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Canadian Journal of Anesthesia 50:1061-1068 (2003)
© Canadian Anesthesiologists' Society, 2003
Neuroanesthesia and Intensive Care

Hypercapnia increases cerebral tissue oxygen tension in anesthetized rats

[L’hypercapnie augmente la tension en oxygène du tissu cérébral chez des rats anesthésiés]

Gregory M.T. Hare, MD PhD*, Brian P. Kavanagh, MB{dagger}, C. David Mazer, MD*, Kathryn M. Hum*, Steve Y. Kim*, Carla Coackley*, Aiala Barr, PhD{ddagger} and Andrew J. Baker, MD*

* From the Department of Anaesthesia,
{ddagger} the Department of Public Health, St. Michael’s Hospital;
{dagger} and the Department of Critical Care Medicine, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Address correspondence to: Dr. Gregory M.T. Hare, Department of Anaesthesia, University of Toronto, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada. Phone: 416-864-5259; Fax: 416-864-6014; E-mail hareg{at}smh.toronto.on.ca


   Abstract
TOP
 Abstract
Introduction
 Material and methods
 Results
 Discussion
 References
 
Purpose: To test the hypotheses that deliberate elevation of PaCO2 increases cerebral tissue oxygen tension (PBrO2) by augmenting PaO2 and regional cerebral blood flow (rCBF).

Methods: Anesthetized rats were exposed to increasing levels of inspired oxygen (O2) or carbon dioxide (CO2; 5%, 10% and 15%, n = 6). Mean arterial blood pressure (MAP), PBrO2 and rCBF were measured continuously. Blood gas analysis and hemoglobin concentrations were determined for each change in inspired gas concentration. Data are presented as mean ± standard deviation with P < 0.05 taken to be significant.

Results: The PBrO2 increased in proportion to arterial oxygenation (PaO2) when the percentage of inspired O2 was increased. Proportional increases in PaCO2 (48.7 ± 4.9, 72.3 ± 6.0 and 95.3 ± 15.4 mmHg), PaO2 (172.2 ± 33.1, 191.7 ± 42.5 and 216.0 ± 41.8 mmHg), and PBrO2 (29.1 ± 9.2, 49.4 ± 19.5 and 60.5 ± 23.0 mmHg) were observed when inspired CO2 concentrations were increased from 0% to 5%, 10% and 15%, respectively, while arterial pH decreased (P < 0.05 for each). Exposure to CO2 increased rCBF from 1.04 ± 0.67 to a peak value of 1.49 ± 0.45 (P < 0.05). Following removal of exogenous CO2, arterial blood gas values returned to baseline while rCBF and PBrO2 remained elevated for over 30 min. The hypercapnia induced increase in PBrO2 was threefold higher than that resulting from a comparable increase in PaO2 achieved by increasing the inspired O2 concentration (34.9 ± 14.5 vs 11.4 ± 5.0 mmHg, P < 0.05).

Conclusion: These data support the hypothesis that the combined effect of increased CBF, PaO2 and reduced pH collectively contribute to augmenting cerebral PBrO2 during hypercapnia.


   Introduction
TOP
 Abstract
 Introduction
Material and methods
 Results
 Discussion
 References
 
OPTIMIZING cerebral tissue oxygen (O2) delivery is a key concern in caring for the critically ill and in patients undergoing anesthesia.1 Accepted strategies for augmenting tissue O2 delivery include the use of supplemental O2, different modalities of mechanical ventilation, red blood cell transfusion and inotropic support. However, many of these techniques have not been demonstrated to be effective,2–4 and in some cases may have resulted in increased mortality.5

"Permissive hypercapnia", first implemented in neonatal practice by Wung et al.,6 was demonstrated to improve survival in patients with adult respiratory distress syndrome in studies by Hickling et al.7,8 The concept of 'therapeutic hypercapnia', whereby PaCO2 is deliberately elevated in order to attenuate end-organ injury, has evolved from studies which have demonstrated reduced tissue injury in association with hypercapnia.9,10 Elevation of PaCO2 attenuated injury resulting from myocardial ischemia,11 stroke12 and lung reperfusion13 and has been associated with improved neurological outcome following cardiopulmonary bypass.14 Although the mechanisms of protection have not been clearly delineated, improved balance between tissue O2 supply and demand may play a significant role.9,10

