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(Stroke. 1995;26:1620-1626.)
© 1995 American Heart Association, Inc.

Articles

Hemorheological and Hemodynamic Analysis of Hypervolemic Hemodilution Therapy for Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage

Kentaro Mori, MD; Hajime Arai, MD; Keiji Nakajima, MD; Atsushi Tajima, MD Minoru Maeda, MD

From the Department of Neurosurgery, Juntendo University Izunagaoka Hospital, Shizuoka, Japan.

Correspondence to Kentaro Mori, Department of Neurosurgery, Juntendo University Izunagaoka Hospital, 1129 Nagaoka Izunagaoka-cho, Tagata-gun, Shizuoka 410-22, Japan.

	Abstract

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Background and Purpose Hypervolemic hemodilution therapy is effective for treating neurological deficits due to cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). We monitored various hemorheological and hemodynamic parameters to assess the effects of hypervolemic hemodilution therapy in SAH patients with cerebral vasospasm.

Methods Ninety-eight patients who underwent early craniotomy for aneurysm clipping surgery after SAH were studied. Fifty-one patients (52.0%) developed symptomatic vasospasm. The hematocrit level and red blood cell aggregability were measured daily from day 1 to day 14, whereas the circulating blood volume and cerebral blood flow were measured periodically. Cardiac output and pulmonary capillary wedge pressure were also measured using a Swan-Ganz catheter.

Results The hematocrit level was decreased significantly to 29% to 32% by hypervolemic hemodilution therapy. Red blood cell aggregability increased until day 6 but was significantly reduced by therapy. Hypovolemia tended to develop after SAH. However, patients receiving hypervolemic hemodilution therapy became normovolemic to hypervolemic, with a significant increase of cardiac output and pulmonary capillary wedge pressure. At the onset of vasospasm, cerebral blood flow was significantly lower on the operated side than on the contralateral side, and it increased on both sides with therapy.

Conclusions Patients with SAH develop hypovolemia, hemodynamic depression, and increased red blood cell aggregability. Hypervolemic hemodilution therapy decreases hematocrit level and red cell aggregability while increasing cardiac output. Improvement of hemorheological and hemodynamic parameters by this therapy can reverse neurological deterioration due to cerebral vasospasm.

Key Words: erythrocyte aggregation • hemodilution • subarachnoid hemorrhage • vasospasm

	Introduction

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The phenomenon of delayed cerebral vasospasm after SAH was originally described by Ecker and Riemenschneider in 1951.¹ It is well known that cerebral vasospasm is most likely to occur between 5 and 14 days after SAH and that it causes cerebral ischemia and delayed neurological deficits.² Even today, delayed cerebral vasospasm is still a major cause of mortality and morbidity after aneurysmal SAH.

Hypervolemic therapy (intravascular volume expansion therapy) and hemodilution therapy have been shown to be effective for reducing neurological deficits due to delayed cerebral vasospasm.^{3 4 5 6 7} Hypervolemic hemodilution therapy increases the blood volume and cardiac output and therefore theoretically improves the rheological properties of the cerebral circulation.

The purpose of the present study was to monitor hemorheological and hemodynamic parameters in patients with vasospasm after aneurysmal SAH and to assess how hypervolemic hemodilution therapy altered these factors.

