Robert H.

Ackerman
Cerebral Blood Flow and Neurological Change in Chronic Heart Failure
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Cerebral Blood Flow and Neurological Change
in Chronic Heart Failure
Robert H. Ackerman, MD, PhD
I
n their article in this issue of Stroke, Gruhn et al report
that cerebral blood flow (CBF) is reduced about 30% in
patients with NYHA III/IV heart failure but has normal-
ized when retested in 5 subjects 30 days after successful heart
transplantation. The authors suggest that (1) the reduced CBF
found before transplantation is responsible for neurological
signs and symptoms reported in patients with chronic heart
failure (CHF), and (2) that the resolution of such symptoms
after transplantation, as reported in other studies, and the
normalization of CBF, as found in their investigation, are
parallel phenomena, both resulting from an improvement in
central hemodynamics.
This editorial explores whether the increase in CBF 30
days after transplantation found by Gruhn et al could be on
another basisa perisurgical fall in hematocritand whether
the reduced CBF values found before surgery are sufficient to
cause neurological disturbances. It also considers the types
and etiologies of neurological changes in CHF.
Hematocrit and CBF Relationships
Hematocrit is the main determinant both of whole-blood
viscosity
1
and arterial O
2
content,
2
each of which has power-
ful effects on CBF. Viscosity accounts for 56% of the
decrease in CBF that occurs as hematocrit rises from 20% to
40%.
3
In dilated cardiomyopathy, viscosity is further in-
creased due to elevated fibrinogen and decreased red cell
deformability,
4
which can compound the inverse effect of
hematocrit on CBF. A reduction in arterial oxygen content
can account for 40% to 60% of the increase in CBF that
accompanies a fall in hematocrit.
2
A drop in hematocrit can
occur perisurgically from blood loss or relative hemodilution.
Some years ago we noted (data reported at meetings but
unpublished) that paired CBF measurements, done shortly be-
fore and after unilateral carotid endarterectomy (CEA) in pa-
tients with single-vessel disease, showed a statistically signifi-
cant postoperative increase in CBF (15%) in only 9 of 33
subjects studied. However, in these 9 the increase was bilateral.
The bilaterality of the response could not be explained by
clinical, blood gas, or vascular pathoanatomic findings. Because
of a focus on CBF/viscosity relationships at the time, we were
able to examine correlative data on hematocrit and fibrinogen.
See article on page 2530
We found a significant postoperative percentage fall in hemat-
ocrit in the 9 in whom CBF rose significantly compared with the
24 in whom it did not (Table). The between-group differences in
percent change in CBF and hematocrit, before versus after CEA,
were significant at P0.001 and P0.005, respectively (1-tailed
t test). The fibrinogen changes were not significant.
We concluded that the global CBF rise in the 9 patients
resulted primarily from rheological rather than hemodynamic
changes and that the rheological changes were most directly
related to the significant fall in hematocrit.
Few published reports provide quantitative bilateral CBF data
within weeks before and after CEA. Only 1 such communication
that we have identified, by Schroeder et al,
5
gives hematocrit or
hemoglobin data. In 32 subjects, these authors found a global
CBF rise of about 35% and a coincident mean hemoglobin drop
of about 7% on the first day after CEA. Over the next week, the
initially observed bilateral CBF increase declined toward preop-
erative levels, based on studies done at 2 to 4 and 5 to 11 days
postoperatively. (It is not clear from the report how the patients
examined at day 1 overlapped with those studied during the later
intervals.) The authors postulated that hemodilution may have
accounted for the initial bilateral global flow increase. They did
not find a direct correlation between the decrease in hemoglobin
and the increase in CBF, nor did they present hematocrit data.
Gruhn et al do not provide data on hematocrit before or after
cardiac transplantation. For the purposes of this editorial, we
reviewed hematocrit data on 10 recent consecutive cardiac trans-
plantation cases at the Massachusetts General Hospital. In 7 patients
hematocrit values before transplant were significantly higher than at
30 days after transplant (P0.026). The mean hematocrit value for
the 7 fell from 36.37.7 to 29.66.1, which represents an 18.5%
fall. In the other 3 patients, the mean hematocrit value rose from
31.83.31 to 35.61.61, an increase of 11.9%. The net hematocrit
change for all 10 patients was 8.30%.
Based on the aggregate observations above, one may reason-
ably suggest that a lower mean hematocrit value could have
accounted in part or in full for the increase in mean CBF found
by Gruhn et al in their 5 cases studied 30 days after
transplantation.
Similar rheological considerations theoretically could underlie
the differences in the CBF response to captopril reported in
back-to-back articles in the American Journal of Medicine in
1984,
6,7
one of which is cited by Gruhn et al. Patients in both
investigations had NYHA class III/IV heart failure. In the cited
report, Rajagopalan et al
6
did baseline and postcaptopril CBF
studies on 9 hospitalized subjects who received increasing
