(Stroke. 2000;31:383.)
© 2000 American Heart Association, Inc.
Original Contributions |
Effect of Hypervolemic Therapy on Cerebral Blood Flow After Subarachnoid Hemorrhage
A Randomized Controlled Trial
From the Departments of Neurology (L.L., S.A.M., M.E.F., L.M.K., E.C.R.) and Neurosurgery (R.A.S., A.B.), Neurological Institute, College of Physicians and Surgeons, and the Department of Biostatistics (M.C.P., H.Z., Y.C.W.), School of Public Health, Columbia University, New York, NY.
Correspondence to Stephan A. Mayer, MD, Division of Critical Care Neurology, Neurological Institute, 710 West 168th Street, Unit 39, New York, NY 10032. E-mail ras5{at}columbia.edu
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Abstract |
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Background and Purpose—Cerebral blood flow (CBF) is reduced after subarachnoid hemorrhage (SAH), and symptomatic vasospasm is a major cause of morbidity and mortality. Volume expansion has been reported to increase CBF after SAH, but CBF values in hypervolemic (HV) and normovolemic (NV) subjects have never been directly compared.
Methods—On the day after aneurysm clipping, we randomly assigned 82 patients to receive HV or NV fluid management until SAH day 14. In addition to 80 mL/h of isotonic crystalloid, 250 mL of 5% albumin solution was given every 2 hours to maintain normal (NV group, n=41) or elevated (HV group, n=41) cardiac filling pressures. CBF (133xenon clearance) was measured before randomization and approximately every 3 days thereafter (mean, 4.5 studies per patient).
Results—HV patients received significantly more fluid and had higher pulmonary artery diastolic and central venous pressures than NV patients, but there was no effect on net fluid balance or on blood volume measured on the third postoperative day. There was no difference in mean global CBF during the treatment period between HV and NV patients (P=0.55, random-effects model). Symptomatic vasospasm occurred in 20% of patients in each group and was associated with reduced minimum regional CBF values (P=0.04). However, there was also no difference in minimum regional CBF between the 2 treatment groups.
Conclusions—HV therapy resulted in increased cardiac filling pressures and fluid intake but did not increase CBF or blood volume compared with NV therapy. Although careful fluid management to avoid hypovolemia may reduce the risk of delayed cerebral ischemia after SAH, prophylactic HV therapy is unlikely to confer an additional benefit.
Key Words: blood volume • cerebral blood flow • cerebral vasospasm • subarachnoid hemorrhage
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH) have improved over the past 2 decades with advances in neurosurgery and neurocritical care, including an emphasis on early aneurysm clipping to prevent rebleeding.1 However, cerebral ischemia related to vasospasm remains an important cause of morbidity and mortality,2 despite the beneficial effects of the calcium channel blocker nimodipine.3
Excessive natriuresis and intravascular volume contraction occur frequently after SAH and have been implicated as risk factors for delayed cerebral ischemia related to vasospasm.4 5 6 SAH causes progressive reduction of CBF for up to 3 weeks7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 and can result in loss of the normal capacity to autoregulate.21 22 23 Experimental studies indicate that volume expansion can improve CBF in ischemic regions independent of perfusion pressure because of beneficial effects on cardiac output and blood rheology,24 25 26 and uncontrolled case series27 28 29 30 have reported that hypervolemic therapy can reverse ischemic deficits in symptomatic patients.
Accordingly, postoperative hypervolemic therapy is now routinely performed at most medical centers, on the assumption that this intervention may augment CBF, prevent delayed ischemia, and improve clinical outcomes.31 32 However, both increases33 34 and decreases35 in CBF have been reported after volume expansion in SAH patients, and CBF measurements in hypervolemic (HV) and normovolemic (NV) subjects have never been directly compared. We performed this randomized controlled study to test the hypothesis that postoperative HV therapy increases CBF after SAH.
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Subjects and Methods |
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Study Population
Patients with aneurysmal SAH admitted to the Neurological Intensive Care Unit (NICU) of Columbia–Presbyterian Medical Center between June 1991 and October 1994 were eligible for enrollment if they had surgery to clip the ruptured aneurysm on or before SAH day 6 (with the calendar day of bleeding referred to as SAH day 0), were Hunt-Hess grades I to IV after surgery, were between the ages of 18 and 80 years, and did not have symptomatic vasospasm. Exclusion criteria included congestive heart failure, pregnancy, and renal insufficiency (creatinine >2.0 mg/dL). Aneurysmal SAH was documented by CT or lumbar puncture and angiography in all patients. Solicitation of study subjects was approved by the Institutional Review Board of Columbia–Presbyterian Medical Center.
Perioperative and ICU Management
All subjects were managed according to a standard treatment
protocol. Spinal drainage and mannitol (1 g/kg) were used during
surgery for brain relaxation, and standard microsurgical techniques
were used to clip the aneurysm and exclude it from the
intracranial circulation. Total fluid input on the day of surgery
ranged from 4 to 6 liters in most patients.36
Pulmonary artery catheters were placed at the time of surgery
and were replaced with internal jugular venous catheters on the third
postoperative day (study day 3) until SAH day 14 to minimize the risks
associated with prolonged pulmonary artery
catheterization. All patients received nimodipine
throughout the study period; phenytoin and dexamethasone
were given perioperatively. All patients were evaluated
hourly for signs of neurological deterioration.
