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(Stroke. 1996;27:1328-1332.)
© 1996 American Heart Association, Inc.

Articles

Effects of Defibrination on Hemorheology, Cerebral Blood Flow Velocity, and CO₂ Reactivity During Hypocapnia in Normal Subjects

Yoshinari Izumi, MD; Yoshiyasu Tsuda, MD; Shin-Ichiro Ichihara, MD; Tsutomu Takahashi, MD Hirohide Matsuo, MD

the Second Department of Internal Medicine, Kagawa (Japan) Medical School.

Correspondence to Yoshinari Izumi, MD, Second Department of Internal Medicine, Kagawa Medical School, 1750-1 Ikenobe, Miki-Cho, Kagawa, 761-07 Japan. E-mail izumi@kms.ac.jp.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Plasma fibrinogen is reported to be an independent risk factor for stroke and cardiovascular diseases. The effects of defibrination on hemorheology, middle cerebral artery (MCA) blood flow velocity, and CO₂ reactivity during hypocapnia were evaluated in normal subjects.

Methods Twenty-five healthy subjects (mean age, 31.8±5.7 years) were included in the study. Measurements were done at rest and repeated 24 hours after administration of 10 batroxobin units. Plasma fibrinogen, plasma viscosity, and whole blood viscosity were measured as hemorheological factors. MCA blood flow velocity was measured with a transcranial Doppler flowmeter. Blood flow velocity was corrected to 40 mm Hg of end-tidal CO₂ partial pressure (PETCO₂), and expressed as CV₄₀. CO₂ reactivity was measured as percent change in mean blood flow velocity per millimeter of mercury PETCO₂.

Results Plasma fibrinogen (from 7.04 to 2.29 µmol/L; P<.001), whole blood viscosity, and plasma viscosity decreased after administration of batroxobin. Mean MCA blood flow velocity at rest, CV₄₀, and CO₂ reactivity during hypocapnia increased significantly (from 67.4 to 73.6 cm/s, from 71.7 to 77.7 cm/s, and from 2.9%/mm Hg to 3.2%/mm Hg, respectively; P<.01) after defibrination. Mean arterial blood pressure and PETCO₂ at rest were constant before and 24 hours after administration of batroxobin. There was a significant positive correlation between CV₄₀ and CO₂ reactivity (r=.623, P<.0001).

Conclusions The increase in MCA blood flow velocity was associated with improved CO₂ reactivity and reduced blood viscosity after defibrination. The data may suggest that defibrination increases cerebral blood flow by reducing blood viscosity.

Key Words: carbon dioxide • cerebral blood flow • fibrinogen • rheology • ultrasonics

	Introduction

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Recent studies have shown that plasma fibrinogen is an independent risk factor for stroke and ischemic heart disease.^{1 2 3 4} Since fibrinogen is highly viscous, elevated plasma fibrinogen levels increase blood viscosity. The increased shear stress due to high blood viscosity may injure the endotheliocyte of vessel walls and activate platelets, all of which may lead to further impairments of the cerebral microcirculation. With decreased plasma fibrinogen, on the other hand, reduced blood viscosity may accelerate CBF. Regarding the effects of rheological changes on CBF, several studies on the effect of hemodilution demonstrated an inverse correlation between the values of CBF and hematocrit.^{5 6 7 8 9} Blood viscosity may influence CBF if the perfusion pressure and vessel caliber are constant.¹⁰ Whether hemorheological improvements by blood defibrination influence CBF is a matter of debate. Batroxobin, a venom of Bothrops atrox (Tobishi Pharmaceutical Industries Co, Ltd), converts plasma fibrinogen to readily water-soluble fibrin microclots, which are eliminated as fibrin degradation products in the urine without significantly affecting the platelet count and other blood clotting factors.¹¹ The objective of this study was to evaluate the effects of enzymatic blood defibrination on hemorheology, MCA blood flow velocity, and CO₂ reactivity during hypocapnia in young adults who have a normal cerebral microcirculation before evaluating patients with cerebrovascular disease.