Experimental studies help to explain how hypercapnia may improve cerebral tissue oxygenation. Although not predicted by the alveolar gas equation, elevated PaCO2 has been demonstrated to increase arterial PaO2, possibly by improved ventilation perfusion matching in the lung.15–18 In addition to augmenting PaO2, hypercapnia has been shown to increase arterial blood O2 carrying capacity19,20 and increase cardiac output.15,21 Hypercapnia might also improve tissue O2 delivery due to a right shift in the O2 hemoglobin dissociation curve.22 Finally, elevated PaCO2 causes a well described increase in cerebral blood flow (CBF),23,24 while reducing systemic and cerebral metabolic demands,25–27 thereby optimizing the balance between cerebral tissue O2 supply and demand.

Although global O2 delivery appears to be enhanced by hypercapnia, the specific effects on cerebral tissue oxygen tension (PBrO2) are incompletely understood. Because of the potential vulnerability of cerebral function during critical illness the current study attempts to determine the contribution of increased PaO2 and elevated CBF on cerebral PBrO2 following hypercapnia. To achieve this goal we tested the hypotheses that deliberate elevation of PaCO2 causes an increase in cerebral PBrO2 as a result of elevated PaO2, and increased CBF in anesthetized rats.


   Material and methods
TOP
 Abstract
 Introduction
 Material and methods
Results
 Discussion
 References
 
Animal model
All animal protocols were approved by the Animal Care and Use Committee at St. Michael’s Hospital in accordance with the requirements of the Canadian Animal Care Committee. Anesthesia was induced in male Sprague Dawley rats (Charles River, St. Constant, PQ, Canada) with ketamine/xylazine (100/7.5 mg•kg-1 ip, Parke-Davis/Bayer, Toronto, ON, Canada) and maintained with 1 to 2% isoflurane (Abbott, St. Laurent, PQ, Canada) following tracheostomy and ventilation with a pressure controlled ventilator (Kent Scientific, Litchfield, CT, USA). Cannulation of the tail artery (PE 50) was performed for direct measurement of mean arterial blood pressure (MAP) and arterial blood gas determinations. Ventilation was adjusted to achieve normocapnia and normoxia as determined by blood gas analysis (Radiometer ALB 500, London Scientific, London, ON, Canada). Hemoglobin concentrations were determined using a co-oximeter (Radiometer OSM 3).

Animals were placed in a stereotaxic frame (ADI Instruments, Harvard Apparatus, Saint-Laurent, PQ, Canada) and the scalp incised sagitally. Bilateral 5-mm diameter burr holes were trephined at the level of the bregma, 2 to 3 mm lateral to the sagital sinus, exposing the intact dura. Bilateral calibrated polarographic O2 sensing electrodes, with a maximal diameter of 500 µm and a sensing aperture 1 mm in diameter (LICOX GMS, Harvard Apparatus, Saint-Laurent, PQ, Canada), were then inserted about 6 mm past the dura into the region of the right and left caudate nuclei.28 Corresponding bilateral temperature probes were placed at similar coordinates. Bilateral caudate PBrO2 measurements were averaged for each animal (mmHg). Bilateral laser Doppler flow probes (Oxyflo, Oxford Optronix, Oxford, UK) were positioned over the dura to measure regional cortical regional cerebral blood flow (rCBF). rCBF values were normalized to the baseline and then averaged for each animal. After a one-hour equilibration period, a steady baseline was measured for 20 min, while a heating pad and heating lamp were utilized to maintain the brain temperature near 37°C. Caudate PBrO2, temperature, CBF and MAP, were recorded using a computerized data acquisition system (DASYLab, Kent Scientific, Litchfield, CT, USA).

