Abstract
Background:
Hypoxemia and respiratory compromise occur in very low birthweight (VLBW, <1500 grams) infants and may be associated with shunting across a patent ductus arteriosus (PDA). The impact of pharmacologic PDA treatment on acute hypoxemia and respiratory metrics is unclear.
Objective:
To determine whether pharmacologic PDA treatment is associated with acute improvement in hypoxemia and respiratory metrics in VLBW infants.
Study Design:
At a single center (2012–2022), all VLBW infants with echocardiographic evidence of a PDA and without exclusions were classified as having received or not received pharmacologic PDA treatment (PDA-T, PDA-NT). Mean daily FiO2 and Respiratory Acuity Score (RAS, PMID 30374050) were compared at baseline (day 0) and 3 days after treatment start. For PDA-T infants with archived 0.5Hz (every-2-second) SpO2 data, mean daily SpO2 and the percentage of time with severe hypoxemia (SpO2 <80%) were compared before and after treatment. Severe hypoxemia was further analyzed after stratification by clinical variables (sex, medication, gestational age, postnatal age).
Results:
We analyzed 125 VLBW infants with a PDA, of whom 66 received pharmacologic PDA treatment. We analyzed a subgroup of 43 PDA-T infants with every-2-second SpO2 data available. PDA-T infants had higher baseline FiO2 and RAS and lower SpO2 than PDA-NT infants (p<0.05). Compared to baseline, RAS decreased from median 258 (IQR 171, 348) to 254 (IQR 174, 419) three days after the start of treatment (p=0.012), but median FiO2 increased from 37% (IQR 28, 46) to 40% (IQR 29, 52) (p=0.008). SpO2 and the percent time with severe hypoxemia were unchanged.
Conclusions:
In this 10-year retrospective single-center analysis, pharmacologic PDA treatment in VLBW infants was not associated with a major improvement in acute measures of oxygenation or level of respiratory support.
Keywords: Patent ductus arteriosus, respiratory compromise, prematurity, hypoxemia
BACKGROUND
Hypoxemia and respiratory compromise may be associated with the presence of a patent ductus arteriosus (PDA) in very low birth weight (VLBW, <1500 grams) premature infants.1 Left-to-right shunting across a PDA can lead to pulmonary overcirculation, with pulmonary edema contributing to hypoxemia and cardiorespiratory compromise in a population already suffering from lung disease of prematurity.2 Right-to-left shunting may also occur, leading to acute swings in oxygen saturation. An echocardiogram is sometimes performed to evaluate for PDA in VLBW infants based on clinical suspicion, including prolonged or increasing need for respiratory support or supplemental oxygen.3 If a PDA is present, clinicians may elect to treat the infant with non-steroidal anti-inflammatory drugs (indomethacin, ibuprofen) or acetaminophen for PDA closure, with variable efficacy across drugs and patients.4–7
There is increasing evidence that PDA treatment does not impact long-term outcomes such as bronchopulmonary dysplasia.8–10 Still, many clinicians prescribe medications for PDA treatment11 to try to reduce a large ductal shunt and improve an infant’s respiratory status. The immediate impact of PDA treatment on respiratory status has been studied very little, partly because of the challenges involved in data capture and analysis to quantify oxygenation and level of respiratory support. Our research group has routinely archived SpO2 data from all NICU patients, and we have developed methods for studying oxygenation in VLBW infants. We also previously developed a Respiratory Acuity Score (RAS) that incorporates the level of invasive or non-invasive respiratory support and the FiO2 and predicts the diagnosis of bronchopulmonary dysplasia.12 In the current work, we employed these research tools to determine whether pharmacologic PDA treatment is associated with an acute improvement in respiratory or oxygenation status in VLBW infants.
