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Am J Physiol Heart Circ Physiol 285: H17-H25, 2003; doi:10.1152/ajpheart.01112.2002
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TRANSLATIONAL PHYSIOLOGY

Neuroprotection in hypothermia linked to redistribution of oxygen in brain

Masaharu Sakoh 1,2 and Albert Gjedde1

1Center of Functionally Integrative Neuroscience, University of Aarhus, and Pathophysiology and Experimental Tomography Center, Aarhus University Hospitals, Aarhus, Denmark 8000; and 2Department of Neurological Surgery, Ehime University School of Medicine, Ehime, Japan 7910295

Submitted 19 December 2002 ; accepted in final form 21 February 2003


   ABSTRACT
TOP
 ABSTRACT
NONLINEAR FLOW-METABOLISM...
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hypothermia improves the outcome of acute ischemic stroke, traumatic injury, and inflammation of brain tissue. We tested the hypothesis that hypothermia reduces the energy metabolism of brain tissue to a level that is commensurate with the prevailing blood flow and hence allows adequate distribution of oxygen to the entire tissue. To determine the effect of 32°C hypothermia on brain tissue, we measured the sequential changes of physiological variables by means of PET in pigs. Cerebral blood flow and oxygen consumption (cerebral metabolic rate of oxygen) declined to 50% of the baseline in 3 and 5 h, respectively, thus elevating the oxygen extraction fraction to 140% of the baseline at 3 h. The results are consistent with the claim that cooling of the brain to 32°C couples both energy metabolism and blood flow to a lower rate of work of the entire tissue.

cerebral blood flow; cerebral metabolic rate of oxygen

AT NORMAL TEMPERATURE, neurons do not survive an oligemic insult that causes metabolic variables to decline below specific thresholds (49, 51, 58). The rate of the decline limits the period of therapeutic opportunity (51, 57) to no more than 3 h, which is not sufficient for attempted reperfusion of severely oligemic tissue in clinical situations. Preoperative introduction of hypothermia significantly extends this period (51, 50), but the mechanism responsible for this effect is not known with certainty.

Hypothermia is known to provide remarkable protection against the insults of low blood flow (oligemia) to the brain, particularly when thermoregulatory responses are suppressed by sedation or anesthesia. Thus sedation plays an important role in the effect. As exemplary beneficiaries of the remarkably neuroprotective effect of combined sedation and hypothermia, two heavily sedated adult women, unresponsive and apparently lifeless at respective core temperatures of 23°C and 26°C several days after unrelated suicide attempts, tolerated prolonged absences of measurable blood pressure and pulse rate without apparent ill effects, one proceeding to pass a university matriculation test within weeks of the attempt (18).

Iatrogenic hypothermia is used to protect brain tissue during surgery (55) and appears to improve the clinical course of patients with acute ischemic stroke and traumatic brain injury (10, 37, 50, 54). In animals, hypothermia has improved the outcome from acute cerebral ischemia, traumatic brain injury, and inflammatory changes in the brain (1, 5, 6, 27, 38, 62).

The conventional explanation of the neuroprotective effect of hypothermia holds that the hypothermic decline of the cerebral metabolic rate of oxygen (CMRO2) maintains the aerobic metabolism. The same mechanism would explain how hypothermia may substantially attenuate the release of neurotoxic excitatory amino acids during ischemia (29). Older studies, however, led to the claim that the neuroprotection afforded by moderate hypothermia somehow exceeds the effect predicted from the decrease in CMRO2 (5).

The claim that hypothermia protects brain tissue by preserving cellular energy stores and aerobic metabolism is based on observations that CMRO2, like other enzymatically catalyzed biological processes, declines monoexponentially with temperature according to the formula (4, 40, 41)

where Q10 is the temperature coefficient, T and To are two different temperatures, and JO2 and JO2o are the values of CMRO2 at T and To, respectively. Q10 is close to 2 for enzymatically catalyzed reactions but greater for nonenzymic reactions. Between 27°C and 37°C, the mean of Q10 measurements is 2.2 for CMRO2 (4). Assuming a baseline brain temperature of 38°C, this formula predicts that CMRO2 is 25% lower at 34.4°C and 50% lower at 29.4°C. There is a question as to whether reductions of this magnitude explain the neuroprotective effect of hypothermia.

