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Am J Physiol Heart Circ Physiol 276: H1190-H1196, 1999;
0363-6135/99 $5.00
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Vol. 276, Issue 4, H1190-H1196, April 1999

Hemodilution, cerebral O2 delivery, and cerebral blood flow: a study using hyperbaric oxygenation

Yoshinobu Tomiyama, Kevin Jansen, Johnny E. Brian Jr., and Michael M. Todd

Department of Anesthesia, University of Iowa College of Medicine, Iowa City, Iowa 52242


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Hemodilution reduces blood viscosity and O2 content (CaO2) and increases cerebral blood flow (CBF). Viscosity and CaO2 may contribute to increasing CBF after hemodilution. However, because hematocrit is the major contributor to blood viscosity and CaO2, it has been difficult to assess their relative importance. By varying blood viscosity without changing CaO2, prior investigation in hemodiluted animals has suggested that both factors play roughly equal roles. To further investigate the relationship of hemodilution, blood viscosity, CaO2, and CBF, we took the opposite approach in hemodiluted animals, i.e., we varied CaO2 without changing blood viscosity. Hyperbaric O2 was used to restore CaO2 to normal after hemodilution. Pentobarbital sodium-anesthetized rats underwent isovolumic hemodilution with 6% hetastarch, and forebrain CBF was measured with [3H]nicotine. One group of animals did not undergo hemodilution and served as controls (Con). In the three experimental groups, hematocrit was reduced from 44% to 17-19%. Con and hemodiluted (HDil) groups were ventilated with 40% O2 at 101 kPa (1 atmosphere absolute), which resulted in CaO2 values of 19.7 ± 1.3 and 8.1 ± 0.7 (SD) ml O2/dl, respectively. A second group of hemodiluted animals (HBar) was ventilated with 100% O2 at 506 kPa (5 atmospheres absolute) in a hyperbaric chamber, which restored CaO2 to an estimated 18.5 ± 0.5 ml O2/dl by increasing dissolved O2. A fourth group of hemodiluted animals (HCon) served as hyperbaric controls and were ventilated with 10% O2 at 506 kPa, resulting in CaO2 of 9.1 ± 0.6 ml O2/dl. CBF was 79 ± 19 ml · 100 g-1 · min-1 in the Con group and significantly increased to 123 ± 9 ml · 100 g-1 · min-1 in the HDil group. When CaO2 was restored to baseline with dissolved O2 in the HBar group, CBF decreased to 104 ± 20 ml · 100 g-1 · min-1. When normoxia was maintained during hyperbaric exposure in the HCon group, CBF was 125 ± 18 ml · 100 g-1 · min-1, a value indistinguishable from that in normobaric HDil animals. Our data demonstrate that the reduction in CaO2 after hemodilution is responsible for 40-60% of the increase in CBF.

oxygen content; viscosity


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

HEMATOCRIT (Hct) is the primary determinant of whole blood viscosity and arterial O2 content (CaO2) (40). Hemodilution reduces Hct, blood viscosity, and CaO2 and increases cerebral blood flow (CBF) (11, 13, 31, 32). Increased CBF secondary to hemodilution could be the result of active or passive mechanisms or a combination of factors. Reduced CaO2 with reduced O2 delivery (DO2) to the brain may result in active cerebral vasodilation to increase CBF and maintain DO2. Alternatively, because blood flow is inversely related to blood viscosity, reduced viscosity will passively increase flow if blood pressure and vascular diameter remain constant. Reduced blood viscosity may also cause an active vascular response by altering endothelial shear stress and endothelial autacoid release.

It has been difficult to separate the relative importance of blood viscosity and CaO2 in controlling CBF after hemodilution. Previous investigations have been inconsistent. Some investigators have reported that the primary determinant of increased CBF after hemodilution is blood viscosity (13, 27, 29). Other investigators have reported that reduced CaO2 was the primary determinant of increased CBF (6, 16, 20, 32, 36, 37), and some have reported contributions from both mechanisms (7, 12, 22).

Prior experiments have attempted to resolve the issue of blood viscosity vs. CaO2 by separately varying CaO2 or blood viscosity with use of cell-free hemoglobin (Hb) preparations (7, 36, 37), carboxyhemoglobin-containing red blood cells (RBCs) (27), or methemoglobin-containing RBCs (12, 22). There are, however, problems with all the approaches. Cell-free Hb binds nitric oxide (NO) and, thus, may directly increase cerebral vascular tone (8, 19). Carboxyhemoglobin alters the O2 half-saturation pressure of Hb (P50) (18) and may affect DO2 to the brain as well as CBF (18, 28). Some protocols utilizing methemoglobin-containing RBCs altered P50 by exchanging fetal for adult blood, which may have independently affected CBF (12, 17, 22).

