Download A Comparison of Regional Blood Flow and Oxygen

A Comparison of Regional Blood Flow and Oxygen
Utilization During Dynamic Forearm Exercise in
Normal Subjects and Patients with Congestive
Heart Failure
By ROBERT ZELIS, M.D., JOHN LONGHURST, M.D., ROBERT J. CAPONE, M.D.,
AND
DEAN T. MASON, M.D.
With the Technical Assistance of Mr. Robert Kleckner
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SUMMARY
Patients with severe congestive heart failure (CHF) have been found to have a diminished response to the
metabolic arteriolar dilator stimulus of ischemia. In order to evaluate a more physiologic stimulus and the
possible metabolic consequences of this vascular abnormality, 22 normal subjects (N) and seven patients
with severe CHF performed rhythmic forearm exercise by squeezing a rubber bulb to 25, 50, or 100 mm Hg
for 5 sec, four times/min, for 5 min. During the last half of the 10 sec relaxation phases, forearm blood flow
(FBF) was measured plethysmographically. Not only was FBF reduced at rest in CHF (CHF: 2.00 i 0.31;
N: 3.10 ± 0.27 ml/min 100 ml, P < 0.02) but it was reduced at each level of exercise as well (CHF:
4.05 0.71, 5.57 + 0.71, 6.68 + 3.09; N: 7.10 ± 0.76, 11.15 ± 1.24, 20.32 ± 1.93 ml/min. 100 ml,
P < 0.01). Forearm oxygen extraction, calculated from brachial venous and systemic arterial blood, was consistently increased in CHF and was sufficient to maintain a normal forearm oxygen consumption at rest
(CHF: 0.14 ± 0.04; N: 0.12 + 0.01 ml 02/min 100 ml, P < 0.5). During exercise the calculated index of
0.04, 0.48 + 0.09, 0.54 + 0.14; N:
oxygen consumption was reduced at all levels of exercise (CHF: 0.30
0.51 ± 0.05, 0.89 i 0.08, 1.63 + 0.13 ml 02/min 100 ml, P < 0.01). These differences persisted despite
alpha-adrenergic blockade with phentolamine and suppression of skin flow in N by epinephrine iontophoresis. Therefore, at comparable levels of dynamic forearm exercise patients with CHF have an inadequate arteriolar dilation and their augmented oxygen extraction is not sufficient to prevent them from shifting more completely to anaerobic metabolism.
Additional Indexing Words:
Arteriolar dilatation
Plethysmography
Forearm blood flow
Hyperemia
Congestive heart failure
Fo rearm oxygen consumption
Alpha-adrenergic tone
Exercise
DURING DYNAMIC EXERCISE patients with
congestive heart failure (CHF) appear to have
an exaggerated sympathoadrenal response which
results in a decreased perfusion of regional circulations that have low metabolic requirements and
adequate alpha-adrenergic receptor sites.'`6 A similar
increase in alpha-adrenergic tone also occurs in exercising skeletal muscle. However, these constrictor impulses are offset by the local accumulation of
metabolites and a vasodilation occurs.7' 8 Therefore, in
exercising muscle, vascular resistance falls and oxygen
delivery increases. It is important to note that patients
with CHF demonstrate a reduced metabolic arteriolar
dilator response following restoration of flow to an
ischemic limb (reactive hyperemia) which is considerably reduced when compared with that of normal
subjects.9 This relative arteriolar stiffness has been
postulated to be a possible protective mechanism for
Laboratory of Clinical Physiology, Cardiology Section,
Dr. Capone is currently at the Rhode Island Hospital in
Providence, Rhode Island.
Presented in part at the 43rd Scientific Sessions of the American
Heart Association in Atlantic City, New Jersey, November 1970.
Address for reprints: Robert Zelis, M.D., Cardiology Section,
University of California at Davis, School of Medicine, Davis,
California 95616.
Received December 26, 1973; revision accepted for publication
From the
University of California at Davis, School of Medicine, Davis,
California.
Supported in part by American Heart Association Grant No. 71
888 and Program Project Grant No. HL 14780 of the National
Institutes of Health. At the time of these studies Dr. Capone was
supported by NHLI Research Fellowship HL 52380 and Dr.
Longhurst was supported by a Bank of America Giannini Foundation Fellowship.