Models of nonlinear flow-metabolism coupling have been formulated since the publication of much of the classic literature on brain metabolism in hypothermia (3, 7, 16, 28, 60, 61). To test whether declines of cerebral blood flow (CBF) and metabolism in hypothermia generally are consistent with these models of nonlinear flow-metabolism coupling, we measured the sequential changes of CBF, cerebral oxygen consumption or CMRO2, and oxygen extraction fraction (OEF) with PET before and every hour during the 6 h after the initiation of hypothermia at 32°C in Danish landrace pigs, as well as in control brain tissue not subjected to hypothermia. From the measurements, we calculated the capillary oxygen tensions necessary to supply the brain tissue by means of the mathematical expression of a recently reported mechanism of nonlinear flow-metabolism coupling. The results of the test allowed us to predict the effect of hypothermia superimposed on a simulated oligemic insult and to show that the effect fully explained the maintenance of oxidative metabolism in hypothermia, despite the decline of CBF, which was similar in magnitude to that seen in oligemic insults.


   NONLINEAR FLOW-METABOLISM COUPLING
TOP
 ABSTRACT
 NONLINEAR FLOW-METABOLISM...
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
To test the null hypothesis of adequate oxygen supply to brain tissue during hypothermia, we applied a model of flow-metabolism coupling, which allowed us to compare the available oxygen in brain capillaries to the oxygen required to supply the entire tissue, both in plain hypothermia and in hypothermia superimposed on oligemia of the tissue.

We previously formulated a mechanism of nonlinear flow-metabolism coupling in normothermia (16, 20, 60) based on the observation of diffusion-limited transport of oxygen to brain tissue (21, 34), and we validated the formulation for the cases of visual cortex activation (20), cortical motor activation (19), and arterial hypoxemia (17). The mechanism dictates the rate of blood flow needed to supply the tissue with an adequate amount of oxygen

(1)
where F is the blood flow to the tissue (per unit weight or volume), jO2 is the average oxygen metabolism of a fraction of the tissue (per unit weight or volume of that fraction), assuming the rest of the tissue does not consume any oxygen, f is that fraction of the tissue, ranging in theory from zero to infinity, that has jO2 (per unit weight or volume), Chb is the arterial hemoglobin concentration, L is oxygen diffusibility, P50 is the half-saturation oxygen tension of hemoglobin, nH is Hill's coefficient (2.65 in pigs; Ref. 48) and PaO2 is the arterial oxygen tension. Values of f exceed unity when the supply of oxygen exceeds the minimum requirement of the tissue as a whole.

The derivation of Eq. 1 was motivated by the well-known absence of a meaningful geometric description of the jumbled capillary network in the brain. Instead, Eq. 1 arose from the simple assumption that every segment of the capillary bed "feeds" the same amount of brain tissue, i.e., that every fraction xyz of the tissue is served by the same fractions of capillary density and oxygen diffusibility and uses the same fraction of the total oxygen consumption. Along the axial dimension of the capillary bed (z), the OEF is proportional to the fraction of capillary segments traversed by the blood flow, and the segmental oxygen tension is given by this corresponding segmental extraction fraction, according to the Hill equation of the relationship between oxygen tension and oxygen-hemoglobin dissociation, as shown in Fig. 1, of the normothermic baseline determined in the present study. The linearity of the extraction fraction as a function of the capillary segmentation shows that the entire axial dimension can be projected onto a single transaxial plane placed at the segmental fraction 0.5, where the extraction fraction is exactly one-half of the total net extraction and where the total oxygen flux to the tissue is the product of the oxygen diffusibility (L) and the oxygen partial pressure at that point. This product is the "available" oxygen, because no more oxygen can enter the tissue than is dictated by the product of the weighted average oxygen tension in the capillary and the weighted average oxygen diffusibility.



