Non-invasive Respiratory Support for Newborns · Non-invasive respiratory support for newborns NNF...

Clinical Practice

Guidelines

Non-invasive

Respiratory Support

for Newborns

January 2020

National Neonatology Forum, India

Non-invasive Respiratory Support for Newborns

© NNF India Online Version www.nnfi.org/cpg January 2020

Guideline Development Group (Alphabetical)

Aparna Chandrasekaran

Ashok K Deorari ( Chairperson)

Srinivas Murki

M Jeeva Sankar

Neeraj Gupta Sindhu Sivanandan

Reviewers (Alphabetical)

Deepak Chawla

Girish Gupta

N Karthik Nagesh

Editorial Board (Alphabetical)

B D Bhatia

Deepak Chawla

Girish Gupta

Nandkishor S Kabra

Praveen Kumar (Chairperson)

Mohit Sahni

M Jeeva Sankar

Sachin Shah

Contents

1. Executive Summary

2. Introduction

3. Scope and Questions for clinical practice

4. Summary of evidence and recommendations

5. References

Annexure 1. GRADE profile tables and search strategies - see online version

Annexure 2. Algorithms and job-aides - see online version

Non-invasive respiratory support for newborns

NNF India Evidence-based Clinical Practice Guidelines January 2020

129

Executive summary

Respiratory distress is a common symptom affecting up to 7% of all term infants and a greater

percentage of preterm infants. It is also a common cause of neonatal intensive care admission

among term and preterm infants (15-30%). Respiratory distress in a newborn infant is

recognized by the presence of any two of the following signs; tachypnea, chest retractions, or

grunting. Common respiratory diseases among term infants include transient tachypnea of

newborn (TTN), pneumonia, meconium aspiration syndrome (MAS), and persistent pulmonary

hypertension of the newborn (PPHN). Among preterm infants, respiratory distress syndrome

(RDS) due to surfactant deficiency, apnea of prematurity, sepsis and bronchopulmonary

dysplasia (BPD) are common. BPD results from lung injury due to mechanical ventilation,

excessive oxygen exposure and inflammation in the developing lung of preterm infant. These

injuries lead to an arrest in alveolarization and scarring from fibrosis.

Various attempts have been made in recent times to prevent and decrease lung injury in

neonates by avoidance of mechanical ventilation, judicious use of oxygen, use of non-

invasive ventilatory strategies, prevention and treatment of sepsis and promotion of optimum

growth. The various non-invasive ventilatory strategies include nasal continuous positive airway

pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), biphasic positive

airway pressure (BiPAP), and high-flow nasal cannula (HFNC). Randomized controlled trials

suggest that the use of non-invasive ventilatory strategies decreases the need for mechanical

ventilation, use of surfactant and lung injury leading to BPD. There are guidelines from the

European1 expert panel on the management of RDS and American Academy of Pediatrics2,3

on non-invasive ventilatory strategies in preterm neonates. National Neonatology Forum, India

(NNF) had published guidelines on the use of CPAP in neonates in 20104. With more evidence

from recently published randomized controlled trials and growing interest with other non-

invasive modalities like HFNC and NIPPV, there was a felt need to update these guidelines and

to provide recommendations suited to the Indian context.

The Guideline Development Group short-listed 14 questions pertaining to the use of non-

invasive respiratory strategies in neonates to be of highest priority. Thirteen of these questions

focus on issues related to use of CPAP, HFNC and NIPPV among preterm for various settings

like respiratory distress syndrome (RDS), apnea of prematurity and post-extubation period. One

of them is a background question on predictors of failure of CPAP and the other addresses the

use of CPAP in term neonates with meconium aspiration syndrome. The Grading of

Recommendations Assessment, Development, and Evaluation (GRADE) approach was used

for grading the quality of evidence after adaptation to the relevant working area. The quality

of evidence for an outcome was graded as high, moderate, low or very low. After grading

the available studies for each outcome, recommendations were formulated, based on the

summary and quality of evidence, balance between benefits and harms, values and

preferences of policy-makers, health-care providers and parents, feasibility and resource use

and whether costs are justifiable relative to benefits in Indian settings.

Each recommendation was graded as strong when there was confidence that the benefits

clearly outweigh the harms, or weak when the benefits probably outweigh the harms, but

there was uncertainty about the trade-offs. A strong or weak recommendation was further

classified as situational /context specific if the benefits outweigh the harms in some situations

but not in others (indicated in the document as appropriate). Table 1 lists the summary of key

recommendations of the guidelines.



130

Table 1: Summary of recommendations for non-invasive respiratory support for newborns

S.

No.

Recommendations

Strength of

recommendations

Quality of

evidence

Initial respiratory support for preterm neonates with or at risk of RDS

1. All preterm neonates with respiratory distress

should be managed with continuous positive

airway pressure (CPAP)

Comment: There is a small but possible risk of

air-leak in neonates started on CPAP

therapy. Facilities offering CPAP support

should have expertise to monitor such

neonates to avoid complications

Strong

Low

2. Continuous positive airway pressure (CPAP)

should be administered at or immediately

after the onset of respiratory distress in

preterm neonates.

Strong

Low

3. Heated humidified high flow nasal canula

(HFNC) is not recommended for the

management of preterm neonates with or at

risk of respiratory distress syndrome (RDS)

Strong Moderate

4. Nasal intermittent positive pressure

ventilation (NIPPV) delivered by a ventilator

using synchronised or non-synchronised

methods may be used as the primary mode

in preterm neonates with or at risk of RDS

Applicable to settings with optimal

availability of ventilators and trained

manpower

Strong, Conditional

High

5. Extreme preterm neonates (gestation <28

weeks) should not be routinely intubated in

the delivery room; intubation and ventilation

should be reserved only for those with severe

perinatal asphyxia requiring resuscitation

Applicable in settings with high antenatal

steroid coverage and adequate expertise in

managing extreme preterm neonates

Strong, Conditional Moderate



131

6. Early rescue surfactant should be

administered along with CPAP in preterm

neonates with respiratory distress syndrome

(RDS)

Comment: Units offering surfactant therapy

should have equipment to offer mechanical

ventilation, blood gas analysis, chest X-ray

and skilled newborn care for adequate

monitoring.

Strong Moderate

Non-invasive respiratory support for preterm neonates with apnea of prematurity

7. a. CPAP therapy should be initiated in

preterm neonates with apnea of

prematurity in conjunction with

methylxanthines.

b. NIPPV (both synchronized and non-

synchronised) may be used for

frequent and severe apneic

episodes, if adequate expertise and

equipment are available

Strong

Weak, Conditional

Low

Very low

Non-invasive respiratory support for preterm neonates in post-extubation setting

8.

Preterm very low birth weight neonates

being extubated after a brief period of

ventilation should be weaned off either to

CPAP or NIPPV.

Comment: If adequate expertise and

equipment are available, NIPPV (both

synchronized and non-synchronised) might

preferably be used, particularly in neonates

at high risk of CPAP failure

Strong Low to

moderate

Non-invasive respiratory support for late preterm and term neonates with

meconium aspiration syndrome

9.

Continuous positive airway pressure (CPAP)

may be employed as the primary mode of

respiratory support in late preterm and term

neonates with meconium aspiration

syndrome (MAS)

Comment: Facilities offering CPAP support

should have the expertise to monitor such

neonates for air-leak.

Weak Low



132

CPAP devices, nasal interfaces, initial pressure and weaning strategies

10. Pressure generators

Bubble CPAP, rather than ventilator CPAP or

variable flow device, may preferably be

used in preterm neonates requiring

continuous positive airway pressure for any

indication

Weak

Low to very

low

11. Nasal interface

CPAP should be delivered by either short

binasal prongs or nasal masks in neonates

Comment: If available, nasal masks may be

preferred, particularly in neonates at high risk

of nasal injury

Strong

Moderate

12. Initial pressures

a. Preterm neonates with respiratory distress

syndrome (RDS) may be initiated on CPAP

pressures of 5 cm H2O

b. Preterm very low birth weight neonates

being extubated to CPAP, after a brief

period of ventilation may be initiated on

pressures of 6 cm H2O or more

Weak

Weak

Low

Very low

13. Weaning

Preterm very low birth weight neonates

being weaned off from CPAP may

preferably be weaned off by sudden

discontinuation of CPAP rather than CPAP

cycling

Weak

Low



133

Introduction

Respiratory distress is a common symptom affecting up to 7% of all term infants and a higher

percentage of preterm infants (30%)5. Respiratory distress a common cause of neonatal

intensive care unit (NICU) admission (15-30%) among neonates and the major contributor

(45%) of neonatal deaths among preterm neonates6. According to the National Neonatal

Perinatal Database of India (NNPD) for the year 2002-03, transient tachypnea of newborn (3.2%

of all live births), meconium aspiration syndrome (1.3%) and respiratory distress syndrome (1.2%)

were the three common causes of respiratory morbidity among inborn neonates admitted to

various hospitals that formed part of the Consortium7.

Respiratory distress in a newborn infant is recognized by the presence of any two of the

following signs; tachypnea, chest retractions, or grunting. Common respiratory diseases

among term infants include transient tachypnea of newborn (TTN), neonatal pneumonia,

meconium aspiration syndrome (MAS), and persistent pulmonary hypertension of the newborn

(PPHN). Among preterm infants, respiratory distress syndrome (RDS) due to surfactant

deficiency, apnea of prematurity, and bronchopulmonary dysplasia (BPD) are common. BPD

results from lung injury due to mechanical ventilation, excessive oxygen exposure and

inflammation in a developing lung of preterm infant. These injuries lead to an arrest in

alveolarization and scarring from fibrosis. The risk of BPD among preterm neonates ≤ 30 weeks

gestation is around 50%8. There is paucity of data from India on the burden of BPD among

preterm neonates. A recent report cites a conservative estimate of (11%) among neonates <

33 weeks gestation with an average survival rate of 63%9.

Various attempts have been made in recent times to prevent and decrease lung injury in

neonates by avoidance of mechanical ventilation, judicious use of oxygen, use of non-

invasive ventilatory strategies, prevention and treatment of sepsis and promotion of optimum

growth. The various non-invasive ventilatory strategies include, nasal continuous positive

airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), biphasic

positive airway pressure (BiPAP), and high-flow nasal cannula (HFNC). Randomized controlled

trials suggest that the use of non-invasive ventilatory strategies decrease the need for

mechanical ventilation, use of surfactant and lung injury leading to BPD10. Among various non-

invasive strategies, there is greater interest with the use of NIPPV and HFNC either for greater

efficacy, ease of use and patient comfort. There are guidelines from the European1 expert

panel on the management of RDS and the American Academy of Pediatrics2,3 on non-invasive

ventilatory strategies in preterm neonates. The National Neonatology Forum, India (NNF) had

published guidelines on the use of CPAP in neonates in 20104. With more evidence from

recently published randomized controlled trials and growing interest with other non-invasive

modalities, there was a felt need to update these guidelines and to provide recommendations

suited to the Indian context.

Scope of the guidelines and target audience

Scope

The Guideline Development Group identified 17 research questions about the use of non-

invasive respiratory strategies in neonates to be of highest priority. Fifteen of these questions

focus on priority issues related to the use of CPAP, HFNC and NIPPV among preterm neonates

beginning with birth and subsequently for various settings like respiratory distress syndrome



134

(RDS), apnea of prematurity and post-extubation period. One of them is a background

question on predictors of failure of CPAP and the other addresses the use of CPAP in term

neonates with meconium aspiration syndrome. The Grading of Recommendations

Assessment, Development, and Evaluation (GRADE) approach was used for grading the

quality of evidence after adaptation to the relevant working area. The quality of evidence for

an outcome was graded as high, moderate, low or very low. After grading the available

studies for each outcome, recommendations were formulated based on the summary and

quality of evidence, balance between benefits and harms, values and preferences of policy-

makers, health-care providers and parents, feasibility and resource use and whether costs are

justifiable relative to benefits in Indian settings.

Target audience

The primary audience for this guideline includes health-care professionals (pediatricians, nurses

and other practitioners) who are responsible for delivering care for neonates in different levels

of health care as well health programme managers and policymakers in all settings. The

information in this guideline will be useful for developing job aids and tools for training of health

professionals to enhance their delivery of neonatal care. These guidelines may also be used

by health policymakers to set up facilities in special care newborn units for optimal care of

infants.

Population of interest

The guidelines focus on the use of non-invasive respiratory support, namely, CPAP, HFNC and

NIPPV among term and preterm neonates admitted to healthcare settings with various

respiratory conditions in India.

METHODOLOGY

Questions relevant to clinical practice

The Guideline Development Group (GDG) short-listed 14 questions about the use of non-

invasive respiratory strategies in neonates to be of highest priority after survey amongst the

GDG and a wider group of NNF members. Thirteen of these questions focus on priority issues

related to the use of CPAP, HFNC and NIPPV among preterm neonates beginning with birth

and subsequently for various settings like respiratory distress syndrome (RDS), apnea of

prematurity and post-extubation period. One of them is a background question on predictors

of failure of CPAP and the other addresses the use of CPAP in term neonates with meconium

aspiration syndrome. Each of these questions deserved separate systematic reviews, taking

into consideration the critical and important outcomes. The performed systematic reviews

were peer reviewed by the GDG and also by external peer reviewers.

The following questions were identified to be of the highest priority :

What should be the primary mode of non-invasive respiratory support among preterm infants

with or at risk of RDS?

1. Among preterm neonates with RDS, what is the effect of continuous positive airway

pressure (CPAP) when compared to oxygen therapy delivered by head box,

facemask or nasal cannula on mortality and severe morbidities?



135

2. Among preterm neonates with RDS, what is the effect of early CPAP therapy when

compared to delayed CPAP therapy on mortality and severe morbidities?

3. Among preterm neonates with RDS, what is the effect of high flow nasal cannula

(HFNC) when compared to CPAP on mortality and severe morbidities?

4. Among preterm neonates with RDS, what is the effect of nasal intermittent positive

pressure ventilation (NIPPV) when compared to CPAP on mortality and severe

morbidities?

5. Among extreme preterm neonates with RDS, what is the effect of CPAP when

compared to routine intubation and ventilation in the first few hours of life on

mortality and severe morbidities?

6. Among preterm neonates with RDS, what is the effect of CPAP alone when

compared to CPAP therapy with early rescue surfactant on mortality and severe

morbidities?

What should be the mode of non-invasive respiratory support among preterm infants with

apnea of prematurity?

7. Among neonates with apnea of prematurity, what is the effect of

a. CPAP therapy compared with no CPAP therapy

b. CPAP therapy compared with HFNC or NIPPV

on the need for ventilation, mortality and severe morbidities?

What should be the mode of non-invasive respiratory support among preterm infants who are

extubated following a period of intubation and mechanical ventilation?

8. Among preterm neonates being extubated following a period of intubation and

mechanical ventilation, what is the effect of

a. continuous positive airway pressure (CPAP) therapy compared with no CPAP

therapy

b. high flow nasal cannula (HFNC) therapy compared with CPAP

c. nasal intermittent positive pressure ventilation (NIPPV) therapy compared with

CPAP

on the need for additional ventilatory support, mortality, and severe morbidities?

What should be the mode of non-invasive respiratory support among term infants with

meconium aspiration syndrome?

9. Among term neonates with meconium aspiration syndrome (MAS), what is the effect

of CPAP when compared to oxygen therapy delivered by headbox, facemask or

nasal cannula on mortality and severe morbidities?

What should be the characteristics of optimal CPAP device for use as determined by

comparison of the efficacy and safety of commonly used CPAP devices?



136

Among neonates requiring CPAP therapy, what is the optimal CPAP device for use (as

determined by a comparison of the efficacy and safety of commonly used CPAP devices)

with regard to

10. Patient interfaces: nasal prongs vs. masks vs. nasopharyngeal prongs

11. Pressure generators: Bubble CPAP vs. ventilator CPAP vs. infant flow driver (IFD)

12. Initial pressure: low (5 cm H2O) vs. higher (>5 cm H2O)

13. Weaning: cycling vs. sudden cessation vs. others

Predictors of CPAP failure

14. Among preterm neonates with RDS, which group of neonates are more likely to fail

CPAP?

Outcomes of interest

For each question, the following outcomes (critical and important) were considered. Benefits

and harms in critical outcomes formed the basis of the recommendations. When information

on critical outcomes was not available, other non-critical outcomes were considered. Details

of outcomes and their definitions are available in the online version.

Critical

Neonatal mortality

In-hospital mortality

Bronchopulmonary dysplasia (BPD)

Grade 3 or 4 intraventricular haemorrhage (IVH)

Air leaks

Important

Respiratory failure warranting mechanical ventilation

Need for surfactant

Failure of extubation

Need for re-intubation

Sepsis

Necrotising enterocolitis (NEC)

Retinopathy of prematurity (ROP)

Duration of hospitalisation

Nasal trauma

Duration of oxygen therapy

Selection of studies

Search strategy

Using the assembled list of priority questions and critical outcomes from the scoping exercise,

the guideline development group, identified systematic reviews that were either relevant or

potentially relevant and assessed whether they needed to be updated. A systematic review



137

was considered to be out of date if the last search date was one year or more prior to the

date of assessment. If any relevant review was found to be out of date, it was updated.

Cochrane systematic reviews were the primary source of evidence for the recommendations

included in this guideline. In addition, key databases searched included the Cochrane

database of systematic reviews of RCTs, the Cochrane controlled trials register and MEDLINE

(1966 to 2019). The reference lists of relevant articles were also searched to identify relevant

studies.

Data abstraction and summary tables of individual studies

A standardized form was used to extract information from relevant studies. Systematically

extracted data included: study identifiers, setting, design, participants, sample size,

intervention or exposure, control or comparison group, outcome measures and results. The

following quality characteristics were recorded for RCTs: allocation concealment, blinding of

intervention or observers, loss to follow up, and intention to treat analysis. The studies were

stratified according to the type of intervention or exposure, study design, birth weight and

gestational age, where possible. Effects were expressed as relative risks (RR) or odds ratios (OR)

for categorical data, and as mean differences (MD) or weighted mean differences (WMD) for

continuous data where possible.