Circulation, Volume 50, July 1974
March 12, 1974.
137
ZELIS ET AL.
138
the heart failure patient which might serve to maintain an adequate systemic blood pressure in the face of
a limited cardiac output response to dynamic exercise. Although this abnormality might be partially
advantageous, it is not known whether any adverse
metabolic consequences result from this reduced
dilator capacity. The purpose of these studies was to
evaluate total forearm blood flow (FBF), oxygen extraction, and oxygen consumption during steady-state
graded dynamic forearm exercise.
'
Material and Methods
Studies were performed in seven patients with CHF (ages
41 to 67 yrs) and 22 normal volunteers (ages 23 to 59 yrs). All
patients had rheumatic etiologies for their heart failure,
were in functional class III-IV (New York Heart Association
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classification), and had evidence of right-sided decompensation and fluid retention. The normal subjects were inmate
volunteers from the California Medical Facility and patients
admitted to the Sacramento Medical Center for cardiac
evaluation who were found to have no heart disease. The
protocol of these studies was evaluated and approved by the
Chancellor's Advisory Committee for Research Involving
Physiological or Clinical Studies of Human Subjects. The
research proposal was also evaluated and approved by a
comparable committee of the Solano Institute for Medical
and Psychiatric Research, a noninstitutional group supervising all research on inmate volunteers. Informed consent
was obtained in all cases.
Forearm blood flow was measured by the venous occlusion technique with a single strand mercury-in-rubber strain
gauge plethysmograph placed at mid forearm in the nondominant extremity using a Parks bridge.9' 11-14 A collection
of 30 mm Hg was used. The forearm was elevated
above heart level and the hand was occluded from the circulation by inflation of a wrist cuff to suprasystolic pressures
at least one minute prior to any determination of FBF."
Arterial pressure was measured directly with a Statham
P23db pressure transducer by means of a needle placed in
the contralateral brachial or radial artery which was also
used for the sampling of arterial blood. A 19 gauge Deseret
Intracath was inserted in the antecubital vein of the extremity to be exercised and the catheter passed percutaneously to the midbrachial vein for the sampling
of mixed forearm venous blood. Oxygen saturation and
hemoglobin were determined with a model 182 IL CoOximeter and oxygen content was calculated. Recordings were
made with a Hewlett Packard model 4560 optical recorder
with a rapid developer.
All subjects were studied in the basal postabsorptive state
and were allowed to rest for 15 to 30 min following instrumentation. Following the determination of six to ten
control measurements of FBF, the subjects performed
rhythmic grip exercise by squeezing a pneumatic bag which
was inflated to a basal pressure of 50 mm Hg prior to exercise. The ;.ibjects varied the intensity of their grip to increase tue pressure in the manometer by 25, 50, or 100 mm
Hg. The grips were held for 5 sec and were repeated four
times/min for 5 min. Blood flow was measured during the
last 5 sec of the 10 sec rest period between grips. Venous and
arterial blood samples were drawn in duplicate prior to the
beginning of exercise and during each minute of the exercise
pressure
period. Oxygen extraction was calculated as the arterialvenous difference (vols %) x 100 divided by the averaged
arterial oxygen content. In all instances, venous oxygen content varied little over the last 3 min of exercise, and an
average value was therefore taken for calculations. Forearm
oxygen consumption (ml 0,/min . 100 ml) during the basal
state was calculated as the arterial-venous oxygen difference
(vols %9) X FBF (ml/min. 100 ml) divided by 100. During
exercise an index of oxygen consumption was similarly
calculated during each minute of exercise and averaged
after a steady-state was achieved between 2 and 5 min of exercise. It is acknowledged that FBF measured in this
manner during exercise is not true mean FBF. Muscle blood
flow has a regular phasic pattern during exercise and is
reduced during the period of time when the muscle
develops tension. Previously, it was determined that blood
flow calculated in this manner was proportionally related to
mean integrated blood flow averaged throughout the exercise period as measured by a flowmeter placed on the
brachial artery at the time of cardiac catheterization."8 A
steady-state flow pattern develops after 2 min of exercise
whether measured with flowmeter or plethysmograph and
was highly reproducible. Importantly, the relationship
between mean integrated flowmeter blood flow and average
plethysmographic blood flow was linear and the function
did not vary with the severity of exercise; plethysmographic
flow was always 1.7 times higher. Thus, the systematic error
that was introduced in the calculation of forearm oxygen
consumption was the same for both high and low exercise
flows.