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  		Fig. 1. Oxygen tension, oxygen extraction fraction (OEF; EO2), and oxygen diffusibility (L) as function of axial segmentation of cortical capillary bed, calculated for baseline state (0th h of hypothermia) of current study. EO2(z), tension [PcapO (z)], and L(z) as functions of axial segment of capillary bed (z) were calculated from the relationships EO2(z) = zJO2/[FCaO2], PcapO (z) = P50{[1/EO2(z)] - 1} 1/nH, and L(z) = jO2/PcapO (z), where jO2 is the measured cerebral metabolic rate of oxygen (CMRO2; 201.4 µmol · hg-1 · min-1), F the measured blood flow (46.4 ml · hg-1 · min-1), CaO2 the measured arterial oxygen concentration (6.7 mM), P50 the calculated half-saturation tension of oxygen (30.3 mmHg at baseline), and nH the Hill coefficient (2.65). PcapO (0) was assumed to equal the arterial oxygen tension (PaO2; 131 mmHg).

 

In Eq. 1, the whole tissue oxygen consumption (CMRO2) is the product of f and jO2 if f < 1 and is just jO2 if f ≥ 1. The introduction of f allows the tissue to respond to contingencies either by changing the metabolic rate of all cells (constant f) or by changing the fraction of the cells (variable f) that maintain the baseline metabolic rate. In reality, combinations of both may occur, of course, but for the purposes of this study they are presumed to be either one or the other.

Equation 1 predicts how low blood flow and low oxygen consumption, or low metabolizing tissue fraction, would be coupled nonlinearly. In the equation, the term f2jO2/LP50 raised to the power of nH greatly exceeds zero when f2jO2 >> LP50. The term P50/PaO2 raised to the power of nH, on the other hand, remains close to zero when P50 << PaO2. These relations explain why blood flow must change much more when the rate of oxygen metabolism is changed than when the arterial oxygen tension is changed. Applied to oligemia, the nonlinear flow-metabolism couple predicts that lowering of the fraction of fully oxygenated tissue (f), caused by blood flow restriction, can be prevented by an alternative reduction of jO2, caused by hypothermia.

Equation 1 follows from the relationship between oxygen supply and oxygen consumption. The utilization of the oxygen supply by a given fraction (x) of the tissue volume can be predicted as the difference between the available oxygen (60) and the oxygen consumption of the fraction (x)

(2)
where RO2(x) is the rest of the oxygen available to the remaining fraction (1 - x) of the tissue, and EO2 is the OEF, equal to fjO2/FCaO2, where CaO2 is the arterial oxygen concentration. Equation 2 is a line of slope -jO2 and ordinate intercept .

The ordinate intercept of Eq. 2 is the oxygen available in the capillary bed, equal to the product of the capillary oxygen pressure and the diffusibility in the transaxial plane at the segmental fraction 0.5, shown in Fig. 1. The available oxygen is less than the arterial supply of oxygen because it depends on the oxygen tensions in the capillary, which are reduced by the extraction of oxygen. The discrepancy between the arterial delivery of oxygen and the weighted average availability of oxygen is the result of the observed diffusion limitation of oxygen delivery to brain tissue (21, 34).

By definition, the tissue fraction f is the value of x at which the available oxygen is exhausted

(3)
where EO2, as above, equals fjO2/FCaO2. Values of f less than unity indicate situations in which a fraction of the tissue exhausts the entire oxygen supply, whereas values of f higher than unity represent the situations in which the oxygen supply exceeds the demand. Equation 3 can be rearranged to Eq. 1 when CaO2 is expressed as a function of the arterial oxygen tension by means of the Hill equation of the oxygen hemoglobin dissociation curve.