Pooled effects

Pooled effects for developing recommendations were considered, wherever feasible. Pooled

effects from published systematic reviews were used if the meta-analysis was appropriately

done, and the reviews were up to date. Where pooling of results was not possible, the range

of effect sizes observed in the individual studies was used in the development of

recommendations.

Grading the quality of evidence

Quality assessment of the body of evidence for each outcome was performed using the

Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

The GRADE approach was used for all the critical outcomes identified in the research question,

and a GRADE profile was prepared for each quantitative outcome. Accordingly, the quality

of evidence for each outcome was rated as “high”, “moderate”, “low”, or “very low” based

on a set of criteria. As a baseline, RCTs provided “high-quality” evidence, while non-

randomized trials and observational studies provided “low-quality” evidence. This baseline

quality rating was then downgraded based on consideration of the risk of bias, inconsistency,

imprecision, indirectness and publication bias.

The following briefly describes how these criteria were used:

Study design

We included only Randomized controlled studies. Observational studies, and non-randomized

experimental studies were considered for narrative review. Four criteria were used for assessing

limitations in the methods of included studies; 1) Selection bias was assessed by analysing how

randomization and allocation concealment was done 2) Measurement bias can be minimized

by blinding the participants and researchers to the intervention. If that is not possible, the



138

observers measuring outcome can be blinded. Measurement bias was less likely if the

outcome is "objective". If the majority of evidence was from studies where any of the above

was done, the risk was low, otherwise it was considered high 3) Loss to follow-up: A large loss

to follow-up can lead to bias in results; 20% loss to follow-up was chosen arbitrarily as the cut-

off point. If the majority of evidence was from studies where loss to follow-up was less than 20%,

the risk was low 4) Appropriateness of analysis: If the majority of evidence was from RCTs which

had analysis by intention to treat the risk of bias was low, else it was high.

Inconsistency of the results

The similarity in the results for a given outcome was assessed by exploring the magnitude of

differences in the direction and size of effects observed from different studies. The quality of

evidence was not downgraded when the directions of the findings were similar and

confidence limits overlapped, whereas quality was downgraded when the results were in

different directions and, confidence limits showed minimal overlap.

Indirectness

Rating of the quality of evidence was downgraded where there were serious or very serious

concerns regarding the directness of the evidence, i.e. where there were important

differences between the research reported and the context for which the recommendations

are being prepared. Such differences were related, for instance, to populations, interventions,

comparisons or outcomes.

Imprecision

The degree of uncertainty around the estimate of effect was assessed. As this was often a

function of sample size and number of events, studies with relatively few participants or events

(and thus wide confidence intervals around effect estimates) were downgraded for

imprecision.

Publication bias

The quality rating could also be affected by perceived or statistical evidence of bias that may

have led to underestimation or overestimation of the effect of an intervention as a result of

selective publication based on study results. Where publication bias was strongly suspected,

evidence was downgraded by one level.

Formulation of recommendations

After grading the available studies for each outcome, recommendations were formulated

based on the summary and quality of evidence, balance between benefits and harms, values

and preferences of policy-makers, health-care providers and parents, feasibility and resource

use and whether costs are justifiable relative to benefits in Indian settings.

Each recommendation was graded as strong when there was confidence that the benefits

clearly outweigh the harms, or weak when the benefits probably outweigh the harms, but

there was uncertainty about the trade-offs. A strong or weak recommendation was further

classified as situational /context specific if the benefits outweigh the harms in some situations

but not in others (indicated in the document as appropriate).



139

Document review

The GDG personally met on two occasions and prepared a draft of the full guideline

document with revisions to accurately reflect the deliberations and decisions of the GDG

participants. This draft guideline was then sent electronically to the GDG participants for further

comments. The inputs of the peer reviewers were included in the guideline document and,

further revisions were made to the guideline draft as needed. After the peer review process,

the revised version was prepared.



140

Questions, Evidence summary and Recommendations

Practice Question 1: Among preterm neonates with RDS, what is the effect of CPAP when

compared to oxygen therapy delivered by headbox, facemask or nasal cannula on mortality

and severe morbidities?

Summary of evidence- values and benefits

• Evidence for the use of CPAP as compared to standard treatment (oxygen hood, nasal

prongs, oxygen by face-mask) is derived from a Cochrane review from 2015 11 that

included 6 randomized/quasi-randomized trials12-17. No new studies were identified in

the updated search for this review. Most of these studies were done during 1960-70s

when antenatal steroid coverage was low (20-35%) and, surfactant use was

uncommon in contrast to the current era with higher rates of antenatal steroid

coverage and greater availability of surfactant. All the studies were conducted in high-

income countries and all except one in level-3 neonatal intensive care units (NICU).

The type of CPAP used in the studies are uncommon now; two used negative-pressure

chambers, two used face-mask CPAP and one used negative pressure for less severe

illness and endotracheal CPAP for severe illness.

• Pooled analysis showed low -quality evidence of a reduction in the risk of mortality

during the initial hospital stay RR 0.53; 95% CI (0.32-0.87) and need for mechanical

ventilation; RR 0.72; 95% CI (0.56, 0.91) in the CPAP group compared to oxygen therapy

alone. There was no difference in the rate of BPD and the need for surfactant therapy

(Table 2 enlists the summary of findings for this comparison).

• There is low- quality evidence of higher risk of air leaks in the CPAP group; RR 2.64; 95%

CI (1.39, 5.04). The risk of pneumothorax was 14% in the CPAP group and 6% in the

oxygen therapy group. This increased risk of pneumothorax may be because of various

reasons; low coverage of antenatal steroids and surfactant use, late initiation of CPAP

(mean age of 3 hours in one study and 10 hours in others), delivery of distending

pressures through a facemask and negative pressure chambers- delivery techniques

which are obsolete today.

• There are no randomized controlled trials from low middle-income settings comparing

CPAP with oxygen therapy. In a meta-analysis published in 2016, authors analysed the

efficacy and safety of CPAP in low and middle income (LMIC) settings. Pooled analysis

from four observational studies showed that CPAP therapy resulted in 66% reduction in

in-hospital mortality (odds ratio 0.34, 95% CI; 0.14 to 0.82). One study from Fiji reported

a 50% reduction in the need for mechanical ventilation following the introduction of

bubble CPAP (RR 0.5, 95% CI 0.37 to 0.66)18. The incidence of air leaks varied from 0 to

7.2% (in nine studies from LMIC set up). This risk is much less compared to 14% in the

pooled analysis from studies from the earlier era.

• The benefits of CPAP namely reduction in in-hospital mortality and need for

mechanical ventilation far outweigh the small risk of pneumothorax. Hence, health

care providers, policy-makers, and parents in both high-income and low-and middle-

income countries are likely to give a high value to the use of CPAP. Also, CPAP is a non-

invasive method and delivered through nasal interface (binasal prongs or masks).



141

• Studies from LMIC set up have shown bubble CPAP to be a highly cost-effective

strategy compared to oxygen therapy.

Table 2: Summary of findings for the comparison CPAP vs oxygen therapy in RDS

Patient or population: Preterm neonates with RDS

Setting: Hospital (neonatal intensive care unit)

Intervention: CPAP

Comparison: Oxygen therapy (head box or free flow oxygen or face mask)

Outcomes

Anticipated absolute

effects* (95% CI)

Relative effect

(95% CI)

№ of participants

(studies)

Certainty of the evidence

(GRADE)

Risk with

head box

or free

flow

oxygen

Risk with

CPAP

Mortality

179 per 1,000

93 per

1,000

(57 to 156)

RR 0.52

(0.32 to 0.87)

355 (6 RCTs) ⨁⨁◯◯

LOW a,b

Bronchopulmonary dysplasia assessed with:

Oxygen requirement at day 28 of life

45 per 1,000

55 per

1,000

(20 to

152)

RR 1.22

(0.44 to 3.39)

260 (3 RCTs)

⨁◯◯◯

VERY LOW b,c,d

Respiratory failure warranting mechanical

ventilation

525 per 1,000

378 per

1,000

(294 to 478)

RR 0.72

(0.56 to 0.91)

314 (5 RCTs) ⨁⨁◯◯

LOW b,c

Need for surfactant

269 per 1,000

116 per

1,000

(32 to 398)

RR 0.43

(0.12 to 1.48)

52 (1 RCT) ⨁◯◯◯

VERY LOW b,c,d,e

Any air-leak

61 per 1,000

162 per

1,000

(85 to

310)

RR 2.64

(1.39 to 5.04)

351 (6 RCTs) ⨁⨁◯◯

LOW b,c

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed

risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

Explanations

a. Unclear or high risk of bias of random sequence generation and allocation concealment

in two studies that had weight of >65% in pooled analysis b. All studies are from high income countries. The use of antenatal steroids and surfactant was low in most studies- contrary to the current situation. The type of CPAP used in some

studies is no longer used now. c. Neither outcome assessors nor treatment team was blinded to group allocation

d. 95% confidence interval around the pooled estimate includes both 1) no effect and 2) appreciable benefit or appreciable harm e. Single study



142

Practice Question 2: Among preterm neonates with RDS, what is the effect of early initiation of

CPAP when compared to delayed initiation of CPAP on mortality and severe morbidities?


• The evidence for this review is derived from a Cochrane systematic review that

examined the effect of early CPAP therapy as compared to delayed CPAP therapy

for RDS in preterm neonates19 that included six trials20-25. We identified one more eligible

study from LMIC setting (Iran) for this review26.

• The earlier six trials were conducted in the pre surfactant era and required clinical and

radiological evidence of RDS for trial entry. The FiO2 required at entry ranged from 0.3

to 0.7 or more. Early CPAP was initiated at trial entry and, late CPAP was initiated at

higher FiO2 ranging from 0.5 up to 1.0. Thus, there was considerable variation and

overlap in the criteria used for initiating early and late CPAP. In contrast, the recent

Iranian study had early CPAP and delayed CPAP initiated based on time since birth

(early initiated within 5 minutes, whereas delayed initiated 30 minutes after birth).26 Also,

the CPAP therapy was used in adjunct with antenatal steroids and surfactant

treatments.

• There is low- quality evidence that early CPAP reduces the need for mechanical

ventilation (RR 0.55; 95% CI: 0.32 to 0.96) and surfactant (RR 0.64; 95% CI: 0.44 to 0.93),

and the risk of sepsis (RR 0.46; 95% CI: 0.27 to 0.79) when compared to late CPAP in

preterm neonates with RDS. No difference was observed in the risk of mortality or severe

morbidities like BPD and air leaks (Table 3 enlists the summary of findings for this

comparison).

• Health care providers and policy-makers are likely to give a high value to the benefits

observed with early CPAP. It could also result in cost savings by reducing the need for

ventilation and surfactant as well as by reducing the incidence of sepsis.

RECOMMENDATION 1

Preterm neonates with respiratory distress should be managed with continuous positive

airway pressure (CPAP).

There is a small but, possible risk of air-leak in neonates started on CPAP therapy. Facilities

offering CPAP support should have expertise to monitor such neonates to avoid

complications.

Strong recommendation, based on low-quality evidence for benefit in one critical

outcome viz. in-hospital mortality and an important outcome-respiratory failure requiring

mechanical ventilation but the consensus among experts for other beneficial effects of

CPAP including cost-effectiveness.



143

Table 3: Summary of findings for early compared to delayed initiation of CPAP for Preterm

neonates with RDS


Setting: Hospital

Intervention: Early

Comparison: delayed initiation of CPAP

Outcomes Anticipated absolute

effects* (95% CI)

Relative effect

(95% CI)

№ of participants

(studies)

Certainty of the evidence (GRADE)

Comments Risk with

delayed

initiation of

CPAP

Risk with

Early

Neonatal

mortality

53 per 1,000 49 per 1,000

(7 to 358)

RR 0.93

(0.13 to 6.81)

61 (2 RCTs)

⨁⨁◯◯

LOW a,b

In-hospital

mortality

188 per

1,000 131 per 1,000

(75 to 232)

RR 0.70

(0.40 to

1.24)

237

(7 RCTs)

⨁⨁⨁◯

MODERATE b,c

BPD

assessed with:

Oxygen

requirement at

day 28 of life

55 per 1,000 38 per 1,000

(7 to 217)

RR 0.70

(0.12 to

3.98)

108

(2 RCTs)

⨁◯◯◯

VERY LOW b,d,e

Need for

mechanical

ventilation

315 per

1,000 173 per 1,000

(101 to 303)

RR 0.55

(0.32 to

0.96)

165

(6 RCTs)

⨁⨁⨁◯

MODERATE a,d

Need for

surfactant

therapy

778 per

1,000 498 per 1,000

(342 to 723)

RR 0.64

(0.44 to

0.93)

72

(1 RCT)

⨁⨁◯◯

LOW d

Air-leak 148 per

1,000 124 per 1,000

(55 to 283)

RR 0.84

(0.37 to

1.91)

144

(5 RCTs)

⨁◯◯◯

VERY LOW a,b,d

Neonatal sepsis 667 per

1,000 307 per 1,000

(180 to 527)

RR 0.46

(0.27 to

0.79)

72

(1 RCT)

⨁⨁◯◯

LOW d,f




Explanations

a. Allocation concealment unclear in most studies

b. 95% CI around pooled estimate includes both 1) no effect and 2) appreciable harm c. Allocation concealment mentioned in 2 studies with a combined weightage of >50% d. neither treatment team nor outcome assessors were masked to group allocation

e. Only 2 and 3 events in the two groups (both groups combined) f. Single study



144

RECOMMENDATION 2

Continuous positive airway pressure (CPAP) should be administered at or immediately after

the onset of respiratory distress in preterm neonates.

Strong recommendation, Low quality evidence for significant benefits in need for

ventilation/surfactant and risk of sepsis but the consensus among experts for other beneficial

effects of CPAP including cost- effectiveness.

Practice Question 3: Among preterm neonates, at risk of or with respiratory distress at birth,

what is the effect High flow nasal cannula (HFNC) as compared to CPAP therapy as the primary

mode of respiratory support on the need for mechanical ventilation, need for surfactant

treatment, mortality, and severe morbidities?


• We identified three systematic reviews that addressed this question27-29. We used data

from the most recent review29 that included ten studies 30-39 and an additional study

from updated search34.

• There is moderate-quality evidence that HFNC results in more treatment failures than

CPAP (RR 1.93; 95% CI 1.51 to 2.5). There is moderate-quality evidence that there is no

difference need for mechanical ventilation within 7 days of trial entry, partly because

neonates failing HFNC were rescued using CPAP (Table 4 enlists the summary of findings

for this comparison). There is moderate-quality evidence that there is no difference in

mortality and very low-quality evidence that it does not lower BPD rates when

compared to CPAP. There is moderate quality evidence that HFNC decreases the

nasal trauma among these infants when compared to Nasal CPAP (RR 0.51; 95% CI

0.36-0.71) – for every 1000 neonates treated, 46 fewer neonates would have nasal

trauma (95% CI 27 to 60). Most trials enrolled neonates > 28 weeks’ gestation.

• Health care providers are likely to be concerned regarding the high failure rates with

HFNC and would need to be prepared with a backup CPAP. Parents32 and nurses40

generally prefer HFNC to CPAP as neonates are more comfortable41 with HFNC prongs.

• In a cost-effectiveness evaluation of CPAP and HFNC therapy42, CPAP therapy was

noted to be highly cost-effective and, units opting to buy a single therapy should

choose CPAP over HFNC alone.



145

Table 4: Summary of findings for HFNC compared to CPAP for preterm infants as the primary

respiratory support

Patient or population: preterm infants as the primary respiratory support

Setting: Hospital

Intervention: Heated humidified high flow nasal cannula (HFNC)

Comparison: CPAP

Outcomes


effects* (95% CI)

Relative effect

(95% CI)

№ of participants

(studies)


(GRADE)

Risk with

CPAP

Risk with

Heated

humidified

high flow

nasal

cannula

(HFNC)

Failure of primary

respiratory support (Treatment failure) assessed with: need

for mechanical ventilation or need for CPAP in HFNC

group follow up: mean 7 days

101 per

1,000 195 per

1,000

(153 to 253)

RR 1.93

(1.51 to 2.50)

2244

(8 RCTs)

⨁⨁⨁◯

MODERATE a,b

Need for intubation and mechanical

ventilation (Mechanical ventilation)

follow up: mean 7 days

94 per 1,000 103 per

1,000

(80 to 133)

RR 1.10

(0.86 to 1.42)

2186 (7 RCTs)

⨁⨁⨁◯

MODERATE c

Bronchopulmonary dysplasia (BPD)

33 per 1,000 44 per

1,000

(21 to 93)

RR 1.35

(0.64 to 2.85)

1461 (7 RCTs)

⨁◯◯◯

VERY LOW a,c

In-hospital mortality 5 per 1,000 6 per

1,000

(2 to 15)

RR 1.36

(0.38 to 3.32)

2168

(8 RCTs)

⨁⨁⨁◯

MODERATE c

Air leak 42 per 1,000 35 per

1,000

(23 to 53)

RR 0.84

(0.55 to 1.26)

2183 (7 RCTs)

⨁⨁◯◯

LOW a,c

Nasal trauma 93 per 1,000 48 per

1,000

(34 to 66)

RR 0.51

(0.36 to 0.71)

1933 (7 RCTs)

⨁⨁⨁◯

MODERATE a

*The risk in the intervention group (and its 95% confidence interval) is based on the

assumed risk in the comparison group and the relative effect of the intervention (and its

95% CI).


Explanations

a. Unblinded studies b. Treatment failure included both need for back up CPAP in HFNC group or need for

intubation c. 95% CI for the outcome is crossing the clinical decision



146

RECOMMENDATION 3

Heated humidified high flow nasal canula (HFNC) is not recommended for the management

of preterm neonates with or at risk of respiratory distress syndrome (RDS).

Strong recommendation based on moderate quality of evidence against HFNC with higher

risk of treatment failure, an important outcome and lack of benefit in reducing the need for

ventilation, mortality and BPD and the consensus among experts for other beneficial effects

of CPAP including cost- effectiveness.