	Subjects and Methods

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Ninety-eight patients who underwent early clipping surgery for aneurysmal SAH at our institution between August 1990 and April 1993 were studied. There were 61 women and 37 men with a mean age of 56 years (range, 31 to 77 years). The diagnosis was confirmed by CT and four-vessel cerebral angiography. The ruptured aneurysm was located on the anterior communicating artery in 31 patients, on the anterior cerebral artery in 8, on the internal carotid artery in 25, and on the middle cerebral artery in 34. A summary of the clinical data for the patients is given in Table 1. Ruptured aneurysms were successfully clipped within 48 hours after the onset of symptoms in all patients without any major complications. At the time of surgery, cerebrospinal fluid drainage was initiated from either the lateral ventricle or the basal cistern to maintain the cerebrospinal fluid pressure between 10 to 15 cm H₂O and prevent hydrocephalus. The patients were rested in bed with intravenous fluids and oral food intake if possible. If clinical deterioration occurred several days after SAH and if the CT findings and blood gas and electrolyte levels were normal, carotid angiography was performed. When the caliber of any artery was less than 50% of that observed on the admission angiogram, ischemia due to cerebral vasospasm was diagnosed.¹⁰ Fifty-one patients (52.0%) showed clinical deterioration and had angiographic verification of vasospasm. All these patients with symptomatic vasospasm were treated with hypervolemic hemodilution therapy according to a uniform protocol that involved administration of human albumin solution (Plasma Protein Fraction, Baxter Healthcare Corp) at 500 mL/d, low-molecular-weight dextran (Otuka Corp) at 500 mL/d, and 10% glycerol (Chugai) at 900 mL/d. The total fluid intake was set at 4000 to 5000 mL/d. Human albumin and low-molecular-weight dextran were not administered, and the total fluid intake was kept below 3000 mL/d in the patients without symptomatic vasospasm. At our institution, glycerol is routinely used for all patients with SAH to reduce the intracranial pressure. Blood transfusion was performed only when the hematocrit level was less than 29%. If necessary, desmopressin acetate (Kyowa Hakko Corp) was given to maintain a positive water balance of at least 500 mL/d. If hyponatremia developed, NaCl was added to the infusion fluid. Since most of the patients developed a raised systolic blood pressure (150 to 180 mm Hg) after hypervolemic therapy, pressor agents were used in only two patients (dopamine and dobutamine in one each) who had a systolic pressure less than 120 mm Hg. Steroids were used only for the first few days after aneurysm clipping surgery. Nimodipine was not used (this drug is unavailable in Japan).

View this table: [in this window] [in a new window]   Table 1. Clinical Data for the 98 Patients With Aneurysmal Subarachnoid Hemorrhage

Hypervolemic hemodilution therapy was continued until the resolution of symptoms of vasospasm, usually after 5 to 7 days.

To monitor hemorheological parameters, the hematocrit level, hemoglobin concentration, and RBC aggregation rate were measured daily from days 1 through 14. The RBC aggregation rate was measured using a whole blood aggregometer (Nihon Kohden Corp)¹¹ on the basis of changes in light transmittance due to rouleau formation by fresh heparinized whole blood in a vinyl tube. The optical density was recorded continuously during momentary forward movement and sudden cessation of movement of the blood in the tube to apply a shear force. The aggregation rate (K) was calculated as K=-10^-1xln(L₂₀-L₁₀/L₁₀-L₀) where L₀, L₁₀, and L₂₀ are the measured optical density at 0, 10, and 20 seconds after the destruction of rouleaux by the application of shear force.¹¹

The circulating blood volume was measured periodically by the indicator dilution method using ^99mTc-labeled human serum albumin diethylenetriaminepenta-acetic acid (^99mTc-HSA-D, Nihon Medi-Physics, Co). The predicted blood volume was calculated using the height-cubed body mass formula of Nadler et al¹² as revised by Fujita¹³ for the Japanese population: for men, predicted blood volume in liters equals 0.1682H³+0.05048W+0.4444 and for women, predicted blood volume equals 0.2502H³+0.06253W-0.6620, where H is height in meters and W is weight in kilograms. All patients were weighed daily on a bed scale.

Quantitative measurements of CBF were also periodically obtained by the external counting method using N-isopropyl-p-[¹²³I]iodoamphetamine (¹²³I-IMP, Nihon Medi-Physics Co). A two-head, calibrated lead collimator detector equipped with two-channel renograms (Shimazu Corp) was specially designed to permit continuous determination of brain tissue activity. The heads of the collimator were symmetrically positioned over the coronal sutures 5 cm from the midline, and CBF was calculated from the ¹²³I activity of the arterial blood and brain tissue. The CBF value of a normal population determined at this institution was 61.0±7.8 mL/100 g per minute (mean±SD, n=20).¹⁴

To assess the hemodynamic state and prevent pulmonary edema, a Swan-Ganz catheter (Baxter Healthcare Corp) was positioned via a subclavian approach in the patients with symptomatic vasospasm to monitor the pulmonary artery pressure and PCWP. The cardiac output and cardiac index were periodically measured by the thermodilution method using cold physiological saline. The PCWP was maintained at or below 18 mm Hg to prevent cardiopulmonary complications.⁵

Statistical Methods
Results were analyzed for statistical significance using Student's t test, Fisher's exact test,¹⁵ Scheffé's multiple comparison test,¹⁶ and Dunnett's multiple comparison test,¹⁷ with P<.05 being considered significant. Data are represented as mean±SEM.

