Download Chronically Impaired Autoregulation of Cerebral Blood Flow

Chronically Impaired Autoregulation of
Cerebral Blood Flow in Long-Term Diabetics
BY NIELS BENTSEN, M.D., BO LARSEN, M.D.,
AND NIELS A. LASSEN, M.D.
Abstract:
Chronically
Impaired
Autoregulation
of Cerebral
Blood Flow in
Long-Term
Diabetics
• Using the arteriovenous oxygen difference method autoregulation of cerebral blood flow
(CBF) was tested in 16 long-term diabetics and eight control patients. Blood pressure was raised
by angiotensin infusion and lowered by trimethaphan camsylate infusion, in some cases combined with head-up tilting of the patient. Regression analysis was carried out on the results in
order to quantify autoregulatory capacity.
In the control patients CBF did not vary with moderate blood pressure variations, indicating normal autoregulation. In four of the 16 diabetic patients CBF showed significant
pressure dependency, indicating impaired autoregulation. The cause of impaired autoregulation
in some long-term diabetics is believed to be diffuse or multifocal dysfunction of cerebral
arterioles due to diabetic vascular disease. Other conditions with impaired autoregulation are
discussed and compared with that seen in long-term diabetes.
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Additional Key Words
diabetic angiopathy
arteriovenous oxygen difference method
arterial hypertension
Introduction
Patients and Methods
• Autoregulation of the cerebral circulation is a
mechanism that ensures a constant cerebral blood
flow (CBF), and thereby a sufficient oxygen supply,
despite variations in arterial blood pressure. This
mechanism is believed to be dependent on normally
functioning cerebral arterioles (resistance vessels),
capable of dilating when blood pressure is lowered,
and of constricting when blood pressure is raised.
Autoregulation is only operating in a certain blood
pressure interval around the resting mean arterial
blood pressure (MABP), breaking down at a lower
and upper limit. At the lower limit, which is 60 to 70
mm Hg MABP for a normotensive person with a
resting MABP of about 90 mm Hg, 13 CBF begins to
decrease, but sufficient oxygen supply is still ensured
by an increase in the arteriovenous (AV) oxygen extraction. At still lower blood pressures (for a normotensive person about 35 to 40 mm Hg) also this
mechanism fails, and cerebral hypoxia develops.2 At
the upper limit the capacity of the arterioles to resist
the increased intraluminal pressure is overcome
resulting in a sudden rise in blood flow, the so-called
"breakthrough" phenomenon.3'4
Long-term diabetes mellitus and arterial hypertension are known to be associated with arteriolar disease and therefore could very well be conditions in
which cerebral autoregulation was not functioning
properly. The present study was undertaken in order
to investigate the autoregulatory capacity in long-term
diabetics.
Sixteen long-term diabetics were examined (table 1), of
whom two (Cases 1 and 6) were examined on two separate
occasions. Long-term diabetes in this study signifies either a
duration of diabetes of 15 years or more, or unequivocal
signs of diabetic retinopathy, regardless of known duration
of diabetes. Ages ranged from 35 to 77 years, average 57
years. Known duration of diabetes ranged from 4 to 34
years, average 17 years.
All were outpatients in such physical and mental condition that they could live a normal or nearly normal life at
home. Cases 3, 4, 7, and 11 were temporarily hospitalized at
the time of study.
Thirteen of the patients had diabetic retinopathy to a
varying degree and three patients (Cases 12, 15, and 16) had
arterial hypertension. One patient (Case 8) had previously
had myocardial infarction, but at the time of study none of
the patients had any cardiorespiratory complaints. No
specific investigations were undertaken to determine blood
flow in the lower extremities, renal function or the presence
or degree of diabetic neuropathy. Eight patients had or had
previously had intermittent claudication or gangrene in the
lower extremities. Albuminuria was present in eight
patients, of whom three also had increased serum creatinine.
This was attributed to diabetic nephropathy.
