Hyperoxic 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 Findings
We 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.
In 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.
Hyperoxic ventilation leads to responses in brain areas that modify hypothalamus-mediated sympathetic and hormonal outflow; these responses can be diminished by addition of CO2 to the gas mixture.
All cells in the human body need oxygen (O2) to keep them alive. O2 is absorbed into the blood from the air by the lungs (which also release carbon dioxide [CO2], a waste product of cells, from the blood into the air). The blood then delivers O2 to the rest of the body. For healthy people, breathing air (which contains 21% O2) is sufficient to keep their tissues healthy. But there are medical situations in which O2 delivery to tissues needs improving. For example, during resuscitation or after a stroke when the O2 supply to a part of the brain is disrupted. Premature babies often need help with O2 delivery because their immature lungs don't absorb O2 efficiently. In situations like these, the O2 supply can be increased by providing an O2-rich gas mixture to the lungs—so-called “hyperoxic (i.e., high O2) ventilation.” But, paradoxically, hyperoxic ventilation can make matters worse. Hyperoxia increases the exchange of air between the lungs and the atmosphere (hyperventilation), which reduces the CO2 level in the blood. This “hypocapnia,” i.e. low CO2, reduces the blood flow to the brain by narrowing the blood vessels. Hyperoxia also alters the heart rate and blood pressure and the blood levels of some hormones. It probably causes these changes by affecting the brain regions that control autonomic functions (body functions such as heart rate, insulin and other hormone release, sweating and gland action that are not controlled by conscious thought). All told, although hyperoxic ventilation saves lives, it can also have serious adverse effects. In premature babies, for example, although it is often essential for their survival, hyperoxic ventilation can cause serious heart muscle and brain injury or lung problems (bronchopulmonary dysplasia) if it is not carefully monitored.
Why Was This Study Done?
The addition of a little CO2 to the hyperoxic gas mix can reduce the adverse effects of hyperoxic ventilation on blood flow to the brain. However, it is unclear whether this alteration can also modify responses of brain areas that control autonomic functions and hormone release to hyperoxia. If it does, then CO2 supplementation could prevent those adverse effects of hyperoxic ventilation that affect the whole body. In this study, the researchers investigated whether hyperoxic ventilation increases neural responses in brain regions that regulate the activity of the hypothalamus (the part of the brain that controls autonomic bodily functions) and whether the addition of CO2 reduces these responses.
What Did the Researchers Do and Find?
The researchers used a technique called functional magnetic resonance imaging (fMRI) to measure the activity of different brain regions in 14 healthy young people (aged 8–15 years). Active regions of the brain draw more O2 out of the blood than inactive regions, and fMRI measures changes in blood O2 levels. fMRI images were obtained for all the study participants when they were breathing normal air and during two-minute challenges with 100% O2 or a 95% O2, 5% CO2 mix. Hyperoxic ventilation produced rapid and marked changes in the activity of brain areas involved in autonomic and hormonal control, including the hypothalamus and regions that control the hypothalamus. After the challenge with 95% O2, 5% CO2, these responses were either absent or greatly reduced in the brain regions that had responded to 100% O2.
What Do These Findings Mean?
These findings show that hyperoxic ventilation induces brain activity changes that are likely to affect autonomic functions and hormone release throughout the body. In addition, they show that the addition of CO2 to the gas mixture greatly diminishes these responses. Because the autonomic and hormonal changes induced by 100% O2 can potentially injure organs throughout the body, the addition of CO2 to hyperoxic gas mixtures could reduce many of the adverse effects of hyperoxic ventilation. These results, therefore, could influence how hyperoxic ventilation is used in medical practice. However, CO2 supplementation still needs to be tested in adults and newborn babies. Although the results presented here will probably hold true for adults, and both neonatal and developmental animal studies suggest that hyperoxia results in serious side effects in newborns over room air or hyperoxia with added CO2, the brain findings need to studied in babies, the portion of the population most likely to be treated with hyperoxic ventilation.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040173
The American Lung Association has patient information on the lungs and lung diseases, including bronchopulmonary dysplasia (in English and Spanish)
The Medlineplus encyclopedia contains pages on hyperventilation and on premature babies, and links to other information on premature babies (in English and Spanish)
Wikipedia has pages on the lungs, oxygen toxicity, mechanical ventilation, and hypocapnia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)