METHODS
Study design, patient population, and PDA diagnosis and treatment
This is a single-center retrospective analysis of data from very low birth weight infants (VLBW <1500 grams) admitted to the University of Virginia NICU, a level IV Vermont Oxford Network Type C unit. The Institutional Review Board approved the study. We used a clinical database (NeoData, Isoprime) to identify VLBW infants diagnosed with a PDA between 2012–2022. The presence of a PDA was confirmed by reviewing echocardiogram reports. During the study period, the practice in our NICU was to obtain an echocardiogram for infants with clinical suspicion of a PDA, often those with a significant murmur, hemodynamic instability, or prolonged or increasing need for respiratory support. The decision to treat a PDA was left to the discretion of the primary team. There were several exclusions. First, we excluded infants with PDA diagnosed in the first three days after birth since our unit guideline includes giving prophylactic indomethacin in this period to reduce intraventricular hemorrhage. Second, we excluded those on no respiratory support at the time of the initial echocardiogram since they would typically not be considered for PDA treatment, and infants transferred to our unit after seven days of age since they might have received PDA treatment before transfer. Finally, we excluded infants with genetic syndromes or major cardiac or lung anomalies and those who died before NICU discharge.
The electronic medical record was used to obtain demographic and clinical data. Infants with echocardiographic evidence of a PDA and without exclusions were classified into two groups: those who were never treated for a PDA while in the NICU (PDA-NT) and those who were treated pharmacologically with indomethacin, ibuprofen, or acetaminophen (PDA-T). Dose regimens were based on standard NICU pharmacy guidelines. The dosing guideline for acetaminophen was 15 mg/kg/dose q6h for 3 days if IV and for 3–7 days if enteral. The dosing guideline for ibuprofen was 10 mg/kg initial dose followed by 5 mg/kg/dose at 24 and 48 hours. The dosing guideline for indomethacin was 0.2 mg/kg q12h for 3 doses if the infant was less than or equal to 7 days old and 0.25 mg/kg q12–24h for 3–5 doses if the infant was greater than 7 days old. In earlier years, the primary medication was indomethacin (or ibuprofen when indomethacin was unavailable). In later years, acetaminophen was the more common PDA treatment choice. Bronchopulmonary dysplasia (BPD) was defined as the need for supplemental oxygen or positive pressure support at 36 weeks postmenstrual age (PMA).13 Infants discharged or transferred in room air before 36 weeks PMA were classified as not having BPD. BPD diagnosis and supplemental oxygen at discharge or transfer were not determined for infants who were transferred on supplemental oxygen before 36 weeks PMA.
FiO2 and Respiratory Acuity Score
Hourly FiO2 values obtained from the electronic medical record were used to determine the mean daily FiO2. A Respiratory Acuity Score (RAS) was calculated using our previously published method.12 In brief, RAS for a given day is the product of mean FiO2 and a coefficient corresponding to the mode of respiratory support, ranging from 0 (room air) to 8 (high-frequency ventilator). Thus, RAS ranges from 0 to 800 (high-frequency ventilator, 100% FiO2). For infants on low-flow nasal cannula, we calculated the effective FiO2 accounting for flow rate and patient weight.14
SpO2 analysis
We analyzed pulse oximetry SpO2 data displayed on standard NICU bedside monitors. SpO2 was measured at 0.5 Hz (every 2 seconds) using Masimo technology with 8-second averaging and archived using BedMaster technology (Hillrom, Chicago, IL). In the years of the study, the target SpO2 for VLBW infants receiving supplemental oxygen and less than 36 weeks postmenstrual age was 88–94%. We calculated mean daily SpO2 and percent of time per day in severe hypoxemia, defined as SpO2 <80% for at least 10 seconds.12
Statistical analysis
RAS, mean FiO2, mean SpO2, and the percent of time with severe hypoxemia were compared between PDA-NT and PDA-T groups using Mann-Whitney tests at baseline (day 0) defined as the day of PDA diagnosis for PDA-NT and the day of treatment initiation for PDA-T. We used multivariable logistic regression to compare baseline RAS, FiO2, SpO2, and severe hypoxemia between PDA-NT and PDA-T infants while accounting for expected differences in gestational age, birth weight, and sex. We used Wilcoxon signed rank tests to compare RAS, FiO2, SpO2, and severe hypoxemia on day 0 versus day 3 for both groups. We plotted daily mean SpO2 and percent time with severe hypoxemia from 3 days before to 3 days after the start of treatment by performing sign rank tests, using the null hypothesis that daily averages were equal from the same patient the day prior. To evaluate trends by subgroups, we plotted daily severe hypoxemia stratified by gestational age, sex, age at treatment initiation, and drug group (non-steroidal anti-inflammatory drugs (NSAID) were grouped and compared to acetaminophen). All statistical analyses were performed using GraphPad Prism 9 or R version 4.1.
