Abstract
Introduction: The aim of this study was to systematically review the benefits and harms of using a high-flow nasal cannula (HFNC) for weaning continuous positive airway pressure (CPAP) support in preterm infants. Methods: Cochrane Central, EMBASE, Medline, and Web of Science were searched from inception to July 15, 2023. Randomised clinical trials (RCTs) comparing weaning CPAP using HFNC versus weaning CPAP alone and evaluating predefined outcomes were included. Two authors independently performed data extraction and methodological quality assessment. Meta-analysis was conducted using a random-effects model, and the certainty of evidence was assessed using Cochrane GRADE. Results: Among 843 identified records, seven RCTs involving 781 preterm infants were eligible for analysis. The meta-analysis found no statistically significant difference in duration of respiratory support when using HFNC for weaning compared to weaning CPAP alone (mean difference (95% confidence interval) 3.52 (−0.02, 7.05); 5 RCTs; participants = 488; I2 = 29%). The evidence certainty was downgraded to low due to study limitations and imprecision. There were no significant differences in secondary outcomes, except for a lower occurrence of nasal trauma with HFNC for weaning CPAP compared to weaning CPAP alone (relative risk (95% confidence interval) 0.61 (0.38, 0.99); 4 RCTs; participants = 335; I2 = 0%). The evidence certainty for the secondary outcomes was low to very low. Conclusion: Low certainty of evidence suggests using HFNC for weaning CPAP in preterm infants may not impact the duration of respiratory support. Caution is advised when considering HFNC for weaning CPAP, especially in extremely preterm infants, until additional supportive evidence on its safety becomes available.
Introduction
Preterm infants often require respiratory support in neonatal intensive care units due to their immature lungs and respiratory system. Nasal continuous positive airway pressure (CPAP) is a widely used form of respiratory support for preterm infants, providing a constant positive pressure to the airways, thereby improving oxygenation and preventing alveolar collapse. However, there is ongoing debate and limited evidence regarding the optimal weaning strategies for CPAP in preterm infants [1]. Traditionally, weaning from CPAP involves a gradual reduction in pressure until reaching a minimum threshold, usually around 4 or 5 cm H2O, before complete discontinuation. However, certain approaches involve a more gradual reduction in CPAP pressure, tapering off to 3 or 4 cm H2O before discontinuation. Further, weaning approaches include cycling the CPAP off for shorter periods and gradually increasing the duration of off periods based on the infant's tolerance. However, this method may pose a risk of atelectrauma, a condition characterised by lung injury caused by repetitive opening and closing of the alveoli [2].
In recent years, the use of high-flow nasal cannula (HFNC) as an alternative weaning strategy for CPAP has gained increasing attention. HFNC delivers a heated and humidified blend of oxygen and air at a high flow rate, creating a positive pressure in the airways. It offers several advantages over traditional weaning methods, including better patient comfort [3], reduced nasal trauma [4], and improved access to feeding and care. HFNC can aid in maintaining oxygenation, optimising ventilation, and enhancing respiratory mechanics during the weaning process, much like CPAP, while also providing the additional benefits mentioned earlier.
Despite the increasing use of HFNC as a weaning strategy for CPAP, the available evidence remains limited and contradictory [5‒7]. Few randomised controlled trials (RCTs) have shown encouraging outcomes, indicating that HFNC is effective and comparable to CPAP [5, 6]. However, others have raised concerns about possible lung derecruitment, inconsistent pressure delivery, and prolonged respiratory support duration associated with HFNC [7]. Given these knowledge gaps and conflicting findings, conducting a systematic review becomes essential to consolidate the existing evidence and provide a comprehensive evaluation of the efficacy and safety of HFNC as a weaning strategy for CPAP in preterm infants. By synthesising the results from relevant RCTs, this systematic review aims to inform clinical decision-making and guide future research in this field.
Methods
This systematic review and meta-analysis were conducted and reported following the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [8]. The systematic review protocol was registered with PROSPERO, the international prospective register of systematic reviews, under the registration number CRD42022370322 (https://www.crd.york.ac.uk/prospero/.).
Search Strategy
We conducted a comprehensive search across Cochrane Central, EMBASE, Medline, and Web of Science from inception through July 15, 2023. No language restrictions were applied. We also reviewed reference lists and citations of included studies and searched the clinical trial registry at https://beta.clinicaltrials.gov/ for potential studies (online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000536464).