To further investigate the relative importance of blood viscosity and CaO2 in controlling CBF after hemodilution, we used the novel approach of restoring CaO2 to normal with hyperbaric O2 after hemodilution. By elevating PO2 to several thousand millimeters of Hg, dissolved O2 can be increased to compensate for the reduced CaO2 after hemodilution. We hypothesized that, after hemodilution, increasing dissolved O2 and restoring CaO2 to baseline would return CBF partially or completely to baseline, indicating that CaO2 or cerebral DO2 controls CBF. Conversely, if CBF remained unchanged on restoration of CaO2 to control levels, then the increase in CBF would be solely due to reduced blood viscosity.

Hemodilution reduces mean arterial pressure (MAP), and hyperbaric compression can elevate MAP. No information is available on the impact of hemodilution on the upper limit of cerebral autoregulation. However, progressive hemodilution shifts the lower limit of cerebral autoregulation to the right, so that, after hemodilution, CBF begins to decline at greater perfusion pressures (21). Because hemodilution and hyperbaric compression result in changes in MAP, we performed separate studies on CBF response to increased MAP after hemodilution.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animal Preparation

All experimental protocols were approved by the University of Iowa Animal Care and Use Committee. Male Sprague-Dawley rats (n = 48; Harlan Sprague Dawley, Indianapolis, IN) weighing 320-390 g were anesthetized with 4-5% halothane in 100% O2 in a plastic box. When anesthetized, animals were removed from the box, 1% lidocaine was infiltrated subcutaneously, and a tracheostomy was performed. Animals were ventilated by a small animal ventilator with an inspired gas mixture of 1.0% halothane in 40% O2-60% N2. Ventilator settings were adjusted to achieve normocarbia. After infiltration with lidocaine, bilateral femoral arterial and venous catheters (PE-50) were inserted. Arterial pressure was continuously measured from the left femoral artery (Transpac IV, Abbott, Abbott Park, IL). Arterial blood was intermittently sampled for determination of pH and arterial blood gas tensions at normobaric pressure (system 1306, Instrumentation Laboratory, Lexington, MA). Hct was determined by microcapillary tube centrifugation. Rectal temperature was maintained at 37-38°C with a heating pad. After preparation (~45 min) the halothane was discontinued and animals were loaded with pentobarbital sodium at 50 mg/kg followed by a maintenance infusion of 18 mg · kg-1 · h-1).

Experimental Protocols

CBF during hemodilution and hyperbaric O2. Rats were randomly assigned to one of three groups: 1) control (Con), 2) hemodilution (HDil), and 3) hemodilution with hyperbaric O2 (HBar). In the Con group (n = 8), rats were ventilated with 40% O2 at 101 kPa (1 atmosphere absolute). In the HDil group (n = 8) the Hct was reduced to ~17% by isovolumic hemodilution and rats were ventilated with 40% O2 at 101 kPa. Hemodilution was accomplished by incremental removal of whole blood and replacement with an equal volume of 6% hetastarch in saline (Hespan, DuPont Critical Care, Wilmington, DE). In the HBar group (n = 8), rats were hemodiluted as described above but ventilated with 100% O2 at 506 kPa. Con and HBar conditions were chosen to yield CaO2 of ~19-20 ml O2/dl. A fourth group (HCon, n = 8) of rats served as hyperbaric controls. These animals were hemodiluted as described above but ventilated with 10% O2 at 506 kPa to attain hyperbaric normoxia.

After preparation was complete, all animals were placed in a small animal hyperbaric chamber (Mechidyne Systems, Houston, TX) and ventilated with a small animal ventilator (Harvard, Holliston, MA) specially modified for use in the chamber. The chamber was sealed and flushed for 3 min with N2 to remove O2. In Con and HDil groups the chamber remained at 101 kPa, and 40% O2-60% N2 was supplied to the ventilator circuit. In the other groups (HBar and HCon) compression of the chamber was performed with N2. The ventilator was supplied with 100% O2 (HBar group) or 10% O2-90% N2 (HCon group) from a reservoir bag inside the chamber, which was connected to a gas supply outside the chamber. The reservoir bag was kept partially inflated by adjusting the gas supply to the bag while watching the bag through a viewing port. The ventilator exhausted expired gas into the chamber, and a constant flush of N2 was maintained to prevent O2 accumulation inside the chamber. Pressure was maintained at constant 506 kPa for 10 min before measurement of CBF. The arterial pressure transducer was placed inside the hyperbaric chamber and zeroed before compression.

To measure CBF, 10 mCi of [3H]nicotine (New England Nuclear, Boston, MA) in 0.5-0.6 ml of saline were infused at a calibrated rate of 0.508 ml/min for 40 s. Blood was simultaneously withdrawn at the same rate from the right femoral artery into a heparinized syringe. At the end of this interval, the infusion pumps were turned off, saturated KCl solution was injected intravenously, and infusion and withdrawal lines were immediately clamped before decompression of the chamber.

SAMPLE PROCESSING. 1) Brain: After decompression of the hyperbaric chamber (1-2 min), the brain was quickly removed from the skull. The dura and sagittal sinus were excised, and the hemispheres were divided and sectioned into thirds. Each sample was placed in a scintillation vial and weighed, and 2 ml of TS-2 tissue solubilizer were added (Research Products International, Mount Prospect, IL). The vials were placed in an oven at 50°C for 24 h. The contents of each vial were then neutralized by addition of 70 µl of glacial acetic acid. Each sample was suspended in 16 ml of 3a20 scintillation cocktail (Research Products International). 3H activity was determined with a liquid scintillation analyzer (1900 TR Tricarb, Packard Instrument, Meriden, CT).

