First name
Haresh
Last name
Kirpalani

Title

Use of ventilation/perfusion mismatch to guide individualised CPAP level selection in preterm infants: a feasibility trial.

Year of Publication

2022

Date Published

09/2022

ISSN Number

1468-2052

Abstract

OBJECTIVE: To measure within-subject changes in ventilation/perfusion (V'/Q') mismatch in response to a protocol of individualised nasal continuous positive airway pressure (CPAP) level selection.

DESIGN: Single-arm, non-randomised, feasibility trial.

SETTING: Three centres in the Children's Hospital of Philadelphia neonatal care network.

PATIENTS: Twelve preterm infants of postmenstrual age 27-35 weeks, postnatal age >24 hours, and receiving a fraction of inspired oxygen (FiO) >0.25 on CPAP of 4-7 cm HO.

INTERVENTIONS: We applied a protocol of stepwise CPAP level changes, with the overall direction and magnitude guided by individual responses in V'/Q' mismatch, as determined by the degree of right shift (kilopascals, kPa) in a non-invasive gas exchange model. Best CPAP level was defined as the final pressure level at which V'/Q' improved by more than 5%.

MAIN OUTCOME MEASURES: Within-subject change in V'/Q' mismatch between baseline and best CPAP levels.

RESULTS: There was a median (IQR) within-subject reduction in V'/Q' mismatch of 1.2 (0-3.2) kPa between baseline and best CPAP levels, p=0.02. Best CPAP was observed at a median (range) absolute level of 7 (5-8) cm HO.

CONCLUSIONS: Non-invasive measures of V'/Q' mismatch may be a useful approach for identifying individualised CPAP levels in preterm infants. The results of our feasibility study should be interpreted cautiously and replication in larger studies evaluating the impact of this approach on clinical outcomes is needed.

TRIAL REGISTRATION NUMBER: NCT02983825.

DOI

10.1136/archdischild-2022-324474

Alternate Title

Arch Dis Child Fetal Neonatal Ed

PMID

36104165

Title

Nasal continuous positive airway pressure levels for the prevention of morbidity and mortality in preterm infants.

Year of Publication

2021

Number of Pages

CD012778

Date Published

2021 11 30

ISSN Number

1469-493X

Abstract

<p><strong>BACKGROUND: </strong>Preterm infants are at risk of lung atelectasis due to various anatomical and physiological immaturities, placing them at high risk of respiratory failure and associated harms. Nasal continuous positive airway pressure (CPAP) is a positive pressure applied to the airways via the nares. It helps prevent atelectasis and supports adequate gas exchange in spontaneously breathing infants. Nasal CPAP is used in the care of preterm infants around the world. Despite its common use, the appropriate pressure levels to apply during nasal CPAP use remain uncertain.</p>

<p><strong>OBJECTIVES: </strong>To assess the effects of 'low' (≤ 5 cm HO) versus 'moderate-high' (&gt; 5 cm HO) initial nasal CPAP pressure levels in preterm&nbsp;infants receiving CPAP either: 1) for initial respiratory support after birth and neonatal resuscitation or 2) following mechanical ventilation and endotracheal extubation.</p>

<p><strong>SEARCH METHODS: </strong>We ran a comprehensive search on 6 November 2020 in the following databases: CENTRAL via CRS Web and MEDLINE via Ovid. We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-randomized trials.</p>

<p><strong>SELECTION CRITERIA: </strong>We included RCTs, quasi-RCTs, cluster-RCTs and cross-over RCTs randomizing preterm infants of gestational age &lt; 37 weeks or birth weight &lt; 2500 grams within the first 28 days of life to different nasal CPAP levels.</p>

<p><strong>DATA COLLECTION AND ANALYSIS: </strong>We used the standard methods of Cochrane Neonatal to collect and analyze data. We used the GRADE approach to assess the certainty of the evidence for the prespecified primary outcomes.</p>