In 12 normal subjects and six subjects with CHF, exercise
was repeated at the 50 mm Hg level following alphaadrenergic blockade of the forearm induced by the intraarterial injection of 2 mg of phentolamine. This dose
markedly attenuates the forearm vascular response to ice
applied to the forehead.9 In four normal subjects exercise
was repeated at the 100 mm Hg level following epinephrine
iontophoresis of the forearm as described previously.' This
procedure effectively reduces skin blood flow to indeterminable levels for a period of one to two hours.5 In six normal subjects cardiac output was determined by the dye dilution technique and systemic oxygen consumption measured
during an exercise period in which the subjects gripped the
hand dynamometer and increased the pressure by 150
mm Hg.
Results
Forearm blood flow during the basal state was
3.10 ± 0.27 ml/min . 100 cc in the normal subjects
(N) and 2.00 ± 0.31 ml/min. 100 cc in the patients
with CHF (P < 0.02). During each of the three levels
of exercise, the normal subjects increased their mean
FBF during the steady-state to 7.10 ± 0.76,
11.15 ± 1.24 and 20.32 ± 1.93 ml/min . 100 ml
respectively (P < 0.01) (fig. 1). Although patients with
CHF also increased their FBF during each of the
three levels of exercise, it was considerably less than
that achieved by the normal subjects at each level
(4.05 ± 0.43, P < 0.01; 5.57 ± 0.71, P < 0.01;
6.68 ± 3.09 ml/min * 100 ml, P < 0.01). Forearm
oxygen extraction likewise was considerably greater in the
heart failure subjects than in the normal subjects at
Circulation, Volume 50, July 1974
FOREARM OXYGEN UTILIZATION IN CHF
-..2
a
20
F=
U-
10
-J
C
w 5
CL
pp--.
0
CL
p-, <.02
CONTROL
p= <.OI
25
p-=<.OI
50
p-= <.01
100
LEVEL OF EXERCISE (mm Hg)
Figure 1
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Forearm blood flow (± standard error of the mean, SEM) measured
plethysmographically at rest and during the resting phase of steadystate intermittent grip exercise of increasing intensity in normal
subjects and patients with congestive heart failure (CHF).
rest (N: 34.86 ± 2.45. CHF: 50.20 + 5.99%,
P < 0.05) and during each level of exercise (N:
43.08 + 2.64; 47.21 ± 1.93; 48.31 ± 2.08. CHF:
53.21 i 4.92, P < 0.05; 59.27 ± 4.52, P < 0.05;
55.24 ± 0.35%, P < 0.01) (fig. 2). Forearm oxygen
consumption at rest was similar in the two groups (N:
0.12 ± 0.01. CHF: 0.14 + 0.04 ml 02/min. 100 ml,
P < 0.5). During exercise, however, the calculated
forearm oxygen consumption was considerably
139
reduced at each level of exertion (N: 0.51 + 0.05;
0.89 ± 0.08; 1.63 ± 0.13. CHF: 0.30 ± 0.04,
P < 0.01; 0.48 ± 0.09, P < 0.01; 0.54 ± 0.14 ml
02/min . 100 ml, P < 0.01) (fig. 3).
Following intra-arterial phentolamine basal FBF
significantly increased (N: 9.47 ± 1.08. CHF:
5.76 ± 0.77 ml/min. 100 ml, P < 0.02) as did oxygen
consumption (N: 0.42 + 0.07. CHF: 0.18 + 0.02 ml
02/min. 100 ml, P < 0.01). During the middle level
of exercise, however, the differences persisted
between the two groups (FBF - N: 13.59 ± 1.47.
CHF: 7.88 + 1.05 ml/min. 100 ml, P < 0.01.
Forearm oxygen consumption -N: 0.99 + 0.10.
CHF: 0.49 ± 0.08 ml 02/ml 100 ml, P < 0.01) (fig.