	Subjects and Methods

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Twenty-five healthy subjects (5 women, 20 men; mean age, 31.8±5.7 years) received batroxobin, a venom of B atrox, intravenously for 1 hour as 10 batroxobin units diluted in 100 mL saline. Measurements of rheological variables and blood flow velocity were performed before and 24 hours after administration of batroxobin, respectively, since the plasma fibrinogen concentrations reach a nadir 24 hours after administration of 5 to 10 batroxobin units.^{11 12} During all TCD procedures, PETCO₂ was monitored and recorded continuously with an infrared gas analyzer (Respina, model 1H21A, NEC). Arterial blood pressure and heart rate were recorded simultaneously (model CBM-2000, NEC). tcPO₂ was monitored noninvasively with an oxycapnomonitor (model SMK 365, Hellige) in 20 subjects. The values of PO₂ measured by this monitor are reported to correlate with PaO₂ under stable circulation.^{13 14}

The subjects were informed of the procedures, and their consent was obtained for the study under the guidance of the ethical committee for clinical research of Kagawa Medical School.

Blood Viscosity Measurements
Whole blood viscosity at shear rates of 22.5 to 562.5 s^-1, plasma viscosity, corrected blood viscosity at shear rates of 45 s^-1 and 225 s^-1, serum hematocrit, albumin, and plasma fibrinogen were measured before and 24 hours after administration of batroxobin. A cone-plate viscometer (Biorheolizer, BRL-1000) was used for the measurement of whole blood and plasma viscosity. The corrected blood viscosity for the standard hematocrit level of 45% (₄₅) was calculated by the formula reported by Nicolaides et al¹⁵ :

where is whole blood viscosity and A is a constant at each shear rate. To determine hematocrit, a microhematocrit centrifuge method was used. ESR was measured as an index of erythrocyte aggregation, and the osmotic fragility of erythrocyte membrane was measured as an index of erythrocyte deformability with the use of a coil planet centrifuge (model ST, Sanki Engineering Ltd), which can be used for the evaluations of osmotic fragility of red blood cells.¹⁶

TCD Measurements
Mean MCA blood flow velocity and its CO₂ reactivity were measured by TCD (TC2-64, Eden Medical Electronics Inc) according to the procedures described in previous studies^{17 18 19 20} at rest and during hypocapnia induced by hyperventilation for 1 minute. Each subject was placed in the supine position with both eyes closed. The 2-MHz pulsed Doppler probe was positioned in the temporal region (ultrasonic window), and an elastic bandage was used to avoid the shift of the probe during investigations. The highest signal was sought at a depth ranging from 45 to 55 mm. The mean flow velocity was calculated continuously as the time-averaged maximum velocity over the cardiac cycle computed from the envelope of the maximum frequencies. During continuous monitoring by a capnometer, the subject was instructed to breathe normally until a steady state was reached (PETCO₂ values before and after administration of batroxobin were 38.6±4.2 and 38.8±4.6 mm Hg, respectively). The mean MCA blood flow velocity at rest was obtained in the stable normocapnic condition, and the point of the temporal window was marked for the repeated study afterward. The lowest mean flow velocity of the MCA near the end of the hyperventilation period was examined thereafter. Examinations were repeated during the same conditions 24 hours after administration. All TCD spectra were recorded onto a half-inch videotape for later reviews.

Since blood flow velocity is dependent on the PaCO₂, we calculated the corrected blood flow velocity at 40 mm Hg of CO₂ tension (CV₄₀) according to the study of Markwalder et al¹⁹ :

where b is CO₂ reactivity and V₁ is velocity at P₁CO₂.

CO₂ reactivity referred to the percent change in mean blood flow velocity per millimeter of mercury change in PETCO₂, as calculated by the following formula:

where PETCO₂ is the change in PETCO₂ from baseline to maximal hyperventilation.

Statistical comparisons between the values before and after administration of batroxobin were made with the paired t test, and P<.01 was considered significant. Data are expressed as mean±SD. Linear regression analysis and tests for the significance of differences between means of paired data were performed with a least squares method computed by a microcomputer and commercially available software packages.

	Results

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Plasma fibrinogen concentration (from 7.04 to 2.29 µmol/L; P<.001), whole blood viscosity, and plasma viscosity decreased significantly 24 hours after administration of batroxobin (Table 1). Linear correlations were found between fibrinogen and the corrected blood viscosity at shear rates of 45 s^-1 and 225 s^-1 and between the values of fibrinogen and plasma viscosity (r=.421, P=.0023; r=.511, P=.0002; and r=.581, P<.0001, respectively). ESR decreased significantly, whereas hematocrit, albumin, and the osmotic fragility of erythrocyte membrane with coil planet centrifuge did not change significantly (Table 1). Mean MCA blood flow velocity at rest, corrected flow velocity, and CO₂ reactivity during hypocapnia increased significantly (from 67.4 to 73.6 cm/s; from 71.7 to 77.7 cm/s; and from 2.9%/mm Hg to 3.2%/mm Hg, respectively; P<.01), whereas mean arterial blood pressure, heart rate, tcPO₂, and PETCO₂ at rest did not change significantly before and after administration of batroxobin (Table 2). Data regarding MCA blood flow velocity, corrected flow velocity, and CO₂ reactivity in each subject compared with those before administration of batroxobin are shown in Figs 1 and 2.