2) Blood: Blood remaining in the sampling tubing was drawn into the syringe with 0.3 ml of water. Three 50-µl aliquots of blood were pipetted into scintillation vials and solubilized in 1 ml of TS-2 at 50°C for 30 min. The blood samples were then decolorized with 200 µl of benzoyl peroxide (0.2 g/ml in toluene) at 50°C for an additional 30 min. Blood samples were neutralized with 35 µl of glacial acetic acid and then suspended in 16 ml of 3a20 scintillation cocktail. 3H activity was determined with a liquid scintillation analyzer (1900 TR Tricarb).

Blood viscosity. Blood viscosity was measured in a separate group of animals. Each animal was prepared as outlined above, except for CBF measurement and hyperbaric compression. Three rats served as controls, and three underwent hemodilution. Blood samples were withdrawn from the right femoral vein 2 h and 45 min after induction of anesthesia. This time period approximated the time required from induction of anesthesia to measurement of CBF. One milliliter of blood was used to determine whole blood viscosity, and 1 ml of plasma was separated by centrifugation at 3,000 rpm for 10 min and used for plasma viscosity measurement. Viscosity was measured in a viscometer (model LVDV-I, Brookfield, Stoughton, MA) at shear rates of 100, 20, and 5 s-1 at 37°C.

Hemodilution, CBF, and MAP. The effect of increased MAP on CBF after hemodilution was studied in two separate groups of animals. Rats were prepared for CBF measurement and hemodiluted as outlined above. Because these studies were performed retrospectively, we measured CBF in a concurrent hemodilution control group (AutoCon, n = 5) and in a group of hemodiluted animals (AutoHtn, n = 5) after MAP was increased by infusion of methoxamine to equal MAP in the HBar group. Both groups were ventilated with 40% O2 at 101 kPa. After preparation and stabilization, CBF was measured in the AutoCon group with [3H]nicotine as in other groups. In the AutoHtn group, CBF was measured after MAP had been stabilized for 10 min.

Calculations

CBF. CBF (in ml · 100 g-1 · min-1) was calculated by the indicator fractionation method (24, 26)
CBF = <FR><NU><FENCE><FR><NU>syringe flow × tissue dpm</NU><DE>syringe dpm</DE></FR></FENCE></NU><DE>tissue wt</DE></FR>
Reference syringe flow was 0.508 ml/min.

CaO2 and DO2. We were unable to measure arterial PO2 (PaO2) during hyperbaric O2 exposure because of limitations of our blood gas analyzer. We therefore estimated PaO2 during hyperbaric oxygenation on the basis of solubility of O2 and published PaO2 measurements in normal subjects during hyperbaric O2 exposure (38). In the HDil group, alveolar PO2 (PAO2) was calculated with the alveolar gas equation
P<SC>a</SC><SUB>O<SUB>2</SUB></SUB> = (Pb − 47)(F<SC>i</SC><SUB>O<SUB>2</SUB></SUB>) − Pa<SUB>CO<SUB>2</SUB></SUB> ⋅ <FENCE>F<SC>i</SC><SUB>O<SUB>2</SUB></SUB> + <FR><NU>(1 − F<SC>i</SC><SUB>O<SUB>2</SUB></SUB>)</NU><DE>R</DE></FR></FENCE>
where barometric pressure (Pb) = 3,800 mmHg, inspiratory O2 fraction (FIO2) = 1.0, arterial PCO2 (PaCO2) = 40 mmHg, and respiratory quotient (R) = 0.8. This results in a calculated PAO2 of 3,713 mmHg in the HDil group. PaO2 was then calculated with an equation developed by linear regression of PaO2 values measured under hyperbaric conditions in normal subjects (38)
Pa<SUB>O<SUB>2</SUB></SUB> = 0.903 × P<SC>a</SC><SUB>O<SUB>2</SUB></SUB> − 52.4
This results in a calculated PaO2 of 3,300 mmHg in the HDil group.

CaO2 and DO2 were calculated by
Ca<SUB>O<SUB>2</SUB></SUB> = (1.39 × Hb × Sa<SUB>O<SUB>2</SUB></SUB>) + (0.0031 × Pa<SUB>O<SUB>2</SUB></SUB>)
<A><AC>D</AC><AC>˙</AC></A><SC>o</SC><SUB>2</SUB> = Ca<SUB>O<SUB>2</SUB></SUB> × CBF
where SaO2 is arterial O2 saturation.