Extraction of oxygen from brain capillaries causes the capillary oxygen tension to decline from the arterial oxygen tension at the arterial end of capillaries to the venous oxygen tension at the venous end. The diffusion pressure of oxygen is the difference between the capillary and mitochondrial tensions. The average driving pressure, equal to the average capillary oxygen tension of all segments of the capillary bed, is the ratio fRO2(x)/L for x = 0 in Eq. 2 (60)

(4)
and the corresponding average mitochondrial oxygen tension is thus fRO2(x)/L for x = f in Eq. 2

(5)
where the product fjO2 is the oxidative metabolism of the tissue (CMRO2). It follows from the definition of f that the mitochondrial oxygen tension is effectively zero for f ≤ 1. Thus, for increased extraction fractions, either f or jO2 must decline. If jO2 does not decline, f must.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 NONLINEAR FLOW-METABOLISM...
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The research project and procedures, including the infusion of pancuronium bromide to reduce shivering, was approved by the Danish National Committee on Animal Research Ethics (DaNCARE). Twenty-one female country-bred Yorkshire pigs weighing 38–45 kg were used; ten pigs underwent sequential measurement of physiological variables after hypothermia, and eleven pigs underwent control measurements of CBF and CMRO2.

The use of the porcine model in pathophysiological and experimental tomography has been established in this laboratory and reported in publications detailing the induction, prolonged anesthesia, and PET of the physiology and pathophysiology of major organs of the Danish Yorkshire pig under control conditions as well as in experimental models of functional brain activation, Parkinson's disease, deep-brain stimulation, hepatic encephalopathy, and stroke (13, 48).

In brief, the pigs initially were sedated by intramuscular injection of 20 ml of midazolam (5 mg/ml). After intravenous injection of a mixture of 1.0 mg of fentanyl, 50 mg of midazolam, and 4.0 mg of pancuronium, the pigs were intubated and artificially ventilated (Engström Ventilator, Stockholm, Sweden) with a 70% N2O-30% O2 mixture. Anesthesia was maintained by continuous infusion of 0.05 mg · kg-1 · h-1 fentanyl, 1.25 mg · kg-1 · h-1 midazolam, and 0.2 mg · kg-1 · h-1 pancuronium bromide to reduce shivering. The adequacy of the anesthesia was continuously assessed by monitoring the systolic and diastolic arterial blood pressures and the electrocardiogram. The body of the pig was shaved to accelerate hypothermia. Indwelling femoral arterial and venous catheters were installed surgically for injection of tracers and arterial blood sampling. A probe advanced into the left internal jugular vein monitored the temperature of the brain.

The pigs were positioned supine in the scanner (Siemens/CTI ECAT EXACT HR) with the head in a custom-made head holder. PET studies were performed before and for 6 h after the initiation of hypothermia. Throughout the experiments, brain temperature, blood pressure, heart rate, and expired-air CO2 levels were monitored continuously, and arterial blood samples were withdrawn and analyzed (ABL 300; Radiometer, Copenhagen, Denmark) every hour to monitor blood gases and whole blood acid-base parameters. Disturbances in body fluid and gas balances were corrected by appropriate procedures (e.g., forced ventilation and/or changes in infusion rates) to maintain physiological variables within normal bounds, except for body and brain temperature.

Hypothermia. Eight hours of hypothermia were induced by a forced-air cooling system (Bair Hugger model 600 PolarAir Hyper/Hypothermia System; Augustine Medical). The air of the cooling system was (additionally) cooled to -20°C with dry ice. The brain temperature was reduced to 32°C and maintained at that level during the experiments.

Both oxygen diffusibility and the half-saturation tension of oxygen binding to hemoglobin (P50) decline in hypothermia. The decline of oxygen diffusibility was deemed to be negligible (305°K/310°K = 0.984). P50 was assumed to decline according to the published relationships shown in Fig. 2. The linear relation between the values of P50 in units of millimeters of mercury and the temperature in units of degrees Celsius found in three different studies (4, 11, 23) obeyed the expression

(6)
where T is the temperature in degrees Celsius.



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  		Fig. 2. Reduction of P50 in hypothermia, measured in 3 separate studies by Bacher et al. (4), Coetzee and Swanepoel (11), and Gutierrez et al. (23). Regression line is P50 = 1.54 (±0.20)T - 28 (±7), where T is temperature, which was used to calculate P50 in the present study (see Fig. 4).

 



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  		Fig. 4. Changes of brain temperature, hemoglobin concentration (Chb), and hemoglobin P50 before and during hypothermia in pigs. x-Axis indicates time after induction of hypothermia.

