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Table 5. Available surfactant products in India and approximate selling price (ASP) in Indian rupees

No. 1 2 3 4

Company name Abbott India Ltd Nicholas Piramal Cipla Sun Pharmaceuticals

Brand name Survanta 4 and 8 ml Curosurf 1.5 and 3 ml Neosurf 3 and 5 ml Surfact 5 ml

Generic name Beractant Poractant alfa Bovine lipid extract surfactant Colfosceril palmitate

ASP in Indian rupees (USD) 6,50010,500 (145230) 9,90022,000 (220485) 3,5005,500 (77120) 5,000 (110)

The prices shown were based on values in 2011 and are subject to fluctuation. Note that prices in India are comparatively much lower than in South Africa.

hood had higher mortality compared to those treated with CPAP (80 vs. 18%). Although the numbers were small (total of 22 and 11 in each group) the data suggest that application of nasal CPAP without surfactant in infants at risk of RDS improves survival. After reviewing the available data from developed countries, Ho et al. [43] concluded that in the absence of surfactant therapy, CPAP may reduce the need for intubation and mechanical ventilation (pooled RR 0.72, 95% CI 0.560.91) and effectively reduce respiratory failure and death (pooled RR 0.65, 95% CI 0.520.81). However, CPAP may be associated with complications such as pneumothorax (pooled RR 2.64, 95% CI 1.395.04). Compared to late administration of surfactant, CPAP resulted in low rates of intubation and ventilation (RR 0.55, 95% CI 0.320.96). The findings of good outcomes using CPAP without surfactant are encouraging for developing countries as surfactant cannot be afforded in many countries. The majority of patients included in the studies of developed countries were ELBW or extremely preterm infants who are not often offered mechanical ventilation in developing countries. In a small prospective study from Romania, Zaharie et al. [44] compared the effects of prophylactic versus therapeutic CPAP in preterm infants with gestational ages from 28 to 32 weeks. This is a higher gestational age range than most of those studied in developed countries but it still serves as a reference for clinicians in developing countries where the focus is on preterm infants 128 weeks gestational age. 23% of babies who received prophylactic CPAP within 30 min of birth required SRT and 54% required mechanical ventilation, whereas in the therapeutic CPAP group 40% required SRT and 72% required mechanical ventilation. Patent ductus arteriosus and cerebral hemorrhage were low in the prophylactic CPAP group. Although there was no difference in survival there were trends in favor of prophylactic CPAP.
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In a study from India, Sai et al. [45] reported a randomized controlled trial of early nasal positive pressure ventilation (NIPPV) vs. early CPAP in neonates with gestational ages from 28 to 34 weeks with RDS. The primary outcome was failure of the allocated treatment within 48 h. Of the 76 cases enrolled, 37 were in early NIPPV and 39 in early CPAP groups. The early NIPPV group had a lower failure rate than the early CPAP group (13.5 vs. 39.5%, RR 0.38, 95% CI 0.150.89, p ! 0.024). The need for intubation and mechanical ventilation by 7 days also was lower in the NIPPV group (18.9 vs. 41%, p = 0.036). The subgroup of infants of 2830 weeks gestation had a lower failure rate with NIPPV (p ! 0.023). The need for SRT was also less (p ! 0.018). A recent report from Iran reported the countrys first randomized trial of SRT comparing the effect of two different surfactants [46]. The above studies from developing countries show the beneficial effects of CPAP and NIPPV in the management of RDS. Bubble CPAP with nasal prongs will be particularly simple to use in low-resource countries. In the absence of commercial bubble CPAP devices, physicians have been advised to develop indigenous techniques of CPAP [47]. However, CPAP is not without complications such as the increased risk of pneumothorax. Thus it is imperative that doctors and nurses are well trained to use CPAP appropriately. Healthcare workers at primary healthcare centers and hospitals should be trained in early recognition of signs of RDS and the basic principles of care including clearing the airway, bag and mask ventilation and proper oxygen therapy. The staff at level I and II units must be trained in providing oxygen therapy, applying CPAP and use of surfactant. In level III units, staff should be able to use CPAP, give SRT and provide ventilator support using mechanical ventilation.