RESULTS
Patient population
During the 8-year study period, 125 VLBW infants admitted to the University of Virginia NICU met inclusion criteria, 59 (47%) PDA-NT and 66 (53%) PDA-T. Cohort characteristics are shown in Table 1. The median gestational age, birth weight, and postnatal age at the time of PDA diagnosis were higher for PDA-NT than for PDA-T infants (p<0.05). As a result, the PDA-NT group was included as a reference cohort but was not treated as a control cohort. Of those treated, 36 infants received an NSAID (30 indomethacin, 6 ibuprofen), and 30 received acetaminophen. Every 2 second SpO2 data were available for 83 infants (66% of the total cohort), with 43 (52%) of these in the PDA-T group.
Table 1.
Demographic characteristics
| Entire cohort | |||
|---|---|---|---|
|
| |||
| Total (n=125) | PDA-NT (n=59) | PDA-T (n=66) | |
|
|
|||
| Gestational age, weeksa | 25.4 (24.1, 27.6) | 26.4 (25.3, 28.7) | 25.4 (24.1, 26.6) |
| Birth weight, gramsa | 850 (690, 1030) | 930 (823, 1145) | 720 (620, 933) |
| Female sex | 60 (48.0%) | 32 (54.2%) | 28 (42.4%) |
| Race | |||
| Black | 22 (17.6%) | 9 (15.3%) | 13 (19.7%) |
| White | 100 (80.0%) | 50 (84.7%) | 50 (75.8%) |
| Other | 3 (2.4%) | 0 (0.0%) | 3 (4.6%) |
| Hispanic/Latino | 6 (4.8%) | 4 (6.8%) | 2 (3.0%) |
| Inborn | 95 (76.0%) | 44 (74.6%) | 51 (77.3%) |
| Age at diagnosis, daysa | 14 (8, 23) | 20 (12, 35) | 12 (7, 18) |
| Bronchopulmonary dysplasiaa | 89 (75.4%) | 35 (62.5%) | 54 (87.1%) |
| O2 at discharge/transfera | 63 (53.4%) | 22 (39.3%) | 41 (66.1%) |
n (%) or median (25th, 75th %ile)
p<0.05
Baseline respiratory metrics
At baseline (day of echocardiogram or start of treatment), infants in the PDA-T group were more likely to be on invasive mechanical ventilation (Table 2). In unadjusted analysis, PDA-T infants They had higher mean FiO2, lower mean SpO2, and higher RAS on day 0 than those in the PDA-NT group (Figure 1, p<0.05). There was no significant difference in the percentage of time in severe hypoxemia between groups. After adjusting for gestational age, birth weight, and sex, PDA-T infants had a higher RAS at baseline than PDA-NT infants (p<0.05), but mean FiO2, mean SpO2, and severe hypoxemia did not differ on day 0.
Table 2:
Baseline FiO2 and respiratory support for Respiratory Acuity Score calculation
| Total (n=125) | PDA-NT (n=59) | PDA-T (n=66) | |
|---|---|---|---|
| FiO2 (%) | 32 (22, 44) | 25 (22, 35) | 37 (28, 46) |
| Mode of respiratory support | |||
| High frequency ventilator | 39 (31.2%) | 8 (13.6%) | 31 (47.0%) |
| Conventional ventilator | 35 (28.0%) | 12 (20.3%) | 23 (34.8%) |
| CPAP/NIPPV | 34 (27.2%) | 23 (39.0%) | 11 (16.7%) |
| HFNC >2 L/min | 7 (5.6%) | 7 (11.9%) | 0 (0.0%) |
| HFNC 1–2 L/min | 4 (3.2%) | 4 (6.8%) | 0 (0.0%) |
| LFNC <1 L/min | 6 (4.8%) | 5 (8.5%) | 1 (1.5%) |
n (%) or median (25th, 75th %ile)
CPAP = continuous positive airway pressure, NIPPV = nasal intermittent positive pressure ventilation, HFNC = high flow nasal cannula, LFNC = low flow nasal cannula
Figure 1.
