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P: Preterm neonates

I: High flow nasal cannula

C: Nasal CPAP

O: Treatment failure

One article selected

BACKGROUND:

As a noninvasive respiratory support mode, high-flow nasal cannula (HFNC) is widely used in preterm infants at neonatal care units. HFNC is often used as an alternative to nasal continuous positive airway pressure (NCPAP) for initial or post-extubation respiratory support. The purpose of this meta-analysis is to evaluate and compare the efficacy and safety of HFNC and NCPAP for respiratory support in preterm infants.

METHODS:

We searched PubMed, Web of Science, Embase, Cochrane Library, Clinicaltrials.gov, Controlled-trials.com, Google Scholar, VIP, and Wang Fang for articles from their inception to December 2018. All published randomized controlled trials (RCTs) evaluating and comparing the effects of HFNC and NCPAP therapy for primary respiratory support in newborns were included. All meta-analyses were performed using Review Manager 5.3.

RESULTS:

In total, 21 RCTs involving 2886 preterm infants were included. The results of the meta-analysis revealed the following: (1) for primary respiratory support, the rates of treatment failure at trial entry were similar between HFNC and CPAP (relative risk 1.03, 95% confidence interval 0.79-1.33), and HFNC had reduced nasal trauma (p < .00001); and (2) for respiratory support after extubation, CPAP was associated with a lower likelihood of treatment failure than HFNC (relative risk 1.23, 95% confidence interval 1.01-1.50). The incidences of nasal trauma and pneumothorax in the HFNC group were significantly lower than that in the CPAP group (p < .0001 and p = .03). Serious adverse events did not significantly differ.

CONCLUSIONS:

HFNC had effects similar to those of CPAP regarding the failure of initial respiratory support in premature infants and was associated with reduced nasal trauma compared to CPAP. Following extubation, CPAP had fewer treatment failures than HFNC, but CPAP had a significantly increased rate of nasal trauma and pneumothorax. Further studies are needed to clarify the potential benefits of HFNC as primary respiratory support in extremely low birth weight or extremely preterm infants.

KEYWORDS:

High-flow nasal cannula; nasal continuous positive airway pressure; preterm infants; respiratory distress syndrome; respiratory support

PMID: 30966839 DOI: 10.1080/14767058.2019.1606193

AIM:

We reviewed using a high-flow nasal cannula (HFNC) as first-line support for preterm neonates with, or at risk of, respiratory distress.

METHODS:

This rapid systematic review covered biomedical databases up to June 2017. Weincluded randomised controlled trials (RCTs) published in English. The reference lists of the studies and relevant reviews we included were also screened. We performed the study selection, data extraction, study quality assessment, meta-analysis and quality of evidence assessment following the Grading of Recommendations Assessment, Development and Evaluation system.

RESULTS:

Pooled results from six RCTs covering 1227 neonates showed moderate-quality evidence that HFNC was associated with a higher rate of failure than nasal continuous positive airway pressure (NCPAP) in preterm neonates of at least 28 weeks of gestation, with a risk ratio of 1.57. Low-quality evidence showed no significant differences between HFNC and NCPAP in the need for intubation and bronchopulmonary dysplasia rate. HFNC yielded a lower rate of nasal injury (risk ratio 0.50). When HFNC failed, intubation was avoided in some neonates by switching them to NCPAP.

CONCLUSION:

HFNC had higher failure rates than NCPAP when used as first-line support.Subsequently switching to NCPAP sometimes avoided intubation. Data on the most immature neonates were lacking.

©2018 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

KEYWORDS:

Bronchopulmonary dysplasia; Continuous positive airway pressure; High-flow nasal cannula; Neonate; Respiratory distress

PMID: 29751368 DOI: 10.1111/apa.14396

BACKGROUND:

Treatment with nasal high-flow therapy has efficacy similar to that of nasal continuous positive airway pressure (CPAP) when used as postextubation support in neonates. The efficacy of high-flow therapy as the primary means of respiratory support for preterm infants with respiratory distress has not been proved.

