Oxygen saturation and work of breathing indices in preterm infants with bronchopulmonary dysplasia compared to healthy preterm infants at discharge

Abstract

BACKGROUND:

Thoracoabdominal asynchrony (TAA) is commonly seen in preterm infants. Respiratory inductive plethysmography (RIP) is a noninvasive way to objectively assess work of breathing (WOB) indices. The impact of bronchopulmonary dysplasia (BPD) on TAA at discharge has not been established. The aim of this study is to compare WOB indices in premature infants with a diagnosis of BPD to premature infants without a diagnosis of BPD at discharge.

METHODS:

A prospective, observational study of premature infants (<32 weeks gestation) at discharge during quiet breathing in the supine position. RIP noninvasively measured WOB indices. A high-resolution pulse oximeter collected oxygen saturation and heart rate data.

RESULTS:

This study included thirty-one infants with BPD and thirty-four infants without BPD. Infants diagnosed with BPD had increased phase angle [BPD Φ = 73 . 9⁰ (8.2) vs NoBPD Φ = 52.6 (8.2), p = 0.039]. Infants diagnosed with BPD had decreased saturations [BPD SpO2 = 96% (0.4) vs NoBPD Sp02 98% (0.3), p=<0.001], increased time with saturations less than 85% [BPD % =2.74 (0.7) vs NoBPD % =0.91 (0.4), p = .018], and increased time with saturations less than 80% [BPD % =1.57 (0.5) vs NoBPD % =0.52 (0.3), p = 0.045]. There was no difference in heart rate or breaths per minute for infants with BPD versus controls.

CONCLUSION:

Premature infants with BPD demonstrated increased TAA and had lower saturations compared to infants without BPD at discharge despite being chronologically older and being discharged at an older corrected gestational age. The impact of BPD on breathing patterns persists at discharge and suggests these patients may have residual lung and/or respiratory muscle dysfunction.

Keywords

Bronchopulmonary dysplasia plethysmography premature infants respiratory inductive work of breathing

Abbreviations:

ABD

Abdominal

BPD

Bronchopulmonary Dysplasia

FRC

Functional Residual Capacity

Heart Rate

LBI

labor breathing index

NICU

Neonatal Intensive Care Unit

PDA

Patent Ductus Arteriosus

Pulmonary Function

PFT

Pulmonary Function Test

PMA

Post Menstrual Age

Rib Cage

RIP

Respiratory inductive plethysmography

Respiratory Rate

SEM

Standard Error of the Mean

TAA

Thoracoabdominal asynchrony

WOB

work of breathing

1 Introduction

Premature birth is associated with increased morbidity and mortality, including Bronchopulmonary Dysplasia (BPD) [1]. Contemporary or “new” BPD represents a disease of impaired alveolarization [2]. Alterations in airway and alveolar development have been shown to persist beyond the neonatal period [3].

Studies [4 –6] suggest that infants with BPD have abnormal pulmonary function (PF) that persist into the first year of life. Until recently, pulmonary function testing (PFT) was only performed in older children, and it was unknown whether these abnormalities were present at birth or developed over time. McEvoy demonstrated that late preterm infants had decreased PF compared to term infants and that infants with BPD had decreased PF compared to healthy premature infants at discharge [7, 8]. These studies suggest that premature infants have smaller lung volumes, supporting the hypothesis that disrupted alveolarization may be the cause of contemporary BPD. The authors suggest that therapies should be developed to improve lung volumes [8]. Unfortunately, the ability to develop and evaluate these strategies is limited by traditional PFT because it requires occlusions of the airway, involves complex calculations, and can only provide intermittent measurements of pulmonary function.

Respiratory inductive plethysmography (RIP) measures thoracoabdominal motion and can provide objective, non- invasive diagnostic measurements of thoraco-abdominal asynchrony (TAA) and work of breathing (WOB) indices. PneuRIP, a palm sized hardware module and associated touchscreen tablet personal computer that displays WOB parameters instantly, has been used in neonatal and pediatric populations [9 –11]. The use of PneuRIP is feasible in the preterm patient population and can be used to explain clinical observations and improve medical care [12, 13]. In previous studies, we demonstrated abnormal WOB indices in preterm infants [12 –14]. The current study compares WOB indices at discharge for premature infants diagnosed with BPD to premature infants without a BPD diagnosis. We hypothesize WOB indices in infants with BPD will be greater than in infants without BPD.

2 Methods

2.1 Patient population

This is a prospective cohort study conducted at a level III Neonatal Intensive Care Unit (NICU) from 11/2020-11/2022. The Institutional Review Board approved the study (CCC38144). Written informed consent was obtained from parents of enrolled infants. All date were de-identified after demographic, clinical, RIP, and pulse oximetry data was extracted from the chart.