Case 10 had complaints of vertigo prior to the study.
Case 13 had organic dementia, probably related to chronic
alcoholism, and two weeks prior to the study had had an
apoplectic attack from which a slight hemiparesis remained..
Except for these two patients none of the patients studied
had any complaints of vertigo, headache, and syncope or
any other symptoms or signs that could be attributed to
diffuse or focal intracranial disease.
In addition eight non-diabetic control patients were examined (table 2). Their ages ranged from 41 to 71 years,
average 52 years.
All patients gave their informed consent to participate
in the study. This also applies to Case 13 with organic
From the Departments of Neurology and Clinical Physiology,
Bispebjerg Hospital, Copenhagen, Denmark.
Reprint requests to Dr. Bentsen (Department of Neurology).
Stroke, Vol. 6, September-October 1975
497
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F
M
M
F
F
12
13
14
51
64
55
35
67
69
56
77
68
56
69
38
47
47
46
45
63
67
Ago
(years)
7
4
16
12
16
30
11
34
18
18
19
16
16
19
14
15
19
23
Known
deration
of diabetes
(years)
•Degree of diabetic retinopathy: ( + )
tSlope of regression line.
^Coefficient of correlation.
15
16
M
11
F
M
F
M
6,i
7
8
9
10
M
M
F
F
F
M
M
In
4
5
6,
M
1[
Sex
2
3
Cut
no*
Diabetic Patients
TAIL!1
113
113
138
113
88
133
141
104
87
83
116
86
90
109
115
86
82
98
MAIP
(rest)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Previous 1
0
0
0
0
0
0
0
Albuarlnarla
0
0
0
0
+
0
0
+
0
0
0
+
0
0
0
0
0
0
seran
srearlnlne
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Vertigo
Vertlae,
heodwhe,
syiKope
slight but manifest, + =• moderate, + + = severe, + + + = proliferative retinopathy.
0
0
Retinopathy*
Internment
deuaicarlon
or gangrene
of lower
extremities
0.4778
0.2713
0.2690
0.2073
0.1339
0.1315
0.1301
0.1255
0.1070
0.0917
0.0906
0.0603
0.0545
0.0452
0.0223
0.0208
0.0158
-0.0537
bt
0.9375
0.6892
0.9434
0.7175
0.5954
0.7319
0.3781
0.4362
0.4451
0.4045
0.3118
0.4222
0.1672
0.1314
0.0794
0.0573
0.0537
-0.1827
rt
NS
NS
NS
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NS
<
C 0.001
<
; 0.05
<
C 0.001
<
; 0.05
NS
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C 0.05
NS
NS
NS
NS
NS
NS
P
P
P
P
CEREBRAL AUTOREGULATION I N DIABETES
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dementia, whose mental condition was not seriously
deteriorated. The control patients were examined as part of
their clinical investigation.
No cerebral, cardiovascular or other complications occurred in the patients during or after the study.
CBF was measured by the arteriovenous oxygen
difference method.2-6 If the cerebral metabolic rate of
oxygen (CMRO2) is assumed to be constant, CBF can be
calculated from the arteriovenous oxygen difference (AV O2)
by means of the Fick principle:
CMRO,
CBF
AV O2
1 gives a relative measure of CBF, which is exwhere
AV
1
pressed as a percentage of the resting . v Q value (CBF%).
CMRO2 has repeatedly been shown to be constant in conscious man in the resting condition and during variations in
MABP, including hypotension with signs of hypoxia.1' *
In each individual study the various CBF% values were
corrected for small variations in Pace. A difference in Paco,
of 1 mm Hg was assumed to correspond to a change in
CBF% of 4%. Corrections were carried out only when no
signs of hypoxia were present.7'8
The study was started at 8 A. M. The patients were not
fasting, and the diabetics had had their usual morning insulin doses. A catheter was placed with the tip in the right
jugular bulb under fluoroscopic control either from a
superficial right arm vein or via one femoral vein by the
Seldinger technique. Another catheter was placed in either a
brachial or femoral artery. A regular intravenous infusion
set was placed in a superficial arm vein and connected to an
infusion pump. Arterial and jugular venous pressures were
continuously measured with transducers (EMT-34, ElemaSchonander). Regardless of the position of the arterial
catheter and the patient, the transducers for blood pressure
monitoring were constantly kept level with the patient's external acoustic meatus to avoid hydrostatic error.