METHODS:

In this international, multicenter, randomized, noninferiority trial, we assigned 564 preterm infants(gestational age, ≥28 weeks 0 days) with early respiratory distress who had not received surfactant replacement to treatment with either nasal high-flow therapy or nasal CPAP. The primary outcome was treatment failure within 72 hours after randomization.Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome; the chosen margin of noninferiority was 10 percentage points. Infants in whom high-flow therapy failed could receive rescue CPAP; infants in whom CPAP failed were intubated and mechanically ventilated.

RESULTS:

Trial recruitment stopped early at the recommendation of the independent data and safety monitoring committee because of a significant difference in the primary outcome between treatment groups. Treatment failure occurred in 71 of 278 infants (25.5%) in the high-flow group and in 38 of 286 infants(13.3%) in the CPAP group (risk difference, 12.3 percentage points; 95% confidence interval [CI], 5.8 to 18.7; P<0.001). The rate of intubation within 72 hours did not differ significantly between the high-flow and CPAP groups (15.5% and 11.5%, respectively; risk difference, 3.9 percentage points; 95% CI, -1.7 to 9.6; P=0.17), nor did the rate of adverse events.

CONCLUSIONS:

When used as primary support for preterm infants with respiratory distress, high-flow therapy resulted in a significantly higher rate of treatment failure than did CPAP. (Funded by the National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12613000303741 .).

Comment in

Nasal continuous positive airway pressure outperforms heated high-flow nasal cannula therapy as primaryrespiratory therapy in preterm infants. [Evid Based Med. 2017]

Is high-flow nasal cannula noninferior to nasal CPAP for the initial management of preterm infants? [Acta Paediatr. 2017]

PMID: 27653564 DOI: 10.1056/NEJMoa1603694

[Indexed for MEDLINE] Free full text

Abstract

IMPORTANCE:

Heated, humidified high-flow nasal cannula (HHHFNC) has gained increasing popularity as respiratory support for newborn infants thanks to ease of use and improved patient comfort. However, its role as primary therapy for respiratory distress syndrome (RDS) of prematurity needs to be further elucidated by large, randomized clinical trials.

OBJECTIVE:

To determine whether HHHFNC provides respiratory support noninferior to nasal continuous positive airway pressure (nCPAP) or bilevel nCPAP (BiPAP) as a primary approach to RDS in infants older than 28 weeks’ gestational age (GA).

DESIGN, SETTING, AND PARTICIPANTS:

An unblinded, monocentric, randomized clinical noninferiority trial at a tertiary neonatal intensive care unit. Inborn infants at 29 weeks 0 days to 36 weeks 6 days of GA were eligible if presenting with mild to moderate RDS requiring noninvasive respiratory support. Criteria for starting noninvasive respiratory support were a Silverman score of 5 or higher or a fraction of inspired oxygen higher than 0.3 for a target saturation of peripheral oxygen of 88% to 93%. Infants were ineligible if they had major congenital anomalies or severe RDS requiring early intubation. Infants were enrolled between January 5, 2012, and June 28, 2014.

INTERVENTIONS:

Randomization to either HHHFNC at 4 to 6 L/min or nCPAP/BiPAP at 4 to 6 cm H2O.

MAIN OUTCOMES AND MEASURES:

Need for mechanical ventilation within 72 hours from the beginning of respiratory support. The absolute risk difference in the primary outcome and its 95% confidence interval were calculated to determine noninferiority (noninferiority margin, 10%). An intention-to-treat analysis was performed.

