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SYSTEMATIC REVIEWS
Efficacy and safety of CPAP in low- and middle-income
countries
A Thukral, MJ Sankar, A Chandrasekaran, R Agarwal and VK Paul
We conducted a systematic review to evaluate the (1) feasibility and efficacy and (2) safety and cost effectiveness of continuous
positive airway pressure (CPAP) therapy in low- and middle-income countries (LMIC). We searched the following electronic
bibliographic databases—MEDLINE, Cochrane CENTRAL, CINAHL, EMBASE and WHOLIS—up to December 2014 and included all
studies that enrolled neonates requiring CPAP therapy for any indication. We did not find any randomized trials from LMICs that
have evaluated the efficacy of CPAP therapy. Pooled analysis of four observational studies showed 66% reduction in in-hospital
mortality following CPAP in preterm neonates (odds ratio 0.34, 95% confidence interval (CI) 0.14 to 0.82). One study reported 50%
reduction in the need for mechanical ventilation following the introduction of bubble CPAP (relative risk 0.5, 95% CI 0.37 to 0.66).
The proportion of neonates who failed CPAP and required mechanical ventilation varied from 20 to 40% (eight studies). The
incidence of air leaks varied from 0 to 7.2% (nine studies). One study reported a significant reduction in the cost of surfactant usage
with the introduction of CPAP. Available evidence suggests that CPAP is a safe and effective mode of therapy in preterm neonates
with respiratory distress in LMICs. It reduces the in-hospital mortality and the need for ventilation thereby minimizing the need for
up-transfer to a referral hospital. But given the overall paucity of studies and the low quality evidence underscores the need for
large high-quality studies on the safety, efficacy and cost effectiveness of CPAP therapy in these settings.
INTRODUCTION Yet, it still remains unclear whether the same benefits pertain to
Of the total 2.9 million neonates who die every year, nearly 1 low- and middle-income countries (LMIC) where the availability of
million (35%) die of preterm birth complications.1 Preterm trained doctors and nursing staff, round the clock monitoring
neonates are not only at high risk of mortality but also are at facilities, and optimal CPAP devices and interfaces is still sub-
risk for developing serious morbidities like respiratory distress optimal. The problem is compounded by difficulty in delivering
syndrome, intraventricular hemorrhage, necrotizing enterocolitis CPAP in the delivery room/during transport, lack of blenders and
and infections. pulse-oximeters, lack of blood gas analyzers, chest x-ray equip-
Despite advances in neonatal intensive care, respiratory distress ment and finally the cost issues.12 Without optimal equipment and
syndrome remains the single, most important cause of mortality skilled manpower, it is likely that CPAP may not be as effective and
among preterm neonates.2 More than 50% of neonates born possibly less safe in LMIC settings. On the other hand, the higher
before 31 weeks of gestation develop respiratory distress costs of exogenous surfactant therapy and newer sophisticated
syndrome, which is due to deficiency of pulmonary surfactant ventilators may make CPAP the way forward for managing
production.3,4 Despite the advent of effective prevention and respiratory distress in these settings.
The question can be answered only by examining available
management strategies such as antenatal steroids, exogenous
evidence on the use of CPAP from LMIC. Therefore, we planned a
surfactant therapy and newer ventilatory techniques, nearly 40%
systematic review to evaluate the efficacy, safety, feasibility and
very-preterm neonates either die or develop bronchopulmonary cost effectiveness of introducing and implementing CPAP at both
dysplasia by 36 weeks postconceptional age.5–7 population and health facility level in LMIC. The findings of the
Continuous positive airway pressure (CPAP), which refers to the review would provide the policy makers available information to
application of continuous distending pressure in a spontaneously
guide the upscale of the intervention in different settings
breathing neonate, increases the functional residual capacity of from LMIC.
the lung resulting in better gas exchange.8 CPAP has been shown
to reduce the risk of mortality by 48%6 and the need for surfactant
and mechanical ventilation by about 50%.9 In addition, the use of
CPAP has been found to decrease hospital stay10 and need for METHODS
referrals and up-transfers to tertiary units, saving nearly $10 000 Objectives
for every six neonates treated.11 Altogether, these benefits have The major objectives of this review were to assess the1 feasibility
made CPAP the standard of care in managing sick preterm and efficacy and2 safety and cost effectiveness of CPAP therapy in
neonates with respiratory distress in high-income countries. preterm neonates from LMICs (Table 1).