Experimental procedures
CHANGES IN CAUDATE PBRO2 INDUCED BY INCREASING THE PERCENTAGE OF INSPIRED O2 OR HYPERVENTILATION
After probe equilibration, the baseline PBrO2 was measured for 20 min. Animals were then exposed to serial increases in the percentage of inspired O2 from 30% to 50% and 100% (n = 12 rats). The percentage of inspired O2 was confirmed using an O2 analyzer (Ohmeda 5100, Datex-Ohmeda, Mississauga, ON, Canada) connected to the inspiratory limb of the ventilatory circuit. Arterial blood gas and hemoglobin measurements were taken at each different level of inspired O2. The effect of hyperventilation was determined in a different group of rats (n = 7). PBrO2 measurements were performed once the PaCO2 was measured near 40 mmHg with an inspired O2 concentration of 100%. Hyperventilation was initiated by increasing the degree of pressure control to achieve a target PaCO2 near 25 mmHg. PBrO2, hemoglobin concentration, MAP and arterial blood gases were measured before and after hyperventilation.

EFFECT OF INCREASED INSPIRED CO2 ON CAUDATE PBRO2 AND RCBF
Anesthetized rats were initially ventilated with 50% O2 in nitrogen (0% CO2) and baseline measurement for arterial blood gases, brain temperature, MAP, cerebral oxygenation and CBF were determined over 20 min (n = 6). Rats were then ventilated with gas mixtures containing an increasing concentration of CO2, from 5% to 10% and then 15% mixed with 50% O2 and nitrogen (Praxair Canada Inc., Mississauga, ON, Canada). Rats were exposed to each concentration of CO2 for 20 min, prior to increasing the CO2 concentration to the next level. After exposure to 15% CO2, the rats were then ventilated with 50% O2 in nitrogen (0% CO2) for an additional 30 min prior to terminating the experiment. Arterial blood gases were taken at baseline (0 and 20 min) and after ten minutes of exposure to each different CO2 concentration (30, 50 and 70 min, respectively). Two subsequent blood gas determinations were performed after the inspired CO2 concentration was reduced to 0% (90 and 110 min). Animals were then euthanized with ketamine (100 mg•kg-1 iv, Parke-Davis, Toronto, ON, Canada) and the position of the bilateral O2 sensing probes confirmed.

Data analysis
A sample size calculation, performed prior to initiating the experiments, indicated that six animals per group would be sufficient to detect a 50% change in PBrO2 given a power of 80% and a type I error of 5%. Data were initially assessed for any time or group effect using a two-way analysis of variance (SAS Institute Inc., Cary, NC, USA). Comparisons between and within groups were performed using Wilcoxon rank sum and signed rank tests, respectively. Following exposure to inspired CO2, values for brain temperature, MAP, PBrO2 and CBF were determined at 0%, 5%, 10%, 15% and 0% CO2, respectively, by averaging ten sequential values for each variable, obtained over a ten-minute period, ten minutes after each change in inspired gas concentration. Correlation between variables was assessed using a correlation coefficient. Statistical significance was assigned at a P value less than 0.05 in all cases. Data are presented as mean ± standard deviation (SD). For clarity of presentation, graphical data are presented as mean ± standard error of the mean (SEM).


   Results
TOP
 Abstract
 Introduction
 Material and methods
 Results
Discussion
 References
 
Effect of increasing the percentage of inspired O2 or hyperventilation on caudate PBrO2
At an inspired O2 concentration of 30%, a PaO2 of 109.5 ± 25.5 mmHg corresponded to a PBrO2 of 17.8 ± 8.3 mmHg (Figure 1Go, column A, n = 12). Increasing the inspired O2 concentration to 50% and 100% resulted in an increase in the PaO2 to 180.6 ± 52.1 and 330.9 ± 83.6 mmHg, respectively. These values corresponded to PBrO2 values of 29.2 ± 9.0 and 43.9 ± 14.3 mmHg, respectively (Figure 1Go, column A, P < 0.05). There were no significant changes in pH (7.38 ± 0.07 mmHg), PaCO2 (40.1 ± 9.0 mmHg), hemoglobin concentration (118 ± 13.3 g•L-1) or MAP (83.6 ± 24.2 mmHg), when compared to baseline values. For the hyperventilation experiments, the baseline values for PaO2, PaCO2 and PBrO2 were 250 ± 89.2, 37.8 ± 3.7 and 40.7 ± 21.6 mmHg, respectively (Figure 1Go, column B, n = 7). Hyperventilation reduced the PaCO2 to 25.5 ± 2.5 mmHg and the PBrO2 to 21.9 ± 15.9 mmHg, respectively (Figure 1Go, column B, P < 0.05), despite a tendency for the PaO2 and pH to increase. The hemoglobin concentration (125 ± 9.8 g•L-1) and MAP (82.6 ± 21.1 mmHg) did not change significantly.