	Results

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The patients who had symptomatic (angiographically confirmed) vasospasm treated with hypervolemic hemodilution therapy were compared with the patients who had no symptoms of vasospasm and did not receive hemodilution therapy.

Hematocrit Level
In the patients without symptomatic vasospasm, hematocrit level did not change throughout the observation period (Fig 1). In the patients with symptomatic vasospasm, hematocrit level did not change significantly on days 1 to 6, but hypervolemic therapy caused a significant decrease (P<.05) (Fig 1).

View larger version (18K): [in this window] [in a new window]   Figure 1. Graph shows hematocrit in patients with and without symptomatic vasospasm. Solid line indicates symptomatic vasospasm; dotted line, no symptomatic vasospasm. Values are the mean±SEM. *P<.05 (Scheffé's multiple comparison test).

Red Blood Cell Aggregation Rate
On days 4 to 6 in the patients without vasospasm and on days 4 and 6 in the patients with vasospasm (Fig 2), the RBC aggregation rate was significantly higher than on day 1 (P<.05). The aggregation rate was also slightly higher in the patients with vasospasm than in those without it on days 1 to 6. Hypervolemic hemodilution therapy significantly reduced the RBC aggregation rate on days 7 to 10 compared with days 4 to 6 (P<.001). These results clearly demonstrate that the RBC aggregation rate increases gradually after SAH and that hypervolemic hemodilution therapy significantly decreases RBC aggregation.

View larger version (20K): [in this window] [in a new window]   Figure 2. Graph shows red blood cell aggregation rate in patients with and without symptomatic vasospasm. Solid line indicates symptomatic vasospasm; dotted line, no symptomatic vasospasm. Values are the mean±SEM. *P<.05 (Dunnett's multiple comparison test), P<.001 (Scheffé's multiple comparison test).

Circulating Blood Volume
The circulating blood volume was measured four times (ie, 2 or 3 days after clipping surgery, on day 5 to 7 at the onset of vasospasm in the vasospasm group, on day 10 to 14 during hypervolemic hemodilution therapy in the vasospasm group, and on the day of discharge). The measured volume is shown plotted against the predicted blood volume in Fig 3. Data points above a 45°-slope regression line indicate a hypervolemic state, and points below the line indicate a hypovolemic state. At 2 to 3 days, most of the patients were approximately normovolemic. However, on days 5 to 7 after SAH, most of the patients tended to be hypovolemic according to our criteria. At the third measurement, most patients receiving hypervolemic therapy were normovolemic to hypervolemic by our criteria, and most patients without such therapy were hypovolemic. The difference between the two groups was statistically significant (P<.01). On the day of discharge, patients in both groups were normovolemic.

View larger version (21K): [in this window] [in a new window]   Figure 3. Plots show circulating blood volume. The measured blood volume is plotted against the predicted blood volume. The data for days 10 to 14 were obtained during hypervolemic hemodilution therapy in patients with vasospasm. indicates symptomatic vasospasm; , no symptomatic vasospasm. P<.01 (Fisher's exact test).

Hemodynamic Data
The hemodynamic data obtained before and after hypervolemic hemodilution therapy are presented in Table 2. At the onset of symptomatic vasospasm, the cardiac output was 4.3±0.4 L/min and the cardiac index was 2.8±0.3 L/min per square meter, both within the lower limit of the normal range.¹⁸ The PCWP was 7.5±1.3 mm Hg, and this was slightly low.¹⁸ Hypervolemic hemodilution therapy caused all three parameters to increase significantly, although they remained within normal limits. During therapy, the PCWP was 11.0±1.2 mm Hg. The systolic blood pressure increased by about 20 mm Hg during therapy but remained below 180 mm Hg in all patients.