Practice Question 4: Among preterm neonates, at risk of or with respiratory distress at birth,

what is the effect nasal intermittent positive pressure ventilation (NIPPV) as compared to CPAP

therapy as the primary mode of respiratory support on the need for mechanical ventilation,

need for surfactant treatment, mortality, and severe morbidities?


• We identified a Cochrane systematic review43 that included 10 RCTs 44-53. In the

updated search, we identified 6 new eligible studies 54-58. These form the basis of this

review.

• There is high-quality evidence that NIPPV reduces the risk of critical outcome namely,

mortality (RR 0.65, 95% CI 0.46 to 0.91) and moderate-quality evidence that it reduces

the need for mechanical ventilation (RR 0.73, 95% CI 0.62 to 0.87) within 7 days of trial

entry, an important outcome when compared to CPAP as the primary mode of

respiratory support among preterm infants (Table 5). There is low-quality evidence that

NIPPV does not decrease BPD, pneumothorax, ROP and IVH (all grades) when

compared to Nasal CPAP. Regardless of the population (a receipt of the surfactant or

not before randomization), results showed no difference in the incidence of

pneumothorax between NIPPV and CPAP groups (RR 0.83, 95%CI 0.50 to 1.37). Pooled

results showed a reduction in NEC (RR 0.53, 95%CI 0.30 to 0.91) although none of the

individual trials showed this benefit.

• Type of device: The benefits in a reduction in mechanical ventilation and mortality

were observed when NIPPV was administered via a ventilator than using bi-level

devices.

• Synchronization: Non-synchronized devices showed a reduction in the need for

mechanical ventilation, and synchronized devices showed a trend toward benefit.

Non-synchronized devices also showed benefit in mortality and BPD in subgroup

analysis.



147

• Given the possible beneficial effects observed with NIPPV, especially the decrease in

mortality, health care providers, policymakers and parents are likely to value the

intervention high.

• NIPPV requires a ventilator or a bi-level CPAP machine and needs expertise and

training. CPAP can be easily administered by nurses after training. Setting up a CPAP

machine is easy compared to NIPPV.

• No cost-effectiveness or cost-minimisation studies are available for the comparison of

NIPPV and CPAP. Unlike CPAP, NIPPV requires the use of a ventilator that is much

costlier than typical CPAP devices. Also, the availability of ventilators and trained

personnel who can use them optimally is a major issue in most neonatal units,

particularly in level-2 units, across the country.

Table 5: Summary of findings for NIPPV compared to CPAP for preterm infants as the

primary respiratory support


Setting: hospital

Intervention: NIPPV

Comparison: CPAP

Outcomes


effects* (95% CI) Relative effect

(95% CI)

№ of participants

(studies)

Certainty of the

evidence (GRADE)

Risk with

CPAP

Risk with NIPPV

Need for intubation and mechanical ventilation

(Intubation) follow up: mean 7

days

249 per 1,000

182 per 1,000

(154 to 217)

RR 0.73

(0.62 to 0.87)

1745 (15 RCTs)

⨁⨁⨁◯

MODERATE a

Mortality during study period (Mortality)

91 per

1,000 59 per 1,000

(42 to 82)

RR 0.65

(0.46 to 0.91)

1691

(14 RCTs)

⨁⨁⨁⨁

HIGH

Chronic lung disease (CLD) assessed with:

Oxygen need at 36 weeks PMA

136 per 1,000

114 per 1,000

(87 to 149)

RR 0.84

(0.64 to 1.10)

1403 (12 RCTs)

⨁⨁◯◯

LOW b

Pneumothorax 33 per 1,000

27 per 1,000

(16 to 45)

RR 0.83

(0.50 to 1.37)

1776 (15 RCTs)

⨁⨁◯◯

LOW b

Intraventricular

hemorrhage assessed with: All grades

117 per

1,000 115 per 1,000

(83 to 157)

RR 0.98

(0.71 to 1.34)

1085

(10 RCTs)

⨁⨁◯◯

LOW a,b

Necrotizing enterocolitis

assessed with: Bells' stage 2 or more

57 per 1,000

30 per 1,000

(17 to 52)

RR 0.53

(0.30 to 0.91)

1222 (10 RCTs)

⨁◯◯◯

VERY LOW a,b,c

Retinopathy of Prematurity assessed with: Stage

3 or more

52 per 1,000

59 per 1,000

(30 to 117)

RR 1.14

(0.58 to 2.26)

529 (4 RCTs)

⨁⨁◯◯

LOW a,b



148

Table 5: Summary of findings for NIPPV compared to CPAP for preterm infants as the

primary respiratory support


Setting: hospital

Intervention: NIPPV

Comparison: CPAP

Outcomes



(95% CI)

№ of participants

(studies)

Certainty

of the evidence (GRADE)

Risk with

CPAP

Risk with NIPPV

Sepsis assessed with: culture

positive sepsis

144 per 1,000

138 per 1,000

(74 to 265)

RR 0.96

(0.51 to 1.84)

220 (3 RCTs)

⨁⨁◯◯

LOW a,b



95% CI).


Explanations

a. Studies included a varied population of neonates with respect to surfactant therapy and the mode of surfactant administration before enrolment. Studies enrolling neonates without surfactant therapy showed in-consistency in outcome

b. Unblinded studies c. Individual studies did not show any benefit and have wide confidence intervals

RECOMMENDATION 4

Nasal intermittent positive pressure ventilation (NIPPV) delivered by a ventilator using

synchronised or non-synchronised methods may be used as the primary mode in preterm

neonates with or at risk of RDS where equipment and its expertise are available.

Strong Conditional recommendation based on the high-quality of evidence for benefits in

one critical outcome with NIPPV namely a reduction in mortality and moderate quality

evidence for reduction in the need for mechanical ventilation (an important outcome)

Comment: Applicable to settings with optimal availability of ventilators and trained

manpower



149

Practice Question 5: Among extremely preterm neonates (gestation <28 weeks) what is the

effect of CPAP when compared to routine intubation and ventilation regardless of respiratory

status in the first few hours of life on mortality and severe morbidities?


• Prophylactic nasal CPAP is defined as initiating CPAP within the first 5 to 15 minutes of

life regardless of the respiratory status of the infant. Evidence for the role of

prophylactic CPAP is derived from a recent Cochrane systematic review10 that

included three RCTs59-61 compared prophylactic CPAP versus intubation in the delivery

room. All these were parallel multi-centric RCTs conducted in high-income countries

and enrolled neonates < 28 weeks gestation. The use of antenatal corticosteroids was

quite high in all the three studies (>90%).

• There is moderate-quality evidence that prophylactic application of CPAP in extreme

preterm infants (< 28 weeks gestation) results in small but clinically significant reduction

in incidence of BPD (RR 0.89, 95% CI 0.79 to 0.99) and death or BPD (RR 0.89, 95% CI

0.81 to 0.97) (Table 6). Moreover, there is moderate-quality evidence of almost 50%

reduction in the need of surfactant therapy (RR 0.54, 95% CI 0.40 to 0.73) and need of

mechanical ventilation (RR 0.50, 95% CI 0.48-0.62) in infants managed with CPAP. There

is no apparent harm with CPAP - the incidence of pneumothorax and severe

intraventricular hemorrhage was similar between the two groups. The long-term

outcomes are also reassuring with no significant difference in the composite outcome

of death or neurodevelopmental impairment at 18-22 months of corrected age in one

study62.

• Given the benefits without any apparent harm, health care providers, policymakers,

and parents are likely to give a high value to the application of delivery room CPAP.

Low and middle-income countries will be much more benefitted as compared to HICs

in view of high incidence of RDS among very low birthweight infants and RDS being

one of the important causes of neonatal mortality63. Moreover, it is much easier for the

nursing personnel to start and maintain CPAP with minimal training64 when compared

to intubation and mechanical ventilation of extreme preterm neonates.

• The cost of CPAP delivery systems is much less as compared to invasive ventilation18.

Also, the use of CPAP will reduce the need of surfactant by almost half thus resulting in

additional cost saving.



150

Table 6: Summary of findings for CPAP compared to Intubation and mechanical ventilation for

preterm neonates in the delivery room

Patient or population: preterm neonates in the delivery room

Setting: Hospital settings

Intervention: Prophylactic CPAP

Comparison: Intubation and mechanical ventilation

Outcomes


effects* (95% CI)

Relative effect

(95% CI)

№ of participants

(studies)

Certainty of the

evidence (GRADE)

Risk with

Intubation

and

mechanical

ventilation

Risk with

Prophylactic

CPAP

Bronchopulmonary dysplasia

at 36 weeks assessed with: Oxygen

requirement at 36 weeks

PMA

381 per

1,000

339 per 1,000

(304 to 377) RR 0.89

(0.80 to 0.99)

2150

(3 RCTs)

⨁⨁⨁◯

MODERATE a

Death or bronchopulmonary

dysplasia (Death or BPD) assessed with: Death or

oxygen dependency at 36 weeks' post‐menstrual age

470 per

1,000

418 per 1,000

(380 to 455) RR 0.89

(0.81 to 0.97)

2358

(3 RCTs)

⨁⨁⨁◯

MODERATE a


assessed with: Neonatal Death during hospital stay

126 per 1,000

103 per 1,000

(83 to 130)

RR 0.82

(0.66 to

1.03)

2358 (3 RCTs)

⨁⨁⨁◯

MODERATE b

Need for mechanical

ventilation assessed with: Assisted

ventilation

982 per 1,000

491 per 1,000

(413 to 580) RR 0.50

(0.42 to

0.59)

1042 (2 RCTs)

⨁⨁⨁◯

MODERATE c

Need for surfactant therapy 107 per 1,000

58 per 1,000

(43 to 78)

RR 0.54

(0.40 to 0.73)

2274 (3 RCTs)

⨁⨁◯◯

LOW d,e

Pneumothorax 58 per 1,000 82 per 1,000

(39 to 171)

RR 1.42

(0.68 to 2.98)

2357

(3 RCTs)

⨁⨁◯◯

LOW b,d

Intraventricular hemorrhage

(Grade 3 or more) 99 per 1,000

97 per 1,000

(63 to 148)

RR 0.98

(0.64 to 1.50)

2301

(3 RCTs)

⨁⨁◯◯

LOW b,d

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in

the comparison group and the relative effect of the intervention (and its 95% CI).


Explanations

a. Downgraded one level for serious imprecision because the 95% confidence interval includes appreciable benefit and the upper limit exceeds 0.9 b. Downgraded one level for serious imprecision because the 95% confidence interval includes

appreciable benefit and harm/appreciable harm c. Downgraded by 1 level due to lack of blinding and the fact that Control group intervention was

assisted ventilation in 1 study d. Unblinded studies. Outcome assessors unblinded e. Marked heterogeneity between the studies.



151

RECOMMENDATION 5

Extreme preterm neonates (gestation <28 weeks) should not be routinely intubated in the

delivery room; intubation and ventilation should be reserved only for those with severe

perinatal asphyxia requiring resuscitation.

Strong, Conditional recommendation based on moderate-quality of evidence for benefits

in two critical outcomes (BPD and death/BPD) and two important outcomes namely need

for mechanical ventilation and surfactant).

Comment: Applicable in settings with high antenatal steroid coverage and adequate

expertise in managing extreme preterm neonates

Practice Question 6: Among preterm neonates with RDS, what is the effect of CPAP alone when

compared to CPAP therapy with early rescue surfactant on mortality and severe morbidities?


• Evidence for this review is based on an existing systematic review by Isayama et al65

that included nine RCTs. No new eligible RCTs was identified in the updated search.

Infants in the early InSurE group were intubated, given surfactant, and extubated to

CPAP within 1 hour after intubation. Infants in the CPAP alone group continued to

receive NCPAP initially and, were rescued by intubation followed by mechanical

ventilation or InSurE based on pre-determined criteria. The role of Minimally Invasive

Surfactant Therapy (MIST) or Least Invasive Surfactant administration (LISA) is not

addressed in this review.

• The nine studies59,66-73 included in this systematic review were heterogenous with

respect to maternal or infant characteristics (e.g, antenatal corticosteroid coverage

(50% to 90%), gestational age (range from 25 to 35 weeks), timing of the intervention

(from shortly after birth to 72 hours after birth), and back-up measures for CPAP failure.

• There is moderate-quality evidence that early rescue surfactant by InSurE in preterm

infants with RDS reduces the need for mechanical ventilation (RR 0.71; 95% CI 0.54 to

0.92) (Table 7). A trend favouring InSurE therapy was noted with moderate-quality

evidence for BPD (RR 0.86; 95% CI0.71 to 1.03) and death/BPD (RR 0.88; 95% CI0.76 to

1.02), and low quality of evidence for air-leak (RR 0.50; 95% CI 0.24 to 1.07). There was

no difference in the mortality or severe intraventricular hemorrhage between the two

groups. The results were similar for the subgroup of neonates who were symptomatic

with RDS at the time of enrolment.

• Use of surfactant replacement therapy (SRT) in preterm neonates with RDS has shown

to reduce mortality and air-leaks in low-and-middle-income countries (LMIC)74.



152

However, there are concerns with the use of SRT with InSurE in LMIC where the expertise

in such techniques and monitoring facilities may be limited.

• Given the benefits of InSurE therapy, health professionals, parents, and policy makers

are going to give high value to this intervention provided skilled personnel and

adequate support system for monitoring is available along with the surfactant. This is

supported by the fact that surfactant has been included in the WHO Model List of

Essential Medicines for Children75 and use of SRT in symptomatic preterm infants with

RDS is one of the ‘conditional recommendation’ by WHO to improve preterm birth

outcome76.

• The most important concern with SRT is the cost in LMICs settings. However, the

incremental cost-effectiveness ratio is likely to be favourable if the quality- adjusted life

years for survivors of preterm births are taken into account77.



153

Table 7: Summary of findings for CPAP alone compared to CPAP plus early rescue

surfactant for Preterm neonates with RDS


Setting: Hospital

Intervention: CPAP alone

Comparison: CPAP plus early rescue surfactant


effects* (95% CI)

Relative

effect (95% CI)

№ of

participants (studies)

Certainty of the

evidence (GRADE)

Risk with

CPAP plus

early rescue

surfactant

Risk with

CPAP alone

Death or BPD 337 per 1,000 297 per 1,000

(256 to 344)

RR 0.88

(0.76 to 1.02)

1250

(6 RCTs)

⨁⨁⨁◯

MODERATE a

BPD

assessed with:

Oxygen

requirement at

36 weeks PMA

263 per 1,000 226 per 1,000

(187 to 271)

RR 0.86

(0.71 to 1.03)

1128 (6 RCTs)

⨁⨁⨁◯

MODERATE a

Death

assessed with:

In-hospital

mortality

90 per 1,000 85 per 1,000

(60 to 119)

RR 0.94

(0.67 to 1.32)

1394 (7 RCTs)

⨁⨁⨁◯

MODERATE b

Air-leak 56 per 1,000 28 per 1,000

(13 to 60)

RR 0.50

(0.24 to 1.07)

1547 (9 RCTs)

⨁◯◯◯

VERY LOW a,c,d

Severe Intra

ventricular

haemorrhage

44 per 1,000 34 per 1,000

(20 to 61)

RR 0.79

(0.45 to 1.39)

1325

(7 RCTs)

⨁⨁⨁◯

MODERATE a

Need for

mechanical

ventilation

361 per 1,000 257 per 1,000

(195 to 332)

RR 0.71

(0.54 to 0.92)

1549

(9 RCTs)

⨁⨁⨁◯

MODERATE e



95% CI).


Explanations

a. The 95% CIs of the relative risk estimates include an appreciable benefit and a null effect b. The 95% CIs of the relative risk estimates include an appreciable benefit and harm c. The risk of bias was serious because the sensitivity analyses using fixed-effect methods or

excluding studies with a high risk of bias changed the results. d. The inconsistency was serious for air leakage because the point estimate of RR in the

study by Sandri et al was very different from the other studies. There were no overlaps of 95%CIs between the studies by Rojas et al and Sandri et al. In addition, the sensitivity analyses using the fixed-effect model or excluding the study by Sandri et al changed the

significance of the results. e. The confidence intervals of the study by Dunn et al does not overlap with that of Verder et al 1999 and Verder et al 1999. Moreover, the I2 (I square) value of the heterogeneity in

Random effect Model is 73% with p value being 0.0003.



154

RECOMMENDATION 6

Early rescue surfactant should be administered along with CPAP in preterm neonates with

respiratory distress syndrome (RDS).

Strong recommendation based on the moderate-quality of evidence for a reduction in the

need for mechanical ventilation with favourable trend towards a reduction in critical

outcomes namely, BPD and, death or BPD.

Comment: Units offering surfactant therapy should have the equipment to offer mechanical

ventilation, blood gas analysis, chest x-ray and skilled newborn care for adequate

monitoring

What should be the mode of non-invasive respiratory support among preterm infants with

apnea of prematurity?

Practice Question 7a: Among neonates with apnea of prematurity, what is the effect of CPAP

therapy compared with no CPAP therapy on the need for ventilation, mortality, and severe

morbidities?


• We did not find any RCT that compared the effect of CPAP with oxygen therapy by

headbox or cannula in preterm neonates with apnea. A Cochrane systematic review78

included one RCT comparing CPAP therapy delivered using a face mask with

theophylline for apnea among preterm infants79. The quality of evidence was graded

as very low. The requirement of mechanical ventilation was higher in the CPAP group,

but there was no difference in in-hospital mortality. The use of mask CPAP was

associated with a higher treatment failure rate as measured by less than a 50%

reduction in apnea or use of an alternative treatment.

• Sequential application of CPAP therapy in preterm neonates has shown a reduction in

mixed and obstructive apnea episodes, but no effect on central apnea episodes80.

The beneficial effects are postulated to be due to splinting of upper airway and relief

of obstruction. Methylxanthine has been shown to reduce the incidence of apneic

episodes and use of mechanical ventilation. Coupled with better longer-term

outcomes and lower toxicity, caffeine is recommended as the drug of choice for the

treatment of apnoea81. CPAP therapy is generally administered in conjunction with

methyl-xanthines.