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Table 6. Available surfactant products in South Africa and prices in South African Rands (ZAR) and USD in parentheses (February 2011)

Company name Abbott Safe Line

Brand name Survanta 4 ml 8 ml Curosurf 1.5 ml 3 ml

Private hospital

Public hospital

3,379 (467) 6,759 (935) 5,313 (735) 10,626 (1,470)

1,388 (192) 2,776 (384) 2,254 (311) 3,963 (547)

Note that prices in India are comparatively much lower than in South Africa. These observations suggest that drug prices vary according to many factors, trade agreements and local regulations. Prices are subject to fluctuation.

Delivery of drugs by aerosol may avoid invasive intubation. In order to deliver surfactant successfully using an aerosol, the preparation has to be in an appropriate form and be able to reach the alveoli. Mazela et al. [52] reported a study with Aerosurf , an aerosolized form of Surfaxin (lucinactant) a surfactant that is still in the investigational phase and is not yet approved for clinical use. The pilot trial of prophylactic treatment was conducted in 17 patients with a gestational age of 2932 weeks. Treatment was given within 30 min of birth and continued up to 48 h of age. Up to three re-treatments were allowed. All 17 infants survived, only 4 developed RDS and only 3 met criteria for treatment failure. No significant complications occurred. This pilot trial, whilst encouraging, lacked a control group and further evaluation will be needed before surfactant can be delivered to infants with RDS without endotracheal intubation. These methods, once perfected, will enable health workers in resource-poor countries to administer surfactant more easily.

Surfactant Preparations and Methods of Delivery

Numerous surfactant preparations are on the market in the USA and Europe. Some of these preparations are available in developing countries. Tables 5 and 6 list available surfactant products in India and South Africa, and approximate prices in local currency and equivalent cost in USD. Administration of surfactant requires technologies of CPAP and mechanical ventilation. Commercial CPAP devices are one-fifth of the cost of a ventilator in India [47]. It is essential to have medical and nursing staff trained in caring for infants managed with these devices. These are major constraints in developing countries. It is important to put efforts in capacity building prior to institution of surfactant therapy. These requirements were underscored in the recommendations made by WHO while surfactant preparations were approved to be included in the EDL [6]. Intratracheal administration is the most common method of administration of surfactants around the world. However, there is great interest in use of simpler methods of delivering surfactant into the lungs without need for endotracheal intubation. A variety of methods of surfactant delivery without intubation or short-term intubation have been reported: gastric tube [48], laryngeal mask [49, 50] or administration through a fine catheter [51]. The INSURE [39] method involving a short intubation to administer surfactant and extubation to CPAP has been used by several investigators.

Problems with Prophylactic Therapy

Although both antenatal steroid and prophylactic surfactant therapy have been shown to improve survival of preterm babies, they are difficult to implement in resource-poor developing countries for several reasons. There is inadequate infrastructure to admit and manage all women in preterm labor. Also prophylactic surfactant administration requires availability of skilled physiciannurse teams, and this is often not the case in developing countries and thus might result in inappropriate use of an expensive drug. Furthermore, it has been shown that about one-third of the at-risk babies would do well without prophylactic surfactant. Thus routine prophylactic administration in the delivery room may not be cost-effective. It would seem more practical to adopt a policy of rescue therapy in most hospitals in resource-poor countries. However, even in developing countries in several centers with level III/VI facilities and availability of perinatal/neonatal specialists, prophylactic therapy is possible and is common [13, 14, 19].