<p><strong>MAIN RESULTS: </strong>Eleven trials met inclusion criteria of the review. Four trials were parallel-group RCTs reporting our prespecified primary or secondary outcomes. Two trials randomized 316 infants to low versus moderate-high nasal CPAP for initial respiratory support, and two trials randomized 117 infants to low versus moderate-high nasal CPAP following endotracheal extubation. The remaining seven studies were cross-over trials reporting short-term physiological outcomes. The most common potential sources of bias were absent or unclear blinding of personnel and assessors and uncertain selective reporting. Nasal CPAP for initial respiratory support after birth and neonatal resuscitation None of the six primary outcomes prespecified for inclusion in the summary of findings was eligible for meta-analysis. No trials reported on moderate-severe neurodevelopmental impairment at 18 to 26 months. The remaining five outcomes were reported in a single trial. On the basis of this trial, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcomes of: death or bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.56 to 1.85; 1 trial, 271 participants); mortality by hospital discharge (RR 1.04, 95% CI 0.51 to 2.12; 1 trial, 271 participants); BPD at 28 days of age (RR 1.10, 95% CI 0.56 to 2.17; 1 trial, 271 participants); BPD at 36 weeks' PMA (RR 0.80, 95% CI 0.25 to 2.57; 1 trial, 271 participants), and treatment failure or need for mechanical ventilation (RR 1.00, 95% CI 0.63 to 1.57; 1 trial, 271 participants). We assessed the certainty of the evidence as very low for all five outcomes due to risk of bias, a lack of consistency across multiple studies, and imprecise effect estimates. Nasal CPAP following mechanical ventilation and endotracheal extubation One of the six primary outcomes prespecified for inclusion in the summary of findings was eligible for meta-analysis. On the basis of these data, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcome of treatment failure or need for mechanical ventilation (RR 1.52, 95% CI 0.92 to 2.50; 2 trials, 117 participants; I = 17%; risk difference 0.15, 95% CI -0.02 to 0.32; number needed to treat for an additional beneficial outcome 7, 95% CI -50 to 3). We assessed the certainty of the evidence as very low due to risk of bias, inconsistency across the studies, and imprecise effect estimates. No trials reported on moderate-severe neurodevelopmental impairment at 18 to 26 months or BPD at 28 days of age. The remaining three outcomes were reported in a single trial. On the basis of this trial, we are uncertain whether low or moderate-high nasal CPAP levels improve the outcomes of: death or BPD at 36 weeks' PMA (RR 0.87, 95% CI 0.51 to 1.49; 1 trial, 93 participants); mortality by hospital discharge (RR 2.94, 95% CI 0.12 to 70.30; 1 trial, 93 participants), and BPD at 36 weeks' PMA (RR 0.87, 95% CI 0.51 to 1.49; 1 trial, 93 participants). We assessed the certainty of the evidence as very low for all three outcomes due to risk of bias, a lack of consistency across multiple studies, and imprecise effect estimates.&nbsp; AUTHORS' CONCLUSIONS: There are insufficient data from randomized trials to guide nasal CPAP level selection in preterm infants, whether provided as initial respiratory support or following extubation from invasive mechanical ventilation. We are uncertain as to whether low or moderate-high nasal CPAP levels improve morbidity and mortality in preterm infants. Well-designed trials evaluating this important aspect of a commonly used neonatal therapy are needed.</p>

DOI

10.1002/14651858.CD012778.pub2

Alternate Title

Cochrane Database Syst Rev

PMID

34847243

Title

Loop Diuretics in Severe Bronchopulmonary Dysplasia: Cumulative Use and Associations with Mortality and Age at Discharge.

Year of Publication

2020

Date Published

2020 Nov 02

ISSN Number

1097-6833

Abstract

<p><strong>OBJECTIVES: </strong>To measure between-center variation in loop diuretic use for infants developing severe bronchopulmonary dysplasia (BPD) in United States children's hospitals, and to compare mortality and age at discharge among infants from low versus high use centers.</p>

<p><strong>STUDY DESIGN: </strong>We performed a retrospective cohort study of preterm infants &lt;32 weeks gestational age developing severe BPD. The primary outcome was cumulative loop diuretic use, defined as the proportion of days with exposure between admission and discharge. Infant characteristics associated with loop diuretic use at P &lt; .10 were included in multivariable models to adjust for center differences in case-mix. Hospitals were ranked from lowest to highest in adjusted use, and dichotomized into low or high use centers. We then compared mortality and postmenstrual age at discharge between groups through multivariable analyses.</p>