• Despite the paucity of evidence and based on recommendations from the American

Academy of Pediatrics82, the GDG members recommend CPAP therapy for the

management of apnea in preterm neonates considering the beneficial effects of

CPAP



155

Practice Question 7b: Among neonates with apnea of prematurity, what is the effect of

HFNC therapy and NIPPV therapy as compared with CPAP therapy on the need for ventilation,

mortality and severe morbidities among neonates with apnea of prematurity?

Summary of evidence-values and benefits

• Evidence for this review is based on a Cochrane review that compared NIPPV versus

CPAP for apnea of prematurity83 that included two studies Lin 1998 84 and Ryan 198985.

In the updated search, we identified 2 more studies, Gizzi 2014 86and Pantalitschka

200987. No studies were identified that compared CPAP versus HFNC for apnea of

prematurity.

• Ryan 1989 and Lin 1998 examined only short term (4 - 6 hours) effects of CPAP and

NIPPV in reducing apneic events. Outcomes like the need for intubation beyond the

trial period, in-hospital mortality, air leaks were not looked at. Gizzi et al86 and

Pantalitschka et al87 were crossover RCTs. Gizzi et al compared Flow-synchronized

NIPPV, NIPPV and CPAP all delivered via a ventilator. The authors concluded that flow-

SNIPPV is more effective than NIPPV and CPAP in reducing the incidence of

desaturations, bradycardias and central apnoea episodes.

• Pantalitschka et al compared 4 different modes; NIPPV via a conventional ventilator,

NIPPV and NCPAP via a variable flow device, and CPAP delivered via a constant flow

underwater bubble system. The authors concluded that a variable flow NCPAP device

may be more effective than a conventional ventilator in NIPPV mode. Both examined

short term outcomes (rates of apnea and desaturation) and had a small sample size.

The outcomes were reported in the median and interquartile ranges and the

distribution was skewed. Hence, they were not combined in a meta-analysis.

• There is very low-quality evidence from two older RCTs that non-synchronised NIPPV

decreases the apneic events (for 1000 infants treated with NIPPV, there was 1.19

apneic events lesser as compared to CPAP (95% CI 2.31- 0.07) as compared to nasal

CPAP- a benefit of questionable clinical relevance (Table 8 enlists the summary of

findings for the comparison between NIPPV and CPAP for apnea of prematurity). There

is no difference in the need for mechanical ventilation. The effects of synchronized

NIPPV and NCPAP delivered through variable flow devices in preterm infants with

apnea of prematurity needs further study. The role of Heated humidified nasal cannula

in the management of apnea of prematurity is not known

• Given the lack of clinically important benefits with NIPPV and the need for a ventilator

to deliver the same, health care providers and policymakers are unlikely to give high

value to NIPPV. The cost of variable flow device is higher than the bubble CPAP device.



156

Table 8: Summary of findings table for NIPPV compared to NCPAP for apnea of prematurity

Patient or population: apnea of prematurity

Setting: Hospital

Intervention: NIPPV

Comparison: NCPAP

Outcomes


effects* (95% CI) Relative

effect (95% CI)

№ of



Comments Risk with

NCPAP

Risk with

NIPPV

Failure of

therapy: intubation

28 per 1,000 8 per 1,000

(0 to 190)

RR 0.30

(0.01 to 6.84)

74 (2 RCTs)

⨁◯◯◯

VERY LOW a,b,c

Rate of apnea (events/hr)

assessed with: cardiopulmonary

monitoring

The mean

rate of apnea

(events/hr)

was 0

MD 0.1

lower

(0.53 lower

to 0.33 higher)

- 40

(1 RCT)

⨁◯◯◯

VERY LOW c,d,e

Change in rate of apnea

(events/hr)

The mean change in

rate of

apnea (events/hr)

was 0

MD 1.19

lower

(2.31 lower to 0.07 lower)

- 34

(1 RCT)

⨁◯◯◯

VERY LOW c,d,e



95% CI).

CI: Confidence interval; RR: Risk ratio; MD: Mean difference

Explanations

a. The interventions in both the studies were unblinded. However, the outcome assessors were blinded b. While both studies (n=74) reported this outcome, but only one infant

(randomised to NCPAP) needed intubation (Lin 1998). c. The 95% CI is crossing the line of equivalence and also the threshold for clinical decision d. Investigators unblinded to intervention, but blinded for outcome assessment e. Single RCT

RECOMMENDATION 7

a. CPAP therapy should be initiated in preterm neonates with apnea of

prematurity in conjunction with methylxanthines.

Strong recommendation; Low quality evidence. Strong recommendation

based on consensus among experts for beneficial effects of CPAP.

b. NIPPV (both synchronized and non-synchronized) may be used for frequent

and severe apneic episodes, if adequate expertise and equipment are

available.

(Weak Conditional recommendation based on very low quality evidence

for a reduction in apneic episodes and consensus among experts.)



157

What should be the mode of non-invasive respiratory support among preterm infants who

are extubated following a period of intubation and mechanical ventilation?

Practice Question 8a: Among preterm neonates being extubated following a period of

intubation and mechanical ventilation what is the effect of CPAP therapy compared with no

CPAP therapy on the need for additional ventilatory support, mortality, and severe morbidities?


• The recommendations are based on a Cochrane systematic review that addressed

the above question27 and included nine studies88-97. No new studies were identified in

the updated search.

• There is low-quality evidence that CPAP decreases the incidence of treatment failure

(RR 0.62; 95% CI 0.51 to 0.76) when compared to no CPAP in neonates who were

extubated from mechanical ventilation. There was no difference in the rates of

reintubation and ventilation or BPD in these infants. No information was available for

other critical outcomes including, mortality and air leaks (Table 9a).

Practice Question 8b: Among preterm neonates being extubated following a period of

intubation and mechanical ventilation, what is the effect of HFNC therapy compared to CPAP

therapy on the need for additional ventilatory support, mortality, and severe morbidities?


• We found a recent systematic review that examined the efficacy and safety of

respiratory support by HFNC with nasal CPAP therapy in preterm neonates following a

period of mechanical ventilation29. A total of 10 studies involving 1,201 preterm

neonates were included in the review 39,98-106.

• There is very low-quality evidence that high flow nasal cannula (HFNC) reduces the

incidence of air leaks (RR 0.29; 95% CI 0.11 to 0.76) when compared to CPAP. But there

is low to moderate-quality evidence that HFNC does not reduce the risk of mortality or

BPD, the other two critical outcomes. There is moderate-quality evidence that it

reduces the incidence of nasal trauma in these neonates (RR 0.35; 95% CI 0.27 to 0.46)

(Table 9b).

Practice Question 8c: Among preterm neonates being extubated following a period of intubation

and mechanical ventilation (P), what is the effect of NIPPV compared to CPAP therapy on the

need for additional ventilatory support, mortality, and severe morbidities?


• We identified one Cochrane review on NIPPV versus CPAP therapy following extubation in

preterm neonates (Lemyre 2017) 43. The review had identified 10 trials enrolling a total of 1431

neonates 46,107-115. On updating search, two more studies were found to be eligible for inclusion

in the review 116,117. Only five trials synchronised NIPPV delivery – three trials used the Infant Star

ventilator with Star Synch abdominal capsule while two used more recent ventilators.

• There is low to moderate-quality evidence that NIPPV reduces the risk of two critical outcomes

namely, in-hospital mortality (RR 0.70; 95% CI 0.49 to 0.99) and air leaks (RR 0.65; 95% CI 0.42 to



158

0.98) but does not reduce the risk of the other critical outcome – bronchopulmonary dysplasia.

There is moderate-quality evidence that NIPPV reduces the incidence of extubation failure

requiring re-intubation (RR 0.69; 95% CI 0.60 to 0.79) in the first week following extubation (Table

9c). Benefits were noted both with synchronized and non-synchronized NIPPV

Evidence to recommendations

• Even in the absence of high-quality evidence for or against CPAP therapy vis-à-vis no CPAP

therapy, health care providers are likely to value CPAP intervention high for treating preterm

neonates being extubated after a brief period of ventilation. Indeed, CPAP has long been

accepted as the ‘standard of care’ in these preterm neonates – no studies that compared

the effect of CPAP and no CPAP have been published since 2005; almost all the studies

included in the review were conducted in 1980s and 1990s.

• Health care providers are unlikely to give high value to the beneficial effects of HFNC on air

leaks because of the very low-quality evidence supporting it, no evidence for benefits on other

critical outcomes (BPD and mortality), uncertainty regarding the pressures delivered at

different flow rates, and issues in widespread availability in most settings in India.

• Given the possible beneficial effects observed with NIPPV, health care providers are likely to

value the intervention high for treating preterm neonates post-extubation. However, they are

still likely to prefer using CPAP in these neonates because of its ease of use and possibly lesser

need for intensive monitoring.

• Cost-minimisation analysis by Fleeman et al for National Health Services (NHS), UK estimated

the total cost of all consumables to be £67 per week for HFNC and £55 per week for NCPAP

(major difference was in the equipment cost – CPAP being roughly £3000 costlier than HFNC.118

The threshold analysis showed that if the lifespan of the machines reaches 6.8 years, then CPAP

becomes the less costly option.

• The scenario of HFNC vs. CPAP is likely to be different in India, where the indigenous and

bubble CPAP machines are available at a much lower cost than the standard HFNC

equipment. Also, being a low maintenance equipment, CPAP is likely to be used for more than

6.8 years in most units.

• No cost-effectiveness or cost-minimisation studies are available for the comparison of NIPPV

and CPAP. Unlike CPAP, NIPPV requires the use of a ventilator that is much costlier than typical

CPAP devices. Also, the availability of ventilators and trained personnel who can use them

optimally is a major issue in most neonatal units, particularly in level-2 units, across the country.



159

Table 9a: Summary of findings for the comparison CPAP versus no CPAP in preterm

neonates following extubation from mechanical ventilation

Patient or population: Preterm neonates following extubation from mechanical ventilation

Setting: Hospital (neonatal intensive care unit)

Intervention: CPAP

Comparison: no CPAP

Outcomes



effect (95% CI)

№ of


Certainty of the

evidence (GRADE) Risk with

no CPAP

Risk with

CPAP

Need for

mechanical

ventilation

in the post

extubation period

314 per 1,000

273 per

1,000

(217 to 339)

RR 0.87

(0.69 to

1.08)

726 (9 RCTs)

⨁⨁◯◯

LOW a,b

Failure of

treatment

assessed with:

Apneic episodes, respiratory acidosis

and increasing oxygen requirement

needing the use of additional ventilatory support

438 per 1,000

272 per

1,000

(223 to 333)

RR 0.62

(0.51 to 0.76)

726 (9 RCTs)

⨁⨁◯◯

LOW a,c

Bronchopulmonary

dysplasia (BPD)

assessed with: Oxygen

requirement at 28 days of life

424 per

1,000 424 per

1,000

(343 to 526)

RR 1.00

(0.81 to

1.24)

433

(5 RCTs)

⨁⨁◯◯

LOW a,c



95% CI).


Explanations

a. Neither intervention nor was outcome assessment blinded in all studies b. 95% CI around the pooled estimate of effect includes both 1) no effect and 2)

appreciable benefit or appreciable harm c. P for heterogeneity <0.05



160

Table 9b: Summary of findings for HFNC compared to CPAP in preterm neonates extubated

after a period of endotracheal intubation and mechanical ventilation

Patient or population: preterm neonates extubated after a period of endotracheal

intubation and mechanical ventilation

Setting: Hospital

Intervention: HFNC

Comparison: CPAP

Outcomes



(95% CI)

№ of participants

(studies)


(GRADE) Risk with

CPAP

Risk with

HFNC

In-hospital

mortality

(Mortality)

25 per 1,000

18 per 1,000

(8 to 41)

RR 0.71

(0.31 to 1.60)

1020 (7 RCTs)

⨁⨁⨁◯

MODERATE a,b

Pulmonary air

leaks

29 per

1,000 8 per 1,000

(3 to 22)

RR 0.29

(0.11 to

0.76)

1037

(7 RCTs)

⨁◯◯◯

VERY LOW c,d,e

Bronchopulmonary

dysplasia (BPD)

assessed with:

oxygen supplementation at 36 weeks

233 per 1,000

201 per 1,000

(163 to 247)

RR 0.86

(0.70 to

1.06)

1130 (8 RCTs)

⨁⨁◯◯

LOW b,c

Respiratory failure

requiring re-

intubation assessed with: within 3 days of

extubation

135 per

1,000 168 per 1,000

(110 to 256)

RR 1.24

(0.81 to

1.89)

478

(5 RCTs)

⨁◯◯◯

VERY LOW b,c,d

Nasal trauma

356 per 1,000

125 per 1,000

(96 to 164)

RR 0.35

(0.27 to 0.46)

860 (7 RCTs)

⨁⨁⨁◯

MODERATE c



95% CI).


Explanations

a. Blinding of outcome assessment not done in most studies, but outcome is objective b. 95% CI crosses the clinical decision threshold between recommending and not

recommending treatment c. Blinding of outcome assessment not done in most studies d. Allocation concealment details not provided in studies with >50% weightage in pooled

analysis e. 95% CI does not cross the clinical decision threshold, but the optimal information size is not met (too few events)



161

Table 9c: Summary of findings for NIPPV compared to CPAP in in preterm neonates being

extubated from mechanical ventilation

Patient or population: in preterm neonates being extubated from mechanical ventilation

Setting: Hospital

Intervention: NIPPV

Comparison: CPAP

Outcomes


effects* (95% CI) Relative effect (95%

CI)

№ of


Certainty of the


CPAP

Risk with

NIPPV

In-hospital

mortality

97 per 1,000 68 per

1,000

(48 to

96)

RR 0.70

(0.49 to

0.99)

1338 (7 RCTs)

⨁⨁⨁◯

MODERATE a,b

Pulmonary air

leaks

68 per 1,000 44 per

1,000

(29 to 67)

RR 0.65

(0.42 to 0.98)

1323 (7 RCTs)

⨁⨁◯◯

LOW b,c

Bronchopulmonary

dysplasia (BPD)

assessed with:

oxygen

supplementation

at 36 weeks

338 per 1,000 315 per

1,000

(271 to 369)

RR 0.93

(0.80 to 1.09)

1209 (7 RCTs)

⨁⨁◯◯

LOW c,d

Respiratory failure

post extubation

394 per 1,000 272 per

1,000

(236 to 311)

RR 0.69

(0.60 to 0.79)

1604 (12 RCTs)

⨁⨁⨁◯

MODERATE c,e

Necrotising

enterocolitis (NEC)

114 per 1,000 99 per

1,000

(73 to 136)

RR 0.87

(0.64 to 1.19)

1315

(7 RCTs)

⨁⨁◯◯

LOW c,d

Duration of

hospitalisation

(days)

The mean

duration of hospitalisation

(days) was 0

MD 2.7

higher

(0.01

higher to 5.4

higher)

- 244

(4 RCTs)

⨁⨁◯◯

LOW c,d



95% CI).


Explanations

a. Blinding of outcome assessment not done but outcome is objective

b. 95% CI does not cross the clinical decision threshold, but the optimal information size is not met c. Blinding of outcome assessment not done in most studies

d. 95% CI crosses the clinical decision threshold between recommending and not recommending treatment e. I2 >50% but 95% CI of all the studies overlap with each other



162

RECOMMENDATION 8

Preterm very low birth weight neonates being extubated after a brief period of ventilation

should be weaned off either to CPAP or NIPPV.

Strong recommendation based on low to moderate quality of evidence for benefits in

two critical outcomes with NIPPV and consensus among experts for beneficial effects

with CPAP.

Comment: If adequate expertise and equipment are available, NIPPV (both

synchronized and non-synchronised) might preferably be used, particularly in neonates

at risk of CPAP failure

Practice Question 9: Among term neonates with meconium aspiration syndrome (MAS),

what is the effect of CPAP when compared to oxygen therapy delivered by headbox,

facemask or nasal cannula on mortality and severe morbidities?


• The evidence for this review comes from a study by Pandita et al 119. There is low quality

evidence that CPAP decreases the need for mechanical ventilation (2 [3.0%] vs. 17

[25.0%]); odds ratio, 0.09; 95% CI, 0.02-0.43; P = .002) in the first 7 days of life compared

with no CPAP or oxygen therapy alone. There is very low-quality evidence that CPAP

therapy is associated with less need for surfactant (3 [4.5%] vs. 11 [16.2%]; odds ratio,

0.24; 95% CI, 0.05-0.87). There was no difference in mortality between the two groups

(Table 10)

• CPAP therapy can increase the risk of air-leak syndromes especially, in larger infants with

meconium aspiration syndrome where the lung pathology includes a combination of

hyperinflation and atelectasis. While no significant difference in air-leak was observed,

the event rate was very low and, only one RCT was included.

• One third to half of the neonates with MAS have severe disease that requires

mechanical ventilation. Health care providers are likely to value CPAP intervention high

for treating infants with MAS because of the benefits of decreased need for mechanical

ventilation and surfactant therapy. CPAP therapy is easy to administer and can be

provided by nurses also.

• No cost-effectiveness studies are available for the comparison CPAP versus no CPAP

therapy in MAS. However, CPAP therapy may reduce costs to the healthcare system,

especially in lower resourced settings, by decreasing the need for mechanical

ventilation and surfactant therapy.



163

Table 10: Summary of findings for CPAP compared to oxygen therapy (head box or nasal

prong etc) for late preterm and term infants with meconium aspiration syndrome

Patient or population: late preterm and term infants with meconium aspiration syndrome

Setting: Hospital

Intervention: CPAP

Comparison: oxygen therapy (head box or nasal prong etc)

Outcomes Anticipated absolute effects*

(95% CI)

Relative

effect (95% CI)

№ of


Certainty of

the evidence (GRADE)

Comments Risk with

oxygen

therapy

(head box

or nasal

prong etc)

Risk with CPAP

In-hospital

mortality (In-

hospital

mortality)

15 per 1,000 5 per 1,000

(0 to 110)

OR 0.33

(0.01 to 8.30)

135 (1 RCT)

⨁⨁◯◯

LOW a

Need for

mechanical

ventilation

250 per 1,000

29 per 1,000

(7 to 125)

OR 0.09

(0.02 to 0.43)

135 (1 RCT)

⨁⨁◯◯

LOW b,c

Air leak 0 per 1,000 0 per 1,000

(0 to 0)

OR 3.10

(0.12 to 77.20)

135 (1 RCT)

⨁◯◯◯

VERY LOW a,d

Need for

surfactant

therapy

162 per 1,000

44 per 1,000

(10 to 144)

OR 0.24

(0.05 to 0.87)

135 (1 RCT)

⨁⨁◯◯

LOW a,d



95% CI).