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  		FIGURE 1 Column A: Increased PaO2 levels resulted in increased brain oxygenation. Column B: Hyperventilation resulted in a parallel reduction in PaCO2 and PBrO2.

 
Effect of increasing inspired CO2 on arterial blood gases, caudate PBrO2 and rCBF
Sequential increases in inspired CO2 resulted in an increase in brain temperature from a baseline value of 35.3 ± 1.3°C, to a maximum of 37.0 ± 0.9°C. (Figure 2Go, P < 0.05). Brain temperature reduced to 36.2 ± 0.9°C after reduction of inspired CO2 to 0%. At lower CO2 concentrations, the MAP remained near baseline values of 81.7 ± 8.1 mmHg. At higher inspired CO2 concentrations, the MAP increased significantly, reaching a maximum of 101.3 ± 12.5 mmHg (Figure 2Go, P < 0.05). With removal of CO2, MAP returned to baseline.



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  		FIGURE 2 Brain temperature, mean arterial pressure, brain oxygenation and normalized cerebral blood flow with exposure to increasing percentages of inspired CO2 (n = 6 rats).

 
Caudate PBrO2 increased from a baseline of 14.5 ± 5.6 mmHg to 29.1 ± 9.2, 49.4 ± 19.5 and 60.5 ± 23.0 mmHg after exposure to 5%, 10% and 15% CO2, respectively (Figure 2Go, P < 0.05, for each increase). Removal of CO2 from the inspiratory gas mixture resulted in a reduction of PBrO2. However, 30 min after reduction of the CO2 to 0%, the PBrO2 remained elevated at 25.1 ± 10.1 mmHg, despite the return of PaO2 and PaCO2 to baseline values (Figure 2Go, P < 0.05). CBF followed a similar pattern, increasing from a normalized baseline of 1.04 ± 0.07 to 1.20 ± 0.27, 1.40 ± 0.47 and 1.49 ± 0.45 after exposure to 5%, 10% and 15% CO2, respectively (Figure 2Go, P < 0.05). The maximum CBF (1.59 ± 0.34) was achieved after exposure to 15% CO2. Thirty minutes after reduction of CO2 to 0%, the CBF tended to remain elevated above control values (1.31 ± 0.34).

Increasing the inspired CO2 from 0% to 5%, 10% and 15% resulted in a sequential reduction in the pH from 7.4 ± 0.09 to 7.27 ± 0.02, 7.13 ± 0.02, and 7.03 ± 0.22, respectively (Figure 3, PGo < 0.05, for each increase). The pH returned to 7.39 ± 0.02 following reduction of the inspired CO2 to 0%. Similarly, sequentially increasing the percentage of inspired CO2 raised the PaCO2 from a baseline value of 36.2 ± 19.8 mmHg to 48.7 ± 4.9, 72.3 ± 6.0 and 95.3 ± 15.4 mmHg, respectively (Figure 2Go, P < 0.05, for each increase). The increase in PaCO2 was parallelled by an increase in PaO2 from a baseline of 121.6 ± 36.0 to 172.2 ± 39.1, 191.7 ± 42.5 and 216.0 ± 41.8 mmHg, respectively (Figure 3, PGo < 0.05). Both the PaCO2 and PaO2 returned to baseline values after reduction of inspired CO2 to 0%. There were no statistically significant changes in hemoglobin concentration or arterial blood O2 content. Changes in PBrO2 correlated with the observed increases in PaCO2 and with the decrease in arterial pH (Figure 4, PGo < 0.05 for each correlation).