Statistics

Data were analyzed by ANOVA with a Fisher's post hoc test. P < 0.05 was accepted as significant. Values are means ± SD.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Systemic Variables

Arterial pH, PaCO2, and temperature did not vary between groups (Table 1; P > 0.05). PaO2 did not vary (P > 0.05) among the Con, HDil, and HCon groups. Because we were technically unable to measure PaO2 in the HBar group, we report a PaO2 value as calculated above (38). PaO2 values in HBar animals were consistently >1,000 mmHg when measured on a standard blood gas analyzer. MAP was significantly less in the HDil group than in the three other groups and was significantly greater in the HBar group than in the three other groups (P < 0.05; Table 1). As intended, hemodilution reduced Hct and Hb concentration in the HDil, HBar, and HCon groups compared with the Con group (Table 1). Hemodilution significantly reduced CaO2 in the HDil and HCon groups compared with the Con group (P < 0.05; Table 1). CaO2 in the HBar group was approximately equal to that in the Con group.

                              
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  		Table 1.   Systemic variables in Con, HDil, HBar, and HCon groups

CBF and DO2

CBF was 79 ± 19 (SD) ml · 100 g-1 · min-1 in the Con group and was significantly increased to 123 ± 9 ml · 100 g-1 · min-1 in the HDil group (P < 0.05; Fig. 1). CBF was 104 ± 20 ml · 100 g-1 · min-1 in the HBar group, which is a 44% reduction from the HDil group. CBF during normoxic hyperbaric exposure after hemodilution (HCon) was 125 ± 18 ml · 100 g-1 · min-1, which was not different from the HDil group.


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  		Fig. 1.   Forebrain cerebral blood flow (CBF) in control group (Con) ventilated with 40% O2 at 101 kPa, hemodiluted group (HDil) ventilated with 40% O2 at 101 kPa, hyperbaric hemodiluted group (HBar) ventilated with 100% O2 at 506 kPa, and hyperbaric hemodiluted normoxia group (HCon) ventilated with 10% O2 at 506 kPa. CBF was significantly increased in HDil, HBar, and HCon groups compared with Con group. CBF in HBar group was reduced compared with HDil and HCon groups but remained above CBF in Con group. Values are means ± SD; n = 8 for each group. * P < 0.05 compared with 3 other groups.

Hemodilution reduced cerebral DO2 in HDil and HCon groups (P < 0.05; Fig. 2) compared with Con. Calculated DO2 was slightly higher in the HBar than in the Con group (P < 0.05; Fig. 2).


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  		Fig. 2.   Delivery of O2 to brain (DO2) in Con, HDil, HBar, and HCon groups (see Fig. 1 legend for explanation of groups). DO2 was significantly reduced in HDil and HCon groups. DO2 was slightly but significantly increased in HBar group. Values are means ± SD; n = 8 for each group. * P < 0.05 compared with 3 other groups.

Hemodilution and Viscosity

Before hemodilution, whole blood and plasma viscosities were 4.53 ± 0.18 and 1.32 ± 0.05 cP, respectively, at a shear rate of 20 s-1. Whole blood viscosity was significantly reduced (P < 0.05) after hemodilution to 2.54 ± 0.11 cP and plasma viscosity was significantly increased (P < 0.05) to 1.67 ± 0.09 cP at a shear rate of 20 s-1. Similar changes in viscosity occurred at shear rates of 5 and 100 s-1 (data not shown). The increase in plasma viscosity after hemodilution is consistent with previous observations on the effect of hetastarch on plasma viscosity (2).

Hemodilution and Cerebral Autoregulation

Systemic variables in the AutoCon and AutoHtn groups were similar to those in other groups (Table 2). In the AutoCon group, MAP was 105 ± 4 mmHg and CBF was 121 ± 5 ml · 100 g-1 · min-1. These values are not different from those in the HDil group (MAP = 104 ± 5 mmHg and CBF = 123 ± 9 ml · 100 g-1 · min-1). In the AutoHtn group, MAP was elevated to 146 ± 6 mmHg and CBF increased slightly but significantly (P = 0.05) to 132 ± 9 ml · 100 g-1 · min-1.

                              
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  		Table 2.   Systemic variables in AutoCon and AutoHtn groups


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The major finding of this study is that, after hemodilution, restoration of CaO2 to normal by hyperbaric oxygenation reduced but did not restore CBF to baseline. Our data therefore indicate that CaO2 and blood viscosity are important independent determinants of CBF. Each contributes 40-60% to the increase in CBF that occurs after hemodilution. Hyperbaric exposure with normoxia (HCon) did not alter CBF after hemodilution, which indicates that hyperbaric compression per se did not affect CBF.

Our data confirm and extend the findings of Hudak et al. (12). In our experiment and in that of Hudak et al., hemodilution reduced the Hct by approximately one-half. Hudak et al. used methemoglobin-containing RBCs to increase blood viscosity without changing CaO2 in hemodiluted lambs. They reported that increasing Hct from 20% to 40% with methemoglobin-containing RBCs reduced CBF by 56%, which suggests that blood viscosity was responsible for 56% of the increase in CBF after hemodilution. The results of Hudak et al. suggest that the remaining 44% increase in CBF was due to changes in CaO2. We performed the inverse experiment by using the unique approach of increasing CaO2 without changing blood viscosity. In our study, restoration of CaO2 to prehemodilution values reduced CBF by 44%, which indicates that CaO2 was responsible for 44% of the increase in CBF after hemodilution. Our results are also consistent with the findings of Massik et al. (22), who used methemoglobin-containing RBCs to vary blood viscosity under conditions of polycythemia, rather than anemia. Massik et al. reported that blood viscosity was responsible for 60% of the reduction of CBF that occurred when Hct was increased from 30% to 55%. Together, these results strongly suggest that, in normal brain, blood viscosity and CaO2 are independent variables that control CBF, and each contributes ~50% to the increase in CBF after hemodilution.

