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Opinions/Hypotheses |

Hyperoxia-Induced Hypocapnia*: An Underappreciated Risk FREE TO VIEW

Steve Iscoe, PhD; Joseph A. Fisher, MD
Author and Funding Information

*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@post.queensu.ca



Chest. 2005;128(1):430-433. doi:10.1378/chest.128.1.430
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Published online

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 adults26 and infants,79 a result confirmed by more recent work.10While 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,12the increased Pco213and, more importantly, H+14 stimulate these receptors, increasing ventilation. This increase is greater if not blunted by the resulting arterial hypocapnia.10,15Figure 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.

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 decrease19the Po2 in the umbilical vein and artery; O2 decreases uterine perfusion regardless of the woman’s clinical status.21 The decline in fetal Po2 is related to the degree of maternal hypocapnia22 despite maternal hyperoxia.23Most importantly, maternal hypocapnia worsens fetal outcomes as measured by Apgar scores.24

Pure O2 is the recommended acute treatment for CO poisoning. However, Takeuchi and colleagues25demonstrated 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 study29from 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,32 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.

Hyperoxia, but not hyperventilation,3435 continues to be advocated for treatment of strokes36but 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.

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

In 2000, Greif and colleagues39described 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,44 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.

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,4648 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.

Abbreviation: CBF = cerebral blood flow

Figure Jump LinkFigure 1. Typical effects of hyperoxia on minute ventilation (V̇e), 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.Grahic Jump Location
Oxer, HF (2000) Simply add oxygen: why isn’t oxygen administration taught in all resuscitation training?Resuscitation43,163-169. [CrossRef] [PubMed]
 
Shock, NW, Soley, MH Effect of breathing pure oxygen on respiratory volume in humans.Proc Soc Exp Biol Med1940;44,418-420
 
Dripps, RD, Comroe, JH, Jr The effects of inhalation of high and low oxygen concentrations on respiration, pulse rate, ballistocardiogram and arterial oxygen saturation (oximeter) of normal individuals.Am J Physiol1947;149,277-291. [PubMed]
 
Lambertsen, CJ, Stroud, MW, III, Gould, RA, et al Oxygen toxicity: respiratory responses of normal men to inhalation of 6 and 100 per cent oxygen under 3.5 atmospheres pressure.J Appl Physiol1953;5,487-494. [PubMed]
 
Yamada, M Methodische Untersuchungen über das Haldane-Hendersonsche Verfahren der Bestimmung der alveolären CO2-Spannung und über den Einfluβ von Sauerstoff auf die Erregbarkeit des Atemzentrums.Biochem Ztschr1918;89,27-47
 
Otis, AB, Rahn, H, Brontman, M, et al Ballistocardiographic study of changes in cardiac output due to respiration.J Clin Invest1946;25,413-421. [CrossRef]
 
Howard, PJ, Bauer, AR Respiration of the newborn infant: variation in respiratory minute volume with change in per cent of oxygen in respired mixture.Am J Dis Child1950;79,611-622
 
Graham, BD, Reardon, HS, Wilson, JL, et al Physiologic and chemical response of premature infants to oxygen-enriched atmosphere.Pediatrics1950;6,55-71. [PubMed]
 
Cross, KW, Warner, P The effect of inhalation of high and low oxygen concentrations on the respiration of the newborn infant.J Physiol1951;114,283-295. [PubMed]
 
Becker, HF, Polo, O, McNamara, SG, et al Effect of different levels of hyperoxia on breathing in healthy subjects.J Appl Physiol1996;81,1683-1690. [PubMed]
 
Haque, WA, Boehmer, J, Clemson, BS, et al Hemodynamic effects of supplemental oxygen administration in congestive heart failure.J Am Coll Cardiol1996;27,353-357. [PubMed]
 
Nattie, EE Central chemosensitivity, sleep, and wakefulness.Respir Physiol2001;129,257-268. [CrossRef] [PubMed]
 
Busija, DW, Orr, JA, Rankin, JH, et al Cerebral blood flow during normocapnic hyperoxia in the unanesthetized pony.J Appl Physiol1980;48,10-15. [PubMed]
 
Eldridge, FL, Kiley, JP Effects of hyperoxia on medullary ECF pH and respiration in chemodenervated cats.Respir Physiol1987;70,37-49. [CrossRef] [PubMed]
 
Ren, X, Fatemian, M, Robbins, PA Changes in respiratory control in humans induced by 8 h of hyperoxia.J Appl Physiol2000;89,655-662. [PubMed]
 