<p><strong>RESULTS: </strong>We identified 3252 subjects from 43 centers. Significant variation between centers remained despite adjustment for infant characteristics, with use present in an adjusted mean range of 7.3% to 49.4% of days, p &lt; 0.0001. Mortality (adjusted odds ratio 0.98 [95% CI 0.62, 1.53], p = 0.92) and postmenstrual age at discharge (marginal mean [95% CI]: 47.3 [46.8 , 47.9] versus 47.4 [46.9, 47.9] weeks, p = 0.96) were similar in low and high use groups, respectively.</p>

<p><strong>CONCLUSIONS: </strong>Marked variation in loop diuretic use for infants developing severe BPD exists between US children's hospital, without an observed difference on mortality or discharge age. Research to provide evidence-based guidance for this common exposure is needed.</p>

DOI

10.1016/j.jpeds.2020.10.073

Alternate Title

J Pediatr

PMID

33152371

Title

Individualising care in severe bronchopulmonary dysplasia: a series of N-of-1 trials comparing transpyloric and gastric feeding.

Year of Publication

2019

Date Published

2019 Nov 04

ISSN Number

1468-2052

Abstract

<p><strong>OBJECTIVE: </strong>Compare rates of hypoxaemia during transpyloric and gastric feedings in very preterm infants with severe bronchopulmonary dysplasia.</p>

<p><strong>DESIGN: </strong>N-of-1 multiple crossover trials with individual patient and pooled data analyses.</p>

<p><strong>SETTING: </strong>Level IV intensive care nursery.</p>

<p><strong>PATIENTS: </strong>Infants receiving positive airway pressure between 36 and 55 weeks postmenstrual age were enrolled between December 2014-July 2016.</p>

<p><strong>INTERVENTION: </strong>N-of-1 trial consisting of two blocks, each with a 4-day gastric and 4-day transpyloric feeding period assigned in random order.</p>

<p><strong>MAIN OUTCOME MEASURES: </strong>The primary outcome was the frequency of daily intermittent hypoxaemic events (SpO ≤80% lasting 10-180 s). Secondary outcomes included the daily proportion of time with an SpO ≤80% and mean daily fraction of inspired oxygen.</p>

<p><strong>RESULTS: </strong>Of 15 infants, 13 completed the trial and 2 stopped early for transient worsening in respiratory status during gastric feedings. In the intention-to-treat analyses, transpyloric feedings resulted in increased rates of intermittent hypoxaemia in five infants, greater time per day in hypoxaemia in three infants and more supplemental oxygen use in three infants. One infant received more supplemental oxygen during gastric feedings. The remaining study outcomes were similar between the feeding routes in all other infants. Pooling all data, transpyloric feedings resulted in a higher frequency of intermittent hypoxaemic events (median 7.5/day (IQR 1-23.5) vs 3/day (1-11); adjusted incidence rate ratio 1.8, 95% CI 1.3 to 2.5) and a greater proportion of daily hypoxaemia time (median 0.8% (IQR 0.1-2.3) vs 0.4% (0.07-1.8); adjusted mean difference 1.6, 95% CI 1.1 to 2.5).</p>

<p><strong>CONCLUSIONS: </strong>Transpyloric compared with gastric feedings modestly increased rates of hypoxaemia among study participants.</p>

<p><strong>TRIAL REGISTRATION NUMBER: </strong>NCT02142621.</p>

DOI

10.1136/archdischild-2019-317148

Alternate Title

Arch. Dis. Child. Fetal Neonatal Ed.

PMID

31685527

Title

Nasal Intermittent Positive Pressure Ventilation Versus Nasal Continuous Positive Airway Pressure to Prevent Primary Noninvasive Ventilation Failure in Extremely Low Birthweight Infants.

Year of Publication

2019

Date Published

2019 Oct 08

ISSN Number

1097-6833

Abstract

<p>Reducing the risk of primary noninvasive ventilation failure in extremely low birthweight infants is linked to reducing bronchopulmonary dysplasia. In a secondary analysis of randomized data, we identified that failure rates and time to failure were similar for nasal intermittent positive pressure ventilation vs nasal continuous positive airway pressure.</p>

DOI

10.1016/j.jpeds.2019.08.064

Alternate Title

J. Pediatr.

PMID

31604630

Title

The promise and pitfalls of precision medicine to resolve black-white racial disparities in preterm birth.