Study Selection (Eligibility Criteria)
Type of the Studies
Only RCTs focussing on preterm infants with a gestational age of less than 37 weeks and assessing at least one of the identified outcomes of this systematic review were included. Nonrandomised studies, narrative reviews, systematic reviews, case series, and case reports were excluded. Additionally, studies that included both preterm and term populations without separate data available for preterm infants and studies utilising alternative respiratory support for weaning were excluded.
Populations and Settings
Studies including preterm infants <37 weeks gestational age or a mixed population but providing separate data for preterm infants were included.
Intervention and Comparison
The intervention involved using HFNC for weaning CPAP, with a minimum flow rate of 1 L per minute, whereas the comparator consisted of direct CPAP weaning, irrespective of the weaning plan in either of the groups.
Outcomes
The primary outcome assessed in this study was the duration of respiratory support, which is the duration of respiratory support from randomisation until successful weaning off respiratory support according to the authors’ definition. Secondary outcomes included weaning failure, nasal trauma (any and moderate to severe), chronic lung disease (CLD) (any and moderate to severe), severe retinopathy of prematurity (ROP), time to achieve full feeds, and length of hospital stay. The specific definitions and time points for these outcomes were determined by the authors.
Study Selection and Data Extraction
The study authors (Y.B. and A.R.) independently screened the titles and abstracts and created a list of full-text articles. Further, they independently evaluated the full-text articles for eligibility. They also independently read the eligible articles and extracted the relevant data: the country, inclusion criteria, exclusion criteria, interventions, weaning protocols, primary outcomes data and secondary outcomes data. Lastly, they resolved the discrepancies through discussion and consensus.
Assessment of Risk of Bias
Both authors (Y.B. and A.R.) independently assessed the risk of bias in each study using the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2 version, Aug 22, 2019) outlined in the Cochrane Handbook for Systematic Reviews of Intervention for RCTs [9]. Publication bias analysis was assessed using a funnel plot if ten or more RCTs contributed to the meta-analysis.
Data Synthesis and Statistical Analysis
Random-effects model meta-analyses were conducted using Review Manager 5.4. For dichotomous outcomes, relative risk (RR) was pooled, while mean difference (MD) was pooled for continuous outcomes, along with their respective 95% confidence intervals (CIs). Median and interquartile range data from the included RCTs were converted to mean and standard deviation in an appropriate manner [10]. The certainty of the evidence was assessed independently using the Cochrane Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.
Assessment of Heterogeneity
Forest plots were visually assessed apart from the p value for χ2 (<0.10) and I2 values (>50%) for determining significant heterogeneity. Data and analyses were checked in the presence of significant heterogeneity, and subgroup analyses (<28 weeks GA or >28 weeks GA) were considered to explore the cause for between studies heterogeneity if two or more studies are available.
Results
Figure 1 illustrates the study selection procedure and screening. Out of the initial 843 records reviewed, 50 duplicates were identified and removed. Among the remaining 793 records, 751 were excluded based on title and abstract screening. After thoroughly examining the full texts of 42 records, 35 were further excluded for various reasons, including incorrect interventions (n = 19), inappropriate study design (n = 15), and irrelevant outcomes (n = 1). Consequently, a total of 7 RCTs were included in the analysis (Cresi F, 2023 [11], Clements J, 2022 [5], Gregoraci Fernández A, 2021 [6], Soonsawad S, 2016 [12], Tang J, 2015 [13], Badiee Z, 2015 [14], and Abdel-Hady H, 2011 [7]). Included studies were conducted in Afghanistan, Australia, Egypt, Italy, New Zealand, Spain, and Thailand. Table 1 provides a summary of all included RCTs, while Table 2 presents the meta-analysis findings and the GRADE assessment.
PRISMA study flow diagram illustrating the flow of information through the different stages of the review process.
PRISMA study flow diagram illustrating the flow of information through the different stages of the review process.
