Abstract
Background
Recent clinical practice changes in neonatal care resulted in higher, narrower oxygen saturation target ranges for preterm infants. The effect of targeting higher or lower oxygen saturations on respiratory outcomes of preterm infants and duration of hospitalization has not been extensively reviewed in the context of current care, but could have significant implications.
Methods
A multicentre retrospective cohort of 145 preterm infants was conducted; 105 had lower oxygen saturation targets (88 to 92%), 40 had higher targets (90 to 95%). The primary outcome was bronchopulmonary dysplasia (BPD). Secondary outcomes included duration of invasive/noninvasive respiratory support, oxygen therapy, and hospitalization. The primary outcome was compared using Fisher’s exact test. Secondary outcomes were evaluated with survival analysis and Wilcoxon rank sum test.
Results
The difference in incidence of BPD in the lower (N=56, 53.3%) and higher saturation groups (N=14, 35.0%) was not statistically significant (relative risk [RR]=0.66 [0.41, 1.04], P=0.06). The difference in duration of mechanical ventilation in the lower (median 7.8 days, interquartile range [IQR] 3.7 to 15.9) and higher saturation groups (median 4.5, IQR 1.9 to 12.3) approached statistical significance (P=0.05). There were no statistically significant differences in the durations of other respiratory supports or hospital stay between the two groups.
Conclusions
The results of this study approached statistical significance and suggest that higher, narrower oxygen saturation targets may result in a clinically important reduction in BPD incidence and duration of mechanical ventilation. These results require validation in a larger sample to refine optimal targets.
Keywords: Discharge, Neonatology, Oxygen therapy, Prematurity, Ventilation
Bronchopulmonary dysplasia (BPD), defined as supplemental oxygen requirement at 36 weeks’ corrected gestation, is the most common pulmonary complication of extreme prematurity (1). Its incidence is rising as ever-more preterm infants survive, and is associated with significant morbidity and mortality (1–4). BPD occurs in 41% of infants born prior to 28 weeks’ gestation (5). It arises in preterm infants from underdevelopment of lung tissue and pulmonary vasculature, and the sequelae of prolonged mechanical ventilation and oxygen support (1). Risk of mortality for infants with BPD is positively correlated with the duration of mechanical ventilation and death is usually caused by respiratory failure, sepsis or persistent pulmonary hypertension (PH) with resultant cor pulmonale (6). Other comorbidities of BPD include: persistent pulmonary function abnormalities; high rates of rehospitalization, especially in the first year; increased risk for neurodevelopmental impairment, and poor infantile growth (1,7,8).
Oxygen is routinely used in the treatment of BPD (4,6,9). The frequency of its use initiated clinical trials which evaluated different oxygen saturation targets and their impact on many comorbidities of prematurity. In the 1950s, trials identified an increased incidence of retinopathy of prematurity associated with higher oxygen saturation targets, due to damage from reactive oxygen species (10,11). The first randomized controlled trials comparing oxygen saturation targets of 85 to 89% versus 91 to 95% reported significantly higher mortality rates with lower saturation targets (12–14). The search for optimal oxygen saturation targets in neonatal intensive care units (NICUs), with avoidance of extreme values, continues.
Newer, narrower oxygen saturation targets with tighter ranges of 88 to 92% and 90 to 95% are now used in NICUs. Their clinical implications on the incidence of BPD in the early postnatal period, however, have not been extensively explored. The primary objective of this study was therefore to determine the effect of a higher saturation target (90 to 95%) compared with a lower saturation target (88 to 92%), on the incidence of BPD. Secondary objectives were to determine the effect of a higher saturation target on the duration of various respiratory supports, as well as length of hospital stay. Based on existing literature, we hypothesized that higher saturation targets would result in an increase in the incidence of BPD, and would increase the duration of ventilatory support, oxygen therapy, and hospitalization (10,12,15).