Transcranial Doppler (TCD) sonography was performed
approximately every other day but was not used to diagnose
symptomatic vasospasm or guide clinical management.
Stratification and Treatment Randomization
After written consent was obtained on the first postoperative
day (study day 0), subjects were classified before randomization into 1
of 4 strata based on the number of days since SAH and on postoperative
Hunt-Hess grade37 : stratum 1, SAH days 0 to 3 and
Hunt-Hess grade I or II; stratum 2, SAH days 0 to 3 and Hunt Hess grade
III or IV; stratum 3, SAH days 4 to 7 and Hunt Hess grade I or II; and
stratum 4, SAH days 4 to 7 and Hunt Hess grade III or IV. These
criteria (interval from SAH and Hunt-Hess grade) were selected because
they were expected to have a major impact on CBF, vasospasm risk, and
clinical outcome. After stratification, subjects were randomly assigned
to receive either HV or NV therapy until SAH day 14. Randomization of
the first 40 subjects was based on a probability of 0.50 of assignment
to either treatment. After this "baseline" treatment allocation, to
ensure assignment of an equal number of patients to each treatment
within each stratum, subsequent subjects were randomized with a
biased-coin technique,38 in which the probability of
randomization to the underrepresented treatment within a
given stratum was 0.67.
Fluid Management
All patients received a baseline crystalloid infusion of 80 mL/h
5% dextrose and 0.9% saline preoperatively and postoperatively until
SAH day 14. At the time of enrollment on the first postoperative day
(study day 0), baseline CBF, blood volume, and
cardiovascular hemodynamic measurements
were obtained. After these measurements, patients were assigned to
receive 250 mL of 5% albumin solution every 2 hours in
addition to the baseline crystalloid infusion if cardiac filling
pressures fell below the following target levels (pulmonary
artery diastolic pressure [PADP] on study days 0 to 3 and
central venous pressure [CVP] thereafter): HV group, PADP 14
mm Hg or CVP 8 mm Hg; NV group, PADP 7 mm Hg or CVP 5
mm Hg. This fluid management protocol was strictly adhered to
throughout the entire study period unless symptomatic
vasospasm was diagnosed, in which case the assigned treatment was
stopped and hypertensive hypervolemic therapy (HHT) was given. In these
cases HV fluid management was used, and subjects were given
vasopressors (dopamine, norepinephrine, or
phenylephrine) titrated to the level at which the deficit
resolved or a maximal systolic blood pressure of 200
mm Hg. We did not use pulmonary artery wedge pressures to
guide volume expansion because our NICU nurses were not certified to
perform these measurements.
Primary Outcome Measures
The primary measures of treatment effect were CBF measured
serially during the first 14 days after SAH and BV measured at baseline
and on the third postoperative day. These measurements were performed
and analyzed by investigators blinded to the treatment
assignment of the study subjects.
CBF measurements were performed on study day 0 (before treatment assignment), study day 1, and then approximately every 3 days until SAH day 14. CBF was measured after intravenous injection of 133Xe in saline in 16 symmetrical hemispheric brain regions using 32 external scintillation detectors placed in accordance with skull landmarks (Novo Cerebrograph 32c, Novo Diagnostic Systems).39 Each CBF study was evaluated for data quality by a blinded investigator, and poor-quality or uninterpretable studies (due to motion artifact, gas leak, or equipment malfunction) were excluded from the analysis. CBF studies were performed according to the original study schedule in patients with symptomatic vasospasm; there was no attempt to measure CBF immediately before and after the institution of HHT.
Total BV measurements, based on the volume of distribution of chromium-51–labeled autologous red blood cells, were obtained on study day 0 (before treatment assignment), and once again on study day 3. Twenty milliliters of blood were labeled with 20 to 30 mCi of chromium-51, and washed, labeled cells were reinfused. A second 7-mL sample was obtained 20 minutes after the reinfusion. BV was derived from the calculated red blood cell volume (RBCV) as follows: BV=RBCV/0.9 [venous hematocrit], expressed in milliliters per kilogram of body weight.
Secondary Outcome Measures
Secondary measures of treatment effect included the frequency of
symptomatic vasospasm, medical and neurological
complications, and 5 other physiological
variables (mean arterial blood pressure (MABP), PADP,
CVP, hematocrit, 24-hour fluid intake, and 24-hour net fluid balance);
all were evaluated daily until SAH day 14 except PADP, which was
measured during the first 3 days of the study. Outcome was assessed at
14 days and at 3, 6, and 12 months with the Glasgow Outcome Scale
(GOS).40 Secondary outcome measures were recorded by
investigators who were not blinded to treatment assignment, because it
was not possible to give the treatment in a blinded fashion.