Characteristics of randomised trials included in the systematic review
Study . | Inclusion criteria . | Exclusion criteria . | Interventions . | N . | Outcomes studied . |
---|---|---|---|---|---|
Cresi (2023) Italy [11] | 25–29 weeks (mean 28 weeks), 7 days old or less, suitability for enteral feeding, on CPAP (device not mentioned) | Neurological or surgical disease, sepsis, chromosomal abnormalities, and major malformations | CPAP group: 7 cm H2O, weaning gradually until 4 cm H2O | 247 | Duration of respiratory support, weaning failure, length of hospital stay, time to reach full oral feeding |
HFNC group: 7 LPM, weaning gradually until 2 LPM | |||||
Clements (2022) New Zealand [5] | GA <30 weeks (median 28 weeks) | Previously been off respiratory support for >7 days, CHD, surgical conditions, chromosomal abnormalities, genetic syndromes, or major congenital malformations | CPAP group: 6 cm H2O for 48 h then 5 cm H2O for 48 h then off CPAP in day 5 | 120 | Duration of respiratory supporta (time from randomisation until 72 h off respiratory support), weaning failure, moderate to severe bronchopulmonary dysplasia, any nasal trauma, age of full oral feeding and ROP |
On CPAP 6 cm H2O (bubble CPAP) for at least 48 h | HFNC group: HFNC of 6 L/M then wean by 2 every 24 h to off at day 5 | ||||
Fernández (2021) Spain [6] | GA at birth 25–32 weeks (median 28 weeks), weight >1,000 g, on CPAP support >7 days (variable-flow CPAP) | Congenital anomalies, pulmonary hypoplasia neuromuscular disorder, large IVH, or infarction | CPAP group: Wean by 1 cm H2O every 12–24 h until a pressure of 4 cm H2O then discontinue after 4 h | 84 | Duration of respiratory support, weaning failure, moderate to severe bronchopulmonary dysplasia, any or moderate to severe nasal trauma, age of full oral feeding, ROP, and length of stay in the hospital |
HFNC group: flow set according to baby’s weight (3 LPM for 1,000–1,999 g) and (4 LPM for 2,000–2,999 g). The flow adjusted according to the infant’s needs to a maximum of 3 LPM above the starting flow rate, then lowered by 0.5–1 LPM every 12–24 h until reaching a flow of 3 LPM, then off | |||||
Soonsawad (2016) Thailand [12] | GA <32 weeks (median 29 weeks), weight <1,500 g, on CPAP (variable-flow CPAP) at least 24 h | Weight of <750 g, congenital anomalies, CHD, airway anomalies, pulmonary hypoplasia, neuromuscular disorder | CPAP group: wean by 1 cm H2O every 24 h until stable on CPAP 4 cm H2O and then discontinued | 101 | Duration of respiratory support, weaning failure, moderate to severe bronchopulmonary dysplasia, any or moderate to severe nasal trauma, and ROP |
HFNC group: flow reduced by 1 L/min every 24 h to 2–3 L/min depending on body weight (i.e., < or ≥1,000 g), and then discontinued | |||||
Tang (2015) Australia [13] | GA <30 weeks (mean ∼27 weeks) | Sepsis within previous 48 h, major congenital, or chromosomal | CPAP group: gradual wean from NCPAP if baby stableb | 60 | Duration of respiratory support, moderate to severe bronchopulmonary dysplasia, any nasal trauma, age of full oral feeding, ROP, and length of stay in the hospital |
On CPAP ≤5 cm H2O (mouth closed; bubble CPAP) or any level with mouth open or off nCPAP for at least 6 h | abnormality; or severe neurologic insult or neuromuscular disease | HFNC group: abrupt wean from NCPAP to HFNC of 6LPM and wean if baby stable | |||
Badiee (2015) Afghanistan [14] | GA of 28–36 weeks (mean ∼31 weeks) on CPAP 5 cm H2O (bubble CPAP) | Major congenital malformation, grade 3 or 4 IVH, neuromuscular disorders, pulmonary hypoplasia, cleft lip and palate, chest wall deformity, cyanotic CHD. | CPAP group: wean to RA from pressure 5 once FiO2 reach 21% for 6 h. Low flow O2 start if need O2 needed | 109 | Duration of respiratory supporta, weaning failure, bronchopulmonary dysplasia |
HFNC group: Start flow 2 L/M until FiO2 0.21. After that, the flow weaned by 0.5 LPM every 1 h until a flow of 0.5 LPM, then off | |||||
Abdel-Hady (2010) Egypt [7] | GA 28 weeks (mean 31 weeks) or more on CPAP 5 cm H2O (bubble CPAP) | Congenital anomalies, cyanotic CHD, congenital airway or chest wall abnormalities, pulmonary hypoplasia, neuromuscular disorder, congenital neurological disorder, severe IVH, PVL, and hydrocephalus | CPAP group: wean off directly to RA if FiO2 21% for 24 h | 60 | Duration of respiratory support, weaning failure, bronchopulmonary dysplasia, and length of hospital stay |
HFNC group: start NC (2 LPM) with FiO2 = 0.30. If FiO2 is 21%, the flow decreases by 0.5 LPM every 6 h until a flow of 0.5 LPM is reached, then off |
Study . | Inclusion criteria . | Exclusion criteria . | Interventions . | N . | Outcomes studied . |
---|---|---|---|---|---|