captopril doses over 48 to 72 hours. CBF studies performed after
the completion of the captopril regimen showed a 21% increase
The opinions expressed in this article are not necessarily those of the
editors or of the American Stroke Association.
From the Department of Neurology, Harvard Medical School, and
Neurological Service, Massachusetts General Hospital, Boston, Mass.
Correspondence to Dr Robert H. Ackerman, Massachusetts General
Hospital, Gray Bldg 254, 55 Fruit St, Boston, MA 02114. E-mail
rha@massmed.org
(Stroke. 2001;32:24622464.)
2001 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
2462
by guest on August 21, 2014 http://stroke.ahajournals.org/ Downloaded from
in CBF. In the study by Paulson et al,
7
the investigators
measured CBF in 5 outpatient subjects at baseline and 15, 60,
and 180 minutes after captopril administration. CBF remained
stable at each of the 4 study points.
In a published discussion of the 2 papers, Paulson
8
sought an
explanation for the discrepancy in the CBF findings between the
inpatient and outpatient studies, adding that his group had found
no change in CBF even after 1 to 3 weeks of outpatient captopril
treatment. He queried whether the difference in the CBF results
might have something to do with hospitalization itself and
alluded to a report of increased CBF in severely demented
patients after they had received good hospital care for one or
two weeks with no specific medical treatment. Inhospital
patients can demonstrate a drop in hematocrit, which can alter
CBF, on the basis of daily blood drawing and/or increased
hydration. The hydration can result from intravenously admin-
istered fluids or increased oral consumption with medications.
Consideration of the potential impact of hematocrit change on
CBF in diverse clinical and research situations is important, as it
underscores the fact that unless correlative hematocrit information is
available, one is at risk of misapplying CBF findings due to an
artifact of interpretation. But it must be kept in mind that flow
changes on a rheological basis carry the same physiological signif-
icance as those due to cardiac and neurovascular causes. An
increase in CBF due to a fall in hematocrit can reverse low-flow
ischemic neurological changes, and a fall in CBF due to a rise in
whole-blood viscosity can precipitate or exacerbate them. In our
experience, in a patient with an evolving cerebral ischemic deficit a
peripheral hematocrit of 42% or higher can be part of the focal
pathophysiological process.
CBF Values and Neurological Impairments
Based on 1976 data from Strandgaard,
9
Gruhn et al argue that
the 30% lower mean CBF found in their 5 patients before
transplantation compared with that in normal controls (353
versus 525 mL 100 g
1
min
1
, respectively) is sufficient
to produce symptomatic cerebral hypoperfusion. The authors
do not report neurological deficits in their patients, and they
did not perform pretransplant or posttransplant neuropsycho-
logical testing. Baron
10
has recently summarized the aggre-
gate experimental and human study data on the CBF thresh-
olds that must be reached to produce cerebral dysfunction and
infarction. In the nonhuman primate, the threshold of CBF
below which neuronal function, monitored electrophysiolog-
ically, is impaired is around 22 mL 100 g
1
min
1
(about
40% below normal values). The groups of Boysen
11
and
Sundt
12
demonstrated that during carotid clamping for CEA
in humans, the EEG slows if mean CBF falls below 23 mL
100 g
1
min
1
. Baron
10
cites PET studies in patients with
acute stroke in which the highest CBF for penumbral tissue
that evolved to infarction was 17 to 22 mL 100 g
1
min
1
.
These studies do not necessarily relate to the CBF threshold
required to produce clinical cognitive dysfunction, but they
support the impression that the brain is more tolerant of oligemia
than early investigators had anticipated.
Types of Neurological Deficits in
CHF Patients
In a recent review covering the period 19662000, Almeida and
Flicker
13
found 13 studies that examined the association between
congestive heart failure and cognition, including several done on
heart transplant candidates. Commenting on the enormous
paucity of systematic information, they identified only 5 inves-
tigations which, in their opinion, were suitable for analysis.
Pooled data from these 5 studies suggested an association
between congestive heart failure and generalized cognitive
impairment, including attention and memory deficits.
How the patients are selected and tested affects the range of
deficits detected. In a study before and after cardiac transplan-
tation in patients who were not screened for comorbidities,
Schall et al
14
found impairments in memory, abstract reasoning,
and tactual perceptual processing deficits. In a study that
excluded subjects with other medical and neurological problems,
more limited cognitive deficits were identified. Roman et al,
15
using a battery of 10 neuropsychological tests on 17 patients
before cardiac transplantation who had no prior history of stroke,
anoxic events, renal failure, or other medical illness, found
definite abnormalities only in delayed recall (Rey Auditory
Verbal Learning Test and Bender-Gestalt Test). Tests of diffuse
cerebral dysfunction, such as sustained concentration and
graphomotor learning, were all normal before transplantation.
Changes in cognitive functioning after cardiac transplantation