 
Positron emission tomography. CBF was estimated by intravenous bolus injection of 800 MBq H215O according to the established method (45) used routinely in this laboratory (13, 48). Oxygen consumption was measured by single-breath inhalation of 1 liter of 1,200 MBq [15O]O2 followed by 10-s breath holding according to the similarly established method (46) used routinely in this laboratory (13, 48). Regional OEF values were calculated as the ratio of the rates of unidirectional clearance of oxygen and water, equal to the ratio of the measured oxygen consumption (CMRO2) to the product of the measured arterial oxygen content and the CBF rate, as described below Eq. 2. The CBF, CMRO2, and OEF variables were measured before and every hour for 6 h after the onset of hypothermia. A sequence of 21 arterial blood samples (12, 6, and 3 samples during the first, second, and third minutes, respectively), and 12 brain image frames (6, 4, and 2 images/min, respectively) were obtained. In all experiments, total radioactivity was measured in the blood samples. Brain image and arterial data were corrected for the decay of 15O (half-life 123 s).

The PET images were reconstructed as three-dimensional images by using the two-dimensional data acquisition mode providing 47 contiguous 3.2-mm slices with a Hanning filter with a cutoff frequency of 0.5 pixel-1, resulting in a spatial resolution of 4.6 mm (full width at half-maximum). Correction for attenuation was made on the basis of a transmission scan acquired before the injection of radioactivity.

Regions of interest. The MR imaging used a GE Signa Horizon 1.0-tesla imager (GE Medical Systems, Milwaukee, WI). After a sagittal scout, a longitudinal relaxation time-weighted three-dimensional spoiled gradient echo sequence (time of repetition = 8 ms, time of echo = 1.5 ms, 20° flip angle) was acquired for later coregistration of MRI and PET data. With REGISTER (Montreal Neurological Institute, McGill University, Montreal, Canada), regions of interest (ROIs) were selected in cortex of the middle cerebral artery territory and averaged. The ROIs, once defined for each pig, were used in all subsequent PET studies.

Data analysis. Statistical analysis was carried out by one-way repeated-measures ANOVA to determine whether physiological parameters and/or (absolute) values for CBF, CMRO2, and OEF measured by PET changed significantly over time. A paired t-test with Bonferroni correction for planned comparisons was used to determine whether the effects varied significantly over time. For the statistical significance of each change from baseline to 6 h after hypothermia, the Wilcoxon signed-ranks test was used. A probability threshold of 0.01 was used for statistical significance.


   RESULTS
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 ABSTRACT
 NONLINEAR FLOW-METABOLISM...
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Basic physiological variables and P50. The changes of CBF and CMRO2 in normothermic control animals maintained on the same regimen and for the same period of time as the hypothermic animals are shown in Fig. 3. CBF increased by no more than 10% over this time, and CMRO2 declined by no more than 5%.



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  		Fig. 3. Sequential changes of cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and OEF in normothermic pigs maintained for 6 h.

 

The changes of brain temperature before and after hypothermia are shown in Fig. 4. Brain temperature decreased significantly to 32°C in 3 h (P < 0.01) and then remained stable during the rest of the experiment. The resulting values of P50, calculated according to Eq. 6, are also shown in Fig. 4. As expected from the equation, P50 closely followed the change in temperature.

Table 1 lists the physiological variables before and after hypothermia. At the baseline and 6 h after the induction of the hypothermia, all physiological variables were in the normal range and, with one exception, did not change during the hypothermia. However, arterial PCO2 decreased significantly after 3 h of hypothermia.


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  		Table 1. General physiological variables before and during hypothermia

 

Sequential changes of CBF, CMRO2, and OEF in hypothermia. The sequential changes of CBF, CMRO2, and OEF before and during hypothermia are shown in Fig. 5. CBF decreased to 50% of the baseline in 3 h(P < 0.01) and then remained stable. CMRO2 decreased to 50% of the baseline over the 6 h(P < 0.01). OEF rose to 140% of the baseline in the first 3 h(P < 0.01) and then gradually returned to the baseline.