Cresi (2023) Italy [11] | 25–29 weeks (mean 28 weeks), 7 days old or less, suitability for enteral feeding, on CPAP (device not mentioned) | Neurological or surgical disease, sepsis, chromosomal abnormalities, and major malformations | CPAP group: 7 cm H2O, weaning gradually until 4 cm H2O | 247 | Duration of respiratory support, weaning failure, length of hospital stay, time to reach full oral feeding |
HFNC group: 7 LPM, weaning gradually until 2 LPM | |||||
Clements (2022) New Zealand [5] | GA <30 weeks (median 28 weeks) | Previously been off respiratory support for >7 days, CHD, surgical conditions, chromosomal abnormalities, genetic syndromes, or major congenital malformations | CPAP group: 6 cm H2O for 48 h then 5 cm H2O for 48 h then off CPAP in day 5 | 120 | Duration of respiratory supporta (time from randomisation until 72 h off respiratory support), weaning failure, moderate to severe bronchopulmonary dysplasia, any nasal trauma, age of full oral feeding and ROP |
On CPAP 6 cm H2O (bubble CPAP) for at least 48 h | HFNC group: HFNC of 6 L/M then wean by 2 every 24 h to off at day 5 | ||||
Fernández (2021) Spain [6] | GA at birth 25–32 weeks (median 28 weeks), weight >1,000 g, on CPAP support >7 days (variable-flow CPAP) | Congenital anomalies, pulmonary hypoplasia neuromuscular disorder, large IVH, or infarction | CPAP group: Wean by 1 cm H2O every 12–24 h until a pressure of 4 cm H2O then discontinue after 4 h | 84 | Duration of respiratory support, weaning failure, moderate to severe bronchopulmonary dysplasia, any or moderate to severe nasal trauma, age of full oral feeding, ROP, and length of stay in the hospital |
HFNC group: flow set according to baby’s weight (3 LPM for 1,000–1,999 g) and (4 LPM for 2,000–2,999 g). The flow adjusted according to the infant’s needs to a maximum of 3 LPM above the starting flow rate, then lowered by 0.5–1 LPM every 12–24 h until reaching a flow of 3 LPM, then off | |||||
Soonsawad (2016) Thailand [12] | GA <32 weeks (median 29 weeks), weight <1,500 g, on CPAP (variable-flow CPAP) at least 24 h | Weight of <750 g, congenital anomalies, CHD, airway anomalies, pulmonary hypoplasia, neuromuscular disorder | CPAP group: wean by 1 cm H2O every 24 h until stable on CPAP 4 cm H2O and then discontinued | 101 | Duration of respiratory support, weaning failure, moderate to severe bronchopulmonary dysplasia, any or moderate to severe nasal trauma, and ROP |
HFNC group: flow reduced by 1 L/min every 24 h to 2–3 L/min depending on body weight (i.e., < or ≥1,000 g), and then discontinued | |||||
Tang (2015) Australia [13] | GA <30 weeks (mean ∼27 weeks) | Sepsis within previous 48 h, major congenital, or chromosomal | CPAP group: gradual wean from NCPAP if baby stableb | 60 | Duration of respiratory support, moderate to severe bronchopulmonary dysplasia, any nasal trauma, age of full oral feeding, ROP, and length of stay in the hospital |
On CPAP ≤5 cm H2O (mouth closed; bubble CPAP) or any level with mouth open or off nCPAP for at least 6 h | abnormality; or severe neurologic insult or neuromuscular disease | HFNC group: abrupt wean from NCPAP to HFNC of 6LPM and wean if baby stable | |||
Badiee (2015) Afghanistan [14] | GA of 28–36 weeks (mean ∼31 weeks) on CPAP 5 cm H2O (bubble CPAP) | Major congenital malformation, grade 3 or 4 IVH, neuromuscular disorders, pulmonary hypoplasia, cleft lip and palate, chest wall deformity, cyanotic CHD. | CPAP group: wean to RA from pressure 5 once FiO2 reach 21% for 6 h. Low flow O2 start if need O2 needed | 109 | Duration of respiratory supporta, weaning failure, bronchopulmonary dysplasia |
HFNC group: Start flow 2 L/M until FiO2 0.21. After that, the flow weaned by 0.5 LPM every 1 h until a flow of 0.5 LPM, then off | |||||
Abdel-Hady (2010) Egypt [7] | GA 28 weeks (mean 31 weeks) or more on CPAP 5 cm H2O (bubble CPAP) | Congenital anomalies, cyanotic CHD, congenital airway or chest wall abnormalities, pulmonary hypoplasia, neuromuscular disorder, congenital neurological disorder, severe IVH, PVL, and hydrocephalus | CPAP group: wean off directly to RA if FiO2 21% for 24 h | 60 | Duration of respiratory support, weaning failure, bronchopulmonary dysplasia, and length of hospital stay |
HFNC group: start NC (2 LPM) with FiO2 = 0.30. If FiO2 is 21%, the flow decreases by 0.5 LPM every 6 h until a flow of 0.5 LPM is reached, then off |
Three studies (Cresi 2023, Clements 2022 and Tang 2015) mention the use of caffeine therapy explicitly, while data on caffeine therapy in other studies are not available); in Cresi 2013, babies were randomised while they were on CPAP or HFNC. However, most babies were on CPAP (∼90%) during randomisation, and the authors provided subgroup data for infants who were only on CPAP during randomisation. These babies were randomised then to continue CPAP or HFNC.
