(Stroke. 1996;27:441-445.)
© 1996 American Heart Association, Inc.
Articles |
Effects of Isovolemic Hemodilution on Hemodynamics, Cerebral Perfusion, and Cerebral Vascular Reactivity
From the Division of Neurosurgery, Departments of Surgery (Y.-K.T.) and Radiology (H.-M.L.), National Taiwan University Hospital (Taipei).
Correspondence to Yong-Kwang Tu, MD, PhD, Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, 7 Chung-Shan South Rd, Taipei, Taiwan 10016.
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Abstract |
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 Top Abstract IntroductionSubjects and Methods Results Discussion References |
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Background and Purpose To verify the hemorheological effects of isovolemic hemodilution on hemodynamics and cerebral perfusion of normal humans, we tested the efficacy of isovolemic hemodilution in systemic hemodynamics and cerebral blood flow augmentation and its influences in vascular reserve.
Methods Isovolemic hemodilution was studied in a total of 13 normal healthy subjects. Regional cerebral blood flow was measured by the xenon-enhanced CT method. Cerebral vascular activity was measured by acetazolamide challenge. These measurements, in association with hemorheological and hemodynamic monitoring, were analyzed before and after isovolemic hemodilution with low-molecular-weight dextran.
Result Our results showed significant change in hemodynamic parameters after isovolemic hemodilution, including tachycardia, a 24% increase of cardiac index, and decrease of peripheral vascular resistance. Both left and right heart work index increased as a consequence of increased cardiac index. Regional cerebral blood flow increased 35.0±2.5% at 3 hours after hemodilution and 20.2±3.9% at 1 week after hemodilution. Cerebral vascular reactivity decreased from 32.1±4.1% to 25.3±4.0% after hemodilution, implicating a certain degree of vasodilatation in the process of hemodilution. The whole procedure of hemodilution was completed in 52±6 minutes, and the subjects did not report discomfort during the procedure.
Conclusions Isovolemic hemodilution in subjects with normal cerebral perfusion can augment cerebral blood flow efficiently in a rapid fashion, and this effect can last for at least a week. The mechanism of flow augmentation may be partially attributed to vasodilatation, which could be manifested as tachycardia, increased cardiac output, and decreased cerebral vascular reactivity.
Key Words: cerebral blood flow • hemodilution • hemodynamics • xenon
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Introduction |
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TopAbstractIntroductionSubjects and Methods Results Discussion References |
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Hemodilution to reduce blood viscosity and augment CBF has been considered a potential therapy for cerebral ischemia.1 2 3 Both hypervolemic and isovolemic hemodilution have been used in clinical settings for the augmentation of CBF during cerebral ischemia after vascular occlusion4 5 6 7 8 or vasospasm in subarachnoid hemorrhage.9 10 Isovolemic hemodilution is claimed to have the merits of avoiding fluid overloading and intracranial pressure elevation.11 12 However, because of the lack of effects in volume expansion and the consequent cardiac output enhancement, its efficacy in flow augmentation has also been questioned.5
Although cerebrovascular and cardiac responses of hemodilution have been studied in animals with cerebral ischemia,11 12 13 data from clinical studies have focused mainly on the outcomes in stroke patients treated with hemodilution.14 15 16 Although there are several quantitative measurements of CBF as a function of hematocrit level in humans in the literature,1 17 18 19 20 the effects of isovolemic hemodilution on cardiac and cerebrovascular hemodynamics have not been documented previously in normal subjects. To obtain a better understanding of the therapeutic efficacy of isovolemic hemodilution, we measured its effects on systemic hemodynamics as well as CBF augmentation and CVR with Xe-CT in subjects with normal cerebral perfusion.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and Methods Results Discussion References |
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Study Subject Population
Thirteen volunteers of both sexes (8 men and 5 women) were enrolled in this study. These subjects were admitted for spinal or transsphenoidal pituitary surgery. Neither their clinical conditions nor the surgery they were to receive has any relevance to the situations that can affect cerebral perfusion. The study was carried out 12 hours before their surgery. Blood obtained from bloodletting during isovolemic hemodilution was kept for intraoperative transfusion if necessary. Arterial lines, central venous lines, and Swan-Ganz catheters inserted during the study were kept to be used again in anesthesia. The protocol was approved by the National Council of Science ROC (Taiwan) and the Institutional Review Board of National Taiwan University Hospital. The mean age of the study subjects was 34 years (range, 22 to 51 years). All the subjects had a hematocrit level between 0.40 to 0.45. Cigarette smokers and patients with diabetes, hypertension, or heart disease were excluded from this study. The purpose of this study and the study procedures were thoroughly explained to the volunteers. Written consent was also obtained from these study subjects.