Potential Impact of SRT on Neonatal Mortality Rate

It is difficult to speculate the real impact of CPAP and SRT on overall improvement of neonatal and infant mortality rates (NMR/IMR) in developing countries.
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Experience with randomized clinical trials in developed countries has shown that SRT in RDS results in an overall 40% reduction in mortality and a 3550% reduction in air leaks [24] although the reduction of BPD remains elusive. Extending these findings to developing countries we might expect to see a much larger impact on survival. When the survival data of NNPD (without SRT) from India by birth weight groups is compared with NICHD data from the USA (with SRT) [53], the survival rates in NICHD were 25% higher than those of NNPD, particularly in the !1,250-gram group. Although these differences can be explained by many other factors, lack of SRT for NNDP babies is one major difference. One may speculate that making CPAP and SRT available to all eligible LBW infants with RDS could decrease mortality by 25% in this weight group. On a national scale this would be a saving of a large number of babies. Globally the results could be very impressive. Similar feelings were expressed in personal communications from senior members of the neonatal fraternity from India, Pakistan, Indonesia and South Africa [17, 21, 23, 30].

ful practical suggestions to pediatric and neonatal practitioners in resource-limited countries. Clearly each society must develop guidelines based on its local values and resources.

Summary and Conclusions

Ethical Considerations

According to WHO, Essential medicines are intended to be available within the context of function in health system at all times in adequate amounts, in the appropriate dosage form, with assured quality and at a price the individual and the country can afford [6]. Even though surfactant is rightfully included in the WHO EDL, thus encouraging the use of SRT in developing countries, several ethical concerns remain. These concerns are not limited to cost of the drug alone. Even if surfactant is given free of charge, other socio-economic concerns remain unsolved. For example the survivors of surfactant therapy are usually vulnerable VLBW and extremely low gestation infants who will need ongoing medical and socio-economic support after hospital discharge. These services add to the overall healthcare cost for the family and the country and may be beyond their capabilities. Therefore, SRT should not be initiated without adequate facilities to treat and perform followup. Similar to countries in the developed world [54, 55], each country should develop guidelines for the use of SRT appropriate for their population. Still, clinicians are apt to face many ethical and socio-economic dilemmas in initiating or with holding SRT in their practices. In this regard, Singh [56] from India offers some thought363 62
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Prematurity is a major contributor to burden of disease in developing countries. RDS is the major cause of death in preterm babies. Thus there is a great need to decrease mortality and morbidity from RDS in developing countries. Evidence suggests that SRT and CPAP have significantly decreased mortality and morbidity in infants with RDS. Although SRT is an excellent example of a new therapeutic technological advancement in neonatology, the benefits are dependent on the affordability of the drug, availability of proper devices and skills of the professionals delivering the SRT. The Appendix provides practical guidelines for health professionals engaged in providing rescue SRT [57]. Similar to surfactant, CPAP cannot be used in isolation to realize its full impact. Basic neonatal care such as maintaining normal body temperature, providing appropriate amount of fluids, breast milk feeding and infection control should be provided to get maximum benefits from CPAP. There is a great need for large clinical trials from resource-poor countries to confirm the benefits of CPAP and SRT in these populations. Based on the findings of the available studies, we suggest that in addition to improving basic care, using CPAP should be the first option in management of RDS in developing countries and surfactant should be reserved for those infants who do not get better on CPAP or need intubation for mechanical ventilation. Practitioners in developing countries with limited resources may do well to follow the strategy of treatment in RDS: early initiation of CPAP followed by SRT as indicated.

Disclosure Statement
The authors have no conflict of interest to declare.