aExcluded from the primary outcome meta-analysis due to unavailability or incomplete data, even after attempting to contact the authors.
bThe infants underwent a gradual weaning process from NCPAP by transitioning to crib air or receiving oxygen up to 25% concentration or low-flow nasal cannula oxygen, if needed, at a rate of ≤1 LPM. Initially, infants were placed on 6 h of NCPAP followed by 1 h off, and if they remained stable, the duration of time off NCPAP was extended by 1 h in an alternating pattern until they were successfully weaned off NCPAP.
CHD, congenital heart disease; CPAP, continuous positive airway pressure; FiO2, fraction of inspired oxygen; GA, gestational age; HFNC, high-flow nasal cannula; IVH, intraventricular haemorrhage; LPM, litres per minute; PVL, periventricular leukomalacia; RA, room air.
Cochrane grading of recommendations assessment, development assessment for comparing the use of HFNC for weaning continuous positive airway pressure versus weaning continuous positive airway pressure alone
Studies, n . | Certainty assessment . | Patients, n . | Effect . | Certainty . | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
outcome . | study design . | risk of bias . | inconsistency . | indirectness . | imprecision . | other considerations . | HFNC . | CPAP . | relative (95% CI) . | absolute (95% CI) . | ||
5 | Duration of respiratory support | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 264 | 258 | - | MD 3.52 higher (0.02 lower to 7.05 higher) | ⊕⊕◯◯ Low |
6 | Weaning failure | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 61/352 (17.3%) | 72/348 (20.7%) | RR 0.86 (0.59–1.26) | 29 fewer per 1,000 (from 85 fewer to 54 more) | ⊕⊕◯◯ Low |
4 | Time to achieve full feeds | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 242 | 239 | - | MD 0.4 higher (2.73 lower to 3.53 higher) | ⊕⊕◯◯ Low |
4 | Nasal trauma (all) | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 21/168 (12.5%) | 34/167 (20.4%) | RR 0.61 (0.38–0.99) | 96 fewer per 1,000 (from 147 fewer to 2 fewer) | ⊕⊕◯◯ Low |
2 | Nasal trauma (moderate to severe) | Randomised trials | Seriousa | Not serious | Not serious | Very seriousc | None | 1/94 (1.1%) | 6/91 (6.6%) | RR 0.24 (0.04–1.40) | 50 fewer per 1,000 (from 63 fewer to 26 more) | ⊕◯◯◯ Very low |
5 | ROP | Randomised trials | Seriousa | Seriousd | Not serious | Very seriousc | None | –/293 | –/289 | RR 0.40 (0.10–1.55) | 0 fewer per 1,000 (from 0 fewer to 0 fewer) | ⊕◯◯◯ Very low |
3 | CLD (all) | Randomised trials | Seriousa | Seriousd | Not serious | Very seriousc | None | –/199 | –/196 | RR 0.85 (0.08–8.74) | 0 fewer per 1,000 (from 0 fewer to 0 fewer) | ⊕◯◯◯ Very low |
4 | CLD (moderate to severe) | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 35/168 (20.8%) | 43/167 (25.7%) | RR 0.83 (0.53–1.31) | 44 fewer per 1,000 (from 121 fewer to 80 more) | ⊕⊕◯◯ Low |
4 | Length of hospital stay | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 213 | 208 | - | MD 0.86 lower (5.3 lower to 3.58 higher) | ⊕⊕◯◯ Low |
Studies, n . | Certainty assessment . | Patients, n . | Effect . | Certainty . | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
outcome . | study design . | risk of bias . | inconsistency . | indirectness . | imprecision . | other considerations . | HFNC . | CPAP . | relative (95% CI) . | absolute (95% CI) . | ||
5 | Duration of respiratory support | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 264 | 258 | - | MD 3.52 higher (0.02 lower to 7.05 higher) | ⊕⊕◯◯ Low |
6 | Weaning failure | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 61/352 (17.3%) | 72/348 (20.7%) | RR 0.86 (0.59–1.26) | 29 fewer per 1,000 (from 85 fewer to 54 more) | ⊕⊕◯◯ Low |