CI: Confidence interval; OR: Odds ratio

Explanations

a. CI for the Odds ratio is very wide. Optimal information size is less b. The need for mechanical ventilation was assessed within 7 days of enrolment.

Neonates in oxygen therapy were initially rescued with CPAP prior to intubation. c. Optimal information size is less d. Unblinded study. Outcome assessors unblinded

RECOMMENDATION 9

Continuous positive airway pressure may be employed as the primary mode of respiratory

support in late preterm and term neonates with meconium aspiration syndrome .

Weak recommendation based on low quality of evidence for benefit in two important

outcomes namely; the need for mechanical ventilation and surfactant therapy with CPAP

and consensus among experts for beneficial effects with CPAP.

Comment: Facilities offering CPAP support should have the expertise to monitor such

neonates for air-leak



164

What should be the characteristics of optimal CPAP device for use as determined by a

comparison of the efficacy and safety of commonly used CPAP devices?

Practice Questions 10-13: Among neonates requiring CPAP therapy, what is the optimal CPAP

device for use (as determined by comparison of the efficacy and safety of commonly used

CPAP devices)?

• Pressure generators: Bubble vs. ventilator vs. variable flow device

• Patient interfaces: nasal prongs vs. masks vs. nasopharyngeal prongs.

• Initial pressure: ≤5 cm vs. > 5 cm H2O

• Weaning: cycling vs. sudden cessation vs. others

Practice Question 10: Bubble CPAP vs. ventilator CPAP vs. variable flow device

Summary of evidence -values and benefits

• The evidence for this review is derived from a Cochrane systematic review by DePaoli

et al120, published in 2008 that included two studies121,122 comparing the effects of

different CPAP devices. On updating the search, we identified seven new studies.

o Ventilator versus Bubble CPAP- 3 studies123-125

o Infant flow driver versus ventilator CPAP- 4 studies121,122,126,127

o Infant flow driver versus bubble CPAP- 4 studies128-131

• There is low to very low-quality evidence that ventilator CPAP does not improve any of

the critical or important outcomes when compared to bubble CPAP in preterm

neonates (Table 11a).

• There is low quality evidence that infant flow driver (IFD) is associated with a lower risk

of extubation failure when compared to ventilator CPAP (RR 0.66; 95% CI 0.5 to 0.88),

but without any effect on hard outcomes such as mortality and BPD (Table 11b).

• There is also low-quality evidence that the use of IFD CPAP compared to ventilator

CPAP is associated with a lower incidence of nasal injury (RR 0.12; 95% CI 0.04 to 0.39).

When compared with bubble CPAP, there is moderate-quality evidence that IFD

reduces the severe local (nasal) injury and low-quality evidence that IFD reduces the

duration of CPAP in preterm neonates; no benefits were observed in other critical

outcomes (Table 11c).

• The benefit of reduction in nasal injury needs to be interpreted carefully as the

incidence of nasal injury depends on nasal interfaces, fixation technique, flow delivery

mechanisms, humidification and nursing competence.

• Health care providers and policy-makers in both high-income and low-and middle-

income countries are likely to prefer IFD over ventilator and bubble CPAP, given the

benefits observed in the risk of extubation failure and nasal injury. Nevertheless, the fact

that bubble CPAP can be assembled indigenously would appeal to both health care

providers as well as policy makers from resource-restricted settings.

• Both ventilators and IFD are quite expensive than bubble CPAP. It is difficult to justify

the higher costs of these devices in the absence of evidence for significant benefits

with either of them.



165

Table 11a: Summary of findings for Ventilator CPAP compared to bubble CPAP in preterm neonates

Patient or population: preterm neonates with respiratory distress

Setting: Hospital

Intervention: ventilator CPAP

Comparison: bubble CPAP

Outcomes



effect (95% CI)

№ of


Certainty of the

evidence (GRADE)

Comments

Risk with

bubble

CPAP

Risk with

ventilator CPAP

CPAP failure 133 per 1,000

200 per 1,000

(39 to 1,000)

RR 1.50

(0.29 to 7.73)

30 (1 RCT)

⨁◯◯◯

VERY LOW a,b,c

Bronchopulmonary

dysplasia assessed with: oxygen

requirement at 36 weeks PMA

500 per

1,000

375 per 1,000

(170 to 835) RR 0.75

(0.34 to 1.67)

32

(1 RCT)

⨁◯◯◯

VERY LOW b,c,d

Air leaks 32 per

1,000

48 per 1,000

(8 to 277)

RR 1.50

(0.26 to 8.59)

62

(2 RCTs)

⨁⨁◯◯

LOW c,e

Intraventricular hemorrhage

assessed with: Grade 3 or 4 IVH on USG brain

63 per

1,000

63 per 1,000

(4 to 915) RR 1.00

(0.07 to 14.64)

32

(1 RCT)

⨁◯◯◯

VERY LOW b,c,d

Nasal septal injury 267 per

1,000 29 per 1,000

(3 to 507)

RR 0.11

(0.01 to 1.90)

30

(1 RCT)

⨁◯◯◯

VERY LOW a,b,c

Duration of CPAP

The mean

duration of CPAP

was 0

MD 3.91 lower

(18.03 lower to 10.23 higher)

- 30

(1 RCT)

⨁◯◯◯

VERY LOW b,c,d

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the

comparison group and the relative effect of the intervention (and its 95% CI).


Explanations

a. Outcome assessors were blinded but investigators were not blinded b. Single study c. 95% CI includes 1) no effect and 2) appreciable benefit or appreciable harm

d. Outcome assessment was not blinded e. Outcome assessment was not blinded in the study with > 50% weightage



166

Table 11b: Summary of findings for Variable flow CPAP compared to ventilator CPAP for preterm

neonates with respiratory distress


Setting: Level 2 or 3 NICU

Intervention: variable flow CPAP

Comparison: ventilator CPAP


effects* (95% CI)

Relative effect

(95% CI)

№ of participants

(studies)


Risk with

ventilator

CPAP

Risk with

variable flow

CPAP

In hospital mortality New outcome assessed with: death

before discharge

71 per 1,000

102 per 1,000

(59 to 177)

RR 1.45

(0.84 to 2.50)

538 (3 RCTs)

⨁⨁⨁◯

MODERATE a,b

Extubation failure 395 per 1,000

261 per 1,000

(198 to 348)

RR 0.66

(0.50 to 0.88)

419 (3 RCTs)

⨁⨁◯◯

LOW c,d

Bronchopulmonary

dysplasia assessed with: Oxygen requirement at 36 weeks'

PMA

398 per

1,000 442 per 1,000

(366 to 533)

RR 1.11

(0.92 to

1.34)

538

(3 RCTs)

⨁⨁◯◯

LOW b,c

Air leaks 126 per 1,000

144 per 1,000

(96 to 216)

RR 1.14

(0.76 to 1.71)

538 (3 RCTs)

⨁⨁◯◯

LOW b,c

Severe Intraventricular

haemorrhage assessed with: Grade 3 and 4 IVH by USG brain

82 per

1,000 63 per 1,000

(33 to 121)

RR 0.77

(0.40 to 1.47)

438

(2 RCTs)

⨁⨁◯◯

LOW b,c

Severe nasal injury 178 per

1,000 21 per 1,000

(7 to 69)

RR 0.12

(0.04 to

0.39)

276

(1 RCT)

⨁⨁◯◯

LOW c,e

Duration of CPAP assessed with: Total days on CPAP therapy

The mean duration of CPAP

was 0

MD 0.85

higher

(0.85 higher to 2.54 higher)

- 538 (3 RCTs)

⨁⨁◯◯

LOW b,c




Explanations a. Intervention not blinded but objective outcome b. 95% CI around the pooled estimate includes 1) no effect and 2) no appreciable benefit or appreciable harm

c. Intervention as well as outcome assessment not blinded, subjective outcome d. Test for heterogeneity I2 > 60% e. Single study



167

Table 11 c: Summary of findings for Variable flow CPAP compared to bubble CPAP for preterm

neonates with respiratory distress


Setting: Level 2 or level 3 NICU

Intervention: variable flow CPAP

Comparison: bubble CPAP

Outcomes Anticipated absolute effects*

(95% CI)

Relative effect

(95% CI)

№ of participants

(studies)

Certainty of the


bubble

CPAP

Risk with variable

flow CPAP

In-hospital mortality (assessed with: Death before discharge)

Study population RR 1.02

(0.60 to 1.73)

435 (3 RCTs)

⨁⨁⨁◯

MODERATE a,b 101 per

1,000 103 per 1,000

(61 to 175)

Low

100 per 1,000

102 per 1,000

(60 to 173)

CPAP failure (as assessed with 7 days of

CPAP)


(0.56 to 1.38)

596 (4 RCTs)

⨁⨁◯◯

LOW b,c 164 per 1,000

145 per 1,000

(92 to 227)

Moderate

200 per

1,000 176 per 1,000

(112 to 276)

Bronchopulmonary

dysplasia (assessed as oxygen requirement at

36 weeks postmenstrual age)


(0.86 to

2.75)

310

(2 RCTs)

⨁⨁⨁◯

MODERATE a,b 155 per

1,000 239 per 1,000

(134 to 427)

Low

0 per 1,000 0 per 1,000

(0 to 0)

Moderate

300 per 1,000

462 per 1,000

(258 to 825)

Air leaks Study population RR 1.24

(0.35 to 4.40)

596 (4 RCTs)

⨁⨁◯◯

LOW b,c 13 per 1,000 17 per 1,000

(5 to 59)

Low

30 per 1,000 37 per 1,000

(10 to 132)

Intraventricular hemorrhage (as

assessed by grade 2 or more in USG)


(0.58 to 2.64)

456 (3 RCTs)

⨁⨁◯◯

LOW b,c 57 per 1,000 71 per 1,000

(33 to 151)

Low

50 per 1,000 62 per 1,000

(29 to 132)



168

RECOMMENDATION 10

Bubble CPAP, rather than ventilator CPAP or variable flow device, may preferably be used

in preterm neonates requiring continuous positive airway pressure for any indication.

Weak recommendation based on low to very low-quality evidence for no significant

difference in critical outcomes but the consensus among experts on cost and availability

considerations in low- and middle-income countries.

Question 11: nasal interface- masks vs. Prongs


• A systematic review by King, et al132, published in 2019 comparing the effect of nasal

masks versus short bi-nasal prongs and included seven RCTs 133-139. Four of these trials

enrolled only neonates requiring CPAP for the treatment of RDS while 2 trials enrolled

neonates requiring CPAP in the post-extubation setting134,139 and one trial included

neonates requiring CPAP in either setting138. All 7 trials used same pressure generator in

both groups. The make and brand of the nasal interface varied across trials.

• There is low-quality evidence that using nasal masks reduces the incidence of two

important outcomes – CPAP failure within 72 hours as well as the nasal injury of all

grades compared to short bi-nasal prongs. There is moderate- quality evidence that

nasal masks reduce severe nasal injury. However, both nasal masks and short bi-nasal

prongs are similar with regard to the other important outcomes such as

bronchopulmonary dysplasia, air leaks and duration of CPAP (Table 12).

Moderate to severe nasal injury (as assessed by well designed

scoring systems or uniform clinical criteria)


(0.12 to

0.69)

295 (2 RCTs)

⨁⨁⨁◯

MODERATE c 154 per

1,000 45 per 1,000

(18 to 106)

Duration of CPAP (hours)

The mean duration of

CPAP (hours) was

0 hours

MD 8.5 hours lower


- 331 (2 RCTs)

⨁⨁◯◯

LOW c,d




Explanations

a. Intervention not blinded but objective outcome b. 95% CI around the pooled estimate includes both 1) no effect and 2) appreciable benefit or appreciable harm. c. Intervention not blinded with subjective outcome d. I2 =80% with p<0.05 for heterogeneity



169

• With either interface, the preferences, skills and comfort of nurses should be taken into

consideration. The cost of nasal masks is almost similar to the cost of short bi-nasal

prongs. The cost of other disposables such as nasal tubing and CPAP circuits are also

similar to both the interfaces.

Table 12: Summary of findings for nasal masks compared to short binasal prongs for administering

CPAP

Patient or population: administering continuous positive airway pressure in preterm neonates with

RDS


Intervention: nasal masks

Comparison: short binasal prongs


effects* (95% CI)

Relative

effect (95% CI)

№ of


Certainty of the

evidence (GRADE)

Risk with

short

binasal

prongs

Risk with nasal

masks

In Hospital mortality

(Mortality )

119 per

1,000 108 per 1,000

(70 to 164)

RR 0.91

(0.59 to

1.38)

665

(6 RCTs)

⨁⨁⨁◯

MODERATE a,b

CPAP failure within 72 hours

(CPAP failure) assessed with: Need for intubation

266 per

1,000 192 per 1,000

(141 to 258)

RR 0.72

(0.53 to 0.97)

576

(5 RCTs)

⨁⨁◯◯

LOW b,c

Nasal injury (all grades) (Nasal injury)

assessed with: Standard nasal injury assessment tools

423 per 1,000

300 per 1,000

(249 to 359)

RR 0.71

(0.59 to 0.85)

665 (6 RCTs)

⨁⨁◯◯

LOW c,d

Nasal injury (severe grades) (Nasal injury) assessed with: Standard

nasal injury assessment tools

285 per 1,000

77 per 1,000

(46 to 131)

RR 0.27

(0.16 to

0.46)

396 (4 RCTs)

⨁⨁⨁◯

MODERATE c

Bronchopulmonary

dysplasia (BPD) assessed with: the need for respiratory support at 36

weeks postmenstrual age

110 per

1,000 52 per 1,000

(25 to 105)

RR 0.47

(0.23 to

0.95)

395

(4 RCTs)

⨁⨁◯◯

LOW b,c

Air leaks (Air leaks) 52 per

1,000 36 per 1,000

(14 to 94)

RR 0.70

(0.27 to

1.82)

387

(3 RCTs)

⨁⨁⨁◯

MODERATE a,b

Duration of CPAP

assessed with: days follow up: mean 56 days

The mean

duration of CPAP

was 0

days

MD 0.33 days

higher

(0.37 lower to 1.03 higher)

- 548

(5 RCTs)

⨁⨁◯◯

LOW b,c






170

Table 12: Summary of findings for nasal masks compared to short binasal prongs for administering

CPAP

Patient or population: administering continuous positive airway pressure in preterm neonates with

RDS


Intervention: nasal masks

Comparison: short binasal prongs


effects* (95% CI)

Relative effect

(95% CI)

№ of participants

(studies)


Risk with

short

binasal

prongs

Risk with nasal

masks

Explanations

a. Although all the studies were not blinded for intervention, we have not downgraded the quality of evidence considering that the outcome is a "hard outcome" b. The 95% CI crosses the threshold for change in clinical decision

c. None of the studies were blinded to intervention, few studies were not blinded for outcome assessment. Considering that the outcome is not a "hard" outcome, the quality of evidence has been downgraded in view of lack of blinding

d. 95% CI of studies not overlapping, heterogeneity indicated by I2 = 83% for the meta-analysis

RECOMMENDATION 11

CPAP should be delivered by either short binasal prongs or nasal masks in neonates.

Strong recommendation based on moderate-quality evidence of no difference in critical

outcomes such as bronchopulmonary dysplasia and air leaks and important ones like

duration of CPAP.

Comment: If available, nasal masks may be preferred, particularly in neonates at high risk

of nasal injury

Question 12: Initial CPAP pressures- Low vs. High

Summary of evidence-values and benefits

• We included trials for lower initial pressure (≤ 5cm H2O) versus higher initial pressure (> 5

cm H2O) for two comparisons- initial respiratory support after birth and following MV

and endotracheal extubation. We identified two randomized trials eligible for inclusion.

Murki et al140 studied two different CPAP levels for initial respiratory support after birth

and Buzella et al141 studied two different CPAP levels in the post-extubation setting.

• For initial respiratory support: There is low-quality evidence from a single trial140 that

initiation of CPAP at higher pressure (7 cm of water) does not translate into clinically



171

relevant outcomes like the need for mechanical ventilation and surfactant, in-hospital

mortality and BPD when compared initiation at 5 cm water or lower in preterm

neonates with RDS. There was no increased risk of air leak in this study (Table 13a). In a

systematic review10 that compared prophylactic CPAP versus intubation in the delivery

room for extremely preterm neonates, a subgroup analysis was done for the outcome

of pneumothorax based on the level of initiation of CPAP. Two studies59,61 initiated CPAP

at 5 cmH₂O, and one60 at 8 cm H2O. The risk of pneumothorax was noted to be higher

with 8 cm H2O (RR 3.07, 95% CI 1.47 to 6.40, one study, 610 infants). Hence clinicians

need to execute caution when using higher initial pressures.

• Post-extubation setting: There is very low-quality evidence from a single trial141 that

initiation of CPAP at higher pressure (7-9 cm) post-extubation decreases the rates of

extubation failure and need for re-intubation; especially among those with birth weight

500-750 grams compared to the low pressure of 4-6 cm water. The increased risk of air

leak later during the study period among high CPAP pressure group needs to be

investigated (Table 13b).

• Given the lack of benefit in clinical outcome and the concerns with pneumothorax,

health care providers are likely to consider initiating CPAP with pressures of 5 cm H2O

for neonates with RDS. In the post-extubation setting, health care providers may

consider initiating CPAP at higher pressures among extremely preterm neonates. The

cost of CPAP, whether initiated at low or higher pressure, should remain the same.