View this table: [in this window] [in a new window]   Table 2. Hemodynamic Data Obtained Before and After Hypervolemic Hemodilution Therapy

Cerebral Blood Flow
CBF measurement was performed at the time of circulating blood volume measurement, and the data are shown in Fig 4. At the first CBF measurement in the patients with symptomatic vasospasm, blood flow on the operated side (54±2.8 mL/100 g per minute, mean±SE) was slightly lower than on the contralateral side (55±2.6 mL/100 g per minute), but the difference was not significant. On the day that vasospasm developed, CBF on the operated side decreased significantly (46±1.4 mL/100 g per minute) in comparison with the nonoperated side (52±2.5 mL/100 g per minute) (P<.01). During hypervolemic hemodilution therapy, CBF returned to baseline on both sides. In the patients without symptomatic vasospasm, CBF did not change significantly throughout the observation period. The patients with symptomatic vasospasm showed significantly lower CBF than the patients without symptomatic vasospasm even before the onset of their symptoms (P<.01).

View larger version (19K): [in this window] [in a new window]   Figure 4. Graphs show cerebral blood flow in patients with and without symptomatic vasospasm. Top, patients without symptomatic vasospasm. indicates operated side; , contralateral side. Bottom, patients with symptomatic vasospasm. indicates operated side; , contralateral side. Values are the mean±SEM. *P<.01 (Student's t test).

Overall Outcome
The primary end point for the study was the number of patients achieving a good recovery according to Allen's neurological outcome score.¹⁹ Of the 98 patients who underwent early clipping surgery, 51 (52.0%) developed symptomatic vasospasm. The neurological grades on admission (Hunt-Hess⁸ ), at the onset of vasospasm (Hunt-Hess), and at the end of hypervolemic hemodilution therapy (Allen et al¹⁹ ) are illustrated in Fig 5. After hypervolemic hemodilution therapy, 29 patients (56.9%) were neurologically normal, 13 (25.5%) had mild or moderate disability, and 9 patients (17.6%) died. Six of these patients died of vasospasm in the acute stage, and the other 3 died of pneumonia in the chronic stage. The admission Hunt-Hess grade of the 6 patients dying in the acute stage was grade II in two cases, grade III in three cases, and grade IV in one case. Death or severe disability (leading to death from pneumonia) resulted from vasospasm in 6.1% of all the patients with SAH. Two patients developed pulmonary edema during hypervolemic hemodilution therapy, but both responded well to diuretic therapy.

View larger version (21K): [in this window] [in a new window]   Figure 5. Bar graph shows neurological grades on admission, at the onset of clinical vasospasm, and after hypervolemic hemodilution therapy in 51 patients with clinical vasospasm. H-H grade indicates Hunt-Hess grade (1968)8 ; Neurologic outcome, Allen et al (1983).19

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Cerebral vasospasm produces a reduction of regional CBF to levels that result in cerebral ischemia, and the metabolic consequences of this ischemia produce neurological deficits that may be reversible or irreversible. Hypervolemic hemodilution therapy has been reported to be effective for preventing neurological deficits due to delayed cerebral vasospasm.^{3 4 5 6 7} Manipulation of blood viscosity offers an effective and rapid means of increasing the perfusion of ischemic regions in the brain, and hemodilution therapy improves the microcirculation of the ischemic penumbra by decreasing blood viscosity.²⁰ It is generally thought that blood flow and blood viscosity in the microcirculation vary with hematocrit level, RBC aggregability and flexibility, platelet aggregability, and plasma viscosity. Hematocrit has a major influence on blood viscosity, and its importance increases as the shear rate decreases.^{21 22 23} Although the oxygen content of blood is reduced as the hematocrit decreases, the relative oxygen transport capacity increases as the hematocrit is lowered to 30% to 33%.²⁴ The hematocrit level of our patients undergoing hypervolemic hemodilution therapy was 29% to 32%, which is a reasonable value on the basis of relative oxygen transport capacity.