4 | Time to achieve full feeds | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 242 | 239 | - | MD 0.4 higher (2.73 lower to 3.53 higher) | ⊕⊕◯◯ Low |
4 | Nasal trauma (all) | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 21/168 (12.5%) | 34/167 (20.4%) | RR 0.61 (0.38–0.99) | 96 fewer per 1,000 (from 147 fewer to 2 fewer) | ⊕⊕◯◯ Low |
2 | Nasal trauma (moderate to severe) | Randomised trials | Seriousa | Not serious | Not serious | Very seriousc | None | 1/94 (1.1%) | 6/91 (6.6%) | RR 0.24 (0.04–1.40) | 50 fewer per 1,000 (from 63 fewer to 26 more) | ⊕◯◯◯ Very low |
5 | ROP | Randomised trials | Seriousa | Seriousd | Not serious | Very seriousc | None | –/293 | –/289 | RR 0.40 (0.10–1.55) | 0 fewer per 1,000 (from 0 fewer to 0 fewer) | ⊕◯◯◯ Very low |
3 | CLD (all) | Randomised trials | Seriousa | Seriousd | Not serious | Very seriousc | None | –/199 | –/196 | RR 0.85 (0.08–8.74) | 0 fewer per 1,000 (from 0 fewer to 0 fewer) | ⊕◯◯◯ Very low |
4 | CLD (moderate to severe) | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 35/168 (20.8%) | 43/167 (25.7%) | RR 0.83 (0.53–1.31) | 44 fewer per 1,000 (from 121 fewer to 80 more) | ⊕⊕◯◯ Low |
4 | Length of hospital stay | Randomised trials | Seriousa | Not serious | Not serious | Seriousb | None | 213 | 208 | - | MD 0.86 lower (5.3 lower to 3.58 higher) | ⊕⊕◯◯ Low |
CI, confidence interval; MD, mean difference; RR, risk ratio.
aDowngraded by 1 level for limitations within studies.
bDowngraded by 1 level for imprecision.
cDowngraded by 2 levels for imprecision.
dDowngraded by 1 level for heterogeneity.
A total of 781 preterm infants were assessed in the seven included RCTs. Five of these studies enrolled preterm infants with a mean gestational age of less than 30 weeks. However, in two trials [7, 14], the preterm infants had a mean gestational age of more than 30 weeks. All trials used nasal CPAP as primary support or post extubation support. The studies in the CPAP arm showed some variability in the pressures used, ranging from 5 to 7 cm H2O. Six studies directly weaned babies from CPAP to room air, while one trial [13] followed a gradual weaning approach, alternating periods of CPAP and time off CPAP. In the HFNC arm, the high flow ranged from as low as 2 to as high as 7 L per minute across the studies, and the weaning process varied based on the individual study protocols, as presented in Table 1. The risk of bias assessment is illustrated in Figure 2, and a detailed summary of the assessment can be found in the online supplemental Material.
Overall, six RCTs demonstrated appropriate randomisation methods and allocation concealment. However, one trial had an unclear randomisation generation method, though the allocation was adequate, ensuring no differences between the groups [7]. Three trials [7, 13, 14] were at high risk of performance bias due to unblinded interventions with insufficient information on adherence to the protocol; however, the other trials were rated as low risk, as they were conducted according to suitable protocols, and all participants received the interventions as per protocol with no deviations. Additionally, two trials [5, 11] had unclear detection bias risk due to insufficient information about whether the outcome could be influenced by knowledge of the intervention received, while the other trials were at a high risk of detection bias since knowledge of the intervention received could likely affect the outcome assessment. Attrition bias was not observed in any of the studies, and while four trials were considered low risk for reporting bias, two trials [7, 14] were registered after the study's completion and were therefore scored as unclear.