View this table: [in this window] [in a new window]   Table 1. Hemorheological Variables Before and After Administration of Batroxobin in 25 Healthy Subjects

View this table: [in this window] [in a new window]   Table 2. Hemodynamics, Mean Blood Flow Velocity, Corrected Blood Flow Velocity (at PETCO2=40 mm Hg) and CO2 Reactivity Before and After Administration of Batroxobin in 25 Healthy Subjects

View larger version (21K): [in this window] [in a new window]   Figure 1. Mean MCA blood flow velocity at rest (a) and corrected blood flow velocity at PETCO2=40 mm Hg (b) before and after administration of batroxobin in 25 healthy subjects. P<.01 different from values before administration by paired t test.

View larger version (23K): [in this window] [in a new window]   Figure 2. CO2 reactivity to hypocapnia before and after administration of batroxobin in 25 healthy subjects. P<.01 different from values before administration by paired t test.

The correlation between the values of corrected blood flow velocity at PETCO₂=40 mm Hg (CV₄₀) and CO₂ reactivity (n=50; 25 before and 25 after administration) is shown in Fig 3. The equation of the regression line for the relationship is CO₂ reactivity=1.48±0.021·CV₄₀ (r=.623), where CV₄₀ and CO₂ reactivity are expressed in units of centimeters per second and percent change per millimeter of mercury, respectively. There was a significant correlation, with a coefficient of .623 (P<.0001). However, the correlations between fibrinogen and CO₂ reactivity or CV₄₀ were not significant.

View larger version (20K): [in this window] [in a new window]   Figure 3. Relation between corrected blood flow velocity at PETCO2=40 mm Hg (CV40) and CO2 reactivity. Data before (n=25) and after (n=25) administration of batroxobin are shown. The equation of the regression line is CO2 Reactivity=1.481±0.021·CV40 (r=.623, P<.0001).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our results showed that mean MCA blood flow velocity, corrected blood flow velocity (at PETCO₂=40 mm Hg), and CO₂ reactivity increased significantly after defibrination. We used TCD for the direct measurement of CBF velocity. TCD measures blood flow velocity but not CBF. However, the changes in flow velocity may be proportional to those in CBF if the vessel diameter is constant. In humans, the diameter of a large cerebral artery with an internal diameter greater than 2.5 mm does not change significantly despite alternations in PaCO₂.²¹ We investigated blood flow velocity in the proximal trunk of the MCA (depth of 45 to 55 mm from the skull) and assumed that the diameter of the MCA (3 to 5 mm in diameter²² ) would not change significantly before and after administration of batroxobin. Sorteberg et al²³ reported a significant positive correlation between blood flow velocity in defined brain arteries and the corresponding regional CBF in resting normal subjects. The reproducibility of the TCD velocimetry is acceptable for repeated measurements of MCA blood flow velocity from one day to the next.^{24 25} Therefore, we regarded the change in MCA blood flow velocity as an index of CBF changes in the MCA territory.

Under normal physiological conditions, CBF is not affected by a moderate change in mean arterial blood pressure, ie, between 50 and 130 mm Hg.^{26 27} Mean blood flow velocity remains unaffected by the cardiac index in the range of 2.0 to 4.0 L/min per square meter.²⁸ PaCO₂ and arterial oxygen content can profoundly influence CBF and MCA blood flow velocity.^{29 30 31} We measured PETCO₂ and tcPO₂ instead of PaCO₂ and PaO₂, respectively. PETCO₂ response curves for blood flow velocity in the MCA strongly resembled PaCO₂ response curves for CBF.¹⁷ In adults, tcPO₂ is 20% to 30% lower than PaO₂ because of the properties of their skin³² ; however, they have shown a good correlation within the parameters of normal cardiac output.^{14 33} In the present study both mean arterial blood pressure and heart rate at rest remained within normal range, and hematocrit, PETCO₂, and tcPO₂ under normocapnic conditions did not change significantly before and after administration of batroxobin (Table 2). The oxygen content of blood depends mainly on the volume bound to hemoglobin, together with a relatively small amount of oxygen dissolved in the plasma.³⁴ The oxygen content did not change significantly in this study. Accordingly, we believe it is more likely that the increases in mean MCA blood flow velocity and corrected blood flow velocity (at PETCO₂=40 mm Hg) may indicate an increase in CBF as a result of rheological improvement by defibrination without changes in oxygen content or CO₂ tension.