Baseline respiratory and oxygenation metrics by treatment group Respiratory and oxygenation metrics at baseline are shown for VLBW infants with PDA-NT (n=59) or PDA-T (n=66): (A) Respiratory Acuity Score, (B) mean daily FiO2, (C) mean daily SpO2, and (D) percentage of time in severe hypoxemia (SpO2 <80%). The line within the box represents the median, and the lower and upper bounds of the box are the 25th and 75th percentiles respectively. Whiskers represent the 5th and 95th percentiles, with individual outliers shown as filled circles. Significant differences (p<0.05) in unadjusted comparisons are denoted with an asterisk. Using multivariable analysis adjusted for gestational age, birth weight, and sex, baseline RAS remained significantly higher in PDA-T infants. However, the adjusted differences for the other three metrics were not statistically significant.
Change in respiratory metrics from baseline to day 3
For infants in the PDA-NT group, there was no significant change in mean FiO2, RAS, SpO2, or percentage of time in severe hypoxemia from baseline (day of echocardiogram) to day 3 (Table 3). In the PDA-T group, mean FiO2 increased from 37% on day 0 (first day of treatment) to 40% on day 3 (p=0.008). There was a statistically significant but small improvement in RAS on day 3 and no change in mean SpO2 (91% before and after treatment, Table 3). Percent of time in severe hypoxemia (SpO2<80%) increased from 3.2% on day 0 to 5.1% on day 3, a difference that was not statistically significant (Table 3, p=0.603). Figure 2 shows individual patient data before (x-axis) and 3 days after (y-axis) start of PDA treatment.
Table 3.
Respiratory metrics day 0 versus day 3
| Day 0 | Day 3 | p-value | |
|---|---|---|---|
|
| |||
| PDA-NT | |||
| FiO2 (%) | 25 (22, 35) | 25 (21, 34) | 0.988 |
| RAS | 98 (84, 162) | 93 (63, 178) | 0.074 |
| SpO2* (%) | 92 (91, 97) | 94 (91, 96) | 0.383 |
| Severe hypoxemia a (%) | 1.83 (0.49, 4.93) | 1.65 (0.60, 3.89) | 0.590 |
| PDA-T | |||
| FiO2 (%) | 37 (28, 46) | 40 (29, 52) | 0.008 |
| RAS | 258 (171, 348) | 254 (174, 419) | 0.012 |
| SpO2* (%) | 91 (90, 93) | 91 (89, 93) | 0.359 |
| Severe hypoxemia a (%) | 3.20 (1.35, 8.88) | 5.10 (2.79, 8.00) | 0.603 |
median (25th, 75th %ile)
for infants with every-2-second SpO2 data from archive (n = 83)
Figure 2.
Individual patient respiratory and oxygenation metrics on day 0 versus day 3 relative to the start of PDA treatment Respiratory and oxygenation metrics on the first day of treatment (day 0) and day 3 of treatment are shown for (A) Respiratory Acuity Score, (B) mean daily FiO2, (C) mean daily SpO2, and (D) severe hypoxemia represented as the percentage of time with SpO2 <80%. The line of identity is shown; improvement in RAS, FiO2, and percentage of time with SpO2 <80% are represented by points below the line and improvement in SpO2 is represented by points above the line.
Mean SpO2 and severe hypoxemia before and after PDA treatment
Every-2-second SpO2 data for days −3 to +3 relative to the day pharmacologic therapy started were available for 42 PDA-T infants. We plotted daily mean SpO2 and percent time with severe hypoxemia (SpO2 <80%) and evaluated the change in these measures each day by comparing from the same patient one day prior (Figure 3). Mean SpO2 was significantly lower the day after treatment started compared to the day of treatment (day 1 vs. day 0, p<0.05). The percent time in severe hypoxemia increased from two days before treatment to one day before treatment (day −2 vs. day −1, p<0.05). The remaining comparisons were not statistically significant. Figure 4 shows the percent time with severe hypoxemia after stratification by gestational age, sex, drug category, and day of treatment (panels A-D).
Figure 3.
Mean SpO2 and percent time per day with severe hypoxemia (SpO2 <80%) relative to the start of PDA treatment Medians of daily mean SpO2 and time with severe hypoxemia are shown from 3 days before until 3 days after the start of treatment. Error bars indicate the first and third quartiles.
Figure 4.
