Intermittent hypoxic episodes in preterm infants: do they matter?

Abstract

Intermittent hypoxic episodes are typically a consequence of immature respiratory control and remain a troublesome challenge for the neonatologist. Furthermore, their frequency and magnitude are underestimated by clinically employed pulse oximeter settings. In extremely low birth weight infants the incidence of intermittent hypoxia progressively increases over the first 4 weeks of postnatal life, with a subsequent plateau followed by a slow decline beginning at weeks 6-8. Such episodic hypoxia/reoxygenation has the potential to sustain a proinflammatory cascade with resultant multisystem morbidity. This morbidity includes retinopathy of prematurity and impaired growth, as well as possible longer-term cardiorespiratory instability and poor neurodevelopmental outcome. Therapeutic approaches for intermittent hypoxic episodes comprise determination of optimal baseline saturation and careful titration of supplemental inspired oxygen, as well as xanthine therapy to prevent apnea of prematurity. In conclusion, characterization of the pathophysiologic basis for such intermittent hypoxic episodes and their consequences during early life is necessary to provide an evidence-based approach to their management.

Fig. 1

Overview of the cardiorespiratory factors that influence the magnitude of oxygen desaturation during apnea of prematurity. Hypoxemia is likely enhanced by depletion of pulmonary oxygen stores at low lung volume, decreased blood oxygen carrying capacity, and increased peripheral oxygen consumption [5].

Fig. 2

Number of desaturation episodes [mean (95% CI)] in a cohort of 24-28 weeks’ gestation preterm infants over the first 8 weeks of life. There were relatively few desaturation episodes during the first week, followed by a progressive increase over weeks 2-4, and then a decrease in weeks 6-8 [7].

Fig. 3

Potentially vicious cycle created by immature respiratory control and resultant intermittent hypoxia.

Fig. 4

The role of intermittent hypoxia and resultant generation of reactive oxygen species (ROS) in mediating expression of HIFs and the downstream balance of oxidant and antioxidant pathways [16]. SOD = Superoxide dismutase.

Fig. 5

Proposed morbidities attributable to intermittent hypoxia in early life [57].

Fig. 6

Model-based estimate of intermittent hypoxemic events in preterm infants needing laser therapy for ROP vs. those who had no ROP or did not need laser therapy. Data [mean (95% CI)] are controlled for gestational age, race, sex, multiple births, and SNAPPE-II score. There was an overall higher incidence of hypoxemic events in the laser-treated infants with significant differences at 5, 7, and 8 weeks of age (∗ p < 0.05) [7].

Fig. 7

Potential broad implications of neonatal intermittent hypoxia (IH) on growth patterns and longer-term cardiovascular and metabolic regulation.

Fig. 8

Possible future guidelines for optimizing baseline oxygen saturation in preterm infants and minimizing morbidity. Clearly such an approach needs careful future study before being considered in clinical practice.