Primary Outcome
The meta-analysis incorporated five trials [6, 7, 11‒13] that provided data on the duration of respiratory support. The findings showed that using HFNC for weaning CPAP did not result in a statistically significant difference in the duration of respiratory support compared to weaning CPAP alone (MD (95% CI) in days 3.52 (−0.02, 7.05); 5 RCTs; participants = 488; I2 = 29%). The evidence was downgraded due to limitations within the studies and the imprecision, leading to an overall grade of low certainty (Table 2; Fig. 3). Publication bias was not assessed due to the inclusion of only five RCTs in the meta-analysis. No subgroup analysis was performed due to lack of available data.
Forest plot comparing the duration of respiratory support when using a HFNC for continuous positive airway pressure (CPAP) weaning versus CPAP weaning alone.
Forest plot comparing the duration of respiratory support when using a HFNC for continuous positive airway pressure (CPAP) weaning versus CPAP weaning alone.
Secondary Outcomes
Apart from any nasal trauma, no significant differences were observed in the secondary outcomes. The meta-analysis showed HFNC for weaning CPAP resulted in reduced nasal trauma compared to weaning CPAP alone ((RR (95% CI) 0.61 (0.38, 0.99); 4 RCTs; participants = 335; I2 = 0%) [5, 6, 12, 13] (Table 2; Fig. 4). The evidence certainty was downgraded due to study limitations and imprecision, resulting in low certainty of evidence. No significant differences were observed in other outcomes, such as moderate to severe nasal trauma ((RR (95% CI) 0.24 (0.04,1.40); 2 RCTs; participants = 185; I2 = 0%), weaning failure ((RR (95% CI) 0.86 (0.59,1.26); 6 RCTs; participants = 700; I2 = 30%), any CLD ((RR (95% CI) 0.85 (0.08, 8.74); 3 RCTs, participants = 395; I2 = 78%), moderate to severe CLD ((RR (95% CI) 0.83 (0.53,1.31); 4 RCTs; participants = 335; I2 = 17%), ROP ((RR (95% CI) 0.40 (0.10,1.55); 5 RCTs; participants = 582; I2 = 68%), time to achieve full feeds ((MD (95% CI) 0.40 (−2.73, 3.53); 4 RCTs; participants = 481; I2 = 6%), length of hospital stay ((MD (95% CI) −0.86 (−5.30, 3.58); 4 RCTs; participants = 421; I2 = 0%) (Table 2 and online suppl. e-figures 1–7). The evidence certainty for these secondary outcomes was graded as low to very low certainty, as highlighted in Table 2.
Forest plot comparing the incidence of nasal trauma when using a HFNC for continuous positive airway pressure (CPAP) weaning versus CPAP weaning alone.
Forest plot comparing the incidence of nasal trauma when using a HFNC for continuous positive airway pressure (CPAP) weaning versus CPAP weaning alone.
Discussion
The findings of this systematic review, based on data from seven RCTs encompassing 781 preterm infants, suggest that the utilisation of HFNC for weaning CPAP in preterm infants may not significantly affect the duration of respiratory support but may potentially reduce the occurrence of nasal trauma. It is important to note that the evidence is of low certainty due to limitations in RCTs and imprecision. Additionally, the meta-analysis revealed no statistically significant differences between groups for all other secondary outcomes, with the certainty of evidence ranging from low to very low.
Among the 7 included RCTs in the systematic review, primary outcome data could only be extracted from 5 studies for the meta-analysis. While the meta-analysis did not yield statistically significant differences, a closer examination of the data suggests a potential concern. The pooled estimate indicates that when using HFNC for weaning CPAP compared to weaning CPAP alone, the duration of respiratory support may increase by 3.5 days, with a confidence interval ranging from a slight reduction of 0.02 days to a potential increase of up to 7 days. These findings raise questions about the use of HFNC for weaning CPAP support in preterm infants, as noted in other studies [7, 15‒18], and emphasise the need for further investigation with larger RCTs. Including data from future RCTs may improve the confidence in these estimations.
Similarly, the estimates for all the other evaluated outcomes were imprecise, suggesting that the overall statistical power was inadequate to detect any potential differences between them if they existed. Our findings regarding lower nasal trauma with HFNC align with similar observations in other studies [4, 12], but no significant difference was observed in moderate to severe nasal trauma between the groups. It is crucial to highlight that the confidence in the estimate for any nasal trauma is low due to the imprecise nature of the results, with the smallest observed benefit being either negligible or not clinically meaningful.