Newborn Health Knowledge Centre (NHKC), ICMR Center for Advanced Research in Newborn Health, WHO Collaborating Centre for Training and Research in Newborn Care,
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. Correspondence: Dr MJ Sankar, Department of Pediatrics, All India Institute of Medical Sciences,
Ansari Nagar, New Delhi 110029, India.
E-mail: jeevasankar@gmail.com
Received 3 November 2015; revised 2 December 2015; accepted 3 December 2015
CPAP administration in LMIC settings
A Thukral et al
S22
Types of studies number of participants, the number of events, adjusted odds ratio
For the first objective, we included both observational and (OR) and its 95% confidence interval (CI).
interventional studies (randomized controlled trials and quasi- Given the types of studies expected to be included and the
randomized trials) from LMICs that had evaluated the use of CPAP broad objectives of the review, we did not intend to do any
in preterm neonates. For the second objective, we included all quality assessment of the included studies or meta-analysis of the
studies from LMICs that had reported the use of CPAP in neonates results.
(including case series that reported complications following CPAP
therapy). Statistical analysis
Meta-analysis was performed with user written programs on Stata
Interventions 11.2 software (StataCorp, College Station, TX, USA). Pooled
We included all studies that evaluated the use of CPAP therapy in estimates of the outcome measures were calculated from the
eligible neonates. relative risks or OR and 95% CI of the individual studies by generic
inverse variance method. We examined for heterogeneity among
Outcome measures and their definitions the included studies by inspecting the forest plots and quantifying
Table 1 provides the list of critical outcomes and their definitions. the impact of heterogeneity using a measure of the degree of
inconsistency in the studies’ results (I2 statistic). We intended to
Search methods for identification of studies use the fixed-effect model if the I2 statistic was o60%; if the I2
statistic was 60% or more, we planned to use the random effects
We searched the following electronic bibliographic databases—
model provided no major causes for heterogeneity could be
MEDLINE, Cochrane CENTRAL, CINAHL, EMBASE and WHOLIS—up
identified.
to December 2014. We used the following search terms for
searching Medline—‘continuous positive airway pressure’, ‘respira-
tion, artificial’, ‘positive-pressure respiration’ or the text words:
RESULTS
‘continuous distending pressure’, ‘CPAP’, ‘CDAP’, ‘distending
pressure’, ‘continuous positive transpulmonary pressure’, ‘contin- Figure 1 depicts the number of studies identified by the literature
uous transpulmonary pressure’, ‘continuous inflating pressure’, search and the studies included after reviewing the title/abstract
‘positive pressure’, ‘positive expiratory pressure’, ‘positive end or the full text. The search strategy identified 645 records, of which
expiratory pressure’, ‘PEEP’) AND LMIC. Similar terms were used for 597 were excluded after scanning title and abstract. Among the
searching the other databases—LILACS, Popline and BiblioMap. remaining 48 studies, 22 were eligible for inclusion in the
The search terms for LMIC were adapted from the two systematic review. Description of the included studies has been
systematic reviews on cost effective interventions in LMIC.13,14 provided as and when applicable in the following sections.
No language restrictions were used and no studies were excluded
on the basis of study design. All causes of respiratory distress were Feasibility and efficacy
considered. We scanned the title and abstract of the retrieved In-hospital/neonatal mortality. We did not identify any rando-
citations to exclude those that were obviously irrelevant. We mized trial that had compared the effect of CPAP with other
retrieved the full text of the remaining studies to identify the methods such as oxygen by hood on neonatal mortality. We
relevant articles. The reference lists of included articles were also identified a total of 13 observational studies had reported the
searched. effect of CPAP therapy on in-hospital or neonatal mortality in
preterm neonates (Table 2). These studies can be broadly
Data extraction and management categorized into three groups: time-series/comparison with
Data extraction was done using a data extraction form pre- historical controls, case-control studies (‘typical’ case-control or
designed and tested by the authors. Two reviewers (AT and MJS) analysis of prospective data like a case-control study) and
independently extracted the relevant information including the prospective observational studies of CPAP therapy.