Physiological Monitoring
All study subjects were placed in
the neurosurgical intensive
care unit. A Swan-Ganz catheter was inserted through the right
subclavian vein. This catheter was connected to a pressure monitor
equipped with a cardiac output computer for the monitoring of central
venous pressure, pulmonary arterial pressure,
pulmonary wedge pressure, and cardiac output. An
arterial line was also set through the right radial artery
for the monitoring of systemic arterial blood pressure. A
central venous line was set up at the right femoral vein for blood
withdrawal and diluent infusion. Changes in plasma fibrinogen level,
blood viscosity, electrolyte level, blood gas levels, and
electrocardiogram were also measured before and after
hemodilution.
Isovolemic Hemodilution
Isovolemic hemodilution was
accomplished by repeated withdrawal
of 250 mL blood from the central venous line and infusion of 175 mL
low-molecular-weight dextran (Rheomacrodex, Pharmacia)
until hematocrit level reached 0.31 to 0.33. Dextran, with its high
oncotic pressure, was used as a volume expander. It has been shown in
our previous animal experiments that exchange infusion with this
blood/dextran volume ratio can result in isovolemia.11
Hemorheological Measurement
Blood viscosity was measured with
a porous-type disposable
viscometer.21 This viscometer provides a direct
measurement of apparent viscosity of blood under low shearing stress,
as in the condition of microcirculation. Apparent viscosity by this
method is expressed as the time elapsed (in seconds) for a column of
blood to fall a fixed distance through the porous bed. The plasma
fibrinogen level was determined by the biuret method.
Measurement of Cerebral Blood Flow With Xe-CT
Two sets of
Xe-CT rCBF measurements were performed immediately
before hemodilution and at 2 hours after hemodilution. A third set of
blood flow measurements was performed at 1 week after hemodilution for
seven of the study subjects.
Xe-CT rCBF measurements were carried out while patients inhaled a gas mixture (30% stable xenon+30% oxygen+40% room air) for 5 minutes, and serial CT scans were made with a Picker 1200 SX CT scanner (Picker International) in a lighted room with the subjects' eyes closed. End-tidal xenon concentration, PCO2, PO2, and respiratory rates were continuously monitored during the examination. At the beginning of each study, four levels of CT sections were selected to be examined. During the examination, the study subjects were asked to keep completely still before and during the time in which two baseline scans were obtained and then during a subsequent 5-minute period of xenon gas inhalation. The breathed air was delivered through a face mask by a computerized ventilator.
After two baseline scans were completed, the patients began to breathe the gas mixture. Xe-CT was performed at 1, 3, and 5 minutes after the initiation of xenon inhalation. To obtain multiple-level studies, sequential movements of the table were used coupled with dynamic scanning.
In calculating rCBF, the sequences of CT images obtained at each brain level before and during xenon inhalation were used to characterize local buildup of xenon in tissue. End-tidal xenon concentrations obtained from the thermoconductivity detector were used to indirectly provide an indication of arterial xenon buildup. The two baseline scans obtained before xenon inhalation were averaged to reduce the noise level, and this averaged baseline image was then subtracted from the enhanced images. Each voxel was subsequently defined by a series of enhancement values as a function of time. All these data were used in conjunction to solve the Kety equation with a computed program.
The standard display showed CT images, flow, 
value, and
confidence
maps for each level selected. A desired ROI would appear
simultaneously on the CT images and all other three maps.
The size of the ROI could be set as desired. In all of our patients, we
used a circular ROI with a diameter of 1 cm. The thickness of the
slides was 8 mm. This simultaneous ROI display
capacity enabled easier correlation between rCBF values and values.
rCBF values obtained from cortex or white matter of anterior, middle,
and posterior cerebral artery territories were averaged as the rCBF of
cortex or white matter.