4). Epinephrine iontophoresis in the normal subjects
partially attenuated the blood flow response at the
highest exercise level (16.88 + 0.90 ml/min . 100 ml)
and also reduced the calculated oxygen consumption
(1.22 ± 0.21 ml 02/min. 100 ml); however, these
values were still significantly greater than those of the
heart failure subjects (P < 0.02) (fig. 5). When a
separate group of normal subjects performed exercise
at a level higher than that used for the above comparisons between groups (150 mm Hg level), they
minimally increased their cardiac output from
6170 + 3.81 to 6848 ± 4.19 cc/min (P > 0.05) and
their systemic oxygen consumption from 343 ± 58 to
376 + 52 cc 02/min (P > 0.1), values which were not
significantly different from control.
E
60
0
60
C> Io
NORMAL
0
,
0
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a :X
o 50
C-
1.0
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05 i
/'0
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NORMAL
40
0
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CHF
----
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--:
er
co
11-
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0-
CONTROL
p= <.05
p= <.05
25
50
p= <.O0
100
LEVEL OF EXERCISE (mmrHg)
p>5
P=L<O0
p= <.01
CONTROL
25
50
p- .v.
100
LEVEL OF EXERCISE (mm Hg)
Figure 3
Figure 2
Percent oxygen extraction (+ SEM) of the forearm calculated from
the arterial-brachial vein oxygen difference at rest and during
steady-state forearm exercise of three levels of exertion in normal
subjects and patients with congestive heart failure (CHF).
Circulation, Volume 50, July 1974
Forearm oxygen consumption (± SEM) calculated as tl^e product of
plethysmographically measured forearm blood flow and arterialbrachial vein oxygen difference at rest and duringforearm exercise
of increasing intensity in normal subjects and patients with congestive heart failure (CHF).
ZELIS ET AL.
140
1
IB
p
<.01
<.05
C
p
<oi
<(01
T
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a:c
Azl
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'.
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N CHF
NO
PHENTO.
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A
Figure 4
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Forearm blood flow (A), forearm vascular resistance (B), and
forearm oxygen consumption (C) (± SEM) during forearm exercise
at the 50 mm Hg level of severity before (No Phento.) and after
intra-arterial phentolamine (I. A. Phento.) in normal subjects (N,
clear bars) and patients with congestive heart failure (CHF,
stippled bars). P values indicate comparisons between normal and
heart failure subjects.
Discussion
In the present study it was demonstrated that with
rhythmic grip exercise of three different intensities,
the patients with heart failure did not increase their
FBF to the same extent as normal subjects (fig. 1).
These findings are similar to previous results from this
laboratory which employed the reactive hyperemia
response to evaluate metabolically induced changes in
1|A
10
p4 B
-.
pPa<b1
Figure
<
02
5
Forearm blood flow (A) and forearm oxygen consumption (B) (±
SEM) during forearm exercise (100 mm Hg level) in patients with
congestive heart failure (CHF stippled bars) and normal subjects
who have undergone epinephrine iontophoresis of the exercising extremity (clear bars).
-
skeletal muscle blood flow." This study is also in agreement with those of Epstein et al. and Vatner et al. who
demonstrated that systemic vascular resistance and
limb vascular resistance did not decrease normally in
patients or animals with CHF during exercise. 17, 18 In
part, their results could be explained by the
augmented sympathoadrenal response that is seen
with exercise in heart failure subjects resulting in a
marked increase in resistance in the cutaneous, renal,
and splanchnic vascular beds. It should be noted that
not all investigators have demonstrated a reduced
arteriolar dilator capacity in heart failure. Utilizing an
isolated gracilis muscle preparation, Mayer et al.
found a normal dilator response to papaverine in an
animal model of CHF.19 The reason for this discrepancy is unclear; however, we have found that the abnormal vascular dilator response can only be seen in
patients with chronic severe symptomatic CHF and is
not demonstrable with minimal or moderate cardiac
disease. Despite the significant pump failure which
was present in these patients, the factors which determined FBF during the rhythmic grip exercise
employed in this study were not cardiac in origin but
rather regional. When normal subjects performed exercise at one grade above the most strenuous level
used for intergroup comparisons, there was a small
and insignificant mean increase in cardiac output of
668 ml/min and systemic oxygen consumption of 33
ml 02/min. It is likely that these small increases in
cardiac output during forearm exercise could have
been attained even by patients with considerable impairment in ventricular function.