Is it feasible and effective to In-hospital/neonatal mortality after introduction Mortality before discharge or in the first 28 days of life
introduce and implement CPAP of CPAP Proportion of neonates who develop CPAP failure/
therapy in LMIC settings? Proportion of neonates who require intubation require re-intubation as per pre-defined criteria used in
and mechanical ventilation each study
Proportion of neonates who needed referral to Proportion of neonates who were referred to higher
higher centers immediately after institution of centers (NICU of the same hospital/other hospitals) for
CPAP therapy immediate or late complications including failure of
CPAP therapy
Is it safe to implement CPAP Proportion of neonates developing pulmonary Proportion of neonates developing pneumothorax or
therapy in LMIC settings? air-leak, sepsis, local trauma, shock during CPAP pulmonary interstitial air collection, local nasal trauma
therapy or shock, defined as need for vasopressors to maintain
blood pressure and peripheral perfusion
Is it cost-effective to implement Cost per one neonatal death averted The actual cost to the health system for every neonatal
CPAP therapy in LMIC settings? Cost per one ventilation averted death averted
Cost to the health facility and family Cost per one ventilation averted
Cost to health facility and family
Abbreviations: CPAP, continuous positive airway pressure; LMIC, low- and middle-income countries; NICU, neonatal intensive care unit.
Author, year Country Setting Study design Study population CPAP Strategy Results Comments
A Thukral et al
arterial oxygen (PaO2) Survival to discharge 45.4% (5/11) vs
20%(2/10)
Kawaza, 201418 Malawi Referral hospital Prospective Neonates weighing 1000 g Low-cost bCPAP system Survival rate for neonates receiving Control group
observational study and presenting with severe delivered by Hudson nasal bCPAP was 71.0% (44/62) compared received standard care
with two groups – respiratory distress prongs with 44.0% (11/25) for controls (oxygen by cannula);
CPAP with Hudson 64.6% (31/48) of neonates with RDS they were shifted to
prongs vs standard receiving bCPAP survived to discharge, CPAP group if CPAP
care (oxygen with compared to 23.5% (4/17) of controls device was available
nasal cannulae)
Jeena, 200219 South Africa NICU, teaching Retrospective Nasal CPAP was required by CPAP was considered for 63 neonates (74%) were initially --
hospital review of cases 85 neonates neonates with respiratory successfully supported with nasal CPAP
seen at King Median weight 1659 g and failure alone
Edward VIII Hospital gestation 34 weeks. Maximum CPAP 6 cm and Of these, 50 (79%) required no further
maximum FiO2 60% respiratory support until discharge and
seven received IPPV subsequently
Mortality rate of 25% in the 85 neonates
who received CPAP
Mortality in neonates successfully
managed with CPAP 18%
Mortality on CPAP was only 9% for
those infants who were not offered
ventilation
Table 2. (Continued )
Author, year Country Setting Study design Study population CPAP Strategy Results Comments
A Thukral et al
CPAP administration in LMIC settings
2000 g)
Pillai, 201129 India NICU, teaching Prospective Very low birth weight infants CPAP considered for neonates 16 neonates (25.8%) failed CPAP No details on safety of
hospital observational study o 36 weeks eligible for with any respiratory distress Mortality not reported CPAP delivery,
enrollment (n = 62) Initiating pressure: 4-5 cm outcome of neonates
water, FiO2: 0.4 to 0.5; Target enrolled in study
saturations 88-93%
Koti, 200930 India Level III NICU Prospective 56 Inborn preterm infants BCPAP with bi-nasal prongs Fourteen (25%) babies failed CPAP.
observational study (gestation 28 to 34 weeks) started at 5 cm of water and Of the 14 infants who failed CPAP, in 4
with respiratory distress and adjusted to minimize chest (28.5%) ventilation was started after an
chest x-ray suggestive of RDS retractions. FiO2 was adjusted initial recovery from CPAP.
to maintain SpO2between 87 Six (6/64; 9.4%) babies died during
and 95% hospital stay
Bassiouny, 199431 Oman NICU Prospective 44 preterm infants with RDS CPAP delivered using 27/44 cases successfully treated with Full text could not be
observational study enrolled Beneveniste's valve and silastic CPAP (61%) and 17 cases (39%) failed to retrieved
nasal prongs respond
Journal of Perinatology (2016), S21 – S28
Abbreviations: CPAP, continuous positive airway pressure; INSURE, intubate-surfactant-and-extubate; IPPV, intermittent positive pressure ventilation; LMIC, low- and middle-income countries; NICU, neonatal
intensive care unit; RDS, respiratory distress syndrome.