RESULTS:

A total of 316 infants were enrolled in the study: 158 in the HHHFNC group (mean [SD] GA, 33.1 [1.9] weeks; 52.5% female) and 158 in the nCPAP/BiPAP group (mean [SD] GA, 33.0 [2.1] weeks; 47.5% female). The use of HHHFNC was noninferior to nCPAP with regard to the primary outcome: failure occurred in 10.8% vs 9.5% of infants, respectively (95% CI of risk difference, -6.0% to 8.6% [within the noninferiority margin]; P = .71). Significant between-group differences in secondary outcomes were not found between the HHHFNC and nCPAP/BiPAP groups, including duration of respiratory support (median [interquartile range], 4.0 [2.0 to 6.0] vs 4.0 [2.0 to 7.0] days; 95% CI of difference in medians, -1.0 to 0.5; P = .45), need for surfactant (44.3% vs 46.2%; 95% CI of risk difference, -9.8 to 13.5; P = .73), air leaks (1.9% vs 2.5%; 95% CI of risk difference, -3.3 to 4.5; P = .70), and bronchopulmonary dysplasia (4.4% vs 5.1%; 95% CI of risk difference, -3.9 to 7.2; P = .79).

CONCLUSIONS AND RELEVANCE:

In this study, HHHFNC showed efficacy and safety similar to those of nCPAP/BiPAP when applied as a primary approach to mild to moderate RDS in preterm infants older than 28 weeks’ GA.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT02570217.

PMID:

27532363

DOI:

10.1001/jamapediatrics.2016.1243

Abstract

BACKGROUND:

Nasal continuous positive airway pressure (nCPAP) is the standard noninvasive respiratory support for newborns with respiratory distress. Evidence for high-flownasal cannula (HFNC) as an alternative mode of respiratory support is inconclusive.

OBJECTIVE:

The aim of this work was to evaluate whether HFNC is not inferior to nCPAP in reducing the need for higher respiratory support in the first 72 h of life when applied as a noninvasive respiratory support mode for preterm neonates with respiratory distress.

METHODS:

Preterm infants (gestation ≥28 weeks and birth weight ≥1,000 g) with respiratory distress were randomized to either HFNC or nCPAP in a non-inferiority trial. Failure of the support mode in the first 72 h after birth was the primary outcome. Infants failing HFNC were rescued either with nCPAP or mechanical ventilation, and those failing nCPAP received mechanical ventilation.

RESULTS:

During the study period, 139 and 133 infants were randomized to the nCPAP and HFNC groups, respectively. The study was stopped after an interim analysis showed a significant difference (p < 0.001) in the primary outcome between the 2 groups. The treatment failure was significantly higher in the HFNC group (HFNC, n = 35, 26.3%, vs. CPAP, n = 11, 7.9%, risk difference 18.4 percentage points, 95% CI 9.7-27). Among the infants in the HFNC group who had treatment failure (n = 35), 32 were initially rescued with CPAP. The rate of mechanical ventilation in the first 3 and 7 days of life was similar between the 2 groups. Treatment failure was significantly higher in the HFNC group per protocol and also in the subgroups of infants with moderate (Silverman Anderson score, SAS ≤5) or severe respiratory distress (SAS score >5).

CONCLUSIONS:

When comparing HFNC to nCPAP as a primary noninvasive respiratory support in preterm infants with respiratory distress, HFNC is inferior to nCPAP in avoiding the need for a higher mode of respiratory support in the first 72 h of life.

© 2018 S. Karger AG, Basel.

KEYWORDS:

High-flow nasal cannula; Nasal continuous positive airway pressure; Preterm infant; Respiratory distress

Comment in

• Is High-Flow Nasal Cannula Useful as Primary Respiratory Support in Preterm Infants?[Neonatology. 2018]
• Reply to the Letter to the Editor: “Is High-Flow Nasal Cannula Useful as Primary Respiratory Support in Preterm Infants?” [Neonatology. 2018]

(# of subjects/ studies, cohort definition etc. )