It is recognized that the plethysmograph may not
actually be measuring true averaged blood flow during exercise. However, it has previously been shown
in this laboratory that there is a predictably systematic
error produced when FBF is measured during exercise
by this technique.16 It should be noted that this error
is similar during both high intensity exercise and
lower level exertion. In these studies it was
demonstrated that a steady-state pattern of blood flow
develops after the second minute of exercise, and it
could be reliably and reproducibly quantitated with
both plethysmograph and flowmeter.16 If static exercise were evaluated rather than dynamic exercise, it
might have been easier to measure flow by the
plethysmographic technique ;20 21 however, dynamic
exercise was chosen because it more nearly simulates
the physiologic stress encountered clinically by the
cardiac patient.
A second finding in this study was an increased oxygen extraction at rest and during each level of exercise
in the heart failure patients (fig. 2). This is consistent
with the widened arterial-venous oxygen difference
and the marked depression in pulmonary oxygen
Circutlation,
Volume 50, July 1974
FOREARM OXYGEN UTILIZATION IN CHF
seen when heart failure patients perform
maximal upright exercise.17 Part of the increased oxygen extraction in the heart failure subjects could be
explained if there were a longer than normal transit
time of blood through the metabolically active
muscles. However, it is possible that transit time may
not be prolonged if the reduced flow were caused by a
smaller cross-sectional area of the vascular tree or if
parallel circuits were totally constricted. We have
postulated that the observed inadequate increase in
flow is secondary to an increased arteriolar stiffness
seen in heart failure and may be secondary to increased vascular sodium content.22' 23 This could also
possibly be related to the increased tissue pressure
seen in edematous states which would have a major
saturation
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effect to compress capillaries at their distal end.24-26 If
the inadequate increase in flow led to forearm tissue
hypoxia the resultant acidosis might be expected to
shift the hemoglobin oxygen dissociation curve more
to the right and enhance oxygen transfer to
metabolically active tissues. Similarly, the higher red
blood cell 2,3-diphosphoglyceric acid (DPG) levels
seen in heart failure would also be expected to increase red cell P50 and facilitate oxygen transfer from
hemoglobin to the exercising muscle.27 28
Since oxygen extraction was higher in heart failure
while FBF was abnormally low, it is possible that
forearm oxygen consumption might be normal. This is
true when the forearm was in a nonexercising resting
state (fig. 3). This indicates that the increased extraction of oxygen was sufficient to provide for the basal
metabolic needs despite a lower FBF. In contrast to
the resting state, the calculated oxygen consumption
during each level of exercise was significantly reduced
when the heart failure patients were compared with
the normal subjects (fig. 3). This was the most important finding in this study and one that deserves careful
consideration of possible causes and consequences.
One possible explanation for the abnormally low
forearm oxygen consumption during exercise is that
the heart failure subjects may have had an exaggerated sympathoadrenal response to regional exercise. A functional sympatholysis normally occurs during strenuous exercise in the metabolically active
vascular bed.7' 8 Although this would be expected to
significantly negate the effects of increased alphaadrenergic tone with maximum exercise with the submaximal levels utilized here, the metabolic factors
might compete less effectively with the neurogenic
determinants of regional muscle blood flow. In order
to evaluate this further, representatives of both groups
of subjects repeated the middle level of exercise
following alpha-adrenergic blockade of the forearm
with phentolamine. The amount of drug that was used
provides for complete blockade of the constrictor
Circulation, Volume 50, July
1974
141
effect of circulating catecholamines and markedly
attenuates the cold pressor response. Despite adequate alpha-adrenergic blockade which tended to
enhance blood flow in both groups during exercise,
forearm oxygen consumption was still significantly
lower in the patients with heart failure (fig. 4).
In order to fully accept the conclusion that forearm
oxygen consumption during dynamic exercise fails to
rise normally in heart failure, it must be demonstrated
that possible technical problems involved in venous
blood sample collection and metabolic blood flow estimation were adequately controlled. Since normal
subjects tend to dilate their cutaneous vessels late during an exercise period to dissipate heat, it is possible
that oxygen-rich cutaneous blood may have been
shunted to deep venous sampling sites.29' 30 Although
the valves of the communicating veins might favor
such a redistribution of effluent blood, Wahren has
shown virtual complete separation of forearm
cutaneous and muscle circulations during strenuous
forearm exercise.31 Based on known values for
systemic and forearm muscle mass,32 34 if one assumed
that an individual were to use all body muscle groups
equally at the 100 mm Hg level of exercise and that
the forearm V02 during exercise actually reflected the
true oxygen consumption of the forearm muscle, normal individuals would be expected to utilize about 30
cc 02/kg/min and heart failure subjects 11 cc
02/kg/min. Thus, the higher level of forearm exercise
was in fact strenuous and separation of the circulations should have occurred. To further evaluate
this problem selective catheterization of the median
cubital vein, which drains only forearm muscle, might
have been done.29 35 36 Unfortunately, in our heart
failure patients this was technically impossible to do.