Blood pressure and cardiac filling pressures were measured using fluid-filled catheters with transducers positioned at the level of the right atrium. Complications were classified and defined as follows. Neurological complications: symptomatic vasospasm (a focal neurological deficit or deterioration in level of consciousness, with either confirmation of infarction on a CT scan or exclusion of other possible causes of deterioration, such as rebleeding, surgical complication, hydrocephalus, cerebral edema, electrolyte disorder, infection, or seizure), cerebral infarction (due to surgery, angiography, or other causes), aneurysm rebleeding, symptomatic hydrocephalus (ventricular enlargement on CT treated with a ventricular drain, lumbar puncture, or ventriculoperitoneal shunt), seizures, or cerebral edema (a focal or diffuse lucency on CT); cardiovascular complications: hypertension (systolic blood pressure >150 mm Hg in the absence of vasopressors), arrhythmia, or congestive heart failure (O2 saturation by pulse oximetry <95% on at least 40% oxygen, with clinical and x-ray findings consistent with pulmonary edema); metabolic complications: hyponatremia (plasma sodium measurement <135 mEq/L for 2 consecutive days) or hyperglycemia (plasma glucose >200 mg/dL); and infectious complications: pneumonia (infiltrate on chest x-ray), urinary tract infection, bacteremia, or meningitis/ventriculitis (all defined by positive cultures).
Statistical Analysis
CBF was analyzed on an intention-to-treat basis. For
measurements of CBF on study day 0, correlations of the initial slope
index (ISI) between any of the 32 detectors were high (range,
R=0.74 to 0.98). We measured CBF in 3 ways: global CBF
(gCBF), based on the mean ISI of all 32 detectors; hemispheric CBF
(hCBF), based on the mean ISI of the 16 hemispheric detectors; and
minimum regional CBF (mCBF), based on the lowest ISI among the 32
detectors. CBF measurements on study day 0 are referred to as baseline
CBF.
To test whether there was an overall difference in CBF between the 2 treatment groups, we fitted random-effects models41 using repeated CBF measurements as the outcome variable and using baseline CBF, treatment, stratum, and time as covariates. Because the number of CBF studies performed in each treatment group on any given study day was small, CBF results were grouped into 8 epochs: study days 0, 1, 2 to 3, 4 to 5, 6 to 7, 8 to 9, 10 to 11, and 12 to 14. No subject had >1 CBF study within an epoch. Models were fitted analyzing gCBF, gCBF with patients who received HHT excluded, and mCBF. The random-effects model takes into account correlations among CBF values over time, whereas classical regression assumes that repeated CBF measurements are independent.
To compare other physiological variables, we
fitted random-effects models to estimate the magnitude of treatment
effect over time, using only time as a covariate. These models assumed
no interaction between treatment group and study day. Continuous
variables were compared with 2-tailed t tests, and
proportions were compared with the
2 or Fisher exact test. Independent
risk factors for poor outcome at 3 months (dependent with severe
deficit, vegetative, or dead, according to the GOS) were identified by
fitting a simple logistic regression model after identification of
candidate variables in a univariate analysis.
Significance was judged at the P<0.05 level.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study Population
Of 286 patients admitted to the NICU for SAH during the study period, 99 met the eligibility criteria, and 82 consented to participate and were enrolled in the study (Figure 1
). Forty-one patients were randomized to
HV therapy and 41 to NV therapy. Subjects in the 2 treatment groups
were similar with regard to age, sex, race/ethnic group, route of
admission, Hunt-Hess grade, aneurysm location, and days from
SAH to study enrollment (Table 1).
The numbers of subjects assigned to each treatment within the 4 strata
were not significantly different.
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CBF
Of the 82 study subjects, 3 had CBF studies of such poor quality
that none were included in the CBF analysis, 6 did not have an
adequate CBF study at baseline (study day 0), and 2 had only baseline
CBF studies. These 11 subjects (13%) were excluded from the
random-effects model that analyzed change in CBF over time. The
71 patients included in the CBF analysis had 320 measurements
of good quality (mean 4.5, range 2 to 6 studies per patient); 25 other
measurements of poor quality were excluded. Reasons for failure to
complete scheduled CBF studies included equipment malfunction, subject
refusal or lack of cooperation, and other technical failure.
Mean baseline gCBF on study day 0 (mean 3.4 days after SAH) was 52.3
mL/100 g per minute in the NV group and 48.9 mL/100 g per minute in the
HV group (Table 2), a nonsignificant
difference. Among the entire study group (Figure 2) and within each stratum (Figure 3), gCBF levels were similar between the
2 treatment groups and were stable over time, with a 5% to 10%
reduction from baseline in both groups over the first 2 weeks. Mean
baseline gCBF was higher in Hunt-Hess grades I and II patients (strata
1+3) than in grades III and IV patients (strata 2+4) (54.9 versus 43.0
mL/l00 g per minute, respectively, P<0.0001; Figure 3). Baseline gCBF was not different in subjects enrolled between
SAH days 0 to 3 (strata 1+2) and SAH days 4 to 7 (strata 3+4) (mean
50.0 versus 51.4 mL/l00 g per minute, respectively).
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There was no significant difference in gCBF over time between the HV
and NV groups in the random effects model after adjusting for stratum,
baseline CBF, and study day (P=0.55) (Table 3). However, baseline gCBF was a
significant predictor of subsequent gCBF measurements
(P<0.001). We repeated the random-effects model
analysis using mCBF as the outcome variable, and again
found no differences between the HV and NV groups. Although it violates
the "intention-to-treat" principle, we assessed efficacy of
treatment after excluding 13 subjects treated with HHT. There was still
no difference in gCBF between the 2 treatment groups. There were no
differences in hCBF ipsilateral to the ruptured aneurysm when
compared with the contralateral hemisphere in subjects with lateralized
aneurysms, or between hemispheres in patients with midline
aneurysms.