The arterial blood pressure was raised by intravenous
infusion of angiotensin amide (Hypertensin, CIBA) and
lowered by infusion of trimethaphan camsylate (Arfonad)
via the infusion pump, in some cases combined with head-up
tilting of the patient. In this way observations in a wide
MABP interval above and below the resting MABP were
obtained in each case.
Neither of these drugs has any direct effect on cerebral
circulation; consequently, changes in CBF during their administration must be due to changes in systemic blood
pressure.3-9
Blood samples from the jugular bulb and the femoral
artery were drawn simultaneously in the resting condition
and at various blood pressure levels above and below this
value. Steady state was secured by not drawing the blood
samples until two to five minutes had elapsed after the blood
pressure had stabilized at a particular value. Oxygen content
in arterial and jugular venous blood was determined by
measuring the hemoglobin oxygen saturation spectrophotometrically10 and Paco, was measured with a
Severinghaus electrode.
CBF ^ of rest
100
90
to
70
60
50
40
30
Stroke, Vol. 6, September-October 1975
MABP(mmHg)
Visual interpolation , 0 / the points representing corresponding
observations ofCBF% of rest and MABP in typical study. Dotted
line indicates extrapolation of the curve, x indicates the resting condition.
these values were plotted against MABP and a graph
was obtained by simple visual interpolation of the
points (fig. I).2 In order to further quantify the results
a linear regression analysis was carried out according
to the following principles: Only corresponding values
of CBF% and MABP that seemed to naturally fit a
straight line within the normal range of autoregulation
have been used in the regression analysis (fig. 2). Thus
care was taken not to include observations that
seemed to lie beyond the upper and lower limit of the
MABP interval, in which autoregulation is expected
to function properly in normal and hypertensive man.
In each case the coefficient of correlation (r) was
calculated (tables 1 and 2).
Among the diabetics five out of 18 studies (four
patients [Cases 1, 2, 3, and 5] of whom Case 1 was
reexamined) showed an r-value significantly different
from 0, corresponding to 25% of the diabetic patients
(table 1), whereas among the control patients no rvalue was significantly different from 0 (table 2).
Average resting MABP in diabetics and control
,
CASE No.
r* 0
p < 0.001
CBF%of
rest
110%
»
p< 0.001
3
t
p < 0.05
|
•
•
10
tf
C3
¥
•*
-
• *
N.S.
N.S.
•
|
c
•*
N S.
r*
•
100
Results
Based on AV O2 the relative CBF was calculated as
percent of rest (CBF%) and corrected for differences
in Pacos as described above. In each individual study
200
VO
FIGUIE I
150
MABP(mmHg)
Observations and corresponding regression lines for four diabetics
and two control patients. Only observations included in the regression analysis are indicated, x indicates the resting condition.
499
BINTSIN, LARSIN, LASUN
TA»LI2
Confro/ Patients
(yoars)
MABP
(rort)
rt
r ft 0
Dlagnoilf
M
57
93
0.0928
0.3717
NS
2
3
4
5
6
F
M
M
M
M
45
41
71
61
45
100
100
100
88
92
0.0878
0.0439
0.0323
-0.0367
-0.0538
0.5272
0.2633
0.1720
-0.2991
-0.2117
NS
NS
NS
NS
NS
7
M
49
84
-0.0737
-0.3305
NS
8
F
45
118
-0.1075
-0.3760
NS
Cerebral atrophy,
vertigo
L ICA occlusion
Lipothymia
Lipothymia
Lipothymia
Chronic alcoholism.
vertigo
Chronic alcoholism,
vertigo
Epilepsy, vertigo
Ago
Caso no.