At reduced driving pressures, blood flow is limited by the increase of viscosity that occurs at low shear rates.²⁵ Since RBC aggregation is also shear-rate dependent, aggregation may be enhanced in the cerebral microcirculation, especially in ischemic areas where the shear rate is low.²² Wood et al²³ demonstrated in dogs that the blood viscosity at low shear rates decreases with an increase of total blood volume and plasma volume after plasma infusion. It has also been shown that at lower shear rates, erythrocyte aggregation plays the major role in determining blood viscosity.²⁶ Hasegawa²⁷ reported that hypercoagulability, platelet hyperactivity, and reduced RBC deformability occurred with vasospasm in a canine model of SAH. Such systemic changes of intravascular components could promote cerebral ischemia through an increase of blood viscosity. Measurement of the hematocrit level alone does not give a precise estimate of blood viscosity,^{24 28} and monitoring of RBC aggregability is also desirable. Tomita et al¹¹ reported that the RBC aggregation rate of whole blood varies linearly with the hematocrit at values below 40%. The present study showed that hematocrit was relatively stable for the first 5 days after aneurysm clipping, but the RBC aggregation rate increased during this period. The RBC aggregation rate was decreased by hypervolemic hemodilution therapy both because of a decrease in hematocrit and by the direct effect of the low-molecular-weight dextran, which reduces RBC aggregation, reduces blood viscosity, and improves microcirculatory flow at low shear rates.^{20 29 30} The cause of the increase in RBC aggregability after SAH is not clear, but it may be related to changes of plasma albumin, fibrinogen, ₂-macroglobulin, or RBC surface charge.³¹ SAH itself may alter the RBC surface charge and other RBC membrane properties.

Maroon and Nelson⁶ reported that decrease of circulating blood volume and red cell mass in patients with SAH. Pritz et al⁷ also found a decrease of circulating blood volume at the time of symptomatic vasospasm. Possible causes of the hypovolemia in patients with SAH include bedrest with supine diuresis and pooling in the peripheral vascular bed, negative nitrogen balance, decreased erythropoiesis, iatrogenic blood loss, dehydrating agents (eg, mannitol and glycerol), and hyponatremia.⁶

Evidence has accumulated that patients with cerebral vasospasm show good recovery from ischemic symptoms after intravascular volume expansion therapy.^{3 4 6 7}

In the present study, the circulating blood volume progressively decreased after aneurysm clipping surgery, whereas the patients became normovolemic or hypervolemic after hypervolemic hemodilution therapy. CBF in the ischemic brain is both pressure and volume dependent because cerebral autoregulation is impaired, so monitoring circulating blood volume in patients with SAH can be useful for the prevention and treatment of cerebral vasospasm.³²

There are several reports on the usefulness of hypertensive therapy for cerebral vasospasm.^{4 33 34} Dopamine-induced hypertension improves CBF in the ischemic region in patients with SAH, but the CBF response to dopamine in the nonischemic region is variable.³⁵ In the present study, systemic blood pressure was increased by about 20 mm Hg without vasopressor agents after hypervolemic hemodilution therapy.

The effect of increasing cardiac output in patients with cerebral vasospasm is still controversial. Several authors have reported the reversal of ischemic neurological signs after an increase of the cardiac output.^{36 37} Pritz et al⁷ found improvement of neurological deficits due to cerebral vasospasm when the cardiac output was increased without raising arterial pressure. Davis and Sundt³⁸ showed a significant decrease of cerebral blood flow in cats when cardiac output was decreased by the withdrawal of blood or the administration of propranolol, even though arterial pressure remained essentially constant. However, Wood et al³⁹ reported that elevation of the total blood volume without hemodilution raised the cardiac output but did not improve CBF in either ischemic or normal brain regions in dogs. In the present series, the patients had a low PCWP, suggesting a hypovolemic state, and the mean cardiac output and cardiac index were at the lower limit of normal or below normal. Thus, our patients with SAH were not only hypovolemic but also hemodynamically depressed. Hypervolemic hemodilution therapy improved all of these parameters. A PCWP of 12 to 14 mm Hg is reported to be associated with maximum cardiac performance,⁴⁰ and the PCWP was in this range after hypervolemic hemodilution therapy.