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  		Fig. 5. Sequential changes of CBF, CMRO2, and OEF before and after hypothermia in pigs. x-Axis indicates time after induction of hypothermia. *Significantly different from all other measurements. NS, not significantly different from succeeding measurement of same variable only.

 

The calculated values of Q10 are shown in Fig. 6. The values averaged 2.24 ± 0.06 (SE) in the first 3 h and then rose markedly, as the temperature remained constant but the CMRO2 continued to fall.



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  		Fig. 6. Values of the temperature coefficient Q10 during hypothermia calculated for temperature changes indicated by temperature graph. Numbers indicate hourly interval of Q10 calculation.

 

Flow-metabolism couple. Setting f equal to unity in Eq. 3, the oxygen diffusibility (L) was calculated from the baseline values to be 5.05 µmol · hg-1 · min-1 · mmHg-1, under the assumption of oxygen availability to the entire tissue in the baseline state. This value was used in subsequent calculation of variables during the hypothermia, including calculation of f according to Eq. 3 in the non-baseline states. Assuming L to remain constant, the fraction of tissue supplied with oxygen briefly declined to a little less than unity but eventually exceeded unity slightly when the extraction fractions again tended toward normal.

The correlation between blood flow and oxygen consumption is shown in Fig. 7, in which the continuous curve shows the prediction from Eq. 1 and the points show the actual measurements using the values of P50 and L calculated above. The predicted values closely matched the measured values except for the lowest points, at which the measured flow values slightly, and according to the correlation coefficient insignificantly, exceeded the calculated values despite the apparent constancy.



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  		Fig. 7. Flow-metabolism couple in hypothermia. x-Axis indicates average values of fjO2 (CMRO2) shown in Fig. 5. y-Axis indicates average CBF values measured and predicted by Eq. 1 with values of P50 and Chb shown in Fig. 4, average values of fjO2 (CMRO2) shown in Fig. 5, and values of L (5.05 µmol · hg-1 · min-1 · mmHg-1), nH (2.65), and PaO2 as listed in Table 1 and averaged for intervening times.

 

The mean capillary oxygen pressure heads supplying the tissue with oxygen, calculated by means of Eq. 4 as a function of time spent in hypothermia, are shown in Fig. 8. This capillary pressure first declined as the extraction fractions increased but subsequently tended to return to normal as the extraction fractions declined. Figure 8 also shows the mitochondrial oxygen tensions calculated by means of Eq. 5. The tensions had negligible values ("zero") during the first 4 h but eventually slightly exceeded zero when the extraction fractions tended toward normal.



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  		Fig. 8. Average PcapO and mitochondrial oxygen tension (PmitO) during the course of hypothermia. x-Axis indicates time after induction of hypothermia. y-Axis indicates average PcapO and PmitO calculated from Eqs. 4 and 5, with values of CMRO2 (fjO2) and EO2 shown in Fig. 5 and values of L (5.05 µmol · hg-1 · min-1 · mmHg-1), nH (2.65), and PaO2 as listed in Table 1 and averaged for intervening times.

 


   DISCUSSION
TOP
 ABSTRACT
 NONLINEAR FLOW-METABOLISM...
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Hypothermia has a protective effect on neurons at risk of anoxic damage (1, 5, 6, 27, 31, 38, 41, 62). Well-described neuroprotective effects of hypothermia include less elevated intracranial pressure, maintained mitochondrial function, and suppressed release of excitatory amino acids (glutamate) or glycine (2, 8, 12, 14, 33, 36, 47). However, the fundamental mechanism underlying the improvement is still unknown.

Insufficient perfusion of brain tissue impairs the oxygen supply but does not reduce the need for oxygen. Hence it is possible that the available oxygen is exhausted by a subset of brain cells with normal metabolic demands, leaving the rest of the cells without oxygen. We tested the claim that hypothermia can correct this imbalance.

The current measurements of flow and metabolism are consistent with the null hypothesis that the neuroprotective effect is the result of redistribution of oxygen to a greater fraction of the tissue when the total oxygen supply is limited. The hypothesis is based on the observation that normal nonlinear flow-metabolism coupling was maintained at all times of the present experimental hypothermia. The increased extraction fraction of oxygen and consequent lowering of the weighted average capillary oxygen tension during the hypothermia are consistent with a physiological response to lower metabolism, prescribed by the nonlinear flow-metabolism coupling invoked by current theories of the circulatory reactions to physiological activity and inactivity of brain tissue (3, 7, 27, 61).