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Blood Volume
In the NV group (n=32), mean BV was 67.9 mL/kg at baseline and
63.4 mL/kg on study day 3, a 6.6% reduction. In the HV group (n=35),
mean BV was 63.5 mL/kg at baseline and 64.8 mL/kg on study day 3, a
2.0% increase (normal range 55 to 80 mL/kg for men and 50 to 75 mL/kg
for women). Baseline BV, study day 3 BV, and change in BV were not
significantly different between the 2 groups.
Physiological Variables
Mean PADP (
14 mm Hg) and CVP (9 mm Hg) were
elevated at baseline in both groups (Table 4). Compared with NV patients, HV
patients had significantly higher PADP values (mean difference 1.9
mm Hg, P=0.002) during the first 3 days of the study and
higher CVP values (mean difference 1.25 mm Hg,
P=0.002) and 24-hour fluid intake (mean difference 530 mL,
P=0.006) over the entire study period. There were no
differences (HV-NV) in MABP (mean difference 0.2 mm Hg,
P=0.92) or hematocrit (mean difference -1.7%,
P=0.06) between the 2 groups during the study period. The
higher mean 24-hour fluid intake in HV patients was accompanied with
higher fluid outputs, resulting in no difference in 24-hour fluid
balance between the 2 groups (mean difference -28 mL,
P=0.81) (Figure 4).
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Symptomatic Vasospasm
Eight subjects (20%) in each treatment group developed
symptomatic vasospasm during the study period. Cerebral
infarction from vasospasm occurred in 4 NV patients (10%) and 7 HV
patients (17%). Symptomatic vasospasm was not predicted by
age, gender, treatment assignment, Hunt-Hess grade, SAH day at study
entry, baseline gCBF, baseline mCBF, or mean gCBF over the entire study
period. However, patients with symptomatic vasospasm had
lower minimum gCBF values (the lowest global CBF on any study day was
36.2±7.4 versus 40.9±8.5 mL/100 g per minute, P=0.053) and
lower minimum mCBF values (the lowest CBF recorded in any detector
on any study day was 29.1±7.3 versus 33.3±6.9, P=0.04)
than those who did not. The median value for minimum mCBF among all
subjects was 33.1 mL/100 g per minute; 8% (3/39) of patients with
values above this level developed symptomatic vasospasm
compared with 30% (12/40) of those with values below this level
(P=0.01).
Thirteen subjects (6 NV, 7 HV) were treated with HHT to treat symptomatic vasospasm during the study period. Because of the small number of cases and lack of temporally appropriate CBF measurements, it was not possible to determine whether HHT had an effect on CBF.
Complications
There were no significant differences in the frequency of any of
the complications for which we screened between the 2 treatment groups.
Radiographic cerebral edema occurred in 7 NV patients
(17%) and 6 HV patients (15%). Congestive heart failure occurred in
only 1 patient in the HV group (3%). Hyponatremia
(<135 mEq/L) occurred in only 2 patients (5%) in each treatment
group.
Outcome
On SAH day 14, 27 of the 41 subjects in each treatment group
(66%) were functionally independent, and 1 in each group (2%) was
dead (Table 5). Three additional subjects
died later during their hospitalization, after the study was completed.
GOS scores were not significantly different between the 2 groups at SAH
day 14 or at 3 months, and there was little change in outcome status
between 3, 6, and 12 months after SAH. There were no differences in
3-month outcome between HV and NV subjects within each of the 4
strata.
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In a univariate analysis of the entire study group, significant predictors of poor outcome (dead, vegetative, or dependent with severe deficit) at 3 months included a Hunt-Hess grade of III or IV (43% [13/30] versus 4% [2/49] among Hunt-Hess grade I or II patients, P<0.0001), any neurological complication (38% [13/34] versus 4% [2/45] without, P=0.0002), lower mCBF values during the study period (23.5±5.4 versus 34.7±5.7, P<0.0001), any cardiovascular complication (53% [9/17] versus 10% [6/61] without, P=0.003), and any infectious complication (38% [10/26] versus 9% [5/53] without, P=0.005). In a logistic regression analysis to identify independent predictors of poor outcome, a Hunt-Hess grade of III or IV (odds ratio 16.9, 95% confidence interval [CI] 2.1 to 142.8 P=0.008) and lower mCBF values recorded during the study (odds ratio 0.70, 95% CI 0.56 to 0.86 for each 1.0 mL/100 g per minute increase, P=0.0008) were associated poor outcome at 3 months.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In this study, we found that HV treatment after aneurysm surgery did not increase blood volume or CBF compared with NV treatment. Although fluid administration may be important to avoid hypovolemia after SAH, prophylactic HV therapy probably does not confer an additional benefit.