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  		FIGURE 3 Blood gas analysis following exposure to serial increases in the percentage of inspired CO2 from 0 to 5%, 10% and 15% (n = 6 rats).

 


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  		FIGURE 4 Correlations between cerebral tissue oxygen tension (PBrO2) and arterial blood gas PaCO2 and pH (n = 6 rats).

 
Comparison of changes in caudate PBrO2 in response to increased inspired O2 and CO2
The relative effect of increasing inspired O2 and CO2 on PBrO2 is compared in the Table.Go Increasing the inspired O2 from 30 to 50% increased the mean PaO2 by 71.1 ± 46.4 mmHg and resulted in a mean increase in PBrO2 of 11.4 ± 5.0 mmHg, without changing pH or PaCO2. By contrast, increasing the inspired CO2 from 0 to 10% resulted in an increase in PaCO2 of 36.1 ± 13.9 mmHg with a corresponding average decrease in pH of 0.27 ± 0.09. Under these conditions, an increase in PaO2 of 70.1 ± 41.4 mmHg resulted in a mean increase in PBrO2 of 34.9 ± 14.5 mmHg (TableGo, P < 0.05).


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  		TABLE Comparison of increases in caudate tissue oxygen tension (PBrO2) associated with increased levels of inspired oxygen or carbon dioxide
 

   Discussion
TOP
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
References
 
The current study demonstrates that hypercapnia augments cerebral PBrO2 in proportion to increased PaCO2, by mechanisms which include incremental increases in PaO2 and rCBF and incremental reductions in arterial pH. Previous experimental studies have characterized hypercapnia induced elevation in PaO2 which may result from improved ventilation perfusion matching in the lung.15–18 The significant increase in PaO2 observed during hypercapnia would be expected to enhance cerebral tissue oxygenation, as has been demonstrated in this and other studies.29,30 However, the relative magnitude of the increase in PBrO2 achieved during hypercapnia was threefold higher than that obtained when a comparable increase in PaO2 was achieved by increasing the percentage of inspired O2. This suggests that other important factors contribute to augmenting cerebral PBrO2.

The increase in CBF associated with hypercapnia is a well described phenomenon which is known to augment cerebral O2 delivery.31,32 Increased rCBF measured in this study would significantly contribute to increased cerebral tissue O2 delivery thereby enhancing PBrO2. The transient increase in caudate temperature, which resolved after removal of CO2, provides further indirect evidence of increased blood flow to the caudate nucleus during hypercapnia. Persistent elevation of PBrO2 and rCBF for over 30 min following removal of inspired CO2, despite normalization of arterial blood gas measurements, emphasizes the importance of CBF in contributing to cerebral oxygenation, in the absence of any significant contribution by arterial PaO2, PaCO2 or pH. This persistent elevation of PBrO2 may be due to residual acidification of cerebrospinal fluid,24 however this was not established in the current study. Although previous studies have demonstrated increased cerebral PBrO2 following hypercapnia,29,30 the relative contribution of increased PaO2, and rCBF have not been determined. The results of this study demonstrate a stepwise increase in cerebral PBrO2 following exposure to serial increases in the percentage of inspired CO2. Factors that contribute to this increase in PBrO2 include an increase in arterial oxygenation and an increase in CBF. The reduction in arterial pH also correlated with the increase in PBrO2, suggesting that a rightward shift of the O2-hemoglobin dissociation curve may have favoured O2 delivery to cerebral tissue during hypercapnia.22