Table 13a: Summary of findings for high compared to low CPAP pressure for preterm infants

who require CPAP for RDS

Patient or population: preterm infants who require CPAP for RDS


Intervention: High

Comparison: low CPAP pressure


effects* (95% CI)

Relative effect (95% CI)

№ of participants

(studies)


(GRADE) Risk with

low CPAP

pressure

Risk with High

Need for mechanical

ventilation within 7 days of enrolment

217 per 1,000

215 per 1,000

(122 to 385)

RR 0.99

(0.56 to 1.77)

271 (1 RCT)

⨁⨁◯◯

LOW a,b,c


101 per 1,000

91 per 1,000

(71 to 142)

RR 0.9

(0.7 to 1.4)

271 (1 RCT)

⨁⨁⨁◯

MODERATE c

Pneumothorax 36 per 1,000 25 per 1,000

(14 to 40)

RR 0.7

(0.4 to 1.1)

271 (1 RCT)

⨁⨁◯◯

LOW a,c

Surfactant 493 per

1,000 591 per 1,000

(394 to 986)

RR 1.2

(0.8 to 2.0)

271

(1 RCT)

⨁⨁◯◯

LOW a,c

BPD assessed with: Oxygen

dependency at 36 weeks PMA

36 per 1,000 40 per 1,000

(22 to 80)

RR 1.1

(0.6 to 2.2)

271 (1 RCT)

⨁⨁◯◯

LOW a,c






172

Table 13a: Summary of findings for high compared to low CPAP pressure for preterm infants

who require CPAP for RDS

Patient or population: preterm infants who require CPAP for RDS


Intervention: High



effects* (95% CI)

Relative effect

(95% CI)

№ of


Certainty of


Risk with

low CPAP

pressure

Risk with High

Explanations

a. Unblinded study.

b. The criteria for mechanical ventilation were many and some are subjective c. 95% confidence limits include both benefit and harm GRADE Working Group grades of evidence

Table 13b: Summary of findings for high compared to low CPAP pressure for post extubation

setting among preterm neonates

High compared to low CPAP pressure for post extubation setting among preterm neonates

Patient or population: post extubation setting among preterm neonates


Intervention: High



effects* (95% CI)

Relative

effect (95% CI)

№ of


Certainty of


Comments

Risk with

low CPAP

pressure

Risk with High

Extubation failure

assessed with: Pre-specified criteria clinical and

laboratory criteria

426 per

1,000 238 per 1,000

(128 to 438)

RR 0.56

(0.30 to 1.03)

93

(1 RCT)

⨁◯◯◯

VERY LOW a,b

Extubation failure

(500-750 g strata)

700 per

1,000 266 per 1,000

(126 to 567)

RR 0.38

(0.18 to 0.81)

42

(1 RCT)

⨁◯◯◯

VERY LOW a,c

Need for re-

intubation

511 per

1,000 301 per 1,000

(179 to 511)

RR 0.59

(0.35 to 1.00)

93

(1 RCT)

⨁◯◯◯

VERY LOW b,d

Need for re-

intubation (500-750 g strata)

550 per

1,000 182 per 1,000

(66 to 479)

RR 0.33

(0.12 to 0.87)

42

(1 RCT)

⨁◯◯◯

VERY LOW c,d

BPD

assessed with: Oxygen

requirement at 36 weeks PMA

340 per

1,000 388 per 1,000

(228 to 667)

RR 1.14

(0.67 to 1.96)

93

(1 RCT)

⨁⨁◯◯

LOW b,e






173

Table 13b: Summary of findings for high compared to low CPAP pressure for post extubation

setting among preterm neonates

High compared to low CPAP pressure for post extubation setting among preterm neonates

Patient or population: post extubation setting among preterm neonates


Intervention: High



effects* (95% CI)

Relative effect

(95% CI)

№ of participants

(studies)

Certainty of the

evidence

(GRADE) Comments

Risk with

low CPAP

pressure

Risk with High

Explanations

a. Unblinded study and extubation failure included subjective criteria also

b. Downgraded one level due to serious imprecision because the 95% confidence interval includes both appreciable benefit and harm/appreciable harm c. Downgraded one level for serious imprecision because the 95% confidence interval is

wide d. Unblinded study and the decision to intubation was based on clinician's decision e. Unblinded study

RECOMMENDATION 12

a. Preterm neonates with respiratory distress syndrome (RDS) may be initiated on

CPAP pressure of 5 cm H2O.

Weak recommendation based on low quality of evidence for lack of benefit and

concerns with risk of air leaks at higher pressure.

b. Preterm very low birth weight neonates being extubated to CPAP, after a brief

period of ventilation may be initiated on pressure of 6 cm H2O.

Weak recommendation based on very low quality of evidence for benefit of

reducing extubation failure and need for re-intubation.



174

Practice Question 13: Among neonates requiring CPAP therapy, what is the optimal CPAP

weaning strategy on mortality and severe morbidities?


• Weaning of CPAP may involve the following possible strategies; stopping CPAP

completely and remaining off CPAP, gradually decreasing CPAP pressures before

stopping CPAP, cycling of CPAP: alternating between on and off periods, stopping

CPAP and starting blended oxygen via a nasal cannula or HFNC or a combination of

above strategies. We identified 13 RCTs105,142-152 that examined the various CPAP

weaning strategies, but for the comparison of sudden CPAP cessation vs. cycling, we

found only Rastogi 2013 147and Todd 2012151 suitable for meta-analysis.

• There is low-quality evidence from two studies that sudden cessation of CPAP results in

lesser BPD (RR 0.20; 95% CI 0.08 to 0.50) and other important outcomes; time to wean

CPAP, lesser total duration on CPAP, oxygen requirement, duration of hospitalisation

and earlier discontinuation of CPAP in corrected age (Table 14). Both the studies had

a protocolized method of weaning CPAP after neonates are deemed stable on

minimal settings and specified failure criteria when weaning was deferred. More

evidence is required on other strategies of weaning CPAP (weaning pressures on CPAP,

change to HHHFNC etc).

• Given the benefits of sudden cessation of CPAP, health care providers are likely to

choose this method in preference to CPAP cycling. The sudden CPAP cessation may

in-fact lead to lesser cost of care as evidenced by lesser duration on CPAP, earlier

discontinuation of CPAP, oxygen duration, days of hospitalisation and lesser BPD.

Table 14: Summary of findings for sudden cessation compared to CPAP cycling for weaning CPAP

treatment in preterm neonates

Patient or population: weaning CPAP treatment in preterm neonates

Setting: Hospital

Intervention: Sudden cessation

Comparison: CPAP cycling

Outcomes Anticipated absolute effects* (95% CI) Relative

effect (95% CI)

№ of


Certainty of the

evidence (GRADE)

Risk with CPAP

cycling

Risk with Sudden

cessation

Time to wean CPAP

The mean time to wean CPAP

was 0

MD 5.5 lower


- 125 (1 RCT)

⨁⨁◯◯

LOW a,b

Corrected age at CPAP cessation

The mean corrected age

at CPAP

cessation was 0

MD 2.2 lower

(2.39 lower to 1.85

lower)

- 181 (2 RCTs)

⨁⨁◯◯

LOW a,c

Duration of hospital stay


hospital stay

was 0

MD 15.29 lower


- 181 (2 RCTs)

⨁⨁◯◯

LOW a,c

Total days on CPAP

The mean total days on CPAP

was 0

MD 14.2 lower


- 125 (1 RCT)

⨁⨁◯◯

LOW a,b



175

Table 14: Summary of findings for sudden cessation compared to CPAP cycling for weaning CPAP

treatment in preterm neonates

Patient or population: weaning CPAP treatment in preterm neonates

Setting: Hospital

Intervention: Sudden cessation

Comparison: CPAP cycling

Outcomes Anticipated absolute effects* (95% CI) Relative

effect (95% CI)

№ of


Certainty of the

evidence (GRADE)

Risk with CPAP

cycling

Risk with Sudden

cessation

Duration of oxygen therapy


oxygen

therapy was 0

MD 21.7 lower


- 125 (1 RCT)

⨁⨁◯◯

LOW a,b

BPD at 36 weeks PMA

420 per 1,000 127 per 1,000

(55 to 266)

OR 0.20

(0.08 to 0.50)

125 (1 RCT)

⨁⨁◯◯

LOW a,b

Successful wean at first attempt

429 per 1,000 465 per 1,000

(231 to 713)

OR 1.16

(0.40 to 3.32)

56 (1 RCT)

⨁⨁◯◯

LOW a,b

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the

comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; MD: Mean difference; OR: Odds ratio

Explanations

a. Investigators & outcome assessors unblinded b. Single RCT c. Results not consistent across studies

RECOMMENDATION 13

Preterm very low birth weight neonates being weaned off from CPAP may preferably be

weaned off by sudden discontinuation of CPAP rather than CPAP cycling.

Weak recommendation based on low quality of evidence for benefits in one critical

outcome and five important outcomes.



176

Question 14: Among preterm neonates with RDS, which group of neonates are more likely to

fail CPAP?

Salient findings

• CPAP success is defined as being successfully treated with CPAP for at least 72 hours

of life and CPAP failure as the need for intubation and mechanical ventilation within

the first 72 hours153,154 or in the first 7 days of life.

• We identified 18 studies for this narrative review 125,127,153-166. The studies varied in design,

population (a majority enrolled very low birth weight neonates), disease condition

(most enrolled neonates with RDS and others included respiratory distress due to other

etiologies also), the type of CPAP generator, nasal interface, maximal pressure settings

and treatment with surfactant.

● CPAP failure criteria also varied; but included a combination of high FiO2 requirement,

inadequate ventilation as evidenced by blood gas analysis, frequent or severe

episodes of apnea requiring management or worsening respiratory distress.

● The overall CPAP failure rate varied from 20-40% in studies from LMIC settings. CPAP

failure rates are higher (50% or more) among extremely preterm neonates < 28 weeks

gestation and those with birth weights <750 g.

• Risk factors for CPAP failure include:

o Antenatal: lack of or incomplete coverage of antenatal steroids

o Neonatal: Low gestational age (<28 weeks), birth weight (<1000 g), Need for

resuscitation at birth

o The severity of RDS as evidenced by higher respiratory distress scores, chest X- -

ray findings, higher level of oxygen requirement, blood gas parameters

indicative of poor ventilation, oxygenation indices and clinical estimation of low

surfactant pool size.

o Presence of co-morbidities like air leak, hemodynamically significant patent

ductus arteriosus (PDA), sepsis, intractable apnea, severe grades of

intraventricular hemorrhage and necrotizing enterocolitis161.

● Predictive scores for CPAP failure: Pillai et al devised a composite score to predict CPAP

failure156 based on gestational age at birth, preterm premature rupture of membranes

(PPROM) and receipt of antenatal steroids (ANS). Final weighted score was given as- 20

(gestation <28 weeks) + 18 (PPROM) + 18 (no ANSs) + 11 (product of CPAP pressure and

FiO2 at initiation >1.28). Each variable was assigned a value of ‘1’ if present and ‘0’ if

absent. The final score was ≥18 predicted CPAP failure with 75% sensitivity and 70%

specificity; the positive and negative likelihood ratios were 2.46 and 0.36, respectively.

● Increasing CPAP success rates: Administration of early rescue surfactant by InSurE

technique (moderate-quality evidence for a reduction in the need of mechanical

ventilation), quality of nursing and supportive care167, experience of the unit in using

CPAP167, ongoing Quality Improvement Project for improving CPAP efficacy and safety168.



177

Abbreviations

AOP Apnea of prematurity BPD Bronchopulmonary

dysplasia

CI Confidence interval

CLD Chronic lung disease CPAP Continuous positive

airway pressure

ELBW Extremely low birth

weight

ES Effect size FiO2 Fractional inspired oxygen

concentration

GDG Guideline development

group

GRADE Grading of

Recommendations, Assessment,

Development and Evaluation

HFNC/HHFNC Heated,

humidified, high-flow nasal

cannula

IFD Infant flow driver

LBW Low birth weight MAS Meconium aspiration

syndrome

MD Mean difference

NIMV Non-invasive

mechanical ventilation

NIPPV Non-invasive positive

pressure ventilation

OR Odds ratio

PICO Population, intervention,

comparison, outcome

RCT Randomized controlled trial RDS Respiratory distress

syndrome

ROP Retinopathy of prematurity RR Relative risk SD Standard deviation

SGA Small-for-gestational age VLBW Very low birth weight WMD Weighted mean

difference



178

References

1. Sweet DG, Carnielli V, Greisen G, et al. European Consensus Guidelines on the Management of

Respiratory Distress Syndrome - 2019 Update. Neonatology. 2019;115(4):432-450. 2. Cummings JJ, Polin RA. Committee on, Fetus Newborn, American Academy of Pediatrics.

Noninvasive Respiratory Support. Pediatrics. 2016;137(1).

3. Committee on F, Newborn, American Academy of P. Respiratory support in preterm infants at birth. Pediatrics. 2014;133(1):171-174.

4. The National Neonatology Forum of India. Evidence based Clinical Practical guidelines.

Available at http://aimaonline.org/iap-neochap-2013/uploads/acd-corner/nnf_guidelines-2011.pdf. Accessed on 25th August 2019. 2010.

5. Kumar A, Bhat BV. Epidemiology of respiratory distress of newborns. Indian journal of pediatrics. 1996;63(1):93-98.

6. Muhe LM, McClure EM, Nigussie AK, et al. Major causes of death in preterm infants in selected

hospitals in Ethiopia (SIP): a prospective, cross-sectional, observational study. The Lancet Global health. 2019;7(8):e1130-e1138.

7. Report of National Neonatal Perinatal Database (NNPD) 2002-2003. Available from:

http://www.newbornwhocc. org/nnpo.html. Accesssed November, 1, 2019. 8. Laughon MM, Langer JC, Bose CL, et al. Prediction of bronchopulmonary dysplasia by

postnatal age in extremely premature infants. American journal of respiratory and critical care

medicine. 2011;183(12):1715-1722. 9. Bhunwal S, Mukhopadhyay K, Bhattacharya S, Dey P, Dhaliwal LK. Bronchopulmonary Dysplasia

in Preterm Neonates in a Level III Neonatal Unit in India. Indian Pediatr. 2018;55(3):211-215.

10. Subramaniam P, Ho JJ, Davis PG. Prophylactic nasal continuous positive airway pressure for preventing morbidity and mortality in very preterm infants. Cochrane Database Syst Rev.

2016(6):CD001243. 11. Ho JJ, Subramaniam P, Davis PG. Continuous distending pressure for respiratory distress in

preterm infants. Cochrane Database Syst Rev. 2015(7):CD002271.

12. Belenky DA, Orr RJ, Woodrum DE, Hodson WA. Is continuous transpulmonary pressure better than conventional respiratory management of hyaline membrane disease? A controlled study. Pediatrics. 1976;58(6):800-808.

13. Buckmaster AG, Arnolda G, Wright IM, Foster JP, Henderson-Smart DJ. Continuous positive airway pressure therapy for infants with respiratory distress in non tertiary care centers: a randomized, controlled trial. Pediatrics. 2007;120(3):509-518.

14. Durbin GM, Hunter NJ, McIntosh N, Reynolds EO, Wimberley PD. Controlled trial of continuous inflating pressure for hyaline membrane disease. Arch Dis Child. 1976;51(3):163-169.

15. Fanaroff AA, Cha CC, Sosa R, Crumrine RS, Klaus MH. Controlled trial of continuous negative

external pressure in the treatment of severe respiratory distress syndrome. J Pediatr. 1973;82(6):921-928.

16. Rhodes PG, Hall RT. Continuous positive airway pressure delivered by face mask in infants with the idiopathic respiratory distress syndrome: a controlled study. Pediatrics. 1973;52(1):1-5.

17. Samuels MP, Raine J, Wright T, et al. Continuous negative extrathoracic pressure in neonatal

respiratory failure. Pediatrics. 1996;98(6 Pt 1):1154-1160. 18. Koyamaibole L, Kado J, Qovu JD, Colquhoun S, Duke T. An evaluation of bubble-CPAP in a

neonatal unit in a developing country: effective respiratory support that can be applied by

nurses. Journal of tropical pediatrics. 2006;52(4):249-253. 19. Ho JJ, Henderson-Smart DJ, Davis PG. Early versus delayed initiation of continuous distending

pressure for respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev.

2002(2):CD002975. 20. Rowe JC GR, Hinkes P, Prueitt J, Murphy J, Woodrum DZ, Hodson WA. Time of initiation of CPAP

in HMD (Abstract ). Pediatric Research 1978;12:533.

21. Mockrin LD BE. Early versus delayed initiation of continuous negative pressure in infants with hyaline membrane disease. Journal of Pediatrics 1975;87:596–600.

22. Krouskop RW, Brown EG, Sweet AY. The early use of continuous positive airway pressure in the

treatment of idiopathic respiratory distress syndrome. J Pediatr. 1975;87(2):263-267. 23. Hegyi T, Hiatt IM. The effect of continuous positive airway pressure on the course of respiratory

distress syndrome: the benefits on early initiation. Critical care medicine. 1981;9(1):38-41. 24. Gerard P, Fox WW, Outerbridge EW, Beaudry PH. Early versus late introduction of continuous

negative pressure in the management of the idiopathic respiratory distress syndrome. J Pediatr.

1975;87(4):591-595. 25. Allen LP, Reynolds ER, Rivers RP, Le Souef PM, Wimberley PD. Controlled trial of continuous

positive airway pressure given by face mask for hyaline membrane disease. Arch Dis Child.

1977;52(5):373-378.

http://aimaonline.org/iap-neochap-2013/uploads/acd-corner/nnf_guidelines-2011.pdf

http://aimaonline.org/iap-neochap-2013/uploads/acd-corner/nnf_guidelines-2011.pdf

http://www.newbornwhocc/



179

26. Badiee Z, Naseri F, Sadeghnia A. Early versus delayed initiation of nasal continuous positive airway pressure for treatment of respiratory distress syndrome in premature newborns: A

randomized clinical trial. Adv Biomed Res. 2013;2:4. 27. Davis PG, Henderson-Smart DJ. Nasal continuous positive airways pressure immediately after

extubation for preventing morbidity in preterm infants. Cochrane Database Syst Rev.