Inclusion criteria consisted of infants admitted to the NICU with a birth weight of less than 1500 grams and > 26.0 weeks gestation who are approaching discharge. Infants born at ≤26.0 weeks of gestation were not included because historically most of these infants are diagnosed with BPD at our institution. Infants with skeletal, neuromuscular, or abdominal surgical disorders that affect the accuracy of measurements were excluded.

WOB indices of infants with a diagnosis of BPD were compared to premature infants without the diagnosis of BPD. BPD in this study was defined according to the 2018 NICHD consensus workshop definition [15].

2.2 Study design

WOB indices were measured within 7 days of predicted discharge. WOB indices measurements include the use of the PneuRIP instrument and software package (Creative Micro Designs (CMD), Newark, DE, USA) and the use of a high-resolution pulse oximeter (Radical: Masimo, Irvine, CA, USA) with a two-second sampling rate and two-second averaging time. All measurements were made in the supine position for twenty-five minutes during quiet breathing.

RIP is a non-invasive method to determine WOB indices. RIP instrumentation monitors and records tidal breathing measurements via thoracoabdominal motion analysis on digital signals associated with Rib Cage (RC) and Abdominal (ABD) wall motion. RIP involves the use of two soft, elastic, cloth bands (Respibands Plus, Viasysy San Diego, CA) encircling the RC and the ABD. The bands contain flexible sinusoidal wire that is correlated with thoracic motion. The relative motion of the RC and AB bands are analyzed to determine WOB indices as previously described [16]. The PneuRIP instrument and software package provides the digital transfer (Bluetooth) and instantaneous analysis of RIP data on a tablet device. The validation of this research method has been previously published and has been shown to be consistent with the traditional approach using the Respiritrace system (Sensor-medics, Yorba Linda, CA [9 , 17].

The phase angle (φ) is defined as the phase shift between the RC and the ABD excursions. In healthy infants, the RC moves outward with inspiration in synchrony with the abdominal wall [18]. Because of decreased lung compliance, increased chest wall compliance, increased pulmonary resistance, and ventilatory muscles more susceptible to fatigue; preterm infants have an increased risk of asynchronous breathing [19]. When a premature infant is in distress the rib cage lags the abdominal wall movement. Phase angle is defined by the equation sinθ=m/s, where m is the line parallel to the abscissa on the RC-AB D plot at one half the distance between the maximal RC perpendicular intercept and the origin, and sin (θ) the length of a line from the maximal ABD perpendicular intercept minus the origin. A phase angle of 0^deg represents perfect synchrony whereas a phase angle of 180^deg represents complete asynchrony [19]. Wave forms were manually reviewed and those most representative of quiet respiratory effort were evaluated. Data associated with crying, apnea, and movement artifacts were excluded.

The labored breathing index (LBI) refers to the sum of the maximal excursion of RC and ABD divided by the tidal volume. An LBI = 1.0 represents optimal breathing with respect to pulmonary mechanics. Increasing values of LBI reflects increasing paradoxical motion. Respiratory rate, heart rate, and saturations were also monitored and recorded.

Demographic data were collected from chart review including the following: race, sex, gestational age at birth, birthweight, antenatal steroid exposure, post menstrual age (PMA) at the time of the study, weight at the time of the study, history of hemodynamically significant PDA, history of pulmonary hypertension, need for intubation, type of ventilatory support, duration of invasive and non-invasive respiratory support, caffeine exposure, vitamin A exposure, steroid exposure, last recorded hemoglobin and hematocrit.

2.3 Outcomes

The primary outcomes were phase angle, φ, and LBI determined during quiet breathing in the supine position. Data associated with a respiratory rate of less than 5 breaths per minute or greater than 120 breaths per minute or LBI of less than 1 or greater than five was not included in the analysis. Wave forms were manually reviewed and wave forms most representative of quiet respiratory effort were evaluated. Data associated with crying, apnea and movement artifact were excluded. Secondary outcomes, oxygen saturations, respiratory rate, and heart rate.

2.4 Statistical analysis

Summary statistics were calculated for baseline and demographic characteristic of the infant subjects. For categorical variables count and percent were calculated and for continuous variables mean and standard deviation or standard error of mean are reported. The WOB indices including phase angle, LBI, oxygen saturation between subjects with and without diagnosis of BPD were compared using one-sided t-tests. Categorical data was compared using Pearson Chi Square test.

3 Results

This study included thirty-one premature infants diagnosed with BPD and thirty-four premature infants without BPD. Infant demographic and baseline clinical data are included in Table 1. Infants diagnosed with BPD were chronologically older (p < 0.001), had an older post menstrual age (p < 0.001) and greater weight (P < 0.001) at the time of the study compared to infants without a diagnosis of BPD.