In addition to influencing factors that result in increased cerebral tissue O2 delivery, hypercapnia may also improve cerebral PBrO2 by reducing the systemic and cerebral metabolic rate for O2. Forslid et al. have demonstrated a significant reduction in electroencephalogaphic activity and somatosensory evoked potential amplitude following exposure to 80% CO2 while Sachdeva and Jennings have estimated that hypercapnia may reduce the systemic metabolic rate for O2 by about 40% after exposure to 4% CO2.26,27 In addition to these effects on global and cerebral O2 utilization, Ward describes potential alterations in cellular metabolism, which occur in response to hypercapnia induced cellular acidosis.25 These include an inhibition of the glycolytic enzyme phosphfructokinase, preventing generation of adenosine triphosphate (ATP) by anaerobic metabolism. Compensation for this inhibition of glycolysis include a concurrent increase in oxidative deamination, with subsequent depletion of intracellular amino acids, which are utilized to generate ATP by oxidative processes.25,33 Thus, anaerobic generation of ATP is inhibited and cells become more dependent on aerobic metabolism. Under these circumstances the brain may be relatively protected from injury as long as adequate O2 is available.33 Therefore, the mechanisms by which cerebral tissue oxygenation is augmented during hypercapnia may have evolved teleologically as a defence against respiratory acidosis. These observations may help to explain why hypercapnia reduces tissue injury secondary to ischemia and reperfusion11–13 possibly contributing to the observed increase in survival of critically ill patients treated with permissive hypercapnia.7,8 The ability to exploit the capacity of hypercapnia to augment cerebral tissue oxygenation, and defend tissue against ischemic injury, requires further characterization.

It is unknown whether the observed increase in cerebral PBrO2 would improve aerobic metabolism at the cellular level in critically ill patients. Previous strategies to augment tissue O2 delivery by increasing cardiac output, failed to demonstrate improved outcomes, in part because the tissue O2 utilization can be severely impaired at the cellular level in the setting of multi-organ failure.2,3 However, in specific settings of myocardial ischemia, cerebral ischemia and lung reperfusion, hypercapnia was demonstrated to protect against ischemic end-organ damage.11–13 Furthermore, hypercapnia induced increases in tissue oxygenation may also protect against surgical wound infections.21 Alternately, increased PBrO2 may lead to an increase in reactive O2 species which may promote free radical mediated tissue damage,34,35 demonstrating that excessive elevation of PBrO2 may also have detrimental effects. Further research will be required to define the optimum balance between the potentially beneficial and harmful effects of hypercapnia on end-organ oxygenation and function.

Limitations of this study include creation of local tissue trauma by the invasive O2 sensitive micro-electrodes, leading to inaccurate values of PBrO2. This acknowledged disadvantage of all invasive tissue probes would be expected to influence measurements equally at all levels of CO2 tested and should not interfere with assessment of relative changes following administration of CO2. Furthermore, our current and previously reported measurements of caudate PBrO228 fall within the range of values reported by other experimental studies for rat cerebral cortex, thalamus and hippocampus utilizing invasive O2 electrodes.36–39 Measurement of cortical CBF was not performed at the same site as the O2 electrodes to minimize local tissue damage in the caudate nucleus. Other studies have demonstrated that the caudate nucleus has similar metabolic rate and blood flow as the cerebral cortex suggesting that changes in flow within the cerebral cortex reflect those that occur in the caudate nucleus.40,41

In summary, this study demonstrates that the dramatic increase in caudate PBrO2, associated with hypercapnia, results from a combined increase in PaO2 and CBF. The correlation between changes in PBrO2 and arterial pH suggests that a right shift of the O2 hemoglobin dissociation curve may have also contributed to increasing cerebral tissue O2 delivery. The hypercapnia induced increase in PBrO2 was threefold higher than that achieved by a comparable increase in PaO2 alone, suggesting that augmented CBF and reduced arterial pH contributed to increasing the cerebral PBrO2. These data suggest that the combined effect of elevated PaO2, CBF and reduced pH contribute collectively to augmenting PBrO2 during hypercapnia. Further studies are required to determine if hypercapnia induced augmentation of cerebral tissue oxygenation may protect against hypoxic or ischemic organ injury.


   Footnotes
 
Supported by the Canadian Anesthesiologists’ Society, JP Bickell Foundation, The Physicians Services Incorporated Foundation.

Accepted for publication May 1, 2003. Revision accepted August 11, 2003.


   References
TOP
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 
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