Measurements of CVR
CVR was tested in rCBF measurements
before (rCBF1)
and after (rCBF2) isovolemic hemodilution. In each set of
rCBF measurements, after the first rCBF measurements
(rCBF1a and rCBF2a), the study subjects
received intravenous injection of 20 mg/kg
acetazolamide to challenge cerebral vessels. The second
rCBF measurements (rCBF1b and rCBF2b) then were
performed 30 minutes after the injection of acetazolamide.
CVRs before and after hemodilution (CVR1 and
CVR2) can be calculated from the following equations:
CVR1=[(rCBF1b-rCBF1a)/rCBF1a]x100%
and
CVR2=[(rCBF2b-rCBF2a)/rCBF2a]x100%.
Statistical Analysis
All values are expressed as
mean±SEM. The rCBF values were
calculated from ROIs selected from gray and white matter of the
cerebrum, the putamen, and the thalamus. The differences of rCBFs in
each ROI before and after isovolemic hemodilution were analyzed
with paired or unpaired Student's t test. The differences
of CVRs in each ROI before and after isovolemic hemodilution were also
analyzed with paired Student's t test. A
significant difference in the statistical analysis was
designated as P<.05.
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Results |
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TopAbstractIntroductionSubjects and Methods Results Discussion References |
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General Results
The amount of blood withdrawn from these subjects was 948±76 mL. A total of 658±52 mL of low-molecular-weight dextran was infused for the replacement of the withdrawn blood. The average time from the beginning to the end of hemodilution was 52±6 minutes. The study subjects did not experience any discomfort such as dizziness, palpitation, or dyspnea during the hemodilution process. No change in electrocardiogram results was noticed in any study subject during isovolemic hemodilution.
Hemorheological Parameters
The mean hematocrit level of the
study subjects fell from
0.435±0.013 to 0.316±0.026 after hemodilution
(P<.05).
The hematocrit remained low at 0.323±0.021 1 week after hemodilution
(P<.05). The fibrinogen level fell from 0.28±0.04 to
0.20±0.05 g % after hemodilution (P<.05). Blood viscosity
fell from 27.1±2.5 to 16.1±3.1 s after hemodilution
(P<.05).
Hemodynamic Parameters
The hemodynamic parameters measured
before and after hemodilution are shown in Table 1
.
There was no significant difference between mean systemic
arterial blood pressure, mean pulmonary
arterial pressure, mean pulmonary wedge pressure,
and central venous pressure during the hemodilution process. Heart rate
increased from 74.2±2.5 to 81.3±3.3 beats per minute
(P<.05), and cardiac index increased from 3.7±0.2 to
4.6±0.2 L/min per square meter (P<.05) after hemodilution.
Systemic vascular resistance index decreased from 2048±215 to
1624±101 dyne·s· m2/cm5 after
hemodilution (P<.05); however, there was no change in
pulmonary vascular resistance index. Left and right cardiac
work index increased from 4.8±0.3 to 5.4±0.3
kg·m/m2
(P<.05) and from 0.75±0.08 to 0.94±0.04
kg·m/m2 (P<.05), respectively, after
hemodilution. There was no significant change in blood gas
analysis after hemodilution.
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Cerebral Blood Flow
Compared with the baseline measurements,
rCBF increased
significantly at 3 hours after isovolemic hemodilution
(Figure). The average increase in rCBF was 40.7% in the
cortex, 27.6% in the white matter, 36.8% in the putamen, and 34.9%
in the thalamus. There was still a 22.4% increase of rCBF in the
cortex, 8.9% in the white matter, 26.7% in the putamen, and 23.8% in
the thalamus when measured at 1 week after hemodilution. The values of
rCBF measured at different ROIs before and after isovolemic
hemodilution are listed in Table 2.
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Cerebral Vascular Reactivity
CVR decreased generally at 3
hours after isovolemic hemodilution.
The mean CVR of different ROIs was 32.1±4.1% before hemodilution and
25.3±4.0% after hemodilution or it decreased to 79% of its baseline
value after hemodilution; however, this change was significant only in
cortex. The CVRs of different ROIs measured before and after
hemodilution are listed in Table 3.