The reduction in CBF that typically develops after SAH has been attributed to 2 causes. Within hours of onset, a primary generalized reduction in cerebral oxidative metabolism occurs, in conjunction with a coupled decrease in CBF that is less prominent.7 8 9 10 42 43 44 Although this occurs even in patients in the best clinical condition, these reductions are greatest in patients with depressed levels of consciousness (Hunt-Hess grades III to V).7 8 9 10 11 12 13 14 15 The primary cause of this phenomenon is thought to be a toxic effect of SAH on cerebral metabolism,7 10 44 although hydrocephalus, cerebral edema, and increased intracranial pressure may also contribute.8 15 16 Over the following 2 weeks, further diminution of CBF may occur as a consequence of cerebral vasospasm, and if ischemic levels are reached, additional reductions in cerebral metabolism may occur. These late reductions in CBF are usually focal or topographically heterogenous and are most prominent in patients with focal neurological deficits and severe angiographic narrowing.7 8 9 10 11 12 13 14 17 18 19 20 21 45
On the first postoperative day (mean 3.4 days after SAH) we found the
expected relationship between poor Hunt-Hess grade and lower gCBF
values.7 8 9 10 11 12 13 14 15 However, when plotted from the time of study
entry (Figure 1
), mean gCBF remained slightly below baseline but
did not decline progressively as reported in earlier studies. This lack
of CBF decline may be explained by the fact that neither treatment
group was allowed to become hypovolemic. Alternately, CBF reductions
resulting from vasospasm may have been minimized because
symptomatic patients were treated with HHT and
nimodipine.
Almost all studies demonstrating progressive reduction in CBF after SAH were published before 1985,7 8 9 10 11 12 13 14 15 16 17 18 19 when most patients were treated with fluid restriction and delayed surgery. By contrast, studies performed during the volume-expansion era have shown stable CBF levels after SAH. Origitano et al33 reported an immediate and sustained increase in CBF after instituting HV therapy with albumin shortly after admission for SAH. They did not measure the baseline volume status of their patients, who may have been hypovolemic before treatment. Although we did not observe a similar increase in CBF between study days 0 and 1 in either treatment group, most of our patients were already hypervolemic on the first postoperative day, with elevated PADP values and normal-to-high blood volumes. Similarly, Mori et al34 observed a progressive reduction in hemispheric CBF in patients who developed symptomatic vasospasm, which improved after volume expansion with albumin and dextran. These patients were hypovolemic before they started HV therapy, however, with low-normal pulmonary artery wedge pressures and cardiac outputs. Mizuno et al45 found stable CBF values within 3 weeks of SAH, as did we, but they administered prophylactic hyperdynamic therapy (hydroxyethyl starch and dobutamine) to most patients.
These findings suggest that CBF is dependent on volume status only when
SAH patients are in the hypovolemic-to-normovolemic range. In our
study, HV therapy resulted in higher daily fluid intake and cardiac
filling pressures than NV therapy but had no effect on net fluid
balance, blood volume, or CBF. This observation and those of others
indicate that once a state of normovolemia to mild hypervolemia has
been attained, additional fluids do not lead to further increases in
BV34 36 46 or cardiac output,47 because
additional sodium and fluid intake is matched by equivalent urinary
losses.36 This concept is supported by the observation
that net fluid balance remained well matched in both groups during the
second week of the study, when fluid intake fell from approximately 4
to 2.5 L/d (Figure 4). Progressive BV reduction has been
reported in SAH patients given maintenance crystalloid
infusions (1.5 to 3.0 L/d)48 49 but did not occur in our
subjects or in other studies of patients given prophylactic
HV therapy.36 46 To our knowledge, fluid supplementation
has never been shown to increase BV from normal to hypervolemic levels
after SAH.
It is possible that our study intervention—volume expansion guided by target cardiac filling pressures—was not robust enough to increase CBF. Although additional volume may have significantly increased blood volume or CBF in our HV patients, we doubt this, because the additional fluid would probably be matched by equal urinary losses. There was no difference in MABP between the 2 groups in our study, and while no amount of additional volume may have produced an increase in blood pressure, pharmacologically induced hypertension has been shown to improve CBF in ischemic regions in patients with symptomatic vasospasm.50 51 52 Darby et al50 found that dopamine-induced hypertension led to increased CBF in ischemic (<25 mL/100 g per minute), noninfarcted territories without producing an increase in mean global CBF. We did not analyze CBF values before and after instituting HHT in our patients with symptomatic vasospasm.
Symptomatic vasospasm was associated with lower mCBF during the study period. The association of symptomatic vasospasm with decreased CBF is well established.7 8 9 10 11 12 13 14 17 18 19 20 21 45 Because HV therapy might be able to maintain regional CBF above the ischemic threshold without producing an effect on gCBF, we repeated the random-effects model analysis using mCBF as the outcome variable and again found no difference between the HV and NV groups.
Using logistic regression we identified 2 independent predictors of poor outcome (dependent or dead) at 3 months: a postoperative Hunt-Hess grade of III or IV and lower mCBF values during the study period. Others have also identified poor Hunt-Hess grade37 53 and low CBF11 12 54 55 as predictors of poor outcome after SAH.
