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(Chest. 2005;128:430-433.)
© 2005 American College of Chest Physicians

Hyperoxia-Induced Hypocapnia*

An Underappreciated Risk

Steve Iscoe, PhD and Joseph A. Fisher, MD

* From the Department of Physiology (Dr. Iscoe), Queen’s University, Kingston; and Department of Anaesthesia (Dr. Fisher), Toronto General Hospital, Toronto, ON, Canada.

Correspondence to: Steve Iscoe, PhD, Department of Physiology, Queen’s University, Kingston, ON, Canada K7L 3N6; e-mail iscoes{at}post.queensu.ca

Key Words: clinical outcomes • hyperoxia • hypocapnia • normocapnia • supplementary oxygen


   Introduction
TOP
 Introduction
Labor
 CO Poisoning
 Stroke
 Myocardial Ischemia
 Wound Healing
 Conclusion
 References
 
Administration of supplementary O2 is considered to be safe, as exemplified by one editorial comment1: "Oxygen should be used as soon as possible, in as near 100% as possible in all resuscitation situations, and for the early management of injury and illness. Its use will never disadvantage [our emphasis] a patient under these circumstances." We believe this claim merits examination.

The rationale for administering O2 is that it increases the O2 content of blood and, therefore, O2 delivery to tissues. In a healthy person, hemoglobin is nearly saturated, and switching from air to pure O2 at sea level will increase O2 content by < 10% due almost exclusively to the increase in O2 dissolved in the plasma. In these people, the more influential determinant of O2 delivery is tissue perfusion that is determined by perfusion pressure and local tissue vascular resistance. Vascular resistances in the brain, heart, and placenta are affected by the PCO2 in arterial blood.

At issue is the existence of a strong link between hyperoxia and arterial PCO2. Oxygen has long been known, but seldom recognized, to be a respiratory stimulant resulting in hypocapnia in adults23456 and infants,789 a result confirmed by more recent work.10 While oxygen may not have this effect in patients with a limited ability to increase ventilation because of disease,11 it can be expected to cause at least some hyperventilation in the vast majority of patients. This raises the possibility that hyperoxia-induced hypocapnia would cause vasoconstriction of CO2-resposive vascular beds and paradoxically exacerbate ischemia there, if present. Furthermore, the hypocapnia increases the affinity of hemoglobin for O2, reducing O2 unloading to tissues. These effects are known from basic physiologic principles but are seldom emphasized in clinical texts or taken into account when O2 administration is prescribed.

The link between hyperoxia and hyperventilation can be explained by the Haldane effect. Oxygenated hemoglobin binds less CO2 (the Haldane effect); therefore, CO2 transport must be maintained by increases in bicarbonate and dissolved CO2, the latter increasing local tissue PCO2. In most tissues, this is of no consequence; but in the brainstem, the location of the central chemoreceptors responsible for most of the respiratory drive,12 the increased PCO213 and, more importantly, H+14 stimulate these receptors, increasing ventilation. This increase is greater if not blunted by the resulting arterial hypocapnia.1015 Figure 1 illustrates this effect in a typical subject breathing sequentially air, O2, and O2 with PCO2 returned to and maintained at control values. We now briefly discuss several clinical situations in which hyperoxia-induced hypocapnia may paradoxically not improve—or even worsen—tissue oxygenation.



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  		Figure 1. Typical effects of hyperoxia on minute ventilation (E), end-tidal PCO2 (PETCO2), and middle cerebral artery velocity (MCAV), an index of cerebral blood flow, in one of five normal subjects. Correction of the hyperoxia-induced hypocapnia by addition of CO2 to the inspired gas (normocapnic hyperoxia) returned middle cerebral artery velocity back toward control.

 

   Labor
TOP
 Introduction
 Labor
CO Poisoning
 Stroke
 Myocardial Ischemia
 Wound Healing
 Conclusion
 References
 
Maternal hyperoxia does not necessarily improve oxygenation of the fetus.1617 In women receiving mechanical ventilation during cesarean deliveries, increases of inspired O2 > 50% either do not improve18 or decrease19 the PO2 in the umbilical vein and artery; O2 decreases uterine perfusion regardless of the woman’s clinical status.2021 The decline in fetal PO2 is related to the degree of maternal hypocapnia22 despite maternal hyperoxia.23 Most importantly, maternal hypocapnia worsens fetal outcomes as measured by Apgar scores.24


   CO Poisoning
TOP
 Introduction
 Labor
 CO Poisoning
Stroke
 Myocardial Ischemia
 Wound Healing
 Conclusion
 References
 