Sox
1
b»
*Slope of regression line.
•(Coefficient of correlation.
L = left, ICA = internal carotid artery.
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patients was 105 mm Hg and 97 mm Hg, respectively.
The maximum increase in CBF with increasing
MABP amounted to about 20% (Cases 1 and 3).
Discussion
The crucial point in the AV O2 method is the
constancy of CMR0 2 . In the literature it seems well
established that CMR0 2 remains constant in conscious normal man, when MABP is varied. This
applies even when MABP values are so low that
hypoxia is manifest and syncope imminent.1'6
When evaluating cerebral autoregulation it is essential not to include observations in the regression
analysis from outside of the MABP interval, in which
autoregulation is operating. It is impossible to predict
with certainty the MABP values of the upper and
lower limits from the resting MABP value. In most
cases the interval from the resting MABP to the upper
limit is greater than from the resting MABP to the
lower limit, but this is not always so (fig. 3). Furthermore, as seen in figure 1, CBF very often begins to
decrease at MABP values just below the resting
MABP. Thus, in order to obtain a correct picture of
the patient's autoregulatory function and its range, it
is necessary to measure CBF over a wide range of
MABP values above and below the measured resting
MABP value. Only in this way is it possible to avoid
including observations from outside of the particular
patient's autoregulatory range in the regression
analysis.
If only two observations are made, for instance
one at the resting level and one at a blood pressure
below this level, the risk of including observations
from outside of the particular patient's autoregulatory
range must be faced, thus perhaps resulting in a false
impression of impaired autoregulation. By exploiting
the advantage of the AV O2 method enabling us to
make multiple measurements of CBF over a wide
range of MABP values below and above the resting
500
MABP, we have endeavored to avoid such mistakes.
Autoregulation of the cerebral circulation has
repeatedly been shown to be a very precisely operating
mechanism, i.e., within the autoregulatory range
changes in MABP will elicit practically no change in
CBF. 13
When testing the autoregulatory function in 16
long-term diabetics, we found four patients with
statistically non-horizontal curves (Cases 1, 2, 3, and
5). One of these patients (Case 1) was reexamined five
months later, again resulting in a non-horizontal
curve. None of these four patients had any signs or
symptoms that could be attributed to diffuse or focal
intracranial disease. No cerebral symptoms developed
during the test in these patients, and, in particular, no
signs of hypoglycemia were noted. By visual examination of the regression lines (fig. 4) there appears to be a
continuous spectrum from practically horizontal to
more and more oblique lines, indicating a smooth
transition from normal to definitely impaired
autoregulation.
Our interpretation of thesefindingsis that among
CBF% of rest
100%
/
100%
•
/
100
200
MABP(mmHg)
FIGURE 3
Two fictive autoregulation curves illustrating our experience that
the upper and lower limits of autoregulation cannot be predicted
with certainty from the resting MA BP (indicated by x). A is the type
of curve most often found.
Stroke, Vol. 6. September-October 1975
COUMAL AUTOMOULATION IN DIAUTIS
'AVERAGE
-AVERAGE
FIOUH 4
Slopes of regression lines for diabetics and controls.
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long-term diabetics without clinical signs of diffuse or
focal intracranial disease some have a chronic impairment of cerebral autoregulation.
The degree of impairment in our studies is
relatively small and cannot be expected under normal
conditions to have any clinical significance for the
patient. Thus none of our four patients with
statistically non-horizontal curves had complaints that
could be ascribed to dysfunction of cerebral circulation. In some patients, however, this autoregulatory
impairment might be severe to a degree, where clinical
significance could be expected under special circumstances, e.g., development of cerebral ischemia
during arterial hypotension in connection with general
anesthesia.
