Research Article: Hyperoxic Brain Effects Are Normalized by Addition of CO2

Date Published: May 22, 2007

Publisher: Public Library of Science

Author(s): Paul M Macey, Mary A Woo, Ronald M Harper, Mervyn Singer

Abstract: BackgroundHyperoxic ventilation (>21% O2) is widely used in medical practice for resuscitation, stroke intervention, and chronic supplementation. However, despite the objective of improving tissue oxygen delivery, hyperoxic ventilation can accentuate ischemia and impair that outcome. Hyperoxia results in, paradoxically, increased ventilation, which leads to hypocapnia, diminishing cerebral blood flow and hindering oxygen delivery. Hyperoxic delivery induces other systemic changes, including increased plasma insulin and glucagon levels and reduced myocardial contractility and relaxation, which may derive partially from neurally mediated hormonal and sympathetic outflow. Several cortical, limbic, and cerebellar brain areas regulate these autonomic processes. The aim of this study was to assess recruitment of these regions in response to hyperoxia and to determine whether any response would be countered by addition of CO2 to the hyperoxic gas mixture.Methods and FindingsWe studied 14 children (mean age 11 y, range 8–15 y). We found, using functional magnetic resonance imaging, that 2 min of hyperoxic ventilation (100% O2) following a room air baseline elicited pronounced responses in autonomic and hormonal control areas, including the hypothalamus, insula, and hippocampus, throughout the challenge. The addition of 5% CO2 to 95% O2 abolished responses in the hypothalamus and lingual gyrus, substantially reduced insular, hippocampal, thalamic, and cerebellar patterns in the first 48 s, and abolished signals in those sites thereafter. Only the dorsal midbrain responded to hypercapnia, but not hyperoxia.ConclusionsIn this group of children, hyperoxic ventilation led to responses in brain areas that modify hypothalamus-mediated sympathetic and hormonal outflow; these responses were diminished by addition of CO2 to the gas mixture. This study in healthy children suggests that supplementing hyperoxic administration with CO2 may mitigate central and peripheral consequences of hyperoxia.

Partial Text: Hyperoxic ventilation (>21% O2) is widely used in medical practice, both in acute applications, such as resuscitation and stroke, and for chronic ventilatory supplementation. However, despite the objective of improving tissue oxygen delivery, hyperoxia can accentuate ischemia and impair that outcome. After initially suppressing ventilation through peripheral chemoreceptor action, hyperoxic gas mixtures paradoxically increase ventilation [1], likely by exciting chemosensitive brainstem neurons, possibly by an O2 free radical mechanism [2]. Reduced CO2–hemoglobin binding from increased O2 (the Haldane effect [3]) may additionally contribute to enhanced ventilation. The increase in ventilation due to hyperoxic exposure occurs also in neonates [4] and is long-lasting [5]. The hyperoxia-induced ventilatory increases result in reduced PCO2 and diminished cerebral blood flow (CBF) [1]. Oxygen delivery is further hindered by increasing the affinity of hemoglobin for O2 and reducing O2 unloading to tissues [6].

The physiologic patterns of response to the challenges, reported earlier in a subset of 12 of the current 14 children [31], were similar to those reported elsewhere. The expected decline in heart rate due to hyperoxia [9] appeared after one minute. Respiratory rate showed a brief increase; tidal volume, which was not measured, is responsible for the majority of the reported increased ventilation due to hyperoxia, with respiratory rate not greatly affected [32,33]. Hypercapnia induced a sustained rise in both respiratory and cardiac rates, as anticipated [34]. Trends in end-tidal CO2, an increase due to hypercapnia and decrease to hyperoxia, were also consistent with the established physiologic literature.

We found that a number of brain areas responded to a hyperoxic challenge, especially neural regions that mediate autonomic and hormonal systems. However, addition of 5% CO2 to the hyperoxic mixture substantially reduced reactions of these neural structures. The perfusion and hormonal changes to 100% O2 could initiate a cascade of central and peripheral injuries through oxidative stress processes commonly reported with high oxygen ventilation. Since the structures recruited in hyperoxia control output of hypothalamic sympathetic and hormonal regulatory areas, the reduced responses of those structures with the addition of CO2 may diminish injury to central and peripheral organs following hyperoxia alone, a possibility suggested by others [6].



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