Khaw, KS, Wang, CC, Ngan Kee, WD, et al Effects of high inspired oxygen fraction during elective caesarean section under spinal anaesthesia on maternal and fetal oxygenation and lipid peroxidation.Br J Anaesth2002;88,18-23. [CrossRef] [PubMed]
 
Khaw, KS, Ngan Kee, WD, Lee, A, et al Supplementary oxygen for elective caesarean section under spinal anaesthesia: useful in prolonged uterine incision-to-delivery interval?Br J Anaesth2004;92,518-522. [CrossRef] [PubMed]
 
Baraka, A Correlation between maternal and foetal PO2and PCO2during caesarean section.Br J Anaesth1970;42,434-438. [CrossRef] [PubMed]
 
Rorke, MJ, Davey, DA, Du Toit, HJ Foetal oxygenation during caesarean section.Anaesthesia1968;23,585-596. [CrossRef] [PubMed]
 
Tervila, L, Vartiainen, E, Kivalo, I, et al The effect of oxygen ventilation and a vasodilator on uterine perfusion, foetal oxygen and acid-base balance: I. A study in healthy gravidae.Acta Obstet Gynecol Scand1973;52,177-181. [CrossRef] [PubMed]
 
Tervila, L, Vartiainen, E, Kivalo, I, et al The effect of oxygen ventilation and vasodilator on uterine perfusion, fetal oxygen and acid-base balance: I. A study in abnormal gravidae.Acta Obstet Gynecol Scand1973;52,309-315. [CrossRef] [PubMed]
 
Miller, FC, Petrie, RH, Arce, JJ, et al Hyperventilation during labor.Am J Obstet Gynecol1974;120,489-495. [PubMed]
 
Motoyama, EK, Rivard, G, Acheson, F, et al Adverse effect of maternal hyperventilation on the foetus.Lancet1966;1,286-288. [PubMed]
 
Peng, AT, Blancato, LS, Motoyama, EK Effect of maternal hypocapnia v. eucapnia on the foetus during caesarean section.Br J Anaesth1972;44,1173-1178. [CrossRef] [PubMed]
 
Takeuchi, A, Rucker, J, Vesely, A, et al A simple “new” method to accelerate clearance of carbon monoxide from human subjects.Am J Respir Crit Care Med2000;161,1816-1819. [PubMed]
 
Fortune, JB, Bock, D, Kupinski, AM, et al Human cerebrovascular response to oxygen and carbon dioxide as determined by internal carotid artery duplex scanning.J Trauma1992;32,618-627. [CrossRef] [PubMed]
 
Rahilly, PM Effects of 2% carbon dioxide, 0.5% carbon dioxide, and 100% oxygen on cranial blood flow of the human neonate.Pediatrics1980;66,685-689. [PubMed]
 
Leahy, FAN, Cates, D, MacCallum, M Effect of CO2and 100% O2on cerebral blood flow in preterm infants.J Appl Physiol1980;48,468-472. [PubMed]
 
Rucker, J, Tesler, J, Fedorko, L, et al Normocapnia improves cerebral O2delivery during conventional O2therapy in CO-exposed subjects.Ann Emerg Med2002;40,611-618. [CrossRef] [PubMed]
 
Lambertsen, CJ, Kough, RH, Cooper, DY, et al Oxygen toxicity: effects in man of oxygen inhalation at 1 and 3.5 atmospheres upon blood gas transport, cerebral circulation and cerebral metabolism.J Appl Physiol1953;5,471-486. [PubMed]
 
Omae, T, Ibayashi, S, Kusuda, K, et al Effects of high atmospheric pressure and oxygen on middle cerebral blood flow velocity in humans measured by transcranial Doppler.Stroke1998;29,94-97. [CrossRef] [PubMed]
 
Visser, GH, Van Hulst, RA, Wieneke, GH, et al Transcranial Doppler sonographic measurements of middle cerebral artery flow velocity during hyperbaric oxygen exposures.Undersea Hyperbaric Med1996;23,157-165
 
Floyd, TF, Clark, JM, Gelfand, R, et al Independent cerebral vasoconstrictive effects of hyperoxia and accompanying arterial hypocapnia at 1 ATA.J Appl Physiol2003;95,2453-2461. [PubMed]
 
The integration of brain-specific treatments into the initial resuscitation of the severe head injury patient: Brain Trauma Foundation.J Neurotrauma1996;13,653-659. [CrossRef] [PubMed]
 