METHODS
Study population
This retrospective chart review included all infants born at less than 29 weeks’ gestation, June 1, 2012 through April 18, 2016, at two tertiary-level NICUs, and who underwent at least one echocardiogram prior to their first discharge from hospital. This set of inclusion criteria were chosen as incidence of PH was also examined in this cohort (16). Infants who died or were transferred to another hospital, apart from the Ottawa Hospital and the Children’s Hospital of Eastern Ontario (CHEO), and those who did not receive any respiratory support at birth were excluded. Inclusion of cases was based on a review of existing neonatal databases, to determine gestational age at birth, and was cross-referenced with hospital billing information to determine the provision of an echocardiogram. All other relevant outcomes were obtained from a review of patient medical charts.
Study design
Ethics approval was obtained from the Ottawa Health Science Network Research Ethics Board and the CHEO Research Ethics Board. Information collected from hospital databases and medical charts was de-identified, assigned a research identification number and inputted into a REDCap database.
The first time period of June 1, 2012 through May 31, 2015 (lower oxygen saturation target, 88 to 92%) was compared with June 1, 2015 through April 18, 2016 (higher oxygen saturation target, 90 to 95%).
Outcomes
The primary outcome was incidence of BPD, defined as supplemental oxygen requirements at 36 weeks’ corrected gestation (1). Secondary outcomes included the duration of respiratory support (noninvasive positive pressure respiratory support [continuous or bilevel], conventional invasive mechanical ventilation, high-frequency ventilation [HFV], oscillation, or jet), exclusive oxygen support, and hospitalization.
Statistical analysis
Demographic variables of the two groups were compared in terms of sex, gestational age at birth, birth weight and Apgar scores at 1 and 5 minutes, using the Wilcoxon rank sum for continuous variables and Fisher’s exact test for discrete variables. Fisher’s exact test was used to determine the difference in incidence of BPD and other comorbidities between the two saturation target groups. Overall duration of any respiratory support, noninvasive respiratory support, mechanical ventilation, HFV, exclusive oxygen support, and hospitalization were compared using the Wilcoxon rank sum test. Survival analysis was used to study the effect of oxygen saturation targets on the time to first and the last discontinuation of conventional mechanical ventilation, HFV, noninvasive respiratory support, and exclusive oxygen therapy. Time to first and last discontinuation of respiratory supports was the time from birth to first and last discontinuation of respiratory support. Patients who were discharged prior to the discontinuation of respiratory support were treated as censored. Survival curves for the time to first and last discontinuation of respiratory support were estimated according to the Kaplan–Meier estimator. The two-sided log-rank test was used to compare survival curves between two oxygen saturation target groups. Two-sided P-values less than an alpha level of 0.05 and relative risk with 95% confidence interval not including value of one were considered statistically significant.
RESULTS
The records of 259 infants born at less than 29 weeks gestation at two tertiary care centres were reviewed. One hundred and fourteen were excluded, including 37 deceased, 73 transferred to another hospital, and 4 who did not receive respiratory support after birth, or did not undergo echocardiograms. One hundred and forty-five infants were included in the final analysis, of whom 40 were in the higher saturation group, and 105 were in the lower saturation group.
The study population had a median gestational age of 26.9 weeks (interquartile range [IQR] 25.9, 28.1; Table 1). Forty-eight per cent of the study population developed BPD (Table 2). The difference in incidence of BPD in the lower (N=56, 53.3%) and higher saturation groups (N=14, 35.0%) was not statistically significant (relative risk [RR]=0.66 [0.41, 1.04], P=0.06). PH (RR 0.38 [0.18–0.83], P=0.01) and a patent ductus arteriosus (PDA) (RR 0.71 [0.54–0.92], P=0.003) occurred more frequently in the lower saturation group (Table 2).
Table 1.
Sample demographics in the overall study population, lower, and higher oxygen saturation groups
| Overall N=145 | Lower saturation target N=105 | Higher saturation target N=40 | P-value | |
|---|---|---|---|---|
| Gestational age (weeks); median (IQR) | 26.9 (25.9, 28.1) | 27.0 (25.9, 28.0) | 26.7 (25.7, 28.1) | 0.81 |
| Birth weight (g); median (IQR) | 970 (770, 1,170.) | 970 (770, 1,150.) | 955 (800, 1,185) | 0.48 |
| Prenatal Steroids; n (%) | 35 (24.1) | 27 (25.7) | 8 (20.0) | 0.52 |
| Apgar score at 1 minute; median (IQR) | 5.0 (2.8, 6.0) | 5.0 (3.0, 6.0) | 4.5 (2.0, 6.0) | 0.79 |
| Apgar score at 5 minutes; median (IQR) | 7.0 (6.0, 8.0) | 7.0 (6.0, 8.0) | 7.0 (5.8, 8.0) | 0.73 |
| Male; n (%) | 76 (52.4) | 59 (56.2) | 17 (42.5) | 0.19 |
IQR Interquartile range.