2000(3):CD000143. 28. Hong H, Li XX, Li J, Zhang ZQ. High-flow nasal cannula versus nasal continuous positive airway

pressure for respiratory support in preterm infants: a meta-analysis of randomized controlled

trials. J Matern Fetal Neonatal Med. 2019:1-8. 29. Fleeman N, Dundar Y, Shah PS, Shaw BN. Heated Humidified High-Flow Nasal Cannula for

Preterm Infants: An Updated Systematic Review and Meta-analysis. Int J Technol Assess Health Care. 2019;35(4):298-306.

30. Glackin SJ, O'Sullivan A, George S, Semberova J, Miletin J. High flow nasal cannula versus

NCPAP, duration to full oral feeds in preterm infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2017;102(4):F329-F332.

31. Iranpour R, Sadeghnia A, Hesaraki M. High-Flow Nasal Cannula Versus Nasal Continuous

Positive Airway Pressure in the Management of Respiratory Distress Syndrome. Archives of Disease in Childhood. 2012;97(Suppl 2):A115-A116.

32. Klingenberg C, Pettersen M, Hansen EA, et al. Patient comfort during treatment with heated

humidified high flow nasal cannulae versus nasal continuous positive airway pressure: a randomised cross-over trial. Arch Dis Child Fetal Neonatal Ed. 2014;99(2):F134-137.

33. Lavizzari A, Colnaghi M, Ciuffini F, et al. Heated, Humidified High-Flow Nasal Cannula vs Nasal

Continuous Positive Airway Pressure for Respiratory Distress Syndrome of Prematurity: A Randomized Clinical Noninferiority Trial. JAMA Pediatr. 2016.

34. Manley BJ, Arnolda GRB, Wright IMR, et al. Nasal High-Flow Therapy for Newborn Infants in Special Care Nurseries. N Engl J Med. 2019;380(21):2031-2040.

35. Murki S, Singh J, Khant C, et al. High-Flow Nasal Cannula versus Nasal Continuous Positive

Airway Pressure for Primary Respiratory Support in Preterm Infants with Respiratory Distress: A Randomized Controlled Trial. Neonatology. 2018;113(3):235-241.

36. Nair G KP. Comparison of the effects of vapotherm and nasal CPAP in respiratory distress in

preterm infants. Pediatr Acad Soc 57, 2054. 2005. 37. Roberts CT, Owen LS, Manley BJ, et al. Nasal High-Flow Therapy for Primary Respiratory Support

in Preterm Infants. N Engl J Med. 2016;375(12):1142-1151.

38. Shin J, Park K, Lee EH, Choi BM. Humidified High Flow Nasal Cannula versus Nasal Continuous Positive Airway Pressure as an Initial Respiratory Support in Preterm Infants with Respiratory Distress: a Randomized, Controlled Non-Inferiority Trial. J Korean Med Sci. 2017;32(4):650-655.

39. Yoder BA, Stoddard RA, Li M, King J, Dirnberger DR, Abbasi S. Heated, humidified high-flow nasal cannula versus nasal CPAP for respiratory support in neonates. Pediatrics.

2013;131(5):e1482-1490. 40. Roberts CT, Manley BJ, Dawson JA, Davis PG. Nursing perceptions of high-flow nasal cannulae

treatment for very preterm infants. Journal of paediatrics and child health. 2014;50(10):806-810.

41. Osman M, Elsharkawy A, Abdel-Hady H. Assessment of pain during application of nasal-continuous positive airway pressure and heated, humidified high-flow nasal cannulae in preterm infants. J Perinatol. 2015;35(4):263-267.

42. Huang L, Roberts CT, Manley BJ, Owen LS, Davis PG, Dalziel KM. Cost-Effectiveness Analysis of Nasal Continuous Positive Airway Pressure Versus Nasal High Flow Therapy as Primary Support for Infants Born Preterm. J Pediatr. 2018;196:58-64 e52.

43. Lemyre B, Laughon M, Bose C, Davis PG. Early nasal intermittent positive pressure ventilation (NIPPV) versus early nasal continuous positive airway pressure (NCPAP) for preterm infants. Cochrane Database Syst Rev. 2016;12:CD005384.

44. Armanian AM, Badiee Z, Heidari G, Feizi A, Salehimehr N. Initial Treatment of Respiratory Distress Syndrome with Nasal Intermittent Mandatory Ventilation versus Nasal Continuous Positive Airway Pressure: A Randomized Controlled Trial. Int J Prev Med. 2014;5(12):1543-1551.

45. Bisceglia M, Belcastro A, Poerio V, et al. A comparison of nasal intermittent versus continuous positive pressure delivery for the treatment of moderate respiratory syndrome in preterm

infants. Minerva Pediatr. 2007;59(2):91-95. 46. Kirpalani H, Millar D, Lemyre B, et al. A trial comparing noninvasive ventilation strategies in

preterm infants. N Engl J Med. 2013;369(7):611-620.

47. Kugelman A, Feferkorn I, Riskin A, Chistyakov I, Kaufman B, Bader D. Nasal intermittent mandatory ventilation versus nasal continuous positive airway pressure for respiratory distress syndrome: a randomized, controlled, prospective study. J Pediatr. 2007;150(5):521-526, 526

e521. 48. Lista G, Castoldi F, Fontana P, et al. Nasal continuous positive airway pressure (CPAP) versus bi-

level nasal CPAP in preterm babies with respiratory distress syndrome: a randomised control

trial. Arch Dis Child Fetal Neonatal Ed. 2010;95(2):F85-89.



180

49. Meneses J, Bhandari V, Alves JG, Herrmann D. Noninvasive ventilation for respiratory distress syndrome: a randomized controlled trial. Pediatrics. 2011;127(2):300-307.

50. Ramanathan R, Sekar KC, Rasmussen M, Bhatia J, Soll RF. Nasal intermittent positive pressure ventilation after surfactant treatment for respiratory distress syndrome in preterm infants <30 weeks' gestation: a randomized, controlled trial. J Perinatol. 2012;32(5):336-343.

51. Sai Sunil Kishore M, Dutta S, Kumar P. Early nasal intermittent positive pressure ventilation versus continuous positive airway pressure for respiratory distress syndrome. Acta Paediatr. 2009;98(9):1412-1415.

52. Salama GS AF, Al-Rabadi AJ, Alquran ML, Shakkoury AG. Nasal-IMV versus nasal-CPAP as an initial mode of respiratory support for premature infants with RDS: a prospective randomized

clinical trial. Rawal Journal Medical 2015;40(2):197–202. 2015. 53. Wood F, Gupta S, Tin W, Sinha S. Randomised Controlled Trial of Synchronised Intermittent

Positive Airway Pressure (SiPAP™) Versus Continuous Positive Airway Pressure (CPAP) as a

Primary Mode of Respiratory Support in Preterm Infants with Respiratory Distress Syndrome. Archives of Disease in Childhood. 2013;98(Suppl 1):A78-A78.

54. Aguiar T MI, Voutsen O, Silva P, Nona J. Nasal Bilevel Versus Continuous Positive Airway Pressure

in Preterm Infants: A Randomized Controlled Trial. J Clin Trials 5: 221. doi:10.4172/2167-0870.1000221. 2015.

55. Esmaeilnia T, Nayeri F, Taheritafti R, Shariat M, Moghimpour-Bijani F. Comparison of

Complications and Efficacy of NIPPV and Nasal CPAP in Preterm Infants With RDS. Iran J Pediatr. 2016;26(2):e2352.

56. Oncel MY, Arayici S, Uras N, et al. Nasal continuous positive airway pressure versus nasal

intermittent positive-pressure ventilation within the minimally invasive surfactant therapy approach in preterm infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed.

2016;101(4):F323-328. 57. Gharehbaghi MM, Hosseini MB, Eivazi G, Yasrebinia S. Comparing the Efficacy of Nasal

Continuous Positive Airway Pressure and Nasal Intermittent Positive Pressure Ventilation in Early

Management of Respiratory Distress Syndrome in Preterm Infants. Oman Med J. 2019;34(2):99-104.

58. Silveira CS, Leonardi KM, Melo AP, Zaia JE, Brunherotti MA. Response of Preterm Infants to 2

Noninvasive Ventilatory Support Systems: Nasal CPAP and Nasal Intermittent Positive-Pressure Ventilation. Respir Care. 2015;60(12):1772-1776.

59. Dunn MS, Kaempf J, de Klerk A, et al. Randomized trial comparing 3 approaches to the initial

respiratory management of preterm neonates. Pediatrics. 2011;128(5):e1069-1076. 60. Morley CJ, Davis PG, Doyle LW, et al. Nasal CPAP or intubation at birth for very preterm infants.

N Engl J Med. 2008;358(7):700-708.

61. Network SSGotEKSNNR, Finer NN, Carlo WA, et al. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010;362(21):1970-1979.

62. Vaucher YE, Peralta-Carcelen M, Finer NN, et al. Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med. 2012;367(26):2495-2504.

63. 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:S21-28. 64. Carns J, Kawaza K, Liaghati-Mobarhan S, et al. Neonatal CPAP for Respiratory Distress Across

Malawi and Mortality. Pediatrics. 2019;144(4).

65. Isayama T, Chai-Adisaksopha C, McDonald SD. Noninvasive Ventilation With vs Without Early Surfactant to Prevent Chronic Lung Disease in Preterm Infants: A Systematic Review and Meta-analysis. JAMA Pediatr. 2015;169(8):731-739.

66. Dilmen U, Ozdemir R, Tatar Aksoy H, et al. Early regular versus late selective poractant treatment in preterm infants born between 25 and 30 gestational weeks: a prospective randomized multicenter study. J Matern Fetal Neonatal Med. 2014;27(4):411-415.

67. Imani M DR, Khalili M, Arbabisarjou A. . Comparison of nasal continuous positive airway pressure therapy with and without prophylactic surfactant in preterm neonates. Iranian J Neonatol. 2013;4(3):26-34.

68. Kandraju H, Murki S, Subramanian S, Gaddam P, Deorari A, Kumar P. Early routine versus late selective surfactant in preterm neonates with respiratory distress syndrome on nasal continuous

positive airway pressure: a randomized controlled trial. Neonatology. 2013;103(2):148-154. 69. Reininger A, Khalak R, Kendig JW, et al. Surfactant administration by transient intubation in

infants 29 to 35 weeks' gestation with respiratory distress syndrome decreases the likelihood of

later mechanical ventilation: a randomized controlled trial. J Perinatol. 2005;25(11):703-708. 70. Rojas MA, Lozano JM, Rojas MX, et al. Very early surfactant without mandatory ventilation in

premature infants treated with early continuous positive airway pressure: a randomized,

controlled trial. Pediatrics. 2009;123(1):137-142. 71. Sandri F, Plavka R, Ancora G, et al. Prophylactic or early selective surfactant combined with

nCPAP in very preterm infants. Pediatrics. 2010;125(6):e1402-1409.



181

72. Verder H, Albertsen P, Ebbesen F, et al. Nasal continuous positive airway pressure and early surfactant therapy for respiratory distress syndrome in newborns of less than 30 weeks'

gestation. Pediatrics. 1999;103(2):E24. 73. Verder H, Robertson B, Greisen G, et al. Surfactant therapy and nasal continuous positive

airway pressure for newborns with respiratory distress syndrome. Danish-Swedish Multicenter

Study Group. N Engl J Med. 1994;331(16):1051-1055. 74. Sankar MJ, Gupta N, Jain K, Agarwal R, Paul VK. Efficacy and safety of surfactant replacement

therapy for preterm neonates with respiratory distress syndrome in low- and middle-income

countries: a systematic review. J Perinatol. 2016;36 Suppl 1:S36-48. 75. World Health Organization. WHO Model List of Essential Medicines for Children. 7th list. 2019.

Available at: https://apps.who.int/iris/bitstream/handle/10665/325772/WHO-MVP-EMP-IAU-2019.07-eng.pdf?ua=1.pdf. (Accessed on 25 Nov, 2019).

76. World Health Organization. WHO recommendations on interventions to improve preterm birth

outcomes. 2015. Available at: https://apps.who.int/iris/bitstream/handle/10665/183037/9789241508988_eng.pdf;jsessionid=A1030072B52ED8C397D6C0892D8D0CA8?sequence=1.pdf. (Accessed on 25 Nov, 2019).

77. Salinas-Escudero G, Reyes-Lopez A, Garduno-Espinosa J, Villasis-Keever MA, Martinez-Valverde S, Munoz-Hernandez O. Economic evaluation of the use of exogenous pulmonary surfactants in preterm newborns in a Mexican population. Salud Publica Mex. 2012;54 Suppl 1:S73-81.

78. Henderson-Smart DJ, Subramanian P, Davis PG. Continuous positive airway pressure versus theophylline for apnea in preterm infants. Cochrane Database Syst Rev. 2000(2):CD001072.

79. Jones RA. Apnoea of immaturity. 1. A controlled trial of theophylline and face mask continuous

positive airways pressure. Arch Dis Child. 1982;57(10):761-765. 80. Miller MJ, Carlo WA, Martin RJ. Continuous positive airway pressure selectively reduces

obstructive apnea in preterm infants. J Pediatr. 1985;106(1):91-94. 81. Henderson-Smart DJ, De Paoli AG. Methylxanthine treatment for apnoea in preterm infants.

Cochrane Database Syst Rev. 2010(12):CD000140.

82. Eichenwald EC, Committee on F, Newborn AAoP. Apnea of Prematurity. Pediatrics. 2016;137(1). 83. Lemyre B, Davis PG, De Paoli AG. Nasal intermittent positive pressure ventilation (NIPPV) versus

nasal continuous positive airway pressure (NCPAP) for apnea of prematurity. Cochrane

Database Syst Rev. 2000(3):CD002272. 84. Lin CH, Wang ST, Lin YJ, Yeh TF. Efficacy of nasal intermittent positive pressure ventilation in

treating apnea of prematurity. Pediatr Pulmonol. 1998;26(5):349-353.

85. Ryan CA, Finer NN, Peters KL. Nasal intermittent positive-pressure ventilation offers no advantages over nasal continuous positive airway pressure in apnea of prematurity. Am J Dis Child. 1989;143(10):1196-1198.

86. Gizzi C, Montecchia F, Panetta V, et al. Is synchronised NIPPV more effective than NIPPV and NCPAP in treating apnoea of prematurity (AOP)? A randomised cross-over trial. Arch Dis Child

Fetal Neonatal Ed. 2015;100(1):F17-23. 87. Pantalitschka T, Sievers J, Urschitz MS, Herberts T, Reher C, Poets CF. Randomised crossover trial

of four nasal respiratory support systems for apnoea of prematurity in very low birthweight

infants. Arch Dis Child Fetal Neonatal Ed. 2009;94(4):F245-248. 88. Tapia JL, Bancalari A, Gonzalez A, Mercado ME. Does continuous positive airway pressure

(CPAP) during weaning from intermittent mandatory ventilation in very low birth weight infants

have risks or benefits? A controlled trial. Pediatr Pulmonol. 1995;19(5):269-274. 89. So BH, Tamura M, Mishina J, Watanabe T, Kamoshita S. Application of nasal continuous positive

airway pressure to early extubation in very low birthweight infants. Arch Dis Child Fetal Neonatal

Ed. 1995;72(3):F191-193. 90. Peake M, Dillon P, Shaw NJ. Randomized trial of continuous positive airways pressure to prevent

reventilation in preterm infants. Pediatr Pulmonol. 2005;39(3):247-250.

91. Higgins RD, Richter SE, Davis JM. Nasal continuous positive airway pressure facilitates extubation of very low birth weight neonates. Pediatrics. 1991;88(5):999-1003.

92. Engelke SC, Roloff DW, Kuhns LR. Postextubation nasal continuous positive airway pressure. A

prospective controlled study. Am J Dis Child. 1982;136(4):359-361. 93. Dimitriou G, Greenough A, Kavvadia V, et al. Elective use of nasal continuous positive airways

pressure following extubation of preterm infants. Eur J Pediatr. 2000;159(6):434-439. 94. Davis P, Jankov R, Doyle L, Henschke P. Randomised, controlled trial of nasal continuous

positive airway pressure in the extubation of infants weighing 600 to 1250 g. Arch Dis Child Fetal

Neonatal Ed. 1998;79(1):F54-57. 95. Chan V, Greenough A. Randomised trial of methods of extubation in acute and chronic

respiratory distress. Arch Dis Child. 1993;68(5 Spec No):570-572.

96. Annibale DJ, Hulsey TC, Engstrom PC, Wallin LA, Ohning BL. Randomized, controlled trial of nasopharyngeal continuous positive airway pressure in the extubation of very low birth weight infants. J Pediatr. 1994;124(3):455-460.

https://apps.who.int/iris/bitstream/handle/10665/325772/WHO-MVP-EMP-IAU-2019.07-eng.pdf?ua=1.pdf

https://apps.who.int/iris/bitstream/handle/10665/325772/WHO-MVP-EMP-IAU-2019.07-eng.pdf?ua=1.pdf

https://apps.who.int/iris/bitstream/handle/10665/183037/9789241508988_eng.pdf;jsessionid=A1030072B52ED8C397D6C0892D8D0CA8?sequence=1.pdf

https://apps.who.int/iris/bitstream/handle/10665/183037/9789241508988_eng.pdf;jsessionid=A1030072B52ED8C397D6C0892D8D0CA8?sequence=1.pdf



182

97. Davis PG, Henderson-Smart DJ. Nasal continuous positive airways pressure immediately after extubation for preventing morbidity in preterm infants. Cochrane Database Syst Rev.

2003(2):CD000143. 98. Chen J, Gao WW, Xu F, et al. [Comparison of clinical efficacy of heated humidified high flow

nasal cannula versus nasal continuous positive airway pressure in treatment of respiratory

distress syndrome in very low birth weight infants]. Zhongguo Dang Dai Er Ke Za Zhi. 2015;17(8):847-851.