Pure O2 is the recommended acute treatment for CO poisoning. However, Takeuchi and colleagues25 demonstrated that CO-exposed subjects breathing pure O2 hyperventilate, decreasing end-tidal PCO2 by an average of 2.8 mm Hg, a reduction that would, in the absence of any effect of CO on cerebrovascular resistance, decrease cerebral blood flow (CBF) by approximately 7%26 in adults and 30% in infants.2728 A follow-up study29 from the same laboratory showed that hyperoxia did reduce CBF and thereby cerebral O2 delivery in CO-exposed subjects. This raises questions about the current recommended therapy, normobaric hyperoxia, for CO poisoning. Hyperbaric hyperoxia also decreases PCO2 and CBF,303132 an effect to which the hyperoxia contributes.33 This reduction in CBF has not been taken into account when assessing the efficacy of hyperbaric O2 in treating CO poisoning. The risk of viewing O2 treatment as benign (ie, "it can’t hurt") may result in ignoring its potential contribution to morbidity and attributing all adverse sequelae to CO alone.


   Stroke
TOP
 Introduction
 Labor
 CO Poisoning
 Stroke
Myocardial Ischemia
 Wound Healing
 Conclusion
 References
 
Hyperoxia, but not hyperventilation,3435 continues to be advocated for treatment of strokes36 but no consideration has been given to the effects of hyperoxia-induced hypocapnia. As discussed above with respect to CO poisoning, any hypocapnia-induced decrease in CBF could offset any increase in blood O2 content and reduce actual O2 delivery. To our knowledge, there have been no studies in man of the effects of CO2 on the efficacy of hyperoxia in the management of stroke. However, animal studies37 suggest that hypercapnia better preserves cerebral oxidative metabolism and reduces the extent of postischemic atrophy.


   Myocardial Ischemia
TOP
 Introduction
 Labor
 CO Poisoning
 Stroke
 Myocardial Ischemia
Wound Healing
 Conclusion
 References
 
Breathing 100% O2 impairs left ventricular relaxation, increases end-diastolic pressure, and decreases coronary sinus blood flow in subjects with either heart failure or normal left ventricular function.38 No measurements were made of PCO2, so it is premature to attribute these effects to hypocapnia. Nevertheless, because arterial PCO2 affects the resistance of coronary vessels, there may be little benefit, but considerable risk, in treating myocardial ischemia with hyperoxia without measures to prevent hypocapnia. In patients with congestive heart failure, hypocapnia may explain the detrimental effects of hyperoxia on some cardiovascular parameters.11


   Wound Healing
TOP
 Introduction
 Labor
 CO Poisoning
 Stroke
 Myocardial Ischemia
 Wound Healing
Conclusion
 References
 
In 2000, Greif and colleagues39 described an approximate 50% reduction in the incidence of postoperative infection in patients administered 80% O2 during and for 2 h after an operation vs those receiving 30% O2. Tissue and wound PO2, however, depend not just on the inspired concentration of O2 but also on perfusion; this, in turn, is affected by the arterial PCO2. In humans, "the skin blood flow measured on the chest decreased by an average of 8% during hyperventilation; blood flow on the hand (thenar eminence) decreased by 60%; and blood flow on the foot decreased by 51%."40 In contrast, hypercapnia increased tissue PO2. This raises the question, would maintenance of normocapnia, or even slight hypercapnia, reduce wound infections or improve perfusion to ischemic chronic leg ulcers in diabetics? Hyperbaric O2 is a useful form of treatment for chronic infections and leg ulcers,41424344 but availability and cost limit its use45 and are likely to do so even more as the numbers of such patients increase. For the reasons given above, preventing a fall in PCO2 when breathing O2, whether normobaric or hyperbaric, may increase perfusion and thereby, one hopes, aid in tissue healing.


   Conclusion
TOP
 Introduction
 Labor
 CO Poisoning
 Stroke
 Myocardial Ischemia
 Wound Healing
 Conclusion
References
 
Supplementary O2 is typically administered without knowledge of its effect on CO2 levels. Even when CO2 levels can be monitored, physicians are concerned, perhaps unnecessarily,464748 about hypercapnia and do not consider the potentially detrimental effects of hypocapnia. Moreover, simple breathing circuits to control PCO2 during O2 administration, such as those introduced by Severinghaus and colleagues49 and Banzett and colleagues,50 could be adapted to clinical use. The next challenge is to determine whether maintaining normocapnia, or even slight hypercapnia, during the many clinical situations in which O2 is administered to relieve hypoxia in CO2-responsive vascular beds confers additional benefits and improves clinical outcomes.


   Footnotes
 
Abbreviation: CBF = cerebral blood flow

Received for publication September 24, 2004. Accepted for publication December 14, 2004.


   References
TOP
 Introduction
 Labor
 CO Poisoning
 Stroke
 Myocardial Ischemia
 Wound Healing
 Conclusion
 References
 

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