Table 2.
Incidence of comorbidities in the overall study population, lower, and higher oxygen saturation groups
| Variable | Overall N=145 | Lower saturation target N=105 | Higher saturation target N=40 | P-value |
|---|---|---|---|---|
| RESPIRATORY | ||||
| Bronchopulmonary dysplasia; n (%) | 70 (48.3) | 56 (53.3) | 14 (35.0) | 0.06 |
| CARDIOVASCULAR | ||||
| Patent ductus arteriosus; n (%) | 113 (77.9) | 89 (84.8) | 24 (60.0) | 0.003 |
| Pulmonary hypertension; n (%) | 47 (32.4) | 41 (39.0) | 6 (15.0) | 0.01 |
| GASTROINTESTINAL | ||||
| Necrotizing enterocolitis; n (%) | 14 (9.7) | 11 (10.5) | 3 (7.5) | 0.76 |
| NEUROLOGICAL | ||||
| Intraventricular hemorrhage; n (%) | 68 (46.9) | 48 (45.7) | 20 (50.0) | 0.71 |
| OPHTHALMOLOGIC | ||||
| Retinopathy of prematurity; n (%) | 42 (29.0) | 26 (24.8) | 16 (40.0) | 0.10 |
| INFECTIOUS | ||||
| Sepsis; n (%) | 36 (24.8) | 26 (24.8) | 10 (25.0) | 1.00 |
| Pneumonia; n (%) | 18 (12.4) | 14 (13.3) | 4 (10.0) | 0.78 |
The difference in duration of mechanical ventilation in the lower (median 7.8 days, IQR 3.7 to 15.9) and higher saturation groups (median 4.5, IQR 1.9 to 12.3) approached statistical significance (P=0.05) (Table 3). There were no statistically significant differences in the durations of other respiratory supports between the two groups.
Table 3.
Durations of intubation and mechanical ventilation, high-frequency ventilation, noninvasive ventilation, exclusive oxygen therapy, and room air, in days, in the overall study population, lower, and higher oxygen saturation group
| Respiratory Support (days) | Overall (N=145) median (IQR) | Low Sat (N=105) median (IQR) | High Sat (N=40) median (IQR) | P-value |
|---|---|---|---|---|
| Mechanical ventilation | 7.2 (2.2, 14.6) | 7.8 (3.7, 15.9) | 4.5 (1.9, 12.3) | 0.05 |
| Noninvasive (CPAP, BiPAP) | 29.6 (10.8, 44.2) | 29.6 (10.3, 40.3) | 32.2 (16.0, 49.5) | 0.21 |
| Oxygen only | 22.8 (10.7, 39.6) | 23.0 (11.0, 42.0) | 20.5 (10.7, 26.1) | 0.45 |
| Room air | 18.1 (3.0, 36.1) | 18.6 (2.9, 33.8) | 17.0 (3.1, 44.1) | 0.55 |
BiPAP Bilevel positive airway pressure; CPAP Continuous positive airway pressure; IQR Interquartile range.
Forty-eight per cent (N=69) of the population advanced through a trajectory that initiated with invasive ventilation (HFV or mechanical ventilation), with subsequent weaning to noninvasive respiratory support and finally, exclusive oxygen therapy during their hospital stay. Approximately 52% (N=55) of the lower saturation group advanced through this trajectory of weaning respiratory support, compared with 35% (N=14) in the higher saturation group (P=0.07). Thirty-nine per cent (N=57) of the population was weaned from invasive to noninvasive respiratory support, but required a subsequent period of invasive ventilation, prior to discharge. Of the lower saturation group, 43% (N=45), and of the higher saturation group 30% (N=12) followed this trajectory of requiring an increase in respiratory support (P=0.19).