Our method does not allow us to draw conclusions as to the exact nature of the abnormality that
causes impaired autoregulation in some long-term
diabetics. Neither does it distinguish between multifocal and focal pathology, since what is measured is
the overall cerebral perfusion.
That our findings should be due to impaired function of the sympathetic nervous system as a result of
diabetic neuropathy seems unlikely. No report in the
literature until now has convincingly demonstrated
that an intact sympathetic nervous system is necessary
for proper functioning of the autoregulatory
mechanism.11 On the contrary, evidence is accumulating that neither surgical nor pharmacological
sympathectomy diminishes autoregulatory capacity.
Eklof et al. (1971)12 showed that surgical sympathectomy two weeks prior to the study had no influence on
the autoregulatory function in monkeys. Fitch et al.13
have recently shown that in baboons acute surgical
and pharmacological sympathectomy causes only a
shift to the left of the lower autoregulatory limit,
which rather constitutes an improvement of
autoregulatory capacity.
In autopsy studies of the brains of long-term
diabetics, Reske-Nielsen et al.Ui I6 found abnormalities of the arteriolar walls in all cases. No clearStroke. Vol. 6, September-October 7975
cut correlation between degree of angiopathy and
symptoms and signs of cerebral disease could be established. Neither did degree of retinopathy seem to
correlate with degree of cerebral angiopathy. In our
studies no correlation between slope of curve and
degree of retinopathy, known duration of diabetes,
age or resting MABP could be deduced.
The most probable explanation to our findings
thus seems to be a diffuse or multifocal dysfunction of
cerebral arterioles due to diabetic vascular disease.
The autoregulatory response to variations in
cerebral perfusion pressure seems to be quite
vulnerable, and abnormalities of autoregulation are
described in association with a variety of different conditions, e.g., intracranial tumor, subarachnoid
hemorrhage, cerebral infarction, cerebral hypoxia,
meningitis, encephalitis and brain trauma. Impaired
autoregulation associated with the syndromes of normal pressure hydrocephalus and chronic idiopathic
autonomic insufficiency also has been reported.16"19
Among these different disease states only chronic
idiopathic autonomic insufficiency can be said, in a
strict sense, to represent a condition with chronically
impaired autoregulation in patients with no signs of
intracranial disease, that could be ascribed exclusively
to arteriolar dysfunction. In this respect chronic
idiopathic autonomic insufficiency and chronic
arterial hypertension2 are comparable with long-term
diabetes.
The existence of a condition of chronically impaired autoregulation due exclusively to sympathetic
denervation is, however, for the reasons given above,
difficult to accept. Furthermore, reports of this
phenomenon are few and somewhat conflicting.18"20
Until future studies have finally settled the question of chronically impaired autoregulation associated
with idiopathic autonomic insufficiency, the only two
conditions of chronically abnormal autoregulation
that can be ascribed to arteriolar disease per se thus
seem to be chronic arterial hypertension and longterm diabetes.
When comparing these two conditions, we seem
to be dealing with two different types of chronic autoregulatory abnormality. Whereas the arteriolopathy
in hypertension causes a shift to the right of the
autoregulation curve with preservation of the autoregulatory plateau,2 this plateau is absent in patients
with impaired autoregulation due to diabetic arteriolopathy, where CBF seems to vary continuously with
MABP.