99. Collaborative Group for the Multicenter Study on Heated Humidified High-flow Nasal Cannula

V. [Efficacy and safety of heated humidified high-flow nasal cannula for prevention of extubation failure in neonates]. Zhonghua Er Ke Za Zhi. 2014;52(4):271-276.

100. Collins CL, Holberton JR, Barfield C, Davis PG. A randomized controlled trial to compare heated humidified high-flow nasal cannulae with nasal continuous positive airway pressure postextubation in premature infants. J Pediatr. 2013;162(5):949-954 e941.

101. Elkhwad M DJ, Jennifer G, Harriet F, Anand K. Randomized Control Trial: Heated Humidity High Flow Nasal Cannula in Comparison with NCPAP in the Management of RDS in Extreme Low Birth Infants in Immediate Post Extubation Period. Neonat Pediatr Med 3: 121. 2017.

102. Kadivar MM, Mosayebi ZM, Razi NM, Nariman SM, Sangsari RM. High Flow Nasal Cannulae versus Nasal Continuous Positive Airway Pressure in Neonates with Respiratory Distress Syndrome Managed with INSURE Method: A Randomized Clinical Trial. Iran J Med Sci. 2016;41(6):494-500.

103. Manley BJ, Owen LS, Doyle LW, et al. High-flow nasal cannulae in very preterm infants after extubation. N Engl J Med. 2013;369(15):1425-1433.

104. Mostafa-Gharehbaghi M MH. Comparing the effectiveness of nasal continuous positive airway

pressure (NCPAP) and high flow nasal cannula (HFNC) in prevention of post extubation assisted ventilation. Zahedan J Res Med Sci 17, e984. . 2014.

105. Soonsawad S, Tongsawang N, Nuntnarumit P. Heated Humidified High-Flow Nasal Cannula for Weaning from Continuous Positive Airway Pressure in Preterm Infants: A Randomized Controlled Trial. Neonatology. 2016;110(3):204-209.

106. Kang WQ, Xu BL, Liu DP, et al. [Efficacy of heated humidified high-flow nasal cannula in preterm infants aged less than 32 weeks after ventilator weaning]. Zhongguo Dang Dai Er Ke Za Zhi. 2016;18(6):488-491.

107. O'Brien K, Campbell C, Brown L, Wenger L, Shah V. Infant flow biphasic nasal continuous positive airway pressure (BP- NCPAP) vs. infant flow NCPAP for the facilitation of extubation in infants' </= 1,250 grams: a randomized controlled trial. BMC Pediatr. 2012;12:43.

108. Moretti C, Giannini L, Fassi C, Gizzi C, Papoff P, Colarizi P. Nasal flow-synchronized intermittent positive pressure ventilation to facilitate weaning in very low-birthweight infants: unmasked randomized controlled trial. Pediatr Int. 2008;50(1):85-91.

109. Khorana M, Paradeevisut H, Sangtawesin V, Kanjanapatanakul W, Chotigeat U, Ayutthaya JK. A randomized trial of non-synchronized Nasopharyngeal Intermittent Mandatory Ventilation

(nsNIMV) vs. Nasal Continuous Positive Airway Pressure (NCPAP) in the prevention of extubation failure in pre-term < 1,500 grams. J Med Assoc Thai. 2008;91 Suppl 3:S136-142.

110. Khalaf MN, Brodsky N, Hurley J, Bhandari V. A prospective randomized, controlled trial

comparing synchronized nasal intermittent positive pressure ventilation versus nasal continuous positive airway pressure as modes of extubation. Pediatrics. 2001;108(1):13-17.

111. Kahramaner Z, Erdemir A, Turkoglu E, Cosar H, Sutcuoglu S, Ozer EA. Unsynchronized nasal

intermittent positive pressure versus nasal continuous positive airway pressure in preterm infants after extubation. J Matern Fetal Neonatal Med. 2014;27(9):926-929.

112. Jasani B, Nanavati R, Kabra N, Rajdeo S, Bhandari V. Comparison of non-synchronized nasal

intermittent positive pressure ventilation versus nasal continuous positive airway pressure as post-extubation respiratory support in preterm infants with respiratory distress syndrome: a randomized controlled trial. J Matern Fetal Neonatal Med. 2016;29(10):1546-1551.

113. Gao WW, Tan SZ, Chen YB, Zhang Y, Wang Y. [Randomized trail of nasal synchronized intermittent mandatory ventilation compared with nasal continuous positive airway pressure in preterm infants with respiratory distress syndrome]. Zhongguo Dang Dai Er Ke Za Zhi.

2010;12(7):524-526. 114. Friedlich P, Lecart C, Posen R, Ramicone E, Chan L, Ramanathan R. A randomized trial of

nasopharyngeal-synchronized intermittent mandatory ventilation versus nasopharyngeal continuous positive airway pressure in very low birth weight infants after extubation. J Perinatol. 1999;19(6 Pt 1):413-418.

115. Barrington KJ, Bull D, Finer NN. Randomized trial of nasal synchronized intermittent mandatory ventilation compared with continuous positive airway pressure after extubation of very low birth weight infants. Pediatrics. 2001;107(4):638-641.

116. Komatsu DF, Diniz EM, Ferraro AA, Ceccon ME, Vaz FA. Randomized controlled trial comparing nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure in premature infants after tracheal extubation. Rev Assoc Med Bras (1992). 2016;62(6):568-574.



183

117. Ribeiro SNS, Fontes MJF, Bhandari V, Resende CB, Johnston C. Noninvasive Ventilation in Newborns </= 1,500 g after Tracheal Extubation: Randomized Clinical Trial. Am J Perinatol.

2017;34(12):1190-1198. 118. Fleeman N, Dundar Y, Shah PS, Shaw BN. Heated Humidified High-Flow Nasal Cannula for

Preterm Infants: An Updated Systematic Review and Meta-analysis. Int J Technol Assess Health

Care. 2019:1-9. 119. Pandita A, Murki S, Oleti TP, et al. Effect of Nasal Continuous Positive Airway Pressure on Infants

With Meconium Aspiration Syndrome: A Randomized Clinical Trial. JAMA Pediatr.

2018;172(2):161-165. 120. De Paoli AG, Davis PG, Faber B, Morley CJ. Devices and pressure sources for administration of

nasal continuous positive airway pressure (NCPAP) in preterm neonates. Cochrane Database Syst Rev. 2008(1):CD002977.

121. Stefanescu BM, Murphy WP, Hansell BJ, Fuloria M, Morgan TM, Aschner JL. A randomized,

controlled trial comparing two different continuous positive airway pressure systems for the successful extubation of extremely low birth weight infants. Pediatrics. 2003;112(5):1031-1038.

122. Sun SC, Tien HC. Randomized controlled trial of two methods of nasal CPAP (NCPAP): flow

driver vs conventional NCPAP [Abstract]. Pediatr Res1999;45:322A. 123. Colaizy TT, McEvoy C, Crichton C, Freitag BC, GilhoolyJ, Pillers DM, Smith SA, Wallen L. Bubble

vs. conventional CPAP: a prospective, randomized, pilot study (abstract).Pediatric Academic

Societies [http://www.pas-meeting.org/] 2004; 55:264. 124. Yadav S, Thukral A, Sankar MJ, et al. Bubble vs conventional continuous positive airway

pressure for prevention of extubation failure in preterm very low birth weight infants: a pilot

study. Indian journal of pediatrics. 2012;79(9):1163-1168. 125. Tagare A, Kadam S, Vaidya U, Pandit A, Patole S. Bubble CPAP versus ventilator CPAP in

preterm neonates with early onset respiratory distress--a randomized controlled trial. Journal of tropical pediatrics. 2013;59(2):113-119.

126. Buettiker V, Hug MI, Baenziger O, Meyer C, Frey B. Advantages and disadvantages of different

nasal CPAP systems in newborns. Intensive care medicine. 2004;30(5):926-930. 127. Bober K, Swietlinski J, Zejda J, et al. A multicenter randomized controlled trial comparing

effectiveness of two nasal continuous positive airway pressure devices in very-low-birth-weight

infants. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2012;13(2):191-196.

128. Mazmanyan P, Mellor K, Dore CJ, Modi N. A randomised controlled trial of flow driver and

bubble continuous positive airway pressure in preterm infants in a resource-limited setting. Arch Dis Child Fetal Neonatal Ed. 2016;101(1):F16-20.

129. Bhatti A, Khan J, Murki S, Sundaram V, Saini SS, Kumar P. Nasal Jet-CPAP (variable flow) versus

Bubble-CPAP in preterm infants with respiratory distress: an open label, randomized controlled trial. J Perinatol. 2015;35(11):935-940.

130. Gupta S, Sinha SK, Tin W, Donn SM. A randomized controlled trial of post-extubation bubble continuous positive airway pressure versus Infant Flow Driver continuous positive airway pressure in preterm infants with respiratory distress syndrome. J Pediatr. 2009;154(5):645-650.

131. Hosseini MB, Heidarzadeh M, Balila M, et al. Randomized controlled trial of two methods of nasal continuous positive airway pressure (N-CPAP) in preterm infants with respiratory distress syndrome: underwater bubbly CPAP vs. Medijet system device. The Turkish journal of pediatrics.

2012;54(6):632-640. 132. King BC, Gandhi BB, Jackson A, Katakam L, Pammi M, Suresh G. Mask versus Prongs for Nasal

Continuous Positive Airway Pressure in Preterm Infants: A Systematic Review and Meta-Analysis.

Neonatology. 2019;116(2):100-114. 133. Goel S, Mondkar J, Panchal H, Hegde D, Utture A, Manerkar S. Nasal Mask Versus Nasal Prongs

for Delivering Nasal Continuous Positive Airway Pressure in Preterm Infants with Respiratory

Distress: A Randomized Controlled Trial. Indian Pediatr. 2015;52(12):1035-1040. 134. Kieran EA, Twomey AR, Molloy EJ, Murphy JF, O'Donnell CP. Randomized trial of prongs or mask

for nasal continuous positive airway pressure in preterm infants. Pediatrics. 2012;130(5):e1170-

1176. 135. Say B, Kanmaz Kutman HG, Oguz SS, et al. Binasal Prong versus Nasal Mask for Applying CPAP

to Preterm Infants: A Randomized Controlled Trial. Neonatology. 2016;109(4):258-264. 136. Bashir T, Murki S, Kiran S, Reddy VK, Oleti TP. 'Nasal mask' in comparison with 'nasal prongs' or

'rotation of nasal mask with nasal prongs' reduce the incidence of nasal injury in preterm

neonates supported on nasal continuous positive airway pressure (nCPAP): A randomized controlled trial. PLoS One. 2019;14(1):e0211476.

137. Chandrasekaran A, Thukral A, Jeeva Sankar M, Agarwal R, Paul VK, Deorari AK. Nasal masks or

binasal prongs for delivering continuous positive airway pressure in preterm neonates-a randomised trial. Eur J Pediatr. 2017;176(3):379-386.

http://www.pas-meeting.org/



184

138. Yong SC, Chen SJ, Boo NY. Incidence of nasal trauma associated with nasal prong versus nasal mask during continuous positive airway pressure treatment in very low birthweight infants: a

randomised control study. Arch Dis Child Fetal Neonatal Ed. 2005;90(6):F480-483. 139. Newnam KM, McGrath JM, Salyer J, Estes T, Jallo N, Bass WT. A comparative effectiveness study

of continuous positive airway pressure-related skin breakdown when using different nasal

interfaces in the extremely low birth weight neonate. Appl Nurs Res. 2015;28(1):36-41. 140. Murki S, Nathani PP, Sharma D, Subramaniam S, Oleti TP, Chawla D. Initiating nasal continuous

positive airway pressure in preterm neonates at 5 cm as against 7 cm did not decrease the

need for mechanical ventilation. Acta Paediatr. 2016;105(8):e345-351. 141. Buzzella B, Claure N, D'Ugard C, Bancalari E. A randomized controlled trial of two nasal

continuous positive airway pressure levels after extubation in preterm infants. J Pediatr. 2014;164(1):46-51.

142. Amatya S, Macomber M, Bhutada A, Rastogi D, Rastogi S. Sudden versus gradual pressure

wean from Nasal CPAP in preterm infants: a randomized controlled trial. J Perinatol. 2017;37(6):662-667.

143. Badiee Z, Eshghi A, Mohammadizadeh M. High flow nasal cannula as a method for rapid

weaning from nasal continuous positive airway pressure. Int J Prev Med. 2015;6:33. 144. Eze N, Murphy D, Dhar V, Rehan VK. Comparison of sprinting vs non-sprinting to wean nasal

continuous positive airway pressure off in very preterm infants. J Perinatol. 2018;38(2):164-168.

145. Jensen CF, Sellmer A, Ebbesen F, et al. Sudden vs Pressure Wean From Nasal Continuous Positive Airway Pressure in Infants Born Before 32 Weeks of Gestation: A Randomized Clinical Trial. JAMA Pediatr. 2018;172(9):824-831.

146. O'Donnell SM, Curry SJ, Buggy NA, et al. The NOFLO trial: low-flow nasal prongs therapy in weaning nasal continuous positive airway pressure in preterm infants. J Pediatr. 2013;163(1):79-

83. 147. Rastogi S WW, Gupta A, Bhutada A, Deepa Rastogi, Maimonides Neonatal Group. Gradual

versus sudden weaning from nasal CPAP in preterm infants: a pilot randomized controlled trial.

Respir Care 2013;58:511-516. 148. Singh SD BL, Clark P, Glover K, Pasquill A, Robinson MJ, et al. Is decreasing pressure or increasing

time of a better strategy in weaning VLBW infants from NCPAP. Eur J Paediatr 2006;165 (Suppl

1):48. 149. Soe A HJ, Jani B, Ducker DA. . Nasal continuous positive airway pressure weaning in preterm

infants. Eur J Paediatr 2006;165(Suppl 1):48-49.

150. Tang J, Reid S, Lutz T, Malcolm G, Oliver S, Osborn DA. Randomised controlled trial of weaning strategies for preterm infants on nasal continuous positive airway pressure. BMC Pediatr. 2015;15:147.

151. Todd DA, Wright A, Broom M, et al. Methods of weaning preterm babies <30 weeks gestation off CPAP: a multicentre randomised controlled trial. Arch Dis Child Fetal Neonatal Ed.

2012;97(4):F236-240. 152. Nair V, Swarnam K, Rabi Y, et al. Effect of Nasal Continuous Positive Airway Pressure (NCPAP)

Cycling and Continuous NCPAP on Successful Weaning: A Randomized Controlled Trial. Indian

journal of pediatrics. 2015;82(9):787-793. 153. Ammari A, Suri M, Milisavljevic V, et al. Variables associated with the early failure of nasal CPAP

in very low birth weight infants. J Pediatr. 2005;147(3):341-347.

154. Dargaville PA, Aiyappan A, De Paoli AG, et al. Continuous positive airway pressure failure in preterm infants: incidence, predictors and consequences. Neonatology. 2013;104(1):8-14.

155. Tagliaferro T, Bateman D, Ruzal-Shapiro C, Polin RA. Early radiologic evidence of severe

respiratory distress syndrome as a predictor of nasal continuous positive airway pressure failure in extremely low birth weight newborns. J Perinatol. 2015;35(2):99-103.

156. Pillai MS, Sankar MJ, Mani K, Agarwal R, Paul VK, Deorari AK. Clinical prediction score for nasal

CPAP failure in pre-term VLBW neonates with early onset respiratory distress. Journal of tropical pediatrics. 2011;57(4):274-279.

157. Rocha G, Flor-de-Lima F, Proenca E, et al. Failure of early nasal continuous positive airway

pressure in preterm infants of 26 to 30 weeks gestation. J Perinatol. 2013;33(4):297-301. 158. Fuchs H, Lindner W, Leiprecht A, Mendler MR, Hummler HD. Predictors of early nasal CPAP

failure and effects of various intubation criteria on the rate of mechanical ventilation in preterm infants of <29 weeks gestational age. Arch Dis Child Fetal Neonatal Ed. 2011;96(5):F343-347.

159. Dargaville PA, Gerber A, Johansson S, et al. Incidence and Outcome of CPAP Failure in

Preterm Infants. Pediatrics. 2016;138(1). 160. Gulczynska E, Szczapa T, Hozejowski R, Borszewska-Kornacka MK, Rutkowska M. Fraction of

Inspired Oxygen as a Predictor of CPAP Failure in Preterm Infants with Respiratory Distress

Syndrome: A Prospective Multicenter Study. Neonatology. 2019;116(2):171-178. 161. Koti J, Murki S, Gaddam P, Reddy A, Reddy MD. Bubble CPAP for respiratory distress syndrome

in preterm infants. Indian Pediatr. 2010;47(2):139-143.



185

162. De Jaegere AP, van der Lee JH, Cante C, van Kaam AH. Early prediction of nasal continuous positive airway pressure failure in preterm infants less than 30 weeks gestation. Acta Paediatr.

2012;101(4):374-379. 163. 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. Journal of

tropical pediatrics. 2000;46(3):172-175. 164. Urs PS, Khan F, Maiya PP. Bubble CPAP - a primary respiratory support for respiratory distress

syndrome in newborns. Indian Pediatr. 2009;46(5):409-411.

165. Dani C, Berti E, Barp J. Risk factors for INSURE failure in preterm infants. Minerva Pediatr. 2010;62(3 Suppl 1):19-20.

166. Brix N, Sellmer A, Jensen MS, Pedersen LV, Henriksen TB. Predictors for an unsuccessful INtubation-SURfactant-Extubation procedure: a cohort study. BMC Pediatr. 2014;14:155.

167. Sahni R, Schiaratura M, Polin RA. Strategies for the prevention of continuous positive airway

pressure failure. Semin Fetal Neonatal Med. 2016;21(3):196-203. 168. Waskosky A, Huey TK. Quality improvement project: implementing guidelines supporting

noninvasive respiratory management for premature infants. Neonatal network : NN.

2014;33(5):245-253.



186

This page intentionally blank

Date post:	20-Sep-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

Non-invasive Respiratory Support for Newborns · Non-invasive respiratory support for newborns NNF...

Documents