Blood flow is inversely related to blood viscosity, as described by Poiseuille's law. As viscosity is reduced, blood flow must increase if vascular diameter and blood pressure remain constant. However, blood is a non-Newtonian fluid, the viscosity of which varies with the inverse of the shear rate. As blood flow (shear rate) is reduced, blood becomes progressively more viscous. Although it is difficult to apply Poiseuille's law in vivo because of the nonlinear nature of the circulatory system, the nonlinear viscosity of blood, and constantly changing shear rates in vivo, direct in vivo measurements indicate that blood viscosity can influence CBF. Rosenblum (29) observed that very modest hemodilution (Hct reduced from 44% to 37%) in mice increased the flow velocity of blood in pial arterioles without change in arteriolar diameter, which suggests that reduced blood viscosity increased flow without an active change in arteriolar diameter. Hudak et al. (11) observed that hemodilution constricted pial arterioles while increasing CBF in cats. This suggests that pial arterioles could have constricted to limit the viscosity-driven increase in CBF. Others have demonstrated that hemodilution increased CBF in rats, while there was a small or no change in arteriolar diameter (13, 23). All these studies suggest that change in blood viscosity can change CBF.

Prior studies of hyperbaric O2 have suggested that a hyperbaric-mediated increase in CaO2 could influence CBF. Hyperbaric O2 reduces CBF in normal animals (4, 5, 14, 35), and the reduction in CBF correlates with the increase in CaO2 (4, 5, 14). In these studies, when CaO2 was increased 20-25%, CBF was reduced by 20-25% CaO2 (4, 5, 14). Because the change in CBF paralleled the change in CaO2, this suggests that hyperbaric O2-mediated reduction of CBF could be due to the increase in CaO2.

Limitations of the Current Study

In the present study we were unable to measure PaO2 or CaO2 during exposure of rats to 100% O2 at 506 kPa but, instead, calculated CaO2 on the basis of the alveolar air equation, O2 solubility, and published information on measured PaO2 values during hyperbaric O2 exposure (38). Normobaric measurement of alveolar-arterial O2 gradient or alveolar-to arterial ratio is not useful in prediction of hyperbaric PaO2 values, inasmuch as the alveolar-arterial gradient or alveolar-to-arterial ratio varies with hyperbaric exposure (39). Measured PaO2 values in rats exposed to 95% O2 at 500 kPa are above a calculated value on the basis of the method we utilized (4, 38). Thus we consider it probable that the in vivo PaO2 values in animals exposed to 100% O2 at 506 kPa are close to the value we calculated. Considering the worse case, if the normobaric alveolar-to-arterial ratio (0.75 in the Con group) was unchanged [the alveolar-to-arterial ratio remains the same or improves under hyperbaric conditions (39)] during hyperbaric exposure, the calculated PaO2 would be 2,784 mmHg, CaO2 would be 16.7 ml O2/dl, and DO2 would be 17.4 ml O2 · 100 g-1 · min-1, which are slightly less than the values we report in the HBar group (PaO2 = 3,300 mmHg, CaO2 = 18.5 ml O2/dl, and DO2 = 19.2 ml O2 · 100 g-1 · min-1) but still greater than values in the HDil and HCon groups: CaO2 = 8-9 ml O2/dl and DO2 = 10-11 ml O2 · 100 g-1 · min-1.

MAP was significantly less in the HDil group and greater in the HBar group than in the three other groups. The range of MAP values (104-145 mmHg) lies within the reported range of autoregulated CBF in awake and barbiturate-anesthetized rats (9, 10). No prior studies have addressed the impact of hemodilution on the response of CBF to increased MAP. However, hemodilution shifts the lower limit of cerebral autoregulation to the right (21). We found that, in hemodiluted rats, increasing MAP from 105 to 146 mmHg (the range of MAP values in the HDil and HBar groups) slightly but significantly increased CBF. This suggests that hemodilution alters the response of the cerebral circulation to increased MAP. Because we did not define the upper limit of cerebral autoregulation, we cannot say whether this change is due to a shift of the upper limit of autoregulation to the left or an increase in the slope of the midportion of the autoregulatory response. However, it is possible that the change in the response of the cerebral circulation to increased MAP could contribute to the elevation of CBF in the HBar group. The relative change (slope) of CBF (from 121 ± 5 to 132 ± 9 ml · 100 g-1 · min-1) when MAP was elevated from 105 to 146 mmHg is a 0.2% change in CBF for each 1-mmHg change in MAP. By use of this factor to adjust CBF of all groups to the MAP of the HDil group (104 mmHg), the reduction in CBF in the HBar group becomes 61% (as opposed to the 44% previously calculated). Although this adjustment changes the relative contribution of CaO2 to regulation of CBF after hemodilution, it does not change the overall conclusion that CaO2 and viscosity are independent elements that regulate CBF.