Bishop et al³⁵ showed that changes in MCA blood flow velocity correlated reliably with changes in CBF measured with intravenous ¹³³Xe when hypercapnia was induced, and they expressed CO₂ reactivity as percent change in mean MCA peak velocity per unit change in PETCO₂. Hence, the CO₂ reactivity of blood flow in the cerebral arteries can be determined from changes in flow velocity measured by TCD. Ackerman³⁶ reported that CO₂ reactivity was proportional to resting blood flow values when mean arterial blood pressure was constant. The law of initial values,³⁷ which states that the higher the initial level, the smaller the response to function-raising agents and the greater the response to function-depressing agents, may affect the observed improvement of CO₂ reactivity. In the present study CO₂ reactivity increased significantly after administration of batroxobin, which seems due to the significantly increased resting CBF as the result of improvements in hemorheology. From the significant correlation observed between the values of mean MCA blood flow velocity and PETCO₂ (r=.644, P<.0001) in our study, changes in MCA blood flow velocity are regarded to be proportional to changes in PETCO₂. Therefore, we examined the correlation between CO₂ reactivity and blood flow velocity corrected to a standard value of PETCO₂=40 mm Hg. As shown in Fig 3, the relationship between corrected blood flow velocity and CO₂ reactivity was highly significant, which indicated that the increases in CBF velocity were associated with increases in CO₂ reactivity. Therefore, we might be able to regard CO₂ reactivity as an index of CBF and to consider that CO₂ reactivity after administration of batroxobin increased significantly because of the significant increase of CBF after defibrination.

Theoretically, changes in CBF may be affected by one or more of the following mechanisms: (1) altered blood flow velocity through the perfused capillaries; (2) varied number of perfused capillaries (the capillary recruitment hypothesis^{38 39} ); or (3) modulated diameter of the perfused capillaries. There is a variable distribution of shear stress across the vessel lumen in cerebral microcirculation. Moreover, red cell aggregation and deformability, plasma viscosity, and protein composition have a meaningful influence on blood viscosity in the cerebral microcirculation. Elevated plasma fibrinogen levels result in exaggerated erythrocyte aggregation because plasma fibrinogen plays an important role in overcoming the electronic repulsion between erythrocytes.⁴⁰ In our study the significant reductions in plasma viscosity and ESR as an index of red cell aggregation due to defibrination might have improved the cerebral circulation because of altered blood flow velocity through the perfused capillaries. Moreover, Sugawara et al⁴¹ investigated the effects of batroxobin on the microcirculation by using the rabbit ear chamber method. They observed increases in blood flow and the number of capillaries in the microcirculation after administration of batroxobin. Their results suggest that the mechanism of increases in blood flow velocity after defibrination may be due to increases in the number of perfused capillaries and/or blood flow velocities through the perfused capillaries.

In conclusion, the rheological improvement by defibrination results in increases in MCA blood flow velocity, which are associated with improvements in CO₂ reactivity during hypocapnia in healthy subjects. These results may be of importance in various types of brain ischemia and stroke because rheological factors may likewise be of great importance as the determinants of CBF velocity in ischemic brain, where vasodilation is maximal and autoregulation is impaired.

	Selected Abbreviations and Acronyms

 

CBF = cerebral blood flow ESR = erythrocyte sedimentation rate MCA = middle cerebral artery PETCO2 = end-tidal partial pressure of carbon dioxide TCD = transcranial Doppler sonography tcPO2 = transcutaneous partial pressure of oxygen

	Acknowledgments

 
We would like to express our thanks to Tobishi Pharmaceutical Industries Co Ltd, Japan, for supplying the batroxobin (Defibrase) used in our study.

Received December 4, 1995; revision received April 9, 1996; accepted April 9, 1996.

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