The inverse relationship between OEF and oxygen pressure in the capillary bed occupies a central position in recent revisions of the classic flow-metabolism couple. The inverse relation is explained by the concept that every increase of the extraction fraction represents a depletion of capillary oxygen and hence a reduction of the partial pressure.

The novel element in the revisions is the claim that CBF rates are homeostatically regulated to maintain an adequate mean driving pressure of oxygen in the capillary bed as a whole (7, 16), necessitated by the well-established diffusion-limited oxygen delivery to brain mitochondria (3, 7, 17, 21, 34, 60, 61). In hypothermia, the couple works to downregulate blood flow rates when the energy demands of all neurons are reduced by the low temperature.

It is important to emphasize that low "brain" PO2 in hypothermia, somewhat vaguely defined as an appropriately weighted average of capillary and mitochondrial oxygen tensions, is a physiological response to the lowered metabolism and blood flow, rather than a sign of oxygen deprivation (22).

The flow rates observed in hypothermia approximate those measured during normothermic oligemia, in which primary energy demands are not likely to be lower than under normal circumstances. In the case of hypothermia superimposed on oligemia, the hypothesis claims that the energy needs of more nerve cells in the threatened tissue are satisfied at the prevailing perfusion, causing more cells to receive amounts of oxygen that are adequate for their needs. Because of the uniform effect of hypothermia on most enzymatically catalyzed processes in brain (the range of measured Q10 values is remarkably narrow between 1.5 and 2.5), hypothermia protects both the mechanisms maintaining the cellular integrity and the mechanisms associated with functional activity (2, 44).

In the present study, we compared the dynamically changing cerebral metabolism and perfusion after the initiation of hypothermia. The result is consistent with the explanation that hypothermia helps maintain the nonlinear flow-metabolism relationship at a physiological magnitude, which prevents or delays irreversible damage to the ischemic cortex.

The periods of time spent inducing and maintaining the hypothermia both contribute to the efficacy of the treatment. In the present study in pigs, the time required to cool the brain to 32°C was 3 h, in agreement with previous reports in humans (38, 53). CMRO2 continued to decline during most of the study, reaching 50% in 5 h. Fifty percent reduction in CMRO2 was also reported for dogs during 30°C hypothermia (42). In patients with head injury, 32.5°C hypothermia reduced CMRO2 by 45% (38), close to the 40–50% of baseline that is believed to be the viability threshold of oligemia at normal temperature (25, 49, 51, 58).

Previously reported changes of OEF during hypothermia are equivocal (35, 43), perhaps because the changes were determined only once during hypothermia. In the present study, OEF rose gradually during the first 4 h of hypothermia, during which the measured flow changes closely approximated the changes predicted by the flow-metabolism couple expressed in Eq. 1 (Fig. 7). Thereafter, OEF tended to decline toward the baseline value.

The decline of OEF occurred when oxygen consumption continued to decline but temperature and blood flow remained apparently constant after 3 h. This discrepancy led to a marked increase of the calculated value of Q10 (Fig. 6).

Values of Q10 above 2.5 tend to signify the sensitivity of nonenzymic reactions related to the physicochemical properties of the internal milieu, speculatively including longer-term changes of membrane permeability, cytochrome oxidase affinity, or any of a host of other factors too complex to identify here. The apparent constancy of blood flow after 3 h may represent a failure of physiological flow-metabolism coupling below 20 ml · hg-1 · min-1.