We measured whole blood and plasma viscosity ex vivo to confirm expected effects of hemodilution, with whole blood viscosity decreasing and plasma viscosity increasing. Such measurements provide a relative assessment of changes in viscosity in vivo but do not reflect absolute viscosity in vivo because of the nonlinear vascular architecture, the nonlinear viscosity of blood, and constantly changing shear rates in vivo. The endothelial surface is principally exposed to plasma viscosity because of RBC streaming in vessels, which may influence endothelial autacoid release and vascular tone. It is not known whether whole blood, plasma, or both viscosities mediate viscosity-driven changes in CBF. Although it is unlikely that the results of the present study would be qualitatively different if a different anesthetic, diluent, or species were used, quantitative differences cannot be ruled out.

Several effects of hyperbaric O2 could independently influence CBF. Prolonged exposure to hyperbaric O2 can produce toxic effects in the brain. Exposure to O2 at 405 kPa for 60-90 min produces lipid peroxides in the brain, which might independently affect CBF (25, 41). However, exposures of rats to 506 kPa O2 for 15 min did not cause lipid peroxidation in the brain (33), and exposure of mice to 304 kPa O2 for 5 min did not produce H2O2 or lipid peroxides in the brain (15). Furthermore, other data indicate that short-term exposure to hyperbaric O2 does not affect CBF or cerebral metabolism. Exposure of rats to 506 kPa O2 for 30 min does not change the cerebral metabolic rate of glucose (34). Exposure of rats to 506 kPa O2 for 1 h/day for 8 days does not alter normobaric CBF, which indicates that there is no cumulative effect on CBF (5). We chose a 10-min exposure period, inasmuch as there is no evidence of toxic effects within this time period. We do not believe that toxic effects of hyperbaric O2 contributed to the reduction of CBF in the HBar group.

Hyperbaric O2 exposure has been reported to reduce RBC flexibility and ability to pass through 5-µm pores (1), which suggests that hyperbaric O2 could disturb the microcirculation of the brain. However, reducing RBC flexibility by chemical treatment (independent of hyperbaric O2 exposure) does not change CBF and suggests that RBC flexibility has minimal impact on CBF (30).

Hyperbaric O2 may alter oxygen delivery to the brain by oxygenation of plasma, which could improve distribution of O2 in the brain. Furthermore, the high PaO2 achieved during hyperbaric O2 may enhance oxygen delivery to the brain by the large diffusion gradient. Hyperbaric O2 could also influence CBF by increasing brain PCO2 and cerebral venous PCO2. In the HBar group, dissolved O2 content is likely to have been greater than the rate of O2 utilization in the brain, which would result in cerebral venous Hb being fully saturated. Deoxyhemoglobin is an important transport mechanism for removal of CO2 from the brain, and small increases in brain PCO2 have been observed during hyperbaric O2 exposure in animals (3). Elevated brain PCO2 could independently elevate CBF. We have not assessed the impact, if any, of these factors on CBF in the present study.

In summary, we have demonstrated that hemodilution increased CBF, and increasing dissolved O2 to restore CaO2 to baseline reduced but did not restore CBF to baseline. Our data confirm and extend previous information that CaO2 and blood viscosity are important influences on CBF, with each contributing ~50% of the increase in CBF that occurs after hemodilution.


    ACKNOWLEDGEMENTS

This work was supported by National Institute of Neurological Disorders and Stroke Grants NS-24517 (to M. M. Todd) and NS-24621 (to J. E. Brian, Jr.) and by a grant-in-aid from the American Heart Association (to M. M. Todd).


    FOOTNOTES

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. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: J. E. Brian, Jr., University of Iowa Hospitals and Clinics, Department of Anesthesia 6JCP, 200 Hawkins Dr., Iowa City, IA 52242 (E-mail: eddie-brian{at}uiowa.edu).

Received 30 March 1998; accepted in final form 2 December 1998.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Amin, H. M., W. S. Kaniewski, D. Cohen, E. M. Camporesi, and T. S. Hakim. Effects of acute exposure to hyperbaric oxygen on the rheology and morphology of the red blood cells in the rat. Microvasc. Res. 50: 417-428, 1995[Medline].

2.   Audibert, G., M. Donner, J. Lefevre, J. Stoltz, and M. Laxenaire. Rheologic effects of plasma substitutes used for preoperative hemodilution. Anesth. Analg. 78: 740-745, 1994[Abstract/Free Full Text].

3.   Bennett, P. B. Cortical CO2 and O2 at high pressures of argon, nitrogen, helium, and oxygen. J. Appl. Physiol. 20: 1249-1252, 1965[Abstract/Free Full Text].

4.   Bergö, G. W., and I. Tyssebotn. Cerebral blood flow distribution during exposure to 5 bar oxygen in awake rats. Undersea Biomed. Res. 19: 339-354, 1992[Medline].