References
1. Lassen NA: Cerebral blood flow and oxygen consumption in
man. Physiol Rev 39:183-238, 1959
2. Strandgaard S, Olesen J, Skinh^j E, et ah Autoregulation of
brain circulation in severe arterial hypertension. Brit Med J
1:507-510, 1973
3. Olesen J: Quantitative evaluation of normal and pathologic
cerebral blood flow regulation to perfusion pressure. Arch
Neurol 28:143-149, 1973
501
BINT3IN, L A M I N , LASMN
Downloaded from http://stroke.ahajournals.org/ by guest on July 31, 2017
4. Skinh^j E, Strandgaard S: Pathogenesis of hypertensive
encephalopathy. Lancet 1:461-462, 1973
5. Lennox WG, Gibbs EL: The blood flow in the brain and the
leg of man, and the changes induced by alteration of blood
gases. J Clin Invest 1 111 155-1177, 1932
6. Finnerty FA, Witkin L, Fazekas JF: Cerebral hemodynamics
during cerebral ischemia induced by acute hypotension. J
Clin Invest 33:1227-1232, 1954
7. Olesen J, Paulson OB, Lassen NA: Regional cerebral blood
flow in man determined by the initial slope of the clearance
of intra-arterialry injected '"Xe. Stroke 21519-540, 1971
8. Harper AM, Glass HI: Effect of alterations in the arterial carbon dioxide tension on the blood flow through the cerebral
cortex at normal and low arterial blood pressures. J Neurol
Neurosurg Psychiat 28:449-452, 1965
9. Olesen J: The effect of intracarotid epinephrine,
norepinephrine and angiotensin on the regional cerebral
blood flow in man. Neurology 22:978-987, 1972
10. Holmgren A, Pernow Bi Spectrophotometric measurement of
oxygen saturation of blood in the determination of cardiac
output. A comparison with the van Slyke method. Scand J
Clin Lab Invest 11:143-149, 1959
11. Skinh^j E: The sympathetic nervous system and the regulation
of cerebral blood flow in man. Stroke 3:711-716, 1972
12. Eklof B, Ingvar DH, Kagstrom E, et ah Persistence of cerebral
blood flow autoregulation following chronic bilateral cervical sympathectomy in the monkey. Acta Physiol Scand
82:172-176, 1971
13. Fitch W, Ferguson GG, Senguptg D, et ah Autoregulation of
502
cerebral blood flow during controlled hypotension,
(abstract) Stroke 4:324, 1973
14. Reske-Nielsen E, Lundbaek Kg Diabetic encephalopathy. Acta
Neurol Scand 3 9 (Suppl 4)=273-290, 1963
15. Reske-Nielsen E, Lundbaek K, Rafaelsen OJ: Pathological
changes in the central and peripheral nervous system of
young long-term diabetics. I: Diabetic encephalopathy.
Diabetologia 1:233-241, 1965
16. Mathew NT, Hartmann A, Meyer JS, et ah The importance of
"CSF pressure-regional cerebral blood flow dysautoregulation" in the pathogenesis of normal pressure hydrocephalus. Read at: Second International Symposium on Intracranial Pressure, Lund, June, 1974
17. Raichle ME, Eichling JO, Gado M, et ah Cerebral blood
volume in dementia. Read at: Second International Symposium on Intracranial Pressure, Lund, June, 1974
18. Meyer JS, Shimazu K, Fukuuchi Y, et ah Cerebral
dysautoregulation in central neurogenic orthostatic hypotension (Shy-Drager syndrome). Neurology 23:262-273, 1973
19. Caronna JJ, Plum F: Cerebrovascular regulation in
preganglionic and postganglionic autonomic insufficiency.
Stroke 4:12-19, 1973
20. Skinhatj E, Olesen J, Strandgaard S: Autoregulation and the
sympathetic nervous system: A study in a patient with
idiopathic orthostatic hypotension. In Russell RWR (ed):
Brain and Blood Flow. Proceedings of the Fourth International Symposium on the Regulation of Cerebral Blood
Flow, London, 1970. London, Pitman Ltd., p 351-353, 1971
Slrokt, Vol. b. Stpttmbtr-Octobtr
1973
Chronically Impaired Autoregulation of Cerebral Blood Flow in Long-Term Diabetics
NIELS BENTSEN, BO LARSEN and NIELS A. LASSIN
Stroke. 1975;6:497-502
doi: 10.1161/01.STR.6.5.497
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