The different roles of increased OEF in hypothermia and oligemic anoxia are simulated in Fig. 9, in which tissue reserves of oxygen were calculated from Eq. 2 for the control situation and for reductions of blood flow to 20 or 21 ml · hg-1 · min-1 in hypothermia and normothermia, under the assumption that the basic neuronal demand for oxygen is undiminished in the oligemic brain, whereas it is reduced in hypothermia as measured in the present study. The portions of the tissue supplied with oxygen in the two situations (f) were calculated by means of Eq. 1, and the corresponding capillary and mitochondrial oxygen tensions were calculated by means of Eqs. 4 and 5, once f had been determined, from the value of L estimated in the baseline. The calculation showed that the oligemic reduction to 20 ml · hg-1 · min-1 deprived as much as 30% of the tissue of oxygen, whereas the superimposition of hypothermia at 32°C caused the oxygen to be redistributed to the entire tissue, despite an even further reduction of the driving pressure of oxygen caused by the reduction of P50.



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  		Fig. 9. Available remaining oxygen as function of tissue volume fraction supplied, according to Eq. 2. The coordinate system represents projection of axial dimension on single transaxial plane at capillary fractional segment 0.5, shown in Fig. 1, based on variables measured or calculated (EO2) at 0 h [baseline (control): F = 46 ml · hg-1 · min-1, jO2 = 201.4 µmol · hg-1 · min-1], 6 h (hypothermia: F = 21 ml · hg-1 · min-1, jO2 = 105 µmol · hg-1 · min-1), and a generic case of oligemia at normothermia (oligemia: F = 20 ml · hg-1 · min-1, jO2 = 201.4 µmol · hg-1 · min-1). x-Axis indicates fractional tissue segment in x direction. y-Intercept is product of weighted average oxygen tension, calculated according to Eq. 4, and weighted average oxygen diffusibility (L = 5.05 µmol · hg-1 · min-1 · mmHg-1), calculated in the baseline case by setting f = 1 in Eq. 3, as shown in Fig. 1, and assumed unchanged in all other conditions.

 

Thus, in hypothermia, the reduction of the oxygen driving pressure matched the diminished demand for oxygen. In ischemia, the low oxygen pressure in the capillary bed is imposed by the reduced blood flow to the oligemic brain with normal metabolic demands for oxygen. The simultaneous reduction of CMRO2 and elevation of OEF in oligemic brain tissue demonstrates the need for the neuroprotective lowering of metabolism of the brain tissue at risk (24, 51).

The observation that hypothermia causes CBF to decrease is not new; CBF declined by 5.2%/°C in patients with head injury (36) and 60–70% in monkeys cooled to 29°C (39). Also in the present study, the CBF decreased to a plateau defined by the brain temperature.

Reduction of CBF (and cerebral blood volume) tends to diminish intracranial pressure (ICP) and intracranial hypertension, which are clinically life-threatening complications of brain damage (1, 36), but at least one study did not show the decrease of CBF thought to explain the reduction in ICP during hypothermia in patients with head injury (38). The effect of hypothermia on CBF and ICP may be related in part to decreased nitric oxide levels (9) and maintenance of the blood-brain barrier (15, 53, 56). These effects of hypothermia can prevent reperfusion injury after acutely ischemic stroke and carotid arterectomy or perfusion pressure breakthrough after removal of large arteriovenous malformations (26, 30, 57).

There is a question as to why reduction of metabolism by pharmacological agents at normothermia generally gives much less improvement of the outcome after an oligemic or ischemic insult. One explanation may be the different effects of normothermia and hypothermia on P50. In normothermia, P50 is normal and at the same low levels of flow and metabolism lead to large increases of mitochondrial oxygen tension that may cause free radical formation and result in damage to the tissue.

We conclude that rapid cooling of the brain to 32°C could be neuroprotective, because it restores a physiological relationship between cerebral metabolism and perfusion above the viability threshold of brain tissue, which would otherwise be at risk at normal temperature.


   ACKNOWLEDGMENTS
 
This study was funded by the Scandinavia-Japan Sasakawa Foundation, Danish Medical Research Council Grants 9305246, 9305247, 9601888, and 9802833, and the Institute of Experimental Clinical Research, University of Aarhus, Denmark. The Center of Functionally Integrative Neuroscience is funded by the National Science Foundation of Denmark.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. Gjedde, PET Center, Aarhus Univ. Hospitals, 44 Norrebrogade, Aarhus, Denmark 8000 (E-mail albert{at}gjedde.nu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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