In the present study, the CBF of all the patients on days 2 to 4 was lower than the control value determined in normal individuals. Before the onset of symptomatic vasospasm, the CBF was even lower than in patients who did not develop vasospasm. In agreement with these findings, Knuckey et al¹⁰ reported that during the first week after SAH, patients who developed cerebral ischemia had a significantly lower CBF than patients who did not. Early CBF measurements are reported to be of value in detecting delayed cerebral vasospasm.^{10 41 42} At the onset of symptomatic vasospasm, we found that the CBF on the operated side was significantly lower than that on the contralateral side, whereas hypervolemic hemodilution therapy caused a bilateral increase of CBF. These data demonstrated that hypervolemic hemodilution therapy improved the blood supply to the brain during cerebral vasospasm.

The 52% symptomatic vasospasm rate in the present series was high. There have been several reports about mechanical factors during aneurysm clipping surgery causing vasospasm.⁴³ Mishima et al⁴⁴ reported that the incidence of symptomatic vasospasm is higher on the operated side after early clipping surgery; all the patients in our series had early surgery, so this might have contributed to the high incidence of symptomatic vasospasm.

With respect to outcome, our mortality and severe disability rates due to cerebral vasospasm (6.1%) were lower than those in the international cooperative study on standard therapy reported by Kassel and Torner⁴⁵ (16%) and the nimodipine study reported by Allen et al¹⁹ (13.3%). Results similar to ours have been achieved with hypervolemic hemodilution and arterial hypertension therapy by Awad et al³ and with high-dose nicardipine by Haley et al.⁴⁶ Thus, our hypervolemic hemodilution therapy protocol seems to be reasonably effective in preventing delayed neurological deficits after cerebral vasospasm.

Intravenous infusion of 10% glycerol was routinely used in all our patients. Meyer et al^{47 48} have reported that 10% glycerol decreases the intracranial pressure and increases CBF after acute cerebral infarction, and this is the basis for our routine use of glycerol after aneurysm clipping surgery. Since both groups of patients received glycerol, it should not have influenced our results. Nimodipine was not used in this study because it is not available in Japan, and we wanted to assess the hemodynamic state after SAH without calcium antagonists. However, it is clear that nimodipine is effective for treating cerebral vasospasm.¹⁹ Combined use of hypervolemic hemodilution therapy and another calcium antagonist (nicardipine) for cerebral vasospasm is now under investigation at our institution.

In this study, we followed the hemorheological and hemodynamic state in patients with aneurysmal SAH and assessed how hypervolemic hemodilution therapy improved these factors during cerebral vasospasm. We found that patients with SAH were hypovolemic and hemodynamically depressed with increased RBC aggregability. All of these factors are unfavorable to the cerebral circulation, especially in the ischemic region affected by cerebral vasospasm. Hypervolemic hemodilution therapy decreased the hematocrit level and RBC aggregation rate while increasing systemic blood pressure and cardiac output. The improvement of hemodynamics combined with hypertension increased the perfusion pressure and improved CBF, whereas the optimal hematocrit level improved oxygen transport capacity. The decrease of RBC aggregation and hematocrit led to a decrease in blood viscosity and presumably improved blood flow in the microcirculation at low shear rates.

We conclude that the improvement of hemorheological and hemodynamic parameters induced by hypervolemic hemodilution therapy is effective in reversing progressive neurological deterioration due to cerebral vasospasm.

Cerebral vasospasm after SAH is caused by multiple factors.⁴³ We believe that hypervolemic hemodilution therapy combined with other therapies, such as nimodipine,⁴⁶ cisternal irrigation,⁴⁹ and percutaneous transluminal angioplasty,⁵⁰ may improve the mortality and morbidity due to SAH.

	Selected Abbreviations and Acronyms

 

CBF = cerebral blood flow PCWP = pulmonary capillary wedge pressure RBC = red blood cell SAH = subarachnoid hemorrhage

	Acknowledgments

 
This study was supported by grant A-03770906 from the Ministry of Education, Science, and Culture of Japan. The authors wish to thank Kaoru Uchida for preparation of the manuscript and figures.

Received February 24, 1995; revision received April 27, 1995; accepted May 11, 1995.

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