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Discussion |
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TopAbstractIntroductionSubjects and Methods Results Discussion References |
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In the present study, we demonstrated that isovolemic hemodilution can significantly augment CBF in subjects with normal cerebral autoregulatory function. There are heterogeneities in the magnitude of CBF enhancement in different ROIs. However, magnitudes of flow increase were symmetrical in bilaterally corresponding areas. Normal cerebral cortex demonstrated the most beneficial effects of flow augmentation, as shown in these results. A higher capillary density or a better vascular recruitment ability in the gray matter may be responsible for this phenomenon.22 This distributional pattern of flow augmentation is different from our previous observation of hemodilution effects on canine focal cerebral ischemia, where deep gray matter with the most flow-depleting effects after ischemia had the highest flow augmentation by hemodilution and the nonischemic hemisphere obtained fewest flow-augmenting effects.23 The differences in the results of these two studies indicate a CBF redistribution in ischemic brain after hemodilution.
Heart rate increased significantly after isovolemic hemodilution, possibly resulting from reflex tachycardia caused by vasodilatation after the lowering of blood oxygen content in hemodilution.24 Cardiac index also increased significantly after isovolemic hemodilution. In isovolemic hemodilution, although lacking volume-expanding effects to increase cardiac output, the reduced viscosity lowers the peripheral vascular resistance, which may also increase cardiac output by reducing ventricular afterload and increasing venous return.25 26 Hemodilution elicits venomotor activity dominated by aortic chemoreceptors and results in increased venous return, which may also be a factor that influences cardiac output by lowering viscosity.27
After isovolemic hemodilution, both left and right cardiac work index increased. Since there were no significant changes in mean arterial blood pressure, mean pulmonary arterial pressure, mean pulmonary wedge pressure, and central venous pressure, the increases in cardiac work indexes merely reflected the increase of cardiac output. Although systemic vascular resistance decreased significantly after hemodilution, there was no change in pulmonary vascular resistance, probably because of the existence of a strong autoregulatory function or high vascular reserve in the lung.28
CVR decreased after isovolemic hemodilution. Again, this implies that there are certain degrees of cerebral vasodilatation after hemodilution in subjects with normal cerebral autoregulatory function. Such an effect reflects the compensation for the reduction in oxygen-carrying capacity after hemodilution. Hemodilution reduces vasodilation reserve that, according to some investigators, is detrimental to the ischemic insults.29 The significance of this change to the result of ischemic insult and the correlation between vascular compensatory dilatation and rheological improvement are still unexplainable from our observations.
The mechanism of flow augmentation in hemodilution has been debated in recent years and has caused a great deal of questioning of the therapeutic efficacy of hemodilution. Compensatory vasodilatation by the reduction of oxygen content of blood after hemodilution has been advocated as the cause of CBF increase.20 30 Some authors attribute the ineffectiveness of hemodilution therapy to this mechanism.31 32 33 From the observation of reflex tachycardia, increased cardiac output, and decreased CVR after isovolemic hemodilution in this study, we can conclude that compensatory vasodilatation took place during the hemodilution procedure in subjects with normal cerebral circulation. However, in the condition of cerebral ischemia, autoregulatory functions of CBF controlled by the demand of tissue for oxygen are disrupted, and hemorheological factors may become the predominant determinants of CBF. Korosue and Heros34 observed different responses to CBF between hypoxia caused by reduction of inhaled oxygen concentration and hemodilution in animals with cerebral ischemia, and they concluded that blood viscosity is a major determinant of CBF in cerebral ischemia. Unpublished data from our study of cerebral oxygen transport and metabolism of canine global ischemia also support their hypothesis (Y.K. Tu, M.F. Kuo, H.M. Liu, 1995). To verify that the flow augmentation mechanism is different in ischemic conditions, further study of patients with cerebral ischemia is required.