Several limitations of this study deserve mention. Very-poor-grade patients (Hunt-Hess grades IV and V) were relatively underrepresented, which may limit the generalizability of our findings. However, we found no difference in CBF between the 2 treatment groups even after stratification by Hunt-Hess grade. We analyzed our results according to an intention-to-treat analysis, despite the fact that 13 patients (16%) were switched to HHT at some point during the study period for symptomatic vasospasm. Although we found no difference in CBF between the 2 groups when these patients were removed from the analysis, a significant difference in CBF may have been detected had HHT not been used. We used surface rather than tomographic measurements of CBF, which may have been able to detect clinically relevant areas of ischemia deep in the brain. We were unable to identify predictors of symptomatic vasospasm other than mCBF. However, we did not quantify the amount of SAH on admission CT scans or analyze TCD data, factors that have been predictive of delayed ischemia in other studies.56 57
In summary, we found that HV therapy after aneurysm clipping did not result in increased CBF compared with NV therapy. Although our study was not powered to detect an effect on clinical outcome, our results suggest that postoperative HV therapy probably has no advantage over NV therapy for prevention of delayed ischemia after SAH. However, because invasive hemodynamic monitoring directed toward avoiding hypovolemia may still be of value, we do not feel that our results should change the way patients with SAH are currently treated. Our findings indicate that supplemental albumin given to maintain cardiac filling pressures in the normal range (CVP >5 mm Hg or PADP >7 mm Hg) is an effective and safe method for preventing volume contraction after SAH. We currently reserve prophylactic CVP-guided volume expansion for patients who are Hunt-Hess grades III to V or for patients with thick cisternal SAH (Fisher grade III) on the admission CT scan. We use PADP-guided volume expansion for patients with left ventricular dysfunction, renal insufficiency, or symptomatic vasospasm. A controlled study is needed to determine whether CVP-guided fluid administration is more safe and effective than scheduled periodic fluid administration for preventing hypovolemia after SAH.
In some centers, pharmacologically induced hypertension is given after surgery to asymptomatic patients with elevated TCD velocities or other risk factors for symptomatic vasospasm. Although postoperative HV therapy does not increase CBF, a more robust intervention might. A controlled study that analyzes the effect of prophylactic HHT on CBF is needed to determine whether this approach might reduce the incidence of symptomatic ischemia in high-risk patients.
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Acknowledgments |
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This study was supported by a grant from the National Institutes of Health (RO1-NS27325–01) to Dr Solomon. We thank Marianne Mearon for performing the blood volume measurements; John Mann, MD, and William L. Young, MD, for assistance in analyzing the CBF measurements; Daphne Copeland, MPH, for statistical support; Chris Commichau, MD, for helpful editorial comments; and the nursing staff of the Columbia–Presbyterian Neurological Intensive Care Unit.
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Footnotes |
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Reprint requests to Dr Robert A. Solomon, Department of Neurosurgery, Neurological Institute, 710 West 168th Street, New York, NY 10032.
Received July 20, 1999; revision received October 8, 1999; accepted October 29, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
1. Hop JW, Rinkel GJE, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke. 1997;28:660–664.
2. Kassell NF, Torner JC, Haley EC Jr, Jane JA, Adams HP, Kongable GL. The International Cooperative Study on the Timing of Aneurysm Surgery, part 1: overall management results. J Neurosurg. 1990;73:18–36.[Medline] [Order article via Infotrieve]
3.
Feigin VL, Rinkel GJE, Algra A, Vermeulen M, van Gijn
J. Calcium antagonists in patients with aneurysmal
subarachnoid hemorrhage: a systematic review.
Neurology. 1998;50:876–883.
4. Solomon RA, Post KD, McMurtry JG. Depression of circulating blood volume after subarachnoid hemorrhage: implications for treatment of symptomatic vasospasm. Neurosurgery. 1984;15:354–361.[Medline] [Order article via Infotrieve]
5. Wijdicks EFM, Vermeulen M, Hijdra A, van Gijn J. Hyponatremia and cerebral infarction in patients with ruptured intracranial aneurysms: is fluid restriction harmful? Ann Neurol. 1985;18:137–140.
6. Maroon JC, Nelson PB. Hypovolemia in patients with subarachnoid hemorrhage: therapeutic implications. Neurosurgery. 1979;4:223–226.[Medline] [Order article via Infotrieve]
7. Grubb RL, Raichle ME, Eichling JO, Gado M. The effects of subarachnoid hemorrhage on cerebral blood volume, blood flow, and oxygen utilization in humans. J Neurosurg. 1977;46:446–453.[Medline] [Order article via Infotrieve]
8. Ishii R. Regional cerebral blood flow in patients with ruptured intracranial aneurysms. J Neurosurg. 1977;46:446–453.
9. Powers WJ, Grubb RL, Baker RP, Mintun MA, Raichle ME. Regional cerebral blood flow and metabolism in reversible ischemia due to vasospasm. J Neurosurg. 1985;62:539–546.[Medline] [Order article via Infotrieve]
10. Voldby B, Enevoldsen EM, Jensen FT. Regional CBF, intraventricular pressure, and cerebral metabolism in patients with ruptured intracranial aneurysms. J Neurosurg. 1985;62:48–58.[Medline] [Order article via Infotrieve]
11.
Geraud G, Tremoulet M, Geull A, Bes A. The prognostic
value of noninvasive CBF measurement in subarachnoid
hemorrhage. Stroke. 1984;15:301–305.