Although oxygen-rich cutaneous blood reaching deep
venous channels might have led to an underestimation of forearm oxygen consumption during exercise,
an isolated cutaneous vasodilation per se could have
led to a significant overestimation of forearm oxygen
consumption in normal subjects.
To completely resolve this question and determine
whether or not the variable nature of the cutaneous
circulation in normal subjects during exercise had a
significant effect on the above observations, the
technique of epinephrine iontophoresis was
employed.37 Normal subjects were allowed to exercise
at the higher level of exertion (100 mm Hg) before
and following epinephrine iontophoresis, which effectively suppresses skin blood flow.5' 37-3 The differences
in forearm oxygen consumption persisted despite suppression of cutaneous blood flow in the normal subjects, thereby validating the conclusion that the lower
forearm oxygen consumption seen in heart failure
during exercise is not a function of superficial and
ZELIS ET AL.
142
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deep venous admixture, or a function of a cutaneous
hyperemia, but is in fact a true difference (fig. 5).
One of the reasons for reduced oxygen consumption
in CHF might be simply that oxygen availability is
reduced. In order to compensate, the patient with
heart failure might switch more completely to
anaerobic metabolism than the normal subject.40 41
This hypothesis would be difficult to test since it
would involve a complex analysis of fatty acid utilization, local glycogen breakdown, peripheral lipolysis,
and lactate production.3' ` " Another possibility is
that with chronic hypoxia there may have been
changes induced in the cytoplasmic glycolytic enzymes which facilitated the utilization of the EmdenMyerhof pathway for production of high energy
phosphates. Both of these mechanisms might be
operative to explain or be the consequence of reduced
regional oxygen consumption. Either would result in a
systemic lactic acidemia. This is a common finding in
cases of CHF and accounts in part for the increased
oxygen debt seen when such patients exercise.4' Of interest is that the marked cutaneous vasoconstriction
seen during exercise in the heart failure patients
might result in impaired thermal regulation, induce a
temperature elevation, and might explain why the
alactic portion of the oxygen debt is increased as
well.5 42, 43
In summary, it would appear that patients with
CHF do not adequately dilate their forearm arterioles
when they exercise. This suggests that they would
sacrifice adequate tissue perfusion to maintain blood
pressure during systemic dynamic exercise. The
metabolic cost of this abnormality appears to be
significant. There may be a prolongation of repayment of an increased oxygen debt and an increased
level of circulating lactate. Normally, a considerable
postexercise active hyperemia is seen in normal subjects. This may not be necessary to completely repay
the oxygen debt in the active muscle; however, it
probably plays a role in reduction of recovery time.44
In previous studies it was shown that patients with
heart failure have a reduced postexercise hyperemia.9
Thus, they would be expected to be fatigued longer
than normal patients following simple exercise. Such
symptoms are the hallmark of the low cardiac output
syndrome.
Acknowledgments
The authors gratefully acknowledge the secretarial assistance of
Mrs. Nancy Carston and Mrs. Laurel Harter. We are greatly indebted to the volunteers of the California Medical Facility,
Vacaville, for their cooperation; to Dr. T. Lawrence Clanon,
Superintendent, for permission to perform these studies; and to Mr.
F. R. Urbino, Medical Coordinator, Solano Institute for Medical
and Psychiatric Research.
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A Comparison of Regional Blood Flow and Oxygen Utilization During Dynamic
Forearm Exercise in Normal Subjects and Patients with Congestive Heart Failure
ROBERT ZELIS, JOHN LONGHURST, ROBERT J. CAPONE, DEAN T. MASON and
Robert Kleckner
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Circulation. 1974;50:137-143
doi: 10.1161/01.CIR.50.1.137
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