Long term consequences of oxygen therapy in the neonatal period

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Summary

Preterm and term infants are frequently exposed to high concentrations of oxygen for prolonged periods. In experimental models, high and prolonged oxygen exposures cause delayed alveolar septation and a bronchopulmonary dysplasia phenotype. Often, however, the oxygen exposure is tolerated in that the infants recover without severe lung or systemic injury. Multiple exposures change oxygen sensitivity in adult and newborn animals. Examples are antenatal corticosteroids, inflammatory mediators or preconditioning with oxygen, which will increase tolerance to oxygen injury. Intrauterine growth restriction or postnatal nutritional deficits will increase oxygen injury. Different infants probably have quite variable sensitivities to oxygen injury, but there are no biomarkers available to predict the risk of oxygen injury.

Introduction

Oxygen is the most frequently used effective and essential drug for the care of the newborn. However, recent research reviewed in this monograph demonstrates that surprisingly short exposures to oxygen can alter long term biochemical indicators of oxidant stress and may adversely affect outcomes.1 The use of oxygen thus has a risk to benefit equation just as for any other drug. Therefore, a balanced perspective of the scientific and clinical aspects of oxygen use is needed, especially for the preterm. Much of the data for oxidant injury and long term effects come from animal models, which inform us about what can happen, but do not establish what does happen to sick preterm infants. The focus of this review is on longer term effects of oxygen on the newborn rather than on the acute effects associated with oxygen use for resuscitation, which are reviewed in other papers in this monograph. Our goal is to summarize clinical and animal model observations to build the concept that the effects of oxygen exposure of the newborn are likely to be modulated by multiple mechanisms such that the risk of oxygen toxicity may differ for each infant, depending on antenatal history, age after birth, and care strategies.

Section snippets

Evidence of oxygen toxicity: BPD

Bronchopulmonary dysplasia (BPD) has been the poster child for oxygen toxicity in the preterm since the original description of the disease by Northway et al. in 1967.2 These authors also reported that 100% oxygen caused inflammation, fibrosis, and ‘emphysema’ in the lungs of newborn mice in 1976.3 The clinical contribution of oxygen to BPD has been less clear because sick infants generally require both ventilatory support and supplemental oxygen and the use of both therapies track in parallel

Chronic oxygen use in infants: BPD and retinopathy of prematurity (ROP)

Two large randomized and controlled trials have asked the questions: once an infant is oxygen dependent, does the oxygen saturation change growth, development, or the severity of ROP? The STOP-ROP trial randomized oxygen dependent infants at about 35 weeks of gestation to 89–94% saturation or 96–99% saturation targets with the primary question related to progression of ROP14 (Table 2). There was no important effect on progression of ROP, but the higher oxygen exposure resulted in multiple

Oxygen sensitivity of the newborn

Although we have built the case with clinical and animal model information that supplemental oxygen can harm the newborn, it is also essential to use supplemental oxygen frequently, but carefully, for clinical management of the preterm. Therefore, it is useful to ask the question: How sensitive to oxygen is the newborn relative to the adult? The default answer of most neonatologists is that the newborn is more sensitive to oxidant injury because of immaturity and decreased oxidant protective

Modulation of oxygen sensitivity

There is no information to calibrate the relative sensitivity of preterm humans to supplemental oxygen relative to term humans because oxygen is only used for clinical need. Further complicating any unified assessments of oxygen sensitivity are the multiple clinically relevant variables that profoundly modulate oxygen sensitivity. The concept of decreased oxygen sensitivity or oxygen tolerance has been developed in animal models and cannot ethically be evaluated in humans. We will first briefly

Modulators of oxygen toxicity in the developing lung

If we accept that the newborn is less sensitive to oxygen injury than the adult, there are multiple modulators of oxygen resistance that have been investigated in experimental models. Much of the earlier research focused on changes in antioxidant enzyme levels, although oxygen tolerance is mechanistically much more complicated than simply changes in antioxidant enzyme levels.29 Nevertheless, the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxide increase with

Late effects of neonatal hyperoxia

The lungs of patients with BPD are abnormal into early adulthood. However, those abnormalities need not result primarily from the prolonged oxygen exposure because of the multifactorial nature of BPD. However, the abnormal lungs of 8-month-old baboons caused by oxygen exposure clearly demonstrates the potential for persistence of the structural abnormalities initiated by oxygen in the newborn period.13 Oxygen exposure of newborn rodents with lungs in the saccular stage of development caused a

Clinical correlates to research with oxygen toxicity

Inevitably, there is minimal clinical information about how toxic oxygen might be for the preterm or term infant. The normal preterm infant probably is inherently more oxygen tolerant than the adult. Preterm or term infants who receive significant oxygen therapy are not normal as they are receiving oxygen therapy for a reason. Most preterm infants also will have been exposed to antenatal corticosteroids, and at least half of the very low birth weight population will have chorioamnionitis

Conflicts of interest

The authors have grants from the US National Institutes of Health and Human services to study fetal inflammation and lung injury: HD-57869 to S.K. The authors also participate in studies of the causes of lung injury with the initiation of ventilation funded in part by Fisher & Paykel, New Zealand.

Funding sources

There has been no participation from any funding sources in the preparation of this article.

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