Studies of Peripheral Circulation during Sickle-Cell Crisis
By FELICE MANFREDI, M.D., ANGELO P. SPOTO, M.D., HERBERT A. SALTZMAIAN, M.D.,
AND HERBERT 0. SIEKER, M.D.
gate the peripheral circulation in patients
with sickle-cell disease. In particular, the possibility that peripheral shunting of blood occurs transiently and in relation to episodes
of crisis was considered and investigated.
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IT IS WELL recognized that patients with
sickle-cell disease may have a low saturation and tension of arterial blood oxygen.
Although arterial anioxemia was first observed
in 1942, its exact mechanism is still unknown.1
It has been shown that the hemoglobin dissociation curve of these patients is shifted to
the right, probably because of a decrease in
erythrocyte pH.2, 3 Therefore, a norimal level
of oxygen saturation would not be possible
even in the preselnce of a normal oxygen tension. A block of diffusion at alveolar-capillary
membrane resulting in an inereased pressure
gradient of alveolar-arterial oxygen has also
been suggested as a cause of arterial oxygen
unsaturation.4 It appears more likely, however, that abnormal venous admixture within
the lungs, as reported in other anemias,5 is
responsible for a low arterial oxygen tension.6
Congenital abnormalities in the lunig vasculature, opening of pulmnonary arteriovenious
anastomotic channels, extremely low oxygen
tension in the returning venous blood, or pulmonary parenchymal alterations have been
suggested as mechanisms by which abnormal
venous admixture within the lungs occurs.6
Apparently, shunting of blood within the
lungs accounts for the arterial oxygen unsaturation observed in sickle-cell disease.
The possibility that abnormal shunts are
also present in the peripheral circulation of
these patients has not been investigated, although it has been recently suggested in the
results of experiments intended to show abnormal intrapulmonarv venous admixture.6
The present study was undertaken to investi-
Methods
Eighteen Negro subjects, ranging in age from
16 to 48 years, were studied in a total of 31 observations. The electrophoretic hemoglobin pattern
was SS in 11 patients, SC in 3 patients, and SA
in 1. The 3 remaining subjects had hemoglobinopathies, but the exact electrophoretic pattern
could not be established because of recent blood
transfusions.
Eleven patients were asymptomatic at the time
of the study. Repeated observations were made on
the other 7 patients during and after sicklemic
crises. Abdomuinal pain, joint symptoms, temperature elevation, leukocytosis, and degree of hemolvsis as indicated by changes in hemnatocrit value,
reticulocyte count, and bilirubin level were used
to identify a sickle-cell crisis. The extremities and
in particular the hands of the patients during
crisis were at normal temperature and not flushed
or hot.
Indwelling needles were placed in the brachial
artery and a superficial forearm vein on the same
side. Sufficient time was allowed to obtain a resting state of the subject and to reestablish a free
flow in the vein before blood samples were drawn
simultaneously in oil-heparin syringes from the
artery and the vein. In 2 patients studied during
crisis, blood was also obtained by intravenous catheterization at points from the superior vena eava
to the superficial vein of the forearmn. In 2 patients in crisis, observations were made with and
without a venous tourniquet at the wrist, in order
to determine the effect of blockage of venous drainage fromi the hand.
Similar control studies were performed in 6
anemic patients without the sickle-cell trait with
a mean henmoglobin coneentration of 5.7 Gm. per
cent, and in 3 febrile patients with a imean temperature of 38.7 C.
Oxvoen content and saturation, pH, and hemiio4(lobin were determined on the paired blood samiiples. Oxygen and hemnoglobin were measured by
the spectrophotoimetric nmethod of Hickam and
Frayser.7 At low hemoglobin concentrations the
From the Departmenit of Medicine, Duke Unliversity Medical Center, Durhamli, N.C.
Supported in part by a gianlt from the American
Heart Associationi aind in part by the Life Tlusurancee
Medical Research Fund.
Dr. Manfredi is a Research Fellow of the American
Heart Associationi. His present address is Indiana
Medical Center, Indianapolis, TId.