have been reported as follows: 1 year following transplant, 14 of
16 patients studied by Roman et al
15
who had an abnormal Rey
Auditory Verbal Learning Test before transplant showed normal
results after transplant; however, the Bender Gestalt Test find-
ings showed only a slight improvement that was of dubious
clinical significance. The study had no control group. In the
series of Schall et al,
14
the only significant improvement 4 to 11
months after cardiac transplant was in motor speed. Augustine et
al
16
examined 10 patients before and 1 month after cardiac
transplant. Seventy percent showed a decline on delayed recall
testing. Whether the poorer outcome in these patients reflects
preexisting permanent cerebral damage or secondary periproce-
dural injury is uncertain. Although death and stroke are uncom-
mon events now in cardiopulmonary bypass surgery, in some
reports up to two thirds of patients show new evidence of
neuropsychological dysfunction postoperatively.
17
The findings of improved motor speed by Schall et al
14
and of
normalization of the Rey Auditory Verbal Learn Test results by
Roman et al
15
seem to be the best-documented improvements
reported in studies of neurological function before and after
cardiac transplantation.
Causes of Neurological Deficits in CHF Patients
Roman et al
15
attributed isolated memory impairments to hypo-
perfusion in mesial temporal lobe structures. However, as
Percent Change in CBF and Whole-Blood Viscosity Factors
Before and After CEA
CBF %
Pre-/Post-CEA n
% Pre-/Post-CEA
CBF Hct Fibrinogen
15% 9 2515* 166 318
NS 24 513 87 225
Hct indicates hematocrit; NS, not significant. CBF values are milliliters per
100 g per minute.
*P0.001; P0.005.
Ackerman CBF and Neurological Change in CHF 2463
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documented pathologically by Brierley and Miller in 1966,
18
the
hippocampus should not be involved in cerebral low-flow
watershed ischemic events, whereas the hippocampus is
highly susceptible to hypoxic injury.
Gruhn et al speculate that the neurological impairments reported
by other authors could result from a combination of reduced mean
arterial blood pressure, exhausted cerebrovascular reserve, and/or
failure of systemic mechanisms for redistributing cardiac output to
the brain. As indicated in their discussion, little is known about
cerebral vasoregulation in severe CHF, including whether autoreg-
ulation remains intact and, if so, if the lower limits of autoregulation
have shifted up due to preexisting hypertension, down due to
intervening chronic hypotension or have been modified by the
actions of certain types of drugs such as angiotensin-converting
enzyme (ACE) inhibitors. Vasoregulatory responses may persist but
reserve may be exhausted, as suggested by the study of Georgiadis
et al.
19
In extreme pathophysiological circumstances such as car-
diogenic shock and subarachnoid hemorrhage, an increase in
cardiac output with intraaortic balloon pumping may cause an
increase in CBF independent of arterial blood pressure.
20,21
Except in patients with underlying cerebrovascular obstruc-
tive disease or prior stroke, lateralizing or focal sensorimotor
changes seem to be uncommon in patients with CHF. Although
cognitive deficits may increase with CHF severity (diminished
ejection fraction, cardiac output, and/or cardiac index),
2224
they
may better reflect the effects of generalized disturbances in
systemic and brain homeostatic mechanisms, triggered by CHF,
and often are superimposed on organ functions already compro-
mised by diabetes, hypertension, and atherosclerosis. Impaired
attention and memory difficulties are nonspecific findings that
potentially could occur with or be complicated by severe
hypoperfusion. However, they may be more common with
hypoxic/toxic/metabolic disturbances and, as Alameida and
Flicker
13
point out, depression. Of course, the failing heart is
thrombogenic, and one cannot exclude showers of cerebral
microemboli that may cause diffuse gray matter injury. Such
microemboli can be detected with transcranial Doppler studies,
as has been shown by monitoring during cardiopulmonary
bypass procedures.
17
The fact is that the causes of the neurological deficits in patients
with CHF are not known. Good evidence is wanting at present that
the neurological changes in CHF are on the basis of brain hypoper-
fusion or that a cognitive improvement following cardiac transplant
is due to or even associated with increased CBF. Further investiga-
tion is needed. Future studies of CBF in CHF patients must be
supplemented by sequential neurological and neuropsychological
testing, as well as data on comorbidities, whole-blood viscosity
factors, metabolic functions, and arterial oxygenation.
Acknowledgments
Thanks to Joel Krier, BA, for technical and research assistance
rendered in the preparation of this article, and to the fellows and
technicians in the Neurovascular and Cerebral Blood Flow and
Metabolism Laboratories at the Massachusetts General Hospital
who, over the years, participated in the investigations that permitted
observations reported in this editorial.
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KEY WORDS: blood viscosity

cerebral blood flow

cognition

heart
failure, congestive

hematocrit
2464 Stroke November 2001
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