In the overall study population, the greatest proportion of respiratory support was spent on noninvasive respiratory support with a median of 37.1% (IQR 18.7, 51.5). A median of 35.4% (IQR 16.7, 48.9) of days in hospital was spent on noninvasive respiratory support in the lower saturation group, compared with a median of 46.4% (IQR 27.2, 66.6) of days in the higher saturation group (P=0.02).
Infants in the lower saturation group who received HFV (n=39) spent a shorter duration until the first (median 9.5 days [7.6, 14.5]) discontinuation of HFV compared with the higher saturation group (n=13, median 23.7 days [3.6, 30.9]; P=0.03). The number of days until the first discontinuation of any respiratory support did not differ between the lower (median 1.2 days [0.8, 2.2]), and higher saturation groups (median 2.0 days [0.6, 2.6]; P=0.37; Figure 1). There was no difference between the number of days until the last discontinuation of any respiratory support in the lower (median 61 days [46.4, 71.4]), and higher saturation groups (median 49.7 days [36.9, 64.6]; P=0.25).
Figure 1.
Cumulative probability of persistent need for each type of ventilator support. Kaplan–Meier curves representing time to first and final discontinuation of various respiratory supports for the lower and higher oxygen saturation target groups are depicted. The P-value of the log-rank test between the two saturation groups is also shown.
Length of stay did not differ between the lower (median 83.9 days [76.6, 89.5]) and higher saturation groups (median 73.2 days [56.5, 89.8]; P=0.35). Corrected gestational age at discharge was similar between the lower (median 38.6 days [37.7, 39.7]) and higher saturation groups (median 37.4 days [36.3, 40.0]; P=0.47). The majority of the infants discharged on respiratory supports received home oxygen (N=29 [20%] of the whole population; N=21 [20%] lower saturation group; N=8 [20%] higher saturation group).
DISCUSSION
Our multicentre study compared BPD incidence between two different oxygen saturation target ranges for preterm infants that have been recently implemented as a result of new recommended clinical practices. Previous studies have not compared duration and type of respiratory support required with these newer narrower saturation ranges and as such, this study adds new information to the literature. An 18% absolute reduction in BPD incidence in the higher saturation target group may be a clinically relevant finding, which approached (P=0.06) statistical significance (1,7). The total duration of respiratory support and hospital length of stay did not differ between the two groups.
The trend toward reduction in BPD incidence in the higher oxygen saturation group differs from previous reports in the literature (10,12,15). A possible explanation for the difference between our findings and those of previous studies may be due to different oxygen saturation targets used. The STOP-ROP trials restricted the higher saturation target between 96 and 99% while Askie identified the higher oxygen saturation target range between 95 and 98%. Lower saturation targets were defined between 91 and 94% in the trial by Askie, and 89 and 94% in the STOP-ROP trials (10,15). In addition to the wider differences between lower and higher oxygen saturation groups in other studies, a range of 90 to 95% was the higher saturation target defined in our study, which is more consistent with the lower saturation target of the mentioned trials. In the NeoPrOM trials, published more recently, there was a trend toward higher BPD incidence in the higher saturation target group, although this was not statistically significant. The higher saturation target for those trials was defined as 91 to 95% (12). The COT trial in 2013 also found no difference in the incidence of BPD between the higher and lower saturation groups (17).
There is a plausible physiologic basis for our findings when compared with previous studies. Saturation targets in previous studies allowed greater fluctuation in partial pressure of arterial oxygen as lower saturation ranges (85 to 89%) correspond to the steep part of the slope of the oxyhemoglobin dissociation curve. This means that a 1 to 2% reduction in oxygen saturation could result in a reduction in arterial partial pressure of oxygen of several millimetres of mercury. In contrast, arterial partial pressure of oxygen may be more stable in the upper saturation ranges (above 91%), which are associated with the flat part of the oxyhemoglobin dissociation curve (18). As a result of greater stability in partial pressures of arterial oxygen, oxygen therapy may be weaned more rapidly, resulting in a lower incidence of BPD.