602
Circulation, Volume XXII, October 1960
SICKLE-CELL CRISIS
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oxygen content was determined with a 15 per cent
saponin solution instead of the usual 30 per
cent. Careful attention was given to the completeness of hemolysis in the blood samples for
oxygen determination, since sickle erythrocytes
have an increased resistance to hypotonic solutions.8 Standard Van Slyke determinations for
oxygen content and capacity were made for comparison with the results obtained by the spectrophotometric method on 11 different arterial or
venous samples. The mean difference between the
manometric and the spectrophotonietric technics
was -0.5 vol. per cent for oxygen content and +0.3
vol. per cent for oxygen capacity. The pH of
whole blood was measured with a Cambridge model
R pH meter equipped with an enelosed glass electrode. Measurements were made at room temperature and corrected to 37 C. by Rosenthal's factor.9
603
7400 11
100 1[
A
A
(9)
('I)
"I
90-
7)
A
/4)
A
_{7,'1)
A
7.75-*o
7
80-
:R
pH
7.350n
.,\
0
70-
.
7.325-
.;
60VX
Results
The 11 asymptomatic individuals and the
5 patients studied after resolution of crisis
demonstrated a decrease in mean arterial oxygen saturation to 87.9 per cent (table 1, fig.
1). The mean superficial vein oxygeni saturation was 66.5 per cent, quite comparable to
the value reported by Roddie et al.10 for oxygen saturation in blood from superficial veins
in a group of 15 young healthy subjects. The
mean arteriovenous oxygen difference for the
group was 2.37 vol. per cent. Fourteen sets
of observations were made on 7 patients during sickle-cell crisis, 1 patient (G., J.) being
studied during crisis on 5 different occasions.
In this group, the arterial oxygen saturation
was again found to be low, with a mean of
86.6 per cent. The venous oxygen saturation
was constantly high, with a mean of 81.9 per
cent. The mean arteriovenous oxygen difference during crisis was 0.47 vol. per cent, and
the mean arteriovenous pH difference was
only 0.010, in contrast to the value of 0.042
found in the group not in crisis (fig. 1).
Normal arterial and venous oxygen saturations with a mean arteriovenous difference of
2.16 vol. per cent were observed in the control
group of 9 patients with anemia or fever (fig.
1).
Patients G., J.; H., J.; and L., B. were
studied on 4 to 6 occasions on different days.
They were all asymptomatic during at least
one study. Figure 2 summarizes the essential
data on patients G., J.; and H., J. A small
Circulation, Volume XXII, October 1960
50-
MEAN
L
7.300
VALUES FOR THE GROUPS
Sickle Cell Disease,
Not in Crisis
A = Artery
V = Vein
( No. of Observotions
I
_
_
Sickle Cell Diseose,
In Crisis
Anemia - Fever
(Mean Hb 5.7 Gms%,
meon T° 38.7 CO)
Figure 1
Mean arteriovenous differences for oxygen satura-
tion (left) and pH (right) in a group of asymptomatic patients with sickle-cell disease, in a group
during acute crisis, and in a control group with
anemia or fever of various etiology.
arteriovenous difference for oxygen and pH
was observed during crisis, and widening of
the gradients occurred as symptoms subsided.
When blood samples were obtained from
the superior vena eava or deep venous system
of the arm, a norimal arteriovenous difference
was found even during crisis. Figure 3 presents 2 examples of arteriovenous pairs with
venous blood drawn from deep and superficial venous circulation at the same time.
In 2 symptomatic patients with small oxygen and pH arteriovenous gradients, the application of a venous cuff above the wrist,
which prevented the venous return from the
hand, resulted in decreased oxygen and pH
blood values in the superficial vein. The arteriovenous gradient for oxygen increased from
0.32 to 3.24 vol. per cent in the first patient,
and from 0.44 to 1.31 vol. per cent in the
second patient. Concomitantly, the arterio-
604
MANFREDI, SPOTO, SALTZMAN, SIEKER
Table 1
Data in Eighteen Patients with Sickle-Cell Anemia
Patient
No.
1. B., Jo.
Clinical
condition Age
Hb
Hb
02 cont.
type (Gm. %) (vol. %)
Brachial artery
02 sat.
(%)
pH
A-V
Superficial vein
Hb 02 cont. 02 sat.
(Gm. %)(vol. %) (%)
difference
pH
02 cont.
(vol. %S)
19
MT
SS
9.1
10.3
83.6
-
9.5
9.1
7X0.2
-
1.2
not ill
crisis
19
M
SS
7.4
9.0
89.8
7.367
8.0
5.7
52.5
7.331
3.3
in
21
M
SS
7.5
9.0
88.7
7.362
7.5
8.9
88.1
7.357
.1
7.1
8.4
87.6
7.413
7.0
8.3
87 .0
7.389
.1
.3
Iot ill
Sex
crisis
2. B.,
W.