Large RCTs and systematic reviews investigating the use of HFNC in various contexts, including primary support [4, 19, 20] and post-extubation [4, 21], consistently report unfavourable outcomes. Additionally, data have raised concerns about HFNCs ability to deliver adequate pressure in preterm infants reliably [7, 15‒18]. As a result, the use of HFNC in preterm infants, especially as primary or post-extubation support, is generally limited. However, its use for weaning CPAP support continues [22, 23], partly due to the absence of data demonstrating that HFNC may not be beneficial. Additionally, clinicians may support the use of HFNC for weaning CPAP as it can aid in transitioning neonates from intensive care to special care units. The simplicity of HFNC use and its comfort, particularly during skin-to-skin care, further endorse its adoption. Nonetheless, our meta-analysis, based on up-to-date data synthesis, provides valuable insights into the use of HFNC for weaning CPAP support, offering guidance to clinicians for informed clinical decision-making and future research directions in this field. Moreover, it is crucial to bear in mind that CPAP use in infants may promote lung growth, as highlighted by studies demonstrating a greater increase in functional residual capacity in babies subjected to extended CPAP [24], an effect that may not occur with HFNC.
Our study has several notable strengths. It is the first systematic review dedicated to examining the benefits and harms of using HFNC in weaning CPAP support for stable preterm infants. By conducting an extensive and comprehensive search of important databases, we have ensured the inclusion of all relevant studies exploring this specific question. Additionally, our use of the GRADE framework to appraise the evidence enhances the interpretability of our results for clinicians. These strengths emphasise the importance and relevance of our study in contributing to the existing knowledge on this subject and guiding clinical decision-making for the management of preterm infants during CPAP weaning with HFNC.
Nevertheless, our study is not without its limitations. The primary constraint lies in the relatively smaller number of participants included in the trials, which likely has affected the statistical power and precision of our results. Another significant challenge arises from the nature of the intervention, as blinding is impractical in this context, leading to potential risks of bias. These factors collectively weakened the certainty of evidence in our study. Furthermore, there is a lack of sufficient data on infants with <28 weeks GA, leaving a gap in understanding the applicability of HFNC weaning in this subgroup, and in the current meta-analysis subgroup data was not available to explore the differential treatment effects.
Moreover, the diversity in flow rates and weaning practices, as well as the variability of CPAP devices used and the population studied among the studies, may introduce heterogeneity and potentially impact the reliability of the comparison. Additionally, the heterogeneity in NICU care, including variations in quality, facilities, and staff competency, is noteworthy, especially given that the studies stem from seven different countries, suggesting potential differences in overall NICU care despite some similarities in the protocols. Nevertheless, we employed a random-effects model and did not find any significant statistical heterogeneity for all except two secondary outcomes. Lastly, the flow rates used in the studies might not adequately reflect current clinical practices, further limiting the generalisability of the findings. It is also crucial to highlight that outcomes may vary based on the timing of high-flow therapy application in the course of ongoing respiratory disease, considering factors such as the severity of lung disease and the duration of respiratory support before initiating the therapy.
In summary, this systematic review suggests that using HFNC for weaning CPAP in preterm infants may not significantly impact the duration of respiratory support but may potentially reduce nasal trauma. However, the evidence certainty is low due to limitations in the trials and smaller sample sizes. Clinicians should exercise caution when considering HFNC for weaning CPAP until additional supportive evidence on its safety becomes available. Future research should focus on larger cohorts, including infants with gestational ages less than 28 weeks, using current clinical practice flows and addressing weaning protocol variability to provide more reliable evidence for clinical decision-making in this vulnerable population.
Acknowledgments
We want to express our gratitude to Dr. Francesco Cresi and Dr. Elena Spada for providing the pertinent data for the meta-analysis.
Statement of Ethics
An ethics statement is not applicable because this study is based exclusively on published literature.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
No specific funding was sought for this project. Dr. Razak receives a doctoral scholarship from Monash University and The Lions Cord Blood Foundation. The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Author Contributions
Yasser Balhareth: conception and design, acquisition, analysis, or interpretation of data, and drafting the manuscript. Abdul Razak: conception and design, acquisition, interpretation of data, drafting the manuscript, critical revision of the manuscript for important intellectual content, and supervision. Both authors contributed equally and are joint first co-authors.
Data Availability Statement
All relevant data are submitted with the publication. Further enquiries can be directed to the corresponding author.