12. Meyer CHA, Lowe D, Meyer M, Richardson PL, Neil-Dwyer G. Progressive change in cerebral blood flow during the first three weeks after subarachnoid hemorrhage. Neurosurgery. 1983;12:58–76.[Medline] [Order article via Infotrieve]
13. Mickey B, Vorstrup S, Voldby B, Lindewald H, Harmsen A, Lassen N. Serial measurement of regional cerebral blood flow in patients with SAH using 133-Xenon inhalation and emission computerized tomography. J Neurosurg. 1984;60:916–922.[Medline] [Order article via Infotrieve]
14. Nilsson BW. Cerebral blood flow in patients with subarachnoid hemorrhage studied with an intravenous isotope technique: its clinical significance in the timing of surgery of cerebral arterial aneurysm. Acta Neurochir (Wien). 1977;37:33–48.[Medline] [Order article via Infotrieve]
15. Weir B, Menon D. Regional cerebral blood flow in patients with aneurysms: estimation by Xenon 133 inhalation. Can J Neurol Sci. 1978;5:301–305.[Medline] [Order article via Infotrieve]
16. Menon D, Weir B, Overton T. Ventricular size and cerebral blood flow following subarachnoid hemorrhage. J Comput Assist Tomogr. 1981;5:328–333.[Medline] [Order article via Infotrieve]
17. Ferguson GG, Harper AM, Firch W, Rowan JD, Jennett B. Cerebral blood flow measurements after spontaneous subarachnoid hemorrhage. Eur Neurol. 1972;8:15–22.[Medline] [Order article via Infotrieve]
18. Heilbrun MP, Olesen J, Lassen NA. Regional cerebral blood flow studies in subarachnoid hemorrhage. J Neurosurg. 1972;37:36–44.[Medline] [Order article via Infotrieve]
19. Knuckey NW, Fox RA, Surveyor I, Stokes BAR. Early cerebral blood flow and computerized tomography in predicting ischemia after cerebral aneurysm rupture. J Neurosurg. 1985;62:850–855.[Medline] [Order article via Infotrieve]
20. Talacchi A. Sequential measurements of cerebral blood flow in the acute phase of subarachnoid hemorrhage. J Neurosurg Sci. 1993;1:9–18.
21. Messeter K, Brandt L, Ljunggren B, Svengaard NA, Algotsson L, Romner B, Ryding E. Prediction and prevention of delayed ischemic dysfunction after aneurysmal subarachnoid hemorrhage and early operation. Neurosurgery. 1987;20:548–553.[Medline] [Order article via Infotrieve]
22. Dernbach PD, Little JR, Jones SC, Ebrahim ZY. Altered cerebral autoregulation and CO2 reactivity after aneurysmal subarachnoid hemorrhage. Neurosurgery. 1988;22:822–826.[Medline] [Order article via Infotrieve]
23. Voldby B, Enevoldsen EM, Jensen FT. Cerebrovascular reactivity in patients with ruptured intracranial aneurysms. J Neurosurg. 1985;62:59–67.[Medline] [Order article via Infotrieve]
24. Keller TS, McGillicuddy JE, LaBond VA, Kindt GW. Modification of focal cerebral ischemia by cardiac output augmentation. J Surg Res. 1985;39:420–432.[Medline] [Order article via Infotrieve]
25. Tranmer BI, Keller TS, Kindt GW, Archer D. Loss of cerebral regulation during cardiac output variations in focal cerebral ischemia. J Neurosurg. 1992;77:253–259.[Medline] [Order article via Infotrieve]
26. Matsui T, Asano T. The hemodynamic effects of prolonged albumin administration in beagle dogs exposed to experimental subarachnoid hemorrhage. Neurosurgery. 1993;32:79–84.[Medline] [Order article via Infotrieve]
27. Kassell NF, Peerless SJ, Durward QJ, Beck DW, Drake CG, Adams HP. Treatment of ischemic deficits from vasospasm with intravascular volume expansion and induced arterial hypertension. Neurosurgery. 1982;11:337–343.[Medline] [Order article via Infotrieve]
28. Pritz MB, Gianotta SL, Kindt GW, McGillicuddy JE, Prager RL. Treatment of patients with neurologic deficits associated with cerebral vasospasm by intravascular volume expansion. Neurosurgery. 1978;3:364–368.[Medline] [Order article via Infotrieve]
29. Awad IA, Carter LP, Spetzler RF, Medina M, Williams FW. Clinical vasospasm after subarachnoid hemorrhage: response to hypervolemic hemodilution and arterial hypertension. Stroke. 1987;18;365–372.
30. Kosnik EJ, Hunt WE. Postoperative hypertension in the management of patients with intracranial aneurysms. J Neurosurg. 1976;45:148–154.[Medline] [Order article via Infotrieve]
31. Solomon RA, Fink ME, Lennihan L. Early aneurysm surgery and prophylactic hypervolemic hypertensive therapy for the treatment of aneurysmal subarachnoid hemorrhage. Neurosurgery. 1988;23:699–704.[Medline] [Order article via Infotrieve]
32. Medlock MD, Dulebohn SC, Elwood PW. Prophylactic hypervolemia without calcium channel blockers in early aneurysm surgery. Neurosurgery. 1991;30:12–16.
33. Origitano TC, Wascher TM, Reichman H, Anderson DE. Sustained increased cerebral blood flow with prophylactic hypertensive hypervolemic hemodilution ("triple-H therapy") after subarachnoid hemorrhage. Neurosurgery. 1990;27:729–40.[Medline] [Order article via Infotrieve]
34.
Mori K, Arai H, Nakajima K, Tajima A, Maeda M.
Hemorheological and hemodynamic analysis of
hypervolemic hemodilution therapy for cerebral vasospasm after
aneurysmal subarachnoid hemorrhage.
Stroke. 1995;26:1620–1626.