Muizelaar, JP, Marmarou, A, Ward, JD, et al Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial.J Neurosurg1991;75,731-739. [CrossRef] [PubMed]
 
Sharief, MK, Anand, P Neurological emergencies. Skinner, D Swain, A Peyton, Ret al eds.Cambridge textbook of accident and emergency medicine1997,1057-1077 Cambridge University Press. Cambridge, UK:
 
Vannucci, RC, Towfighi, J, Heitjan, DF, et al Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat.Pediatrics1995;95,868-874. [PubMed]
 
Mak, S, Azevedo, ER, Liu, PP, et al Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure.Chest2001;120,467-473. [CrossRef] [PubMed]
 
Greif, R, Akca, O, Horn, EP, et al Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection.N Engl J Med2000;342,161-167. [CrossRef] [PubMed]
 
Barker, SJ, Hyatt, J, Clarke, C, et al Hyperventilation reduces transcutaneous oxygen tension and skin blood flow.Anesthesiology1991;75,619-624. [CrossRef] [PubMed]
 
Kessler, L, Bilbault, P, Ortega, F, et al Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study.Diabetes Care2003;26,2378-2382. [CrossRef] [PubMed]
 
Kalani, M, Jorneskog, G, Naderi, N, et al Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers: long-term follow-up.J Diabetes Complications2002;16,153-158. [CrossRef] [PubMed]
 
Abidia, A, Laden, G, Kuhan, G, et al The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial.Eur J Vasc Endovasc Surg2003;25,513-518. [CrossRef] [PubMed]
 
Faglia, E, Favales, F, Aldeghi, A, et al Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer: a randomized study.Diabetes Care1996;19,1338-1343. [CrossRef] [PubMed]
 
Wunderlich, RP, Peters, EJ, Lavery, LA Systemic hyperbaric oxygen therapy: lower-extremity wound healing and the diabetic foot.Diabetes Care2000;23,1551-1555. [CrossRef] [PubMed]
 
Bondi, E, Williams, MH, Jr Severe asthma: course and treatment in hospital.N Y State J Med1977;77,350-353. [PubMed]
 
Goldstein, B, Shannon, DC, Todres, ID Supercarbia in children: clinical course and outcome.Crit Care Med1990;18,166-168. [CrossRef] [PubMed]
 
Mountain, RD, Sahn, SA Clinical features and outcome in patients with acute asthma presenting with hypercapnia.Am Rev Respir Dis1988;138,535-539. [PubMed]
 
Severinghaus, J, Ozanne, G, Massuda, Y Measurement of the ventilatory response to hypoxia: a step hypoxia three-minute test.Chest1976;70(Suppl),121-124
 
Banzett, RB, Garcia, RT, Moosavi, SH Simple contrivance “clamps” end-tidal PCO2and PO2despite rapid changes in ventilation.J Appl Physiol2000;88,1597-1600. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Typical effects of hyperoxia on minute ventilation (V̇e), 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.Grahic Jump Location

Tables

References

Oxer, HF (2000) Simply add oxygen: why isn’t oxygen administration taught in all resuscitation training?Resuscitation43,163-169. [CrossRef] [PubMed]
 
Shock, NW, Soley, MH Effect of breathing pure oxygen on respiratory volume in humans.Proc Soc Exp Biol Med1940;44,418-420
 
Dripps, RD, Comroe, JH, Jr The effects of inhalation of high and low oxygen concentrations on respiration, pulse rate, ballistocardiogram and arterial oxygen saturation (oximeter) of normal individuals.Am J Physiol1947;149,277-291. [PubMed]
 
Lambertsen, CJ, Stroud, MW, III, Gould, RA, et al Oxygen toxicity: respiratory responses of normal men to inhalation of 6 and 100 per cent oxygen under 3.5 atmospheres pressure.J Appl Physiol1953;5,487-494. [PubMed]
 
Yamada, M Methodische Untersuchungen über das Haldane-Hendersonsche Verfahren der Bestimmung der alveolären CO2-Spannung und über den Einfluβ von Sauerstoff auf die Erregbarkeit des Atemzentrums.Biochem Ztschr1918;89,27-47
 
Otis, AB, Rahn, H, Brontman, M, et al Ballistocardiographic study of changes in cardiac output due to respiration.J Clin Invest1946;25,413-421. [CrossRef]
 
Howard, PJ, Bauer, AR Respiration of the newborn infant: variation in respiratory minute volume with change in per cent of oxygen in respired mixture.Am J Dis Child1950;79,611-622
 