5.   Bergö, G. W., and I. Tyssebotn. Cerebral blood flow distribution and systemic haemodynamic changes after repeated hyperbaric oxygen exposures in rats. Eur. J. Appl. Physiol. 69: 1-9, 1994.

6.   Brown, M. M., and J. Marshall. Regulation of cerebral blood flow in response to changes in blood viscosity. Lancet 1: 604-609, 1985[Medline].

7.   Cole, D. J., J. C. Drummond, P. M. Patel, and S. Marcantonio. Effects of viscosity and oxygen content on cerebral blood flow in ischemic and normal rat brain. J. Neurol. Sci. 124: 15-20, 1994[Medline].

8.   Faraci, F. M., and J. E. Brian, Jr. Nitric oxide in the cerebral circulation. Stroke 25: 692-703, 1994[Abstract].

9.   Harper, S. L., and H. G. Bohlen. Microvascular adaptation in the cerebral cortex of adult spontaneously hypertensive rats. Hypertension 6: 408-419, 1984[Abstract/Free Full Text].

10.   Hoffman, W. E., G. Edelman, E. Kochs, C. Werner, L. Segil, and R. F. Albrecht. Cerebral autoregulation in awake versus isoflurane-anesthetized rats. Anesth. Analg. 73: 753-757, 1991[Abstract/Free Full Text].

11.   Hudak, M. L., M. D. Jones, Jr., A. S. Popel, R. C. Koehler, R. J. Traystman, and S. L. Zeger. Hemodilution causes size-dependent constriction of pial arterioles in the cat. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H912-H917, 1989[Abstract/Free Full Text].

12.   Hudak, M. L., R. C. Koehler, A. A. Rosenberg, R. J. Traystman, and M. D. Jones, Jr. Effect of hematocrit on cerebral blood flow. Am. J. Physiol. 251 (Heart Circ. Physiol. 20): H63-H70, 1986[Abstract/Free Full Text].

13.   Hurn, P. D., R. J. Traystman, A. A. Shoukas, and M. D. Jones, Jr. Pial microvascular hemodynamics in anemia. Am. J. Physiol. 264 (Heart Circ. Physiol. 33): H2131-H2135, 1993[Abstract/Free Full Text].

14.   Jacoson, I., A. M. Harper, and D. G. McDowall. The effects of oxygen under pressure on cerebral blood-flow and cerebral venous oxygen tension. Lancet 2: 549, 1963[Medline].

15.   Jerrett, S. A., D. Jefferson, and C. E. Mengel. Seizures, H2O2 formation and lipid peroxides in brain during exposure to oxygen under high pressure. Aerospace Med. 44: 40-44, 1973[Medline].

16.   Jones, M. D., Jr., R. J. Traystman, M. A. Simmons, and R. A. Molteni. Effects of changes in arterial O2 content on cerebral blood flow in the lamb. Am. J. Physiol. 240 (Heart Circ. Physiol. 9): H209-H215, 1981[Abstract/Free Full Text].

17.   Koehler, R. C., R. J. Traystman, and M. D. Jones, Jr. Influence of reduced oxyhemoglobin affinity on cerebrovascular response to hypoxic hypoxia. Am. J. Physiol. 251 (Heart Circ. Physiol. 20): H756-H763, 1986.

18.   Koehler, R. C., R. J. Traystman, A. A. Rosenberg, M. L. Hudak, and M. D. Jones, Jr. Role of O2-hemoglobin affinity on cerebrovascular response to carbon monoxide hypoxia. Am. J. Physiol. 245 (Heart Circ. Physiol. 14): H1019-H1023, 1983.

19.   Kontos, H. A., E. P. Wei, and J. Marshall. In vivo bioassay of endothelium-derived relaxing factor. Am. J. Physiol. 255 (Heart Circ. Physiol. 24): H1259-H1262, 1988[Abstract/Free Full Text].

20.   Korosue, K., and R. C. Heros. Mechanism of cerebral blood flow augmentation by hemodilution in rabbits. Stroke 23: 1487-1493, 1992[Abstract/Free Full Text].

21.   Maruyama, M., K. Shimoji, T. Ichikawa, and M. Hashiba. The effects of extreme hemodilutions on the autoregulation of cerebral blood flow, electroencephalogram and cerebral metabolic rate of oxygen in the dog. Stroke 16: 675-679, 1985[Abstract/Free Full Text].

22.   Massik, J., Y.-L. Tang, M. L. Hudak, R. C. Koehler, R. J. Traystman, and M. D. Jones, Jr. Effect of hematocrit on cerebral blood flow with induced polycythemia. J. Appl. Physiol. 62: 1090-1096, 1987[Abstract/Free Full Text].

23.   Muizelaar, J. P., G. J. Bouma, J. E. Levasseur, and H. A. Kontos. Effect of hematocrit variations on cerebral blood flow and basilar artery diameter in vivo. Am. J. Physiol. 262 (Heart Circ. Physiol. 31): H949-H954, 1992[Abstract/Free Full Text].