– Inclusion Criteria: (1) RCTs (2) Infants randomly assigned to CPAP or HFNC for primary respiratory support after birth orrespiratory support after extubation (3)Reporting on one of the following outcome parameters: primary outcome of treatment failure after noninvasive respiratory support defined as requiring invasive respiratory support within 7 days of trial entry; secondary outcomes of days of respiratory support, time until full feeds, and adverse outcomes of bronchopulmonary dysplasia, death, intraventricular hemorrhage, retinopathy of prematurity, persistent ductus arteriosus requiring drug treatment or surgery, necrotizing enterocolitis, confirmed sepsis, pneumothorax, and nasal trauma

– Exclusion Criteria: (1) Nonclinical studies (2) Retrospective studies (3) Duplicate reports or secondary or post hoc analyses of the same study population (4) Lack of sufficient information regarding baseline or outcome data

– Twenty-One RCTs included (n = 2886 preterm infants)

– Data from inception up to December 2018

– RCTs included: seeTable 1 of publication

– Secondary Outcomes = Days of respiratory support, time until full feeds, adverse outcomes

– Authors concluded that “HFNC has similar rates of effect to those of CPAP when used for primary respiratory support in premature infants to prevent treatment failure…”

– Ten trials were classified as having an unclear risk of bias

– Ten trials did not sufficiently describe randomization methods

– Heterogeneity of study characteristics

– Lack of standardization of treatment failure

– Lack of subgroup analyses based on gestational age or birth weight due to lack of patient data

– Performed following Cochrane Handbook Recommendations and GRADE Recommendations

– Inclusion Criteria: (1) RCTs (2)Compared HFNC to NCPAP as primary support for neonates born at <37 weeks gestational age with, or at risk of, respiratory distress and reported the outcomes of treatment failure or intubation

– Six RCTs included (n = 1227 neonates)

– RCTs included: seeTable 1 of publication

– Secondary Outcomes = Need for surfactant, duration of any respiratory support, time to full feeds, length of stay

– Sensitivity analysis was performed which included only studies at low risk of bias in all domains. The results did not change for the primary outcome (HFNC treatmentstill resulted in a significantly higher rate of treatment failure than NCPAP). The authors state that the consistency of these findings indicate the “… robustness of this finding.”

– The authors cannot exclude the possibility that the lack of statistical significance between HFNC and NCPAP in the need for intubation may be the result of the fact that those who failed HFNC could first be switched to NCPAP (which may have “rescued” the patients from requiring intubation)

– Authors’ Recommendation = HFNC should be used as first-line treatment for respiratory distresswith caution andonly in more mature premature infants with mild signs of distress

– Less than optimal sample sizes for clinical outcomes

– Variation in study characteristics (design, population, etc.)

– Inclusion Criteria: (1) Gestational age of 28 weeks  days to 36 weeks 6 days and less than 24h old (2) Had not previously received endotracheal ventilation or surfactant treatment (3) Attending clinician had decided to commence or continue noninvasive respiratory support

– Exclusion Criteria: (1) Urgent need for intubation and ventilation (determined by attending clinician) (2) Already met criteria for treatment failure (3) Had a known major congenital abnormality or pneumothorax (4) Had received 4 hours or more of CPAP support

– n = 564 neonates; 278 patients in HFNC group and 286 patients in CPAP group

(1) FiO2 of 0.4 or higher

(2) pH of 7.2 or less plus a partial pressure of CO2 greater than 60mm Hg on a sample of arterial or free-flowing capillary blood obtained at least 1 hour after commencement of the assigned treatment

(3) Either two or more episodes of apnea requiring positive-pressure ventilation within a 24h period or six or more episodes requiring any intervention within a 6h period.

(4) Infants with an urgent need for intubation and mechanical ventilation (as determined by the treating clinician)

– Secondary Outcomes = Reason for treatment failure, use of mechanical ventilation within 72h after randomization or at any time during admission, nasal trauma and other complications, cost of care

(1) 71/278 (25.5%) in HFNC

(2) 38/286 (13.3%) in CPAP

– Risk difference calculated as 12.3 percentage points, 95% CI, 5.8 to 18.7, p < 0.001

– Subgroup analyses among infants with GA <32 weeks and those with GA of >32 weeks found treatment failure was statistically significantly more common in HFNC than CPAP group

– Trial was stopped (in June 2015) at the recommendation of the independent data and safety monitoring committee since there was highly significant difference (p < 0.001) in the rate of treatment failure between HFNC and CPAP treatment and that continued recruitment was unlikely to show noninferiority of HFNC to CPAP.