S25
CPAP administration in LMIC settings
A Thukral et al
S26
Figure 2. Effect of CPAP therapy on in-hospital mortality. ‘I-V Overall’ refers to the estimate by fixed effects model while ‘D+L Overall’ refers to
the pooled estimate. CPAP, continuous positive airway pressure; ES, effect size; ID, identification.
guideline. However, the specific cost for surfactant replacement The studies on safety of CPAP therapy suggested a very-low risk
therapy was significantly lower in the latter period.38 The cost of of pneumothorax (0 to 7.2%). When considering the lack of skilled
the nine stationary and three portable bCPAP units was much manpower and the sub-optimal equipments available in most
lower than the estimated 2007 cost of replacing the nine out-of- LMIC settings, the low risk is definitely reassuring. The recent
warranty ventilators with new basic model conventional ventila- systematic review on the efficacy and safety of bCPAP in LMIC
tors ($19 500 for bCPAP vs $135 000 for ventilators). settings also reported similar results.39 We found a high risk of
nasal trauma in neonates managed with CPAP. Up to 20%
neonates developed nasal bleeding in one study.34 This reinforces
DISCUSSION the need for good nursing care and monitoring.15,23,25 With
CPAP has now become a standard of care for all preterm neonates improving survival of very preterm neonates and need for longer
with respiratory distress. Evidence from high-quality studies duration of CPAP administration, nasal mucosal injury attains
suggests significant survival advantage in preterm neonates with importance, given that it predisposes to immediate as well as
severe respiratory distress and managed with CPAP as compared long-term functional and cosmetic sequelae.40
with those managed with only oxygen.9 But the evidence is based
on studies from only high-income countries. In the absence of Implications for policy makers
such evidence base from LMICs, one cannot be really sure about CPAP appears to be a promising and a safe technology for
the efficacy and safety of CPAP therapy in LMIC settings. respiratory support in neonates with respiratory distress. In addition,
We found a significant reduction in the risk of in-hospital due to lower initial costs, it has the potential for being up-scaled for
mortality following introduction of CPAP therapy (Figure 2). The management of respiratory distress in developing countries. But
pooled effect size (OR 0.34, 95% CI 0.14 to 0.82) suggested similar, factors like cost and availability of consumables and additional
if not better, beneficial effect when compared with that reported equipment like humidifier and availability of skilled staff can limit
from high-income countries (relative risk 0.52, 95% CI 0.32 to 0.87). the up-scaling of CPAP therapy. In addition, the use of CPAP also
9
Given the nature of studies—before and after and case–control— requires regular training of staff for optimal delivery of CPAP.
included in the present review, the quality of evidence is likely to
be low. There is a need to generate more evidence on the efficacy Strengths and weaknesses
of CPAP in preterm neonates from LMICs. It may not be ethical to
Ours is possibly the first attempt to review and synthesize the
do randomized studies on the effects of CPAP now but it is available evidence on the effect of CPAP therapy on major
definitely possible to have large high-quality observational studies outcomes including mortality and air leaks in preterm neonates.
from these settings. Given the paucity of randomized trials, we included observational
The current review suggested that implementation of CPAP studies so as to inform policy making. The studies in this review
therapy is feasible in level 2 to 3 NICUs of LMICs. Only 25 to 40% of are limited by their study design and quality. We believe that
preterm neonates receiving CPAP therapy required mechanical CPAP is being widely used in LMICs than what is evident from the
ventilation (and referral, if ventilation facilities not available). A present review. Given the detailed search, the discrepancy is more
recent systematic review, which suggested a reduction in to do with the ‘real’ paucity of studies from these settings.
mechanical ventilation by 30 to 50%, had included studies of Possibly, the lack of resources, particularly the manpower, limits
neonates managed with only bCPAP; it did not include other the capacity of health care providers from LMICs to publish their
potential studies that had evaluated the effect of CPAP on experiences in peer-reviewed journals.