Year of Publication

2019

Date Published

2019 Aug 05

ISSN Number

1530-0447

Abstract

<p>Differences in preterm birth rates between black and white women are the largest contributor to racial disparities in infant mortality. In today's age of precision medicine, analysis of the genome, epigenome, metabolome, and microbiome has generated interest in determining whether these biomarkers can help explain racial disparities. We propose that there are pitfalls as well as opportunities when using precision medicine analyses to interrogate disparities in health. To conclude that racial disparities in complex conditions are genetic in origin ignores robust evidence that social and environmental factors that track with race are major contributors to disparities. Biomarkers measured in omic assays that may be more environmentally responsive than genomics, such as the epigenome or metabolome, may be on the causal pathway of race and preterm birth, but omic observational studies suffer from the same limitations as traditional cohort studies. Confounding can lead to false conclusions about the causal relationship between omics and preterm birth. Methodological strategies (including stratification and causal mediation analyses) may help to ensure that associations between biomarkers and exposures, as well as between biomarkers and outcomes, are valid signals. These epidemiologic strategies present opportunities to assess whether precision medicine biomarkers can uncover biology underlying perinatal health disparities.</p>

DOI

10.1038/s41390-019-0528-z

Alternate Title

Pediatr. Res.

PMID

31382269

Title

Medication use in infants with severe bronchopulmonary dysplasia admitted to United States children's hospitals.

Year of Publication

2019

Date Published

2019 Jun 21

ISSN Number

1476-5543

Abstract

<p><strong>OBJECTIVE: </strong>To identify the number of cumulative medication exposures and most frequently used medications in infants with severe BPD.</p>

<p><strong>STUDY DESIGN: </strong>We performed a retrospective cohort study in infants with severe BPD admitted to United States children's hospitals. We measured cumulative medication exposures in individual subjects and between-center variation after adjustment for infant characteristics. We then identified the specific medications and therapeutic classes with the highest rates of use.</p>

<p><strong>RESULTS: </strong>In 3252 subjects across 43 hospitals, we identified a median (interquartile range) of 30 (17-45) cumulative medication exposures per infant. The adjusted mean number of medication exposures varied between centers (p &lt; 0.0001), with a range of 22-50. Diuretics and furosemide were the most frequently prescribed therapeutic class and specific medication for the management of severe BPD.</p>

<p><strong>CONCLUSIONS: </strong>Infants with severe BPD are exposed to alarming number of medications of unclear efficacy and safety, with marked variation between center.</p>

DOI

10.1038/s41372-019-0415-9

Alternate Title

J Perinatol

PMID

31227785

Title

The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants: An Evidence-Based Approach.

Year of Publication

2019

Date Published

2019 Apr 17

ISSN Number

1535-4970

Abstract

<p><strong>RATIONALE: </strong>Current diagnostic criteria for bronchopulmonary dysplasia rely heavily on the level and duration of oxygen therapy, do not reflect contemporary neonatal care, nor adequately predict childhood morbidity.</p>

<p><strong>OBJECTIVE: </strong>To determine which of 18 pre-specified, revised definitions of bronchopulmonary dysplasia, that variably define disease presence and severity according to the level of respiratory support and supplemental oxygen administered at 36 weeks postmenstrual age, best predicts death or serious respiratory morbidity through 18-26 months corrected age.</p>

<p><strong>METHODS: </strong>We assessed infants born &lt;32 weeks' gestation between 2011-2015 at 18 centers of the National Institute of Child Health and Human Development Neonatal Research Network.</p>

<p><strong>RESULTS: </strong>Of 2677 infants, 683 (26%) died or developed serious respiratory morbidity. The criteria that best predicted this outcome defined bronchopulmonary dysplasia according to treatment with the following support at 36 weeks postmenstrual age, irrespective of prior or current oxygen therapy: no bronchopulmonary dysplasia, no support (n=773); grade 1, nasal cannula ≤2L/min (n=1038); grade 2, nasal cannula &gt;2L/min or non-invasive positive airway pressure (n=617); and grade 3, invasive mechanical ventilation (n=249). These criteria correctly predicted death or serious respiratory morbidity in 81% of study infants. Rates of this outcome increased stepwise from 10% among infants without bronchopulmonary dysplasia to 77% among those with grade 3 disease. A similar gradient (33%-79%) was observed for death or neurodevelopmental impairment.</p>

<p><strong>CONCLUSIONS: </strong>The definition of bronchopulmonary dysplasia that best predicted early childhood morbidity categorized disease severity according to the mode of respiratory support at 36 weeks postmenstrual age, irrespective of supplemental oxygen use. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial License 4.0 (http://creativecommons.org/licenses/by-nc/4.0/).</p>

DOI

10.1164/rccm.201812-2348OC

Alternate Title

Am. J. Respir. Crit. Care Med.