Another explanation for the lower BPD incidence in the higher saturation target group may relate to a shift in neonatal practice toward earlier extubation and a greater proportion of time in hospital spent on noninvasive respiratory support, which has traditionally been encouraged as a lung-protective strategy (1,3,19–21). Infants in the lower saturation group spent almost twice the number of days on mechanical ventilation, a finding which approached statistical significance (P=0.05). This is in contrast to a trial by Doyle, which found that limited use of invasive ventilation resulted in no significant decline in oxygen dependence at 36 weeks and no improvement in lung function in childhood (22). Finally, a higher incidence of PDA and PH in the lower saturation group could also explain the higher incidence of BPD in this group, as PDA and PH are associated with an increased incidence of BPD (2,23). Ultimately, however, the incidence of BPD could be independent of or only slightly associated with respiratory support in extremely premature infants, as the pathology of an underdeveloped lung likely plays a bigger role in the pathophysiology of BPD in this population (24).
Our study did not find any beneficial effects of targeting higher or lower oxygen saturations on the duration of respiratory supports or exclusive oxygen therapy, duration of hospitalization; or corrected gestational age at discharge. We found that infants in the lower saturation target group spent fewer days until first discontinuation of HFV. This could indicate that infants whose oxygen saturation targets fall between 88 and 92% met clinical criteria for ‘acceptable saturations’ to prompt ventilation weaning faster when the threshold was set lower and were therefore weaned to noninvasive respiratory support sooner. Ultimately, however, the difference in duration until final discontinuation of HFV between the two groups remained insignificant.
The main limitation of this study is the small sample size, which may have limited our power to detect significant differences between groups. The difference between groups in the incidence of BPD approached statistical significance and had wide confidence intervals. Nonetheless, the absolute difference between groups was large and potentially clinically important. A second limitation of this study is the retrospective nature of the data collection. No information was collected regarding adherence to oxygen saturation target protocol in either time period. Thus, it is possible that some infants may have been subjected to oxygen saturation targets inconsistent with practice recommendations. Further, although we are not aware of any changes in clinical care that occurred over the study period, it is possible that other practice changes may have affected study outcomes. A third limitation of this study is loss to follow up, given that information was not collected about patients transferred to other centres prior to discharge. Further, as only infants who survived to first hospital discharge were included, we were unable to compare survival differences between groups. Finally, discrepancy in the time span of both cohorts, given that records reviewed captured 3 years of lower oxygen saturation and only 11 months of higher oxygen saturation, poses a limitation as it can take up to 2 years before impactful practice changes are recognized. Despite these limitations, this study is the first, to our knowledge, to compare respiratory outcomes using recently applied oxygen saturation targets and provides preliminary information about the implications of this recent change in clinical practice. Although expansion of the timeframe of this retrospective study could have overcome the sample size limitations, our findings will ultimately be used to inform the power and sample size calculation for a future prospective study. The results of this study approached statistical significance and suggest that higher, narrower oxygen saturation targets now recommended in NICUs may result in a clinically important reduction in BPD incidence and duration of mechanical ventilation. While these results require validation in a larger, well-powered, multicentre prospective study, they provide reassurance that an increase in saturation target does not increase incidence of BPD, as has been suggested in previous studies of other saturation target ranges.
Author Contributions
SLK conceptualized and designed the study along with BT and BL, supervised the data collection and contributed to the data analysis and interpretation. She assisted with drafting the initial manuscript and approved the final manuscript as submitted. NB along with VB conducted the statistical analysis for this study and assisted with data interpretation, as well as drafting of the manuscript. He has approved the final manuscript as submitted. NBF contributed to the data collection through interpretation of echocardiograms. She has reviewed and approved the manuscript as submitted. YH contributed substantially to the data collection and drafted the initial manuscript. She has approved the manuscript as submitted. LH supervised the data collection and has reviewed and approved the final version of the manuscript as submitted. CL created the database used to compile the data and contributed substantially to the data collection. She has reviewed and approved the manuscript as submitted. BL conceptualized and designed the study along with SLK and BT and contributed significantly to the data analysis and interpretation. She assisted with drafting the initial manuscript and approved the final manuscript as submitted. BT conceptualized and designed the study along with SLK and BL. He has reviewed and approved the manuscript as submitted.
Funding: This work was supported by Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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