reduction in the need of mechanical ventilation.19,27 Nurses can
institute CPAP easily after 1 to 2 months of training and institution
of CPAP has the potential to bring down the requirement and the CONCLUSION
cost of surfactant therapy.15 This reduction has huge financial Available evidence from observational studies suggests that CPAP
implications for LMIC. is a safe and effective mode of therapy in preterm neonates with
Author, year Country Setting Study design Study population CPAP strategy Results Comments
A Thukral et al
CPAP administration in LMIC settings
CPAP and nasal trauma
Rego, 200232 Brazil NICU level 3 Randomized controlled clinical 99 neonates ⩽ 2500 g Randomized to Hudson or Argyle nasal Argyle nasal prongs associated with Comparison of two
trial prongs more hyperemia CPAP delivery
No cases of pneumothorax reported methods
in either group
Yong, 200533 Malaysia NICU level 3 Randomized controlled clinical 89 neonates o1500 g 41 randomized to mask group and 48 to No significant trauma difference in Comparison of two
trial prong group the two groups CPAP delivery
Almost all neonates developed methods
trauma
Do Nascimento, Brazil Neonatal unit Quantitative, descriptive, cross 147 neonates of which 123 No mention of duration, CPAP settings or 117 neonates had mild (hyperemia), No mention of
200934 maternity sectional (83.7%) o37 weeks other details 29 had moderate (bleeding with duration, CPAP
hospital Nasal protection observed in 142 erosion) and 1 had necrosis in settings, or other
(96.6%). 100% received humidification addition to bleeding and erosion details
while 127 (86.4%) were heated
Journal of Perinatology (2016), S21 – S28
Abbreviations: CPAP, continuous positive airway pressure; LMIC, low- and middle-income countries; NICU, neonatal intensive care unit; ROP, retinopathy of prematurity.
S27
CPAP administration in LMIC settings
A Thukral et al
S28
respiratory distress in LMIC. It reduces the in-hospital mortality 18 Kawaza K, Machen HE, Brown J, Mwanza Z, Iniguez S, Gest A et al. Efficacy of a
and the need for ventilation thereby minimizing the need for up- low-cost bubble CPAP system in treatment of respiratory distress in a neonatal
transfer to a referral hospital. But given the overall paucity of ward in Malawi. PLoS One 2014; 9(1): e86327.
studies and the low-quality evidence, there is an urgent need for 19 Jeena P, Pillay P, Adhikari M. Nasal CPAP in newborns with acute respiratory
failure. Ann Trop Paediatr 2002; 22(3): 201–207.
high-quality studies on not only the safety and efficacy but also on
20 Saxena A, Thapar RK, Sondhi V, Chandra P. Continuous positive airway pressure
the cost effectiveness of CPAP therapy in these settings. for spontaneously breathing premature infants with respiratory distress syn-
drome. Indian J Pediatr 2012; 79(9): 1185–1191.
CONFLICT OF INTEREST 21 Singh M, Deorari AK, Paul VK, Mittal M, Shanker S, Munshi U et al. Three-year
The authors declare no conflict of interest. experience with neonatal ventilation from a tertiary care hospital in Delhi. Indian
Pediatr 1993; 30(6): 783–789.
22 Rojas MA, Lozano JM, Rojas MX, Laughon M, Bose CL, Rondon MA et al. Very early
ACKNOWLEDGEMENTS surfactant without mandatory ventilation in premature infants treated with early
We acknowledge Dr Sushil Kumar, University of Minnesota, Minneapolis, MN, USA, for continuous positive airway pressure: a randomized, controlled trial. Pediatrics
helping us in searching the various databases. The Department of Maternal, 2009; 123(1): 137–142.
Newborn, Child and Adolescent Health and Development (MCA), World Health 23 Hendriks HJ. Is CPAP a feasible treatment modality in a rural district hospital for
Organization, Geneva, Switzerland funded this review. neonates with respiratory distress syndrome?. MSc thesis, University of Stellen-
bosch, South Africa, 2010.
24 Shrestha M, Basnet S, Shrestha P. Bubble CPAP in Neonatal Unit of TUTH. J Nepal
AUTHOR CONTRIBUTIONS Paediatr Soc 2010; 30: 64–68.
25 Van den Heuvel M, Blencowe H, Mittermayer K, Rylance S, Couperus A, Heikens GT
AT applied the search strategy, retrieved articles, extracted data and wrote the
et al. Introduction of bubble CPAP in a teaching hospital in Malawi. Ann Trop
manuscript. MJS developed the study protocol, extracted data, did the
Paediatr 2011; 31(1): 59–65.
statistical analysis, and modified the manuscript. AC retrieved articles, extracted 26 Kirsten GF, Kirsten CL, Henning PA, Smith J, Holgate SL, Bekker A et al. The
data, and modified the manuscript. RA and VKP guided development of the outcome of ELBW infants treated with NCPAP and InSurE in a resource-limited
protocol, supervised data extraction, and modified the manuscript. MJS and RA institution. Pediatrics 2012; 129(4): e952–e959.
act as the guarantors of the paper. 27 Boo NY, Zuraidah AL, Lim NL, Zulfiqar MA. Predictors of failure of nasal continuous
positive airway pressure in treatment of preterm infants with respiratory distress
syndrome. J Trop Pediatr 2000; 46(3): 172–175.
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