Graham, BD, Reardon, HS, Wilson, JL, et al Physiologic and chemical response of premature infants to oxygen-enriched atmosphere.Pediatrics1950;6,55-71. [PubMed]
 
Cross, KW, Warner, P The effect of inhalation of high and low oxygen concentrations on the respiration of the newborn infant.J Physiol1951;114,283-295. [PubMed]
 
Becker, HF, Polo, O, McNamara, SG, et al Effect of different levels of hyperoxia on breathing in healthy subjects.J Appl Physiol1996;81,1683-1690. [PubMed]
 
Haque, WA, Boehmer, J, Clemson, BS, et al Hemodynamic effects of supplemental oxygen administration in congestive heart failure.J Am Coll Cardiol1996;27,353-357. [PubMed]
 
Nattie, EE Central chemosensitivity, sleep, and wakefulness.Respir Physiol2001;129,257-268. [CrossRef] [PubMed]
 
Busija, DW, Orr, JA, Rankin, JH, et al Cerebral blood flow during normocapnic hyperoxia in the unanesthetized pony.J Appl Physiol1980;48,10-15. [PubMed]
 
Eldridge, FL, Kiley, JP Effects of hyperoxia on medullary ECF pH and respiration in chemodenervated cats.Respir Physiol1987;70,37-49. [CrossRef] [PubMed]
 
Ren, X, Fatemian, M, Robbins, PA Changes in respiratory control in humans induced by 8 h of hyperoxia.J Appl Physiol2000;89,655-662. [PubMed]
 
Khaw, KS, Wang, CC, Ngan Kee, WD, et al Effects of high inspired oxygen fraction during elective caesarean section under spinal anaesthesia on maternal and fetal oxygenation and lipid peroxidation.Br J Anaesth2002;88,18-23. [CrossRef] [PubMed]
 
Khaw, KS, Ngan Kee, WD, Lee, A, et al Supplementary oxygen for elective caesarean section under spinal anaesthesia: useful in prolonged uterine incision-to-delivery interval?Br J Anaesth2004;92,518-522. [CrossRef] [PubMed]
 
Baraka, A Correlation between maternal and foetal PO2and PCO2during caesarean section.Br J Anaesth1970;42,434-438. [CrossRef] [PubMed]
 
Rorke, MJ, Davey, DA, Du Toit, HJ Foetal oxygenation during caesarean section.Anaesthesia1968;23,585-596. [CrossRef] [PubMed]
 
Tervila, L, Vartiainen, E, Kivalo, I, et al The effect of oxygen ventilation and a vasodilator on uterine perfusion, foetal oxygen and acid-base balance: I. A study in healthy gravidae.Acta Obstet Gynecol Scand1973;52,177-181. [CrossRef] [PubMed]
 
Tervila, L, Vartiainen, E, Kivalo, I, et al The effect of oxygen ventilation and vasodilator on uterine perfusion, fetal oxygen and acid-base balance: I. A study in abnormal gravidae.Acta Obstet Gynecol Scand1973;52,309-315. [CrossRef] [PubMed]
 
Miller, FC, Petrie, RH, Arce, JJ, et al Hyperventilation during labor.Am J Obstet Gynecol1974;120,489-495. [PubMed]
 
Motoyama, EK, Rivard, G, Acheson, F, et al Adverse effect of maternal hyperventilation on the foetus.Lancet1966;1,286-288. [PubMed]
 
Peng, AT, Blancato, LS, Motoyama, EK Effect of maternal hypocapnia v. eucapnia on the foetus during caesarean section.Br J Anaesth1972;44,1173-1178. [CrossRef] [PubMed]
 
Takeuchi, A, Rucker, J, Vesely, A, et al A simple “new” method to accelerate clearance of carbon monoxide from human subjects.Am J Respir Crit Care Med2000;161,1816-1819. [PubMed]
 
Fortune, JB, Bock, D, Kupinski, AM, et al Human cerebrovascular response to oxygen and carbon dioxide as determined by internal carotid artery duplex scanning.J Trauma1992;32,618-627. [CrossRef] [PubMed]
 
Rahilly, PM Effects of 2% carbon dioxide, 0.5% carbon dioxide, and 100% oxygen on cranial blood flow of the human neonate.Pediatrics1980;66,685-689. [PubMed]
 
Leahy, FAN, Cates, D, MacCallum, M Effect of CO2and 100% O2on cerebral blood flow in preterm infants.J Appl Physiol1980;48,468-472. [PubMed]
 