Stratified daily measures of percent time with severe hypoxemia (SpO2 <80%) relative to the start of PDA treatment Median time with severe hypoxemia is shown from 3 days before until 3 days after the start of treatment. Data are grouped by A) gestational age (GA 22–26w, n=19; GA 27–30w, n=23), B) sex (female, n=23; male, n=19), C) medication (acetaminophen, n= 11; indomethacin or ibuprofen, n=31), and D) postnatal age at start of treatment (< 14 days, n=28; ≥ 14 days, n=14). Error bars indicate the first and third quartiles.
DISCUSSION
In this retrospective study of 125 VLBW infants with echocardiographic evidence of a PDA, we examined oxygenation and respiratory support metrics in infants with and without pharmacologic PDA treatment. We found that infants whose PDA was treated had higher respiratory support needs at baseline. No major improvements in respiratory support requirements or oxygenation metrics were observed immediately following pharmacologic PDA treatment.
Prior studies in VLBW infants have demonstrated that administration of indomethacin, ibuprofen, or acetaminophen may accelerate ductal closure in infants with a PDA.3,15 However, several randomized trials and meta-analyses have shown that pharmacologic treatment of a PDA does not reduce the risk of bronchopulmonary dysplasia or improve other short- or long-term outcomes.15,16 In fact, some studies have suggested an increase in respiratory support needs following NSAID treatment.17,18 Our findings suggest that pharmacologic PDA treatment also does not result in an immediate improvement in respiratory status. We also found that time with severe hypoxemia did not improve during PDA treatment, which may often be one of the desired or expected clinical effects of treatment.
PDA shunting in preterm infants is usually bidirectional, with left-to-right shunting contributing to pulmonary edema and right-to-left shunting leading to intermittent hypoxemia. There is considerable controversy about the indications and benefits of PDA treatment. Determining which infants might benefit is complicated. Our findings indicate that worsening respiratory status may have contributed to a decision to initiate pharmacologic treatment, but that oxygenation worsened despite administering an NSAID or acetaminophen. We did not have documentation of PDA closure in this cohort, and pharmacologic PDA treatment is ineffective for up to 30% of preterm infants, so non-responders may have had a persistent shunt at three days into treatment.7 Clinical predictors of failed PDA closure include higher respiratory support before treatment, lower gestational age, and anemia.19,20 The infants selected for PDA treatment in our study were of lower gestational age and on higher respiratory support at baseline, indicating a high risk of treatment failure. Prospective analysis of respiratory metrics alongside data on the timing of PDA closure would better demonstrate the effect of removing the shunt on short-term respiratory metrics.
A strength of this analysis is our large archive of SpO2 data, which enabled us to examine the acute impact of PDA medications on hypoxemia, and a Respiratory Acuity Score, which factors in both FiO2 and level of respiratory support. We acknowledge several limitations, including the retrospective nature of the study, which precluded our ability to analyze and control for multiple clinical variables, and the lack of suitable controls with which to distinguish natural history from treatment effect. The decision to treat was not strictly protocolized, so it is possible our results would not be reproduced in another center or cohort. The short post-treatment time frame may have been insufficient to demonstrate potential benefit. We reviewed echocardiogram reports but noted that these did not have consistent measurements to assess the hemodynamic significance of shunting across the ductus. We were also limited in that three different medications, as well as different dosing regimens, were used in the 10-year period. Thus, we cannot rule out whether a particular medication, dose, and type of patient might show acute benefit from treatment. Another limitation is that our pulse oximetry data used a standard 8-second averaging time, which underestimates the depth and overestimates the duration of intermittent hypoxemia events.21 We chose to analyze only severe hypoxemia since it is the most likely to have a negative clinical impact. Additionally, the definition that we used for BPD may be less specific than the more recent classification system.13,22 Finally, we did not measure tissue hypoxia and thus cannot evaluate whether PDA treatment impacted cerebral, splanchnic, or renal tissue oxygenation, which might be compromised by PDA shunting.
In conclusion, in this cohort of VLBW infants, we did not find that pharmacologic PDA treatment led to a substantial improvement in respiratory support, and it did not improve a trend of worsening oxygenation status observed before the start of treatment.
Key points.
Infants with pharmacologically treated PDA had worse baseline respiratory and oxygenation metrics
Respiratory Acuity Score decreased but FiO2 increased 3 days after pharmacologic PDA treatment
Pharmacologic PDA treatment did not acutely improve SpO2 or severe hypoxemia
Footnotes
Conflicts/disclosures related to this work: none
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