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Appendix
Suggested practical guidelines to prepare for and administration of surfactant therapy in RDS [modified from 57]. Preamble It is important to emphasize that where possible mothers at risk or those in preterm labor should be cared for at a health facility where adequate support systems are available. These include an obstetric/pediatric team, skilled nursing, a NICU equipped with incubators, oxygen supply and CPAP care. Assessment of RDS and the Need for SRT (1) Once the infant is born, establish diagnosis based on clinical findings and blood gases if available. (2) Pulse oximetry and confirm the diagnosis by chest x-ray when available. (3) Establish criteria and the requirement for CPAP and invasive mechanical ventilation. (4) Establish criteria for SRT. Indications for Rescue SRT: Rescue Therapy Preterm infants (1) Increased work of breathing as indicated by an increase in respiratory rate, sub- and suprasternal retractions, grunting, and nasal flaring (Downes RDS score 1 4 for more than 2 h). (2) Increasing oxygen requirements as indicated by skin color, or by saturation monitor requiring an increase in FiO2. (3) Infants who require CPAP using nasal and/or endotracheal intubation. Contraindications Presence of congenital anomalies incompatible with life beyond the neonatal period. Rule out any cyanotic heart disease. Treat pneumothorax before SRT. Preparedness of Personnel Units intending to use SRT must be well prepared in terms of training of medical and nursing staff and a respiratory therapist (if available). SRT should be performed by a physician or other accredited personnel such as a nurse. The individual performing SRT should (1) Know the proper use of and have understanding of the equipment and technical aspects of SRT including knowledge and understanding of airway management. This includes knowledge and methods of CPAP (nasal CPAP and bubble CPAP). The team of healthcare personnel should undergo training in each unit contemplating provision of NICU care. (2) Have a comprehensive knowledge and understanding of neonatal ventilator management and pathophysiology of RDS. (3) Have skills of clinical assessment of neonates with RDS and patient assessment skills, including the ability to recognize and respond to adverse reactions and/or complications of the procedure. (4) Be able to interpret monitored and measured blood gas variables. (5) Be trained in neonatal resuscitation and have the ability to evaluate and document outcome. (6) Understand and properly apply universal precautions.

Resources Administration procedures recommended for specific preparations of surfactant should be adhered to Equipment. Radiant warmer or incubator/isolette ready for use. Monitoring equipment including heart rate and respiration, pulse oximeter or transcutaneous gases. Nasal prongs. Resuscitator bag with pressure monitor or Neopuff . Equipment for Administration of Drug (1) Syringe containing the ordered dose of surfactant, warmed to room temperature. (2) 5-Fr feeding tube or catheter, or endotracheal tube connector with delivery port. (3) Endotracheal tube, resuscitation bag. (4) Resuscitation equipment: A Laryngoscope and endotracheal tube. B Manual resuscitation bag and airway manometer. C Blended oxygen source. D Suction equipment (i.e., catheters, sterile gloves, collecting bottle and tubing, and vacuum generator). Some Practical Points Too long a delay in rescue therapy may lead to atelectasis and lung injury prior to surfactant administration. (1) Tracheal suctioning should be avoided following surfactant administration. Not all infants who are treated with a single dose of surfactant experience an immediate positive response or the response may be transient. (2) Positioning recommended for surfactant administration may further compromise the unstable infant and is largely unnecessary. Complications Procedural (1) Plugging of endotracheal tube by surfactant (not if INSURE technique is used). (2) Desaturation and increased need for supplemental oxygen. (3) Bradycardia due to hypoxia. (4) Tachycardia due to agitation, with reflux of surfactant into the endotracheal tube. (5) Administration of surfactant to only one lung. (6) Administration of suboptimal dose of surfactant. Physiologic Complications (1) Apnea. (2) Pulmonary hemorrhage. (3) Opening of patent ductus arteriosus. (4) Pneumothorax if CPAP pressures are not monitored properly after SRT. Assessment of Response The response to SRT is assessed using the following criteria: (1) Reduction in work of breathing. (2) Reduction in oxygen requirement. (3) Improvement in oxygenation by pulse oximetry and ratio of arterial to alveolar PO2 (a/A PO2), where blood gas machine is available. (4) Reduction in ventilator requirements (PIP, PEEP, PAW) if on ventilator. (5) Improvement in chest x-ray and on auscultation

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