Rucker, J, Tesler, J, Fedorko, L, et al Normocapnia improves cerebral O2delivery during conventional O2therapy in CO-exposed subjects.Ann Emerg Med2002;40,611-618. [CrossRef] [PubMed]
 
Lambertsen, CJ, Kough, RH, Cooper, DY, et al Oxygen toxicity: effects in man of oxygen inhalation at 1 and 3.5 atmospheres upon blood gas transport, cerebral circulation and cerebral metabolism.J Appl Physiol1953;5,471-486. [PubMed]
 
Omae, T, Ibayashi, S, Kusuda, K, et al Effects of high atmospheric pressure and oxygen on middle cerebral blood flow velocity in humans measured by transcranial Doppler.Stroke1998;29,94-97. [CrossRef] [PubMed]
 
Visser, GH, Van Hulst, RA, Wieneke, GH, et al Transcranial Doppler sonographic measurements of middle cerebral artery flow velocity during hyperbaric oxygen exposures.Undersea Hyperbaric Med1996;23,157-165
 
Floyd, TF, Clark, JM, Gelfand, R, et al Independent cerebral vasoconstrictive effects of hyperoxia and accompanying arterial hypocapnia at 1 ATA.J Appl Physiol2003;95,2453-2461. [PubMed]
 
The integration of brain-specific treatments into the initial resuscitation of the severe head injury patient: Brain Trauma Foundation.J Neurotrauma1996;13,653-659. [CrossRef] [PubMed]
 
Muizelaar, JP, Marmarou, A, Ward, JD, et al Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial.J Neurosurg1991;75,731-739. [CrossRef] [PubMed]
 
Sharief, MK, Anand, P Neurological emergencies. Skinner, D Swain, A Peyton, Ret al eds.Cambridge textbook of accident and emergency medicine1997,1057-1077 Cambridge University Press. Cambridge, UK:
 
Vannucci, RC, Towfighi, J, Heitjan, DF, et al Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat.Pediatrics1995;95,868-874. [PubMed]
 
Mak, S, Azevedo, ER, Liu, PP, et al Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure.Chest2001;120,467-473. [CrossRef] [PubMed]
 
Greif, R, Akca, O, Horn, EP, et al Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection.N Engl J Med2000;342,161-167. [CrossRef] [PubMed]
 
Barker, SJ, Hyatt, J, Clarke, C, et al Hyperventilation reduces transcutaneous oxygen tension and skin blood flow.Anesthesiology1991;75,619-624. [CrossRef] [PubMed]
 
Kessler, L, Bilbault, P, Ortega, F, et al Hyperbaric oxygenation accelerates the healing rate of nonischemic chronic diabetic foot ulcers: a prospective randomized study.Diabetes Care2003;26,2378-2382. [CrossRef] [PubMed]
 
Kalani, M, Jorneskog, G, Naderi, N, et al Hyperbaric oxygen (HBO) therapy in treatment of diabetic foot ulcers: long-term follow-up.J Diabetes Complications2002;16,153-158. [CrossRef] [PubMed]
 
Abidia, A, Laden, G, Kuhan, G, et al The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial.Eur J Vasc Endovasc Surg2003;25,513-518. [CrossRef] [PubMed]
 
Faglia, E, Favales, F, Aldeghi, A, et al Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer: a randomized study.Diabetes Care1996;19,1338-1343. [CrossRef] [PubMed]
 
Wunderlich, RP, Peters, EJ, Lavery, LA Systemic hyperbaric oxygen therapy: lower-extremity wound healing and the diabetic foot.Diabetes Care2000;23,1551-1555. [CrossRef] [PubMed]
 
Bondi, E, Williams, MH, Jr Severe asthma: course and treatment in hospital.N Y State J Med1977;77,350-353. [PubMed]
 
Goldstein, B, Shannon, DC, Todres, ID Supercarbia in children: clinical course and outcome.Crit Care Med1990;18,166-168. [CrossRef] [PubMed]
 
Mountain, RD, Sahn, SA Clinical features and outcome in patients with acute asthma presenting with hypercapnia.Am Rev Respir Dis1988;138,535-539. [PubMed]
 
Severinghaus, J, Ozanne, G, Massuda, Y Measurement of the ventilatory response to hypoxia: a step hypoxia three-minute test.Chest1976;70(Suppl),121-124
 
Banzett, RB, Garcia, RT, Moosavi, SH Simple contrivance “clamps” end-tidal PCO2and PO2despite rapid changes in ventilation.J Appl Physiol2000;88,1597-1600. [PubMed]
 
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