PMID

30995069

Title

Positive end-expiratory pressure for preterm infants requiring conventional mechanical ventilation for respiratory distress syndrome or bronchopulmonary dysplasia.

Year of Publication

2019

Number of Pages

CD004500

Date Published

2019 Feb 26

ISSN Number

1469-493X

Abstract

<p><strong>BACKGROUND: </strong>Conventional mechanical ventilation (CMV) is a common therapy for neonatal respiratory failure. While CMV facilitates gas exchange, it may simultaneously injure the lungs. Positive end-expiratory pressure (PEEP) has received less attention than other ventilation parameters when considering this benefit-risk balance. While an appropriate PEEP level may result in clinical benefits, both inappropriately low or high levels may cause harm. An appropriate PEEP level may also be best achieved by an individualized approach.</p>

<p><strong>OBJECTIVES: </strong>1. To compare the effects of PEEP levels in preterm infants requiring CMV for respiratory distress syndrome (RDS). We compare both: zero end-expiratory pressure (ZEEP) (0 cm HO) versus any PEEP and low (&lt; 5 cm HO) vs high (≥ 5 cm HO) PEEP.2. To compare the effects of PEEP levels in preterm infants requiring CMV for bronchopulmonary dysplasia (BPD). We compare both: ZEEP (0 cm HO) vs any PEEP and low (&lt; 5 cm HO) versus high (≥ 5 cm HO) PEEP.3. To compare the effects of different methods for individualizing PEEP to an optimal level in preterm newborn infants requiring CMV for RDS.</p>

<p><strong>SEARCH METHODS: </strong>We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials, MEDLINE via PubMed, Embase, and CINAHL to 14 February 2018. We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials.</p>

<p><strong>SELECTION CRITERIA: </strong>We included all randomized or quasi-randomized controlled trials studying preterm infants born at less than 37 weeks' gestational age, requiring CMV and undergoing randomization to either different PEEP levels (RDS or BPD); or, two or more alternative methods for individualizing PEEP levels (RDS only). We included cross-over trials but limited outcomes to those from the first cross-over period.</p>

<p><strong>DATA COLLECTION AND ANALYSIS: </strong>We performed data collection and analysis according to the recommendations of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence for prespecified key clinically relevant outcomes.</p>

<p><strong>MAIN RESULTS: </strong>Four trials met the inclusion criteria. Two cross-over trials with 28 participants compared different PEEP levels in infants with RDS. Meta-analysis was limited to short-term measures of pulmonary gas exchange and showed no differences between low and high PEEP.We identified no trials comparing PEEP levels in infants with BPD.Two trials enrolling 44 participants compared different methods for individualizing PEEP in infants with RDS. Both trials compared an oxygenation-guided lung-recruitment maneuver (LRM) with gradual PEEP level titrations for individualizing PEEP to routine care (control). Meta-analysis showed no difference between LRM and control on mortality by hospital discharge (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.17 to 5.77); there was no statistically significant difference on BPD, with an effect estimate favoring LRM (RR 0.25, 95% CI 0.03 to 2.07); and a statistically significant difference favoring LRM for the outcome of duration of ventilatory support (mean difference -1.06 days, 95% CI -1.85 to -0.26; moderate heterogeneity, I = 67%). Short-term oxygenation measures also favored LRM. We graded the quality of the evidence as low for all key outcomes due to risk of bias and imprecision of the effect estimates.</p>

<p><strong>AUTHORS' CONCLUSIONS: </strong>There continues to be insufficient evidence to guide PEEP level selection for preterm infants on CMV for RDS or BPD. Low-quality data suggests that selecting PEEP levels through the application of an oxygenation-guided LRM may result in clinical benefit. Well-conducted randomized trials, particularly to further evaluate the potential benefits of oxygenation-guided LRMs, are needed.</p>

DOI

10.1002/14651858.CD004500.pub3

Alternate Title

Cochrane Database Syst Rev

PMID

30820939

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