3. G., J.
12-14-58
12-17-58
3-24-59
5-8-59
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5-12-59
5-23-59
4. H., J.
12-26-58
7-24-59
7-25-59
7-27-59
5. H., B.
6. I., W.
7. L., B.
5-25-59
5-28-59
6-20-59
8.
7-6-59
M., M.
9. M., J.
10. M., R.
11. N., A.
10-15-58
10-16-58
12. N., E.
13. P., L.
crisis
in
crisis
in
crisis
in
crisis
11ot in
crisis
in
crisis
in
crisis
in
crisis
in
crisis
not in
crisis
in
crisis
in
crisis
ill
crisis
not in
crisis
in
crisis
not in
crisis
not in
crisis
not in
crisis
not in
crisis
in
crisis
not in
crisis
not in
crisis
not ill
27
M
SC
8.3
9.8
89.9
7.377
8.4
9.5
87.1
_
5.7
6.7
86.3
7.429
5.8
6.3
80.1
7.421
.4
6.3
7.5
87.4
7.426
6.3
4.5
52.6
7.345
3.0
7.7
8.6
79.9
7.393
8.2
8.3
77.0
7.383
.3
12.4
16.9
98.3
7.465
12.1
16.1
93.0
7.460
.8
12.0
15.2
93.2
7.318
11.9
13.5
83.0
7.306
1.7
11.4
13.8
88.7
7.359
11.5
13.8
88.2
7.348
0
12.3
15.8
93.9
7.313
12.3
11.4
58.0
7.290
4.4
9.3
11.9
96.2
7.419
9.6
11.5
87.7
7.394
.4
11.0
11.6
76.8
19
M
32
WI
SC
11.0
12.8
85.3
-
30
P
SS
7.0
7.6
75.9
7.336
7.0
6.7
67.1
7.336
.9
7.6
8.7
84.3
7.400
7.3
5.9
59.8
7.394
2.8
8.1
9.6
82.7
-
8.0
9.6
77.1
8.9
11.2
91.8
-
8.9
8.9
67.7
-
2.3
1.2
0
17
F
SS
8.9
10.4
85.9
7.377
9.5
8.4
64.5
7.313
2.0
48
M
SA
11.8
14.6
91.0
7.374
12.0
13.1
80.2
7.347
1.5
46
MI
7.8
7.8
74.0
7.405
8.1
6.4
60.3
7.293
1.4
30
M
5.0
4.8
70.6
-
5.0
4.8
70.6
_
6.0
7.8
95.2
7.190
6.0
6.7
81.4
7.154
1.1
SS
0
16
F
SC
8.1
9.9
89.9
7.360
8.1
6.6
60.4
7.312
3.3
18
F
SS
8.1
10.1
91.3
7.359
7.7
6.7
64.4
7.335
3.4
34
M
SS
10.6
12.5
86.0
-
10.1
10.6
77.7
36
M
SS
11.1
13.6
90.0
7.372
11.1
10.8
71.4
in
crisis
not in
crisis
25
F
SS
6.9
8.4
89.0
-
6.9
8.0
85.0
6.9
8.1
86.5
-
7.0
6.9
72.4
notin
30
MN
7.9
9.1
84.7
-
8.0
5.9
53.8
crisis
not in
crisis
20
F
7.2
8.9
90.4
-
7.2
7.3
74.2
crisis
14. S., J.
15. S., A.
16. W., R.
2-7-59
2-9-59
17. W., W.
18. W., Y.
not in
crisis
not in
crisis
SS
CircuZlat,on,
1.9
7.357
2.8
.4
_
1.2
3.2
-
1.6
Volume XXII, October 1960
SICKLE-CELL CRISIS
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1959
605
Demerol
Demerol
Demero
Codeine
Doriden
00 mg. l. M. I OO mg I. M. I OO mg I. M. 60 mg. I. M. 5mg. p. o.
q2-4h.
q. 2-4h.
x2
q. 2-4h.
x2
7-24
7-25
7-26
7-27
7-28
ARTERY
Discharged
In Crisis
Out
of Crisis
5-8
5-12
_
7-29
1959
--- VEIN
Figure 2
Arteriovenous oxygen differences and clinical course of 2 patients with sickle-cell disease.
venous gradient for pH increased from