Table 1
Characteristics of the study population

No BPD (N = 34) BPD (N = 31) P

Gestational age (weeks) at birth mean (SD) 31.53 (1.73) 28.66 (1.53) <0.001*

Birthweight in grams mean (SD) 1292 (168) 1074 (257) <0.001*

Female, n (%) 19(56) 17 (55) 1.00

White, n (%) 17 (60) 17 (55) 0.78

Subjects with history of PDA, n (%) 1 (3) 9 (29) 0.01*

Received caffeine, n (%) 22 (65) 31 (100) 0.001*

BPD classification 0 31

Mild, n (%) 11 (35)

Moderate, n (%) 14 (45)

Severe, n (%) 6 (13)

	No BPD (N = 34)	BPD (N = 31)	P
Gestational age (weeks) at birth mean (SD)	31.53 (1.73)	28.66 (1.53)	<0.001*
Birthweight in grams mean (SD)	1292 (168)	1074 (257)	<0.001*
Female, n (%)	19(56)	17 (55)	1.00
White, n (%)	17 (60)	17 (55)	0.78
Subjects with history of PDA, n (%)	1 (3)	9 (29)	0.01*
Received caffeine, n (%)	22 (65)	31 (100)	0.001*
BPD classification	0	31
Mild, n (%)		11 (35)
Moderate, n (%)		14 (45)
Severe, n (%)		6 (13)

BPD, Bronchopulmonary Dysplasia; PDA, Patent Ductus Arteriosus; SD, Standard Deviation; SEM, Standard Error of the Mean.

Eighty-four percent of WOB indices data were included in the study and there was no difference in the percent included for the BPD and the NoBPD group (p = 0.117). Phase angle [BPD Φ = 73 . 9⁰ (8.2) vs NoBPD Φ = 52.60 (8.2), p = 0.039] was significantly lower in infants without BPD. [see Table 2, Fig. 1]. LBI did not differ between groups. Of the infants with BPD, Phase Angle and LBI did not differ when stratified by NICHD classification. No difference in respiratory rate was observed but saturations were lower in infants with BPD compared to infants without BPD (BPD vs NoBPD, SpO2 (SD), 96% (0.3) vs 98% (0.4), P=<0.001). [see Table 2]. Infants with BPD spent more time with saturations less than 85% (BPD vs NoBPD, % time (SEM), 2.74 (0.7) vs 0.91 (0.4), p = 0.018) and less than 80% (BPD vs NoBPD, % time (SEM), 1.57 (0.5) vs 0.52 (0.3), p = 0.045. [see Table 2].

Fig. 1

Comparison of Work of Breathing Indices of Infants with and without Bronchopulmonary Dysplasia at discharge. Note the BPD patients have significantly greater phase angles compared to no BPD patients. Mean+/-SEM; P = 0.039.

Table 2

Comparison of work of breathing related matrices between subjects with and without diagnosis of BPD at discharge. The values are mean

	No BPD (N = 34)	BPD (N = 31)	P
Age at test, days (SD)	35.56 (14.58)	84.84 (73.80)	<.001*
Post menstrual age at test, weeks (SD)	36.71 (1.50)	39.09 (2.533)	<.001*
Weight at test, grams (SD)	2038 (299)	2857 (731)	<.001*
Duration of test, minutes (SEM)	26.32 (.96)	27.83 (0.68)	.11
Phase angle, Φ Deg. (SEM)	52.6 (8.2)	73.9 (8.2)	.039*
Labored breathing index, (SEM)	1.55 (.17)	1.61 (.19)	.41
% Saturations, Sp02 (SEM)	98 (0.4)	96 (0.3)	<.001*
% Time with % Saturations<85%	0.91 (0.4)	2.74 (0.7)	.018*
% % Time with % Saturations<80%	0.52 (0.3)	1.57 (0.5)	.045*
Heart rate, BPD (SEM)	158 (1.7)	156 (2.3)	0.243

BPD, Bronchopulmonary dysplasia.

4 Discussion

This study compares WOB indices of premature infants with BPD to premature infants without BPD at discharge. Our study demonstrated that premature infants with BPD had increased TAA and had lower saturations compared to infants without BPD at discharge despite being chronologically older and being discharged at an older corrected gestational age. This suggests that the impact of BPD on breathing patterns persists at discharge and suggests that infants with BPD have residual lung and respiratory muscle dysfunction.