Compared with hypervolemic hemodilution, isovolemic hemodilution has the advantage of avoiding fluid overload, which is a problem in elderly stroke patients with limited cardiac reserve. It also avoids intracranial pressure elevation, which may exacerbate the existing brain edema that results from stroke. In animal studies, isovolemic hemodilution was shown to have the above-mentioned advantages with significant augmentation of CBF, amelioration of neurological deficit, and reduction in infarction size after cerebral ischemia.11 23 However, in recent years, the results regarding the clinical efficacy of isovolemic hemodilution in human patients have been controversial. The first Scandinavian trial showed a beneficial result of hemodilution,35 but this outcome could not be confirmed in a following multicenter study.36 37 The Italian study was also unable to document a positive effect of isovolemic hemodilution.38 These controversial results might be attributed to the fact that hemodilution in these studies was not initiated during the early period of ischemic change and this treatment was completed over a prolonged period.
It is of fundamental importance that the administration of hemodilutional therapy be started as early in the acute phase of ischemia as possible. A delay of even a short period of time may result in the triggering of irreversible changes such as calcium influx and neuronal death. Late reperfusion may evoke free radical–induced cellular damage and enhance the severity of ischemia. It has been suggested that reperfusion begun more than 12 to 24 hours after the onset of symptoms is futile.39 Unfortunately, a majority of stroke patients are sent to the stroke unit with intensive care facilities after a time interval exceeding the above criteria. In addition, because of the concern of fluid overload, rapid hemodilution is intentionally avoided. Thus, hemodilution is usually achieved after a prolonged period. The failure of several clinical trials in recent years can be attributed to these factors. In the present study, we demonstrated that isovolemic hemodilution with concomitant bloodletting and diluent infusion can lower hematocrit level to 0.32 in approximately 1 hour without physical discomfort or cardiac dysfunction to the studied normal subjects. The flow-augmenting effects can be maintained for at least a week after a single hemodilution procedure. Thus, detrimental effects from repetitive fluid infusion can be avoided, making rapid isovolemic hemodilution the most favorable initial treatment in the acute stage of cerebral ischemia. However, since all these results are from the study of normal subjects, it is also important to reevaluate the efficacy of hemorheological therapy with this rapid isovolemic hemodilution and all the pertinent physiological monitoring for stroke patients.
From the results of the present study, we can postulate several directions of clinical application of isovolemic hemodilution. For acute cerebral ischemia that requires rapid installation of hemodilution and restoration of adequate cerebral perfusion, isovolemic hemodilution with bloodletting should be the first step. After the hematocrit reaches the desired level, hemodynamic parameters should be carefully monitored. If there are signs of hypovolemia after the decay of the volume-expanding function of dextran or other diluents, efforts to rebuild adequate volume should be made. In the surgical patient, if temporal or permanent occlusion of artery is to be attempted during the surgery and cerebral hypoperfusion is likely to occur, isovolemic hemodilution should also be applied before surgery. The blood removed during isovolemic hemodilution can also be used if blood transfusion is needed during surgery, highlighting another benefit of this procedure.
We conclude that isovolemic hemodilution is an effective and safe method to increase rCBF rapidly, which may be important in the treatment or prevention of cerebral ischemia. In normal subjects, isovolemic hemodilution causes vasodilatation and results in reflex tachycardia, cardiac output increase, and CVR decrease. These phenomena indicate the important role played by blood oxygen content in the determination of CBF under normal conditions. However, the effects of isovolemic hemodilution in cerebral ischemia may be different from those in the conditions of normal cerebral perfusion. Further studies in diseased subjects are necessary.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by research grant NSC-83-0412-B-002-087 from the National Council of Science, ROC (Taiwan). Thanks are due to Dr Kwang-Tien Chen for his help in statistical analysis of the results and to Carol Hsiao, Dai-Ping Mao, and Andrea Tu for their help in collecting data and preparing the manuscript.
Received September 27, 1995; revision received December 1, 1995; accepted December 1, 1995.
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TopAbstractIntroductionSubjects and Methods Results Discussion References |
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 G. METRY, B. WIKSTRÖM, S. VALIND, B. SANDHAGEN, T. LINDE, S. BESHARA, and B. G. DANIELSON Effect of Normalization of Hematocrit on Brain Circulation and Metabolism in Hemodialysis Patients J. Am. Soc. Nephrol., April 1, 1999; 10(4): 854 - 863. [Abstract] [Full Text]
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