24.   Ohno, K., K. D. Pettigrew, and S. I. Rapoport. Local cerebral blood flow in the conscious rat as measured with 14C-antipyrine, 14C-iodoantipyrine, and 3H-nicotine. Stroke 10: 62-67, 1979[Free Full Text].

25.   Pablos, M. I., R. J. Reiter, J.-I. Chuang, G. G. Ortz, J. M. Guerrero, E. Sewerynek, M. T. Agapto, D. Melchiorri, R. Lawrence, and S. M. Deneke. Acutely administered melatonin reduces oxidative damage in lung and brain induced by hyperbaric oxygen. J. Appl. Physiol. 83: 354-358, 1997[Abstract/Free Full Text].

26.   Patlak, C. S., R. G. Blasberg, and J. D. Fenstermacher. An evaluation of errors in the determination of blood flow by the indicator fractionation and tissue equilibration (Kety) methods. J. Cereb. Blood Flow Metab. 4: 47-60, 1984[Medline].

27.   Paulson, O. B., H.-H. Parving, J. Olsen, and E. Skinhj. Influence of carbon monoxide and of hemodilution on cerebral blood flow and blood gases in man. J. Appl. Physiol. 35: 111-116, 1973[Free Full Text].

28.   Rosenberg, A. A., A. P. Harris, R. C. Koehler, M. L. Hudak, R. J. Traystman, and M. D. Jones, Jr. Role of O2-hemoglobin affinity in the regulation of cerebral blood flow in fetal sheep. Am. J. Physiol. 251 (Heart Circ. Physiol. 20): H56-H62, 1986.

29.   Rosenblum, W. I. Effects of reduced hematocrit on erythrocyte velocity and fluorescein transit time in the cerebral microcirculation of the mouse. Circ. Res. 29: 96-103, 1971[Abstract/Free Full Text].

30.   Simchon, S., K.-M. Jan, and S. Chien. Influence of reduced red cell deformability on regional blood flow. Am. J. Physiol. 253 (Heart Circ. Physiol. 22): H898-H903, 1987[Abstract/Free Full Text].

31.   Todd, M. M., J. B. Weeks, and D. S. Warner. Cerebral blood flow, blood volume, and brain tissue hematocrit during isovolemic hemodilution with hetastarch in rats. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H75-H82, 1992[Abstract/Free Full Text].

32.   Todd, M. M., B. Wu, M. Makatabi, B. J. Hindman, and D. S. Warner. Cerebral blood flow and oxygen delivery during hypoxemia and hemodilution: role of arterial oxygen content. Am. J. Physiol. 267 (Heart Circ. Physiol. 36): H2025-H2031, 1994[Abstract/Free Full Text].

33.   Torbati, D., D. F. Church, J. M. Keller, and W. Pryor. Free radical generation in the brain precedes hyperbaric oxygen-induced convulsions. Free Radic. Biol. Med. 13: 101-106, 1992[Medline].

34.   Torbati, D., J. Greenberg, and C. J. Lambertsen. Correlation of brain glucose utilization and cortical electrical activity during development of brain oxygen toxicity. Brain Res. 262: 267-273, 1983[Medline].

35.   Torbati, D., D. Parolla, and S. Lavy. Blood flow in rat brain during exposure to high oxygen pressure. Aviat. Space Environ. Med. 49: 963-967, 1978[Medline].

36.   Ulatowski, J. A., E. Bucci, T. Nishikawa, A. Razynska, M. A. Willians, R. Takeshima, R. J. Traystman, and R. C. Koehler. Cerebral O2 transport with hematocrit reduced by cross-linked hemoglobin transfusion. Am. J. Physiol. 270 (Heart Circ. Physiol. 39): H466-H475, 1996[Abstract/Free Full Text].

37.   Waschke, K. F., H. Krieter, G. Hagan, D. M. Albrecht, K. Van Ackern, and W. Kuschinsky. Lack of dependence of cerebral blood flow on blood viscosity after blood exchange with a Newtonian O2 carrier. J. Cereb. Blood Flow Metab. 14: 871-876, 1994[Medline].

38.   Weaver, L. K., and S. Howe. Normobaric measurement of arterial oxygen tension in subjects exposed to hyperbaric oxygen. Chest 102: 1175-1181, 1992[Abstract/Free Full Text].

39.   Weaver, L. K., and S. Howe. Arterial oxygen tension of patients with abnormal lungs treated with hyperbaric oxygen is greater than predicted. Chest 106: 1134-1139, 1994[Abstract/Free Full Text].

40.   Wood, J. H., and D. B. Kee, Jr. Hemorheology of the cerebral circulation in stroke. Stroke 16: 765-772, 1985[Free Full Text].

41.   Zirkle, L. G., C. E. Mengel, B. D. Horton, and E. J. Duffy. Studies of oxygen toxicity in the central nervous system. Aerospace Med. 36: 1027-1032, 1965[Medline].

Am J Physiol Heart Circ Physiol 276(4):H1190-H1196
0002-9513/99 $5.00 Copyright © 1999 the American Physiological Society


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