35. Yamakami I, Isobe K, Yamura A. Effects of intravascular volume expansion on cerebral blood flow in patients with ruptured cerebral aneurysms. Neurosurgery. 1987;21:303–9.[Medline] [Order article via Infotrieve]
36. Mayer SA, Solomon RA, Fink ME, Lennihan L, Thomas CE, Stern L, Beckford A, Klebanoff LM. Effect of 5% albumin solution on sodium balance and blood volume after subarachnoid hemorrhage. Neurosurgery. 1998;42:759–768.[Medline] [Order article via Infotrieve]
37. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg. 1968;28:14–20.[Medline] [Order article via Infotrieve]
38. Fleiss JL. The Design and Analysis of Clinical Experiments. New York, NY: John Wiley & Sons; 1986.
39.
Obrist WD, Thompson HK, Wang HS, Wilkinson WE. Regional
cerebral blood flow estimated by Xe-133 inhalation. Stroke. 1975;6:245–256.
40. Jennett B, Bond M. Assessment of outcome after severe brain damage: a practical scale. Lancet. 1975;1:480–484.[Medline] [Order article via Infotrieve]
41. Laird NM, Ware JH. Random-effects model for longitudinal data. Biometrics. 1982;38:963–974.[Medline] [Order article via Infotrieve]
42.
Hino A, Mizukawa N, Tenjin H, Imahori Y, Taketomo S,
Yano I, Nakahashi H, Hirakawa K. Postoperative
hemodynamic and metabolic changes in
patients with subarachnoid hemorrhage.
Stroke. 1989;20:1504–1510.
43. Jakobsen M, Skjodt T, Enevoldsen E. Cerebral blood flow and metabolism following subarachnoid hemorrhage: effect of subarachnoid blood. Acta Neurol Scand. 1991;83:226–233.[Medline] [Order article via Infotrieve]
44. Kawamura S, Sayama I, Yasui N, Uemura K. Sequential changes in cerebral blood flow and metabolism in patients with subarachnoid hemorrhage. Acta Neurochir (Wien). 1992;114:12–15.[Medline] [Order article via Infotrieve]
45. Mizuno M, Nakajima S, Sampei T, Nishimura H, Hadeshi H, Suzuki A, Yasui N, Nathal-Vera E. Serial transcranial Doppler flow velocity and cerebral blood flow measurements for evaluation of cerebral vasospasm after subarachnoid hemorrhage. Neurol Med Chir. 1994;34:164–171.
46. Diringer MN, Wu KC, Verbalis JG, Hanley DF. Hypervolemic therapy prevents volume contraction but not hyponatremia following subarachnoid hemorrhage. Ann Neurol. 1992;31:543–550.[Medline] [Order article via Infotrieve]
47. Levy ML, Giannotta SL. Cardiac performance indices during hypervolemic therapy for cerebral vasospasm. J Neurosurg. 1991;75:27–31.[Medline] [Order article via Infotrieve]
48.
Hasan D, Lindsay KW, Widjicks EFM, Murray GD,
Brouwers JAM, Bakker WH, van Gijn J, Vermeulen M. Effect of
fludrocortisone acetate in patients with subarachnoid
hemorrhage. Stroke. 1989;20:1156–1161.
49. Wijdicks EFM, Vermeulen M, Ten Haaf JA, Bakker WH, Van Gijn J. Volume depletion and natriuresis in patients with ruptured intracranial aneurysm. Ann Neurol. 1985;18:211–216.[Medline] [Order article via Infotrieve]
50. Darby JM, Yonas H, Marks EC, Durham S, Snyder RW, Nemoto EM. Acute cerebral blood flow response to dopamine-induced hypertension after subarachnoid hemorrhage. J Neurosurg. 1994;80:857–864.[Medline] [Order article via Infotrieve]
51.
Mendelow AD, Dharker S, Patterson J, Nath F, Teasdale
GM. The dopamine withdrawal test following surgery for intracranial
aneurysms. J Neurol Neurosurg Psychiatry. 1986;49:35–38.
52. Muizelaar JP, Becker DP. Induced hypertension for the treatment of cerebral ischemia after subarachnoid hemorrhage: direct effect on cerebral blood flow. Surg Neurol. 1986;25:317–325.[Medline] [Order article via Infotrieve]
53.
Hijdra A, van Gijn J, Nagelkerke NJD, Vermeulen M, van
Crevel H. Prediction of. delayed cerebral ischemia, rebleeding,
and outcome after aneurysmal subarachnoid
hemorrhage. Stroke. 1988;19:1250–1256.
54. Matsuda M, Shiino A, Handa J. Sequential changes of cerebral blood flow after aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien). 1990;105:98–106.[Medline] [Order article via Infotrieve]
55. Kotb MM, Symon L, Compton J, Rosenstein J, Jabre A. Grading and outcome prediction of cases of aneurysmal subarachnoid hemorrhage by bedside xenon cerebral flowmetry. Acta Neurochir (Wien). 1991;108:1–6.[Medline] [Order article via Infotrieve]
56. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery. 1980;6:1–9.[Medline] [Order article via Infotrieve]
57. Grossett DG, Stratton J, McDonald I, Cockburn M, Bullock R. Use of transcranial Doppler sonography to predict development of a delayed ischemic deficit after subarachnoid hemorrhage. J Neurosurg. 1993;78:183–187.[Medline] [Order article via Infotrieve]
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