Authors: Thomas M. Raffay, Erik A. Jensen
Categories: Editorials
Source: American Journal of Respiratory and Critical Care Medicine
Bronchopulmonary dysplasia (BPD) is a chronic lung disease that develops in up to half of infants born very premature, with approximately 13,000 infants diagnosed with severe disease in the United States annually (1, 2). Infants who develop BPD are at elevated risk for respiratory impairment and neurodevelopmental disability that can persist through childhood and adulthood (2, 3). Pulmonary hypertension (PH) is a serious comorbidity of BPD that further predisposes to poor outcomes, including early mortality (1). Owing to the risks associated with PH in BPD, the identification of underlying mechanisms involved with the development of PH and novel methods of detection and longitudinal surveillance are important areas of research. Quantification of intermittent hypoxemia (IH) using bedside continuous pulse oximetry downloads has emerged as a promising indicator of cardiorespiratory instability. Higher frequency and longer duration of neonatal IH have been associated with adverse in-hospital and childhood outcomes, including the diagnosis of BPD at 36 weeks postmenstrual age and neurodevelopmental impairment at 18 months corrected age (4–8).
In this issue of the Journal, Gentle and colleagues (pp. 899–907) report the results of a prospective single-center study that examined the associations between IH parameters and the presence or absence of PH in extremely preterm infants with BPD (9). Per the center’s practice, study infants underwent monthly screening echocardiography beginning at 28 days of age. The investigators interrogated the oxygen saturation as measured by pulse oximetry (SpO2~~) recordings obtained during the week preceding the initial echocardiographic diagnosis of PH in 40 infants and compared these results to values recorded in the same number of gestational and postnatal age-matched control subjects without PH. Hypoxemia was defined as an SpO2~~ of less than 80%, and secondary analyses were performed for SpO2~~ of less than 70%.
To our knowledge, this exploratory study is the first to evaluate whether IH may be an important marker of PH in extremely preterm infants. The study results suggest a possible but clinically inconclusive relationship. Both cases and control subjects exhibited a similar daily frequency of hypoxemic episodes (SpO2~~ < 80% for any duration) and cumulative daily duration of time in hypoxemia. However, there was a slight difference in the median duration of IH events (7 s vs. 6 s) between cases and control subjects, which was more pronounced when using an SpO2~~ threshold of less than 70% (105 s vs. 58 s). In a planned secondary analysis restricted to infants with PH, the authors found that the median duration of daily IH episodes with SpO2~~ of less than 70% was twice as long in subjects with subsequent in-hospital mortality than among survivors (145 s vs. 72 s). The median number of severe IH events was similar between the groups (eight vs. seven events per day). There were no differences among survivors and nonsurvivors with PH when the equivalent analyses were performed using an SpO2~~ threshold of less than 80%.
Gentle and colleagues are appropriately cautious to not overstate their findings and largely provide a balanced interpretation. Nonetheless, several study features should be considered when interpreting their results. At present, there is no gold standard definition for hypoxemia in preterm infants. SpO2~~ of less than 80% is commonly used, but higher and lower thresholds have been proposed (4). Notably, the accuracy of pulse oximeters progressively decreases at lower recorded SpO2~~ values and may differ from arterial blood oxygen saturation concentrations by absolute values of 10% or more when SpO2~~ is less than 80% (10). The observed association between longer exposure to SpO2~~ values less than 70% and the presence of PH reported by Gentle and colleagues should be considered with this diagnostic limitation in mind.
The duration of hypoxemia that should define IH is also uncertain. Moreover, the oximeter averaging time and sampling rate can affect the quantification of hypoxemia and should be noted when evaluating study data (11). Using an oximeter averaging time of 8 seconds and a 1-second sampling rate, Gentle and colleagues observed a difference of only 1 second in the median duration of daily IH episodes defined by SpO2~~ values less than 80% between infants with PH compared with those without PH. This difference was not statistically significant when adjusted for baseline infant characteristics, and it is unclear whether such a small distinction has pathologic importance.
However, Gentle and colleagues found that infants with PH versus those without PH were twice as likely to experience hypoxemic events lasting longer than 60 seconds. This finding is noteworthy, as the authors indicate, because a post hoc analysis of data from COT (Canadian Oxygen Trial) suggested that exposure to hypoxemic events lasting longer than 1 minute, but not shorter events, during the first 2–3 months of age was associated with increased risk of death or developmental disability (8). COT employed oximeters set to a 16-second averaging time and 10-second sampling rate. Future studies will need to continue to investigate how the depth, duration, and cumulative exposure to hypoxemia may relate to disease risk in preterm infants and optimal oximeter settings to reliably measure IH (4).
Finally, a key unanswered question is whether recurrent hypoxemia directly contributes to disease pathophysiology in preterm infants or is simply a marker of greater illness acuity (Figure 1). Data from animal models indicate hypoxemia, particularly when accompanied with hyperoxia, may promote inflammation and oxidative stress, both of which are implicated in lung and cardiovascular maldevelopment in BPD (12, 13). To confirm a causal link in infants, randomized trials will need to consistently demonstrate that reductions in hypoxemia result in improved outcomes. Unfortunately, there are limited trial data examining interventions that directly influence IH, and some strategies, such as targeting higher SpO2~~ ranges, may reduce IH but also predispose to certain adverse effects. Resolving this knowledge gap may require studying interventions that minimize exposure to IH but also avoid secondary harmful treatment effects such as hyperoxia, barotrauma, or adverse drug sequelae.
Although questions regarding the potential consequences of recurrent hypoxemia in preterm newborns remain unanswered, the report by Gentle and colleagues provides a valuable contribution to this growing body of literature. Further investigation is needed to understand the longitudinal relationship between IH and pulmonary vascular disease in BPD and whether there are critical time periods or characteristics of IH that predispose preterm infants to poor outcomes.