Fetal lung development is a complex, vulnerable process that starts at 4–6 weeks gestation and is not complete until 2 years after birth. Premature birth disrupts normal lung development. Active breathing against gravity, immature lung tissue, increased pulmonary blood flow, higher oxygen tension, and exposure to invasive respiratory support disrupt alveolarization and impact lung development and function [20]. Studies have suggested that adverse factors affecting lung development during early life decrease lung function that persists into adulthood [21]. Using nitrogen wash out and single breath occlusion techniques, multiple studies have shown that lung function is worse in infants with BPD [21 –25]. In a comparison of fifty infants with BPD to nineteen healthy preterm controls, Hjalmarson et demonstrated decreased functional residual capacity (FRC) and less efficient gas exchange in infants with BPD [22]. In a study conducted by McEvoy et al, infants with BPD at 34–36 weeks PMA had decreased FRC and respiratory compliance than healthy controls at 34–36 weeks [24]. Our study supports these findings and earlier studies using RIP to assess TAA and lung mechanics in infants with BPD [26, 27]. Our study adds to the literature by being the first study to compare infants with BPD to infants without BPD at discharge, highlighting that abnormal breathing patterns persist in infants with BPD even when assessed at an older chronological and corrected gestational age, not receiving respiratory support, and eating exclusively by mouth. In contrast, a study by Ren et al, failed to demonstrate a significant increase in phase angle in infants with BPD compared to infants without BPD at discharge but did note trends toward increased phase angle in infants with BPD who had post discharge respiratory disease compared to those who did not [28]. However, in this study, RIP measurements were performed at thirty-seven weeks post menstrual age rather than at discharge and a substantial portion of the infants included in this study were receiving some respiratory support, caffeine, and enteral feeds through a gastric tube.

Our findings support the observation that infants with BPD have lower saturations than infants without BPD [29]. Our study adds to the literature because previous studies did not assess saturations at discharge and none of the infants included in our study were discharged on respiratory support, suggesting that even when infants have convalesced, infants with BPD continue to have lower saturations than their health preterm control. Although statistically significant, the average saturations may not be considered clinically significant but the greater percentage of time infants with BPD experience extreme desaturations (<85%) may have long term consequences. Severe hypoxia is associated with poor growth and poor neurodevelopmental outcomes [30]. As previously noted, preterm infants with decreased lung compliance and increased airway resistance, decreased ability to compensate breathing with ventilatory muscles are more susceptible to fatigue but more studies are needed to determine how long these observed abnormal breathing patterns persist in BPD infants after discharge and how they impact long term outcomes.

Our study used PneuRIP to objectively, non-invasively, and quickly measure lung function. Traditional pulmonary function testing requires cooperative patients and measurements made using nitrogen wash out and obstruction may alter breathing patterns and FRC [31]. The use of PneuRIP simplifies and quickens WOB measurements and has the potential to be used as a bedside monitor. In this study, we reported on waveforms most representative of quiet respiratory effort. We have found this approach more objectively and accurately evaluates breathing synchrony in premature infants (12–14). In future studies we hope to expand this methodology as an objective, real-time bedside tool to modify care.

As in most clinical trials, there are limitations to our study. We performed WOB measurements after a scheduled feed to minimize movement artifact, but this was not always possible. Additionally, the abdominal distention due to feeds was minimized such that feeds did not impact alterations in lung mechanics [32, 33]. Movement artifact is often cited as a limitation to RIP. To account for the above forementioned issues, we 1) manually reviewed wave forms to ensure the accuracy of the trends in data and 2) eliminated data that fell outside a predetermined respiratory rate range associated with movement artifact. LBI, another measure of TAA, reflects synchrony with respect to tidal volume and in this case amplitude of rib cage and abdomen. For shallow breathing (low rib cage and abdominal amplitude) there can be disconnect in the relationship between phase angle and LBI. We did not evaluate tidal volume since we did not wish to disturb these preterm infants with more invasive tidal volume measurements. Although, our study demonstrated a trend towards increased LBI in infants with BPD, the difference was not statistically significant. LBI is an index of breathing efficiency and since infants with BPD were chronologically and correct gestationally older, this observation may reflect increased respiratory efficiency and compensation for infants with BPD. Finally, it should be noted variable definitions of BPD impact prevalence of the diagnosis and the use of the NICHD definition of BPD may have impacted the observed outcome. We did not find a difference in WOB indices stratified by NICHD BPD classification, but the study was not powered to detect this difference. More studies should be done using PneuRIP to quantify WOB indices in infants with the various definitions of BPD.

5 Conclusions

This was the first study to compare WOB indices for premature infants with BPD to healthy premature controls at discharge. Premature infants with BPD demonstrated increased TAA and had lower saturations compared to infants without BPD at discharge despite being chronologically older and being discharged at an older corrected gestational age. The impact of BPD on breathing patterns persists at discharge and suggests these patients may have residual lung or respiratory muscle dysfunction. This may impact long term morbidity and mortality, but more studies are needed.

Disclosure statements

We have no disclosures.

Footnotes

Acknowledgment

KS is supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number U54-GM104941 (PI: Hicks).

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