– No significant difference in intubation between groups. Similar to Article 2, the authors cannot exclude the possibility that transition from HFNC to NCPAP worked to “rescue” those neonates that may have otherwise required intubation.

– Authors’ Conclusions = HFNC treatments results in a significantly higher rate of treatment failure than does CPAP when used as primary support for preterm infants with respiratory distress

– Inclusion Criteria: (1) GA of 29wks 0d to 36wks 6d (2) mild to moderate RDS requiring noninvasive respiratory support, characterized by a Silverman score of 5 or higher or a fraction of inspired oxygen (FIO2) greater than 0.3 for target saturation of peripheral oxygen (SpO2) 88% to 93% (3) parental consent obtained

– Exclusion Criteria: (1) Severe RDS requiring early intubation according to the American Academy of Pediatrics guidelines for neonatal resuscitation (2) major congenital anomalies that might affect respiratory outcomes (3) severe intraventricular hemorrhage

– n = 316 neonates; 158 in HHHFNC and 158 in nCPAP/BiPAP group (Groups with homogenous baseline characteristics at randomization)

– Secondary Outcomes = days receiving respiratory support, days receiving noninvasive respiratory support, days receiving supplemental O2, days receiving caffeine treatment, need for surfactant, rate of air leaks, rate of bronchopulmonary dysplasia (BPD), rate of sepsis (positive blood culture), necrotizing enterocolitis, retinopathy of prematurity, death, number of days when full enteral feeding was achieved (> or = to 120mL/kg per day), body weight at discharge, exclusive breastfeeding at discharge, length of hospitalization

– No significant differences between the two groups for any secondary respiratory outcomes

– Treatment duration (respiratory support) was similar between both groups

– Inability to blind the intervention

– The authors state that the study was conducted in an “nCPAP-oriented NICU,” declaring that the caregivers were more comfortable with nCPAP/BiPAP than with HHHFNC.

– Inclusion Criteria: (1) Preterm neonates with GA > or = to 28 wks (2) Birth Weight > or = to 1000g (3) Respiratory distress within the first 6h of birth; Respiratory distress was defined as presence of tachypnea, chest retraction, and/or grunting

– Exclusion Criteria: (1) Infants with major malformations

(2) Infants intubated in the delivery room

– n = 272 neonates; 133 in HFNC group, 139 in nCPAP group

– Secondary Outcomes = Need for mechanical ventilation in the first 72h and in the first 7d of life, need for higher respiratory support or intubation for surfactant, duration of noninvasive ventilation, duration of ventilation, duration of oxygen therapy, nasal injury at discharge, neonatal mortality, pulmonary air leaks, hemodynamically significant patent ductus arteriosus, necrotizing enterocolitis, culture-positive sepsis, supplemental oxygen at 28d of life, bronchopulmonary dysplasia (supplemental oxygen at 36wks postmenstrual age), intraventricular hemorrhage (grade III or IV), cystic periventricular leukomalacia, retinopathy of prematurity (requiring laser or surgery)

– Treatment failure occurred significantly later in nCPAP group than HFNC group (Kaplan-Meier survival analysis: HFNC group 3h, nCPAP group 22h, Mantel-Cox log-rank test p = 0.03)

– No statistically significant difference in secondary outcomes

– Authors’ Conclusion: “When comparing HFNC to nCPAP as a primary non-invasive respiratory support in preterm infants with respiratory distress, HFNC is inferior to nCPAP in avoiding the need for a higher mode of respiratory support in the first 72h of life”

– Protocol deviations in 16 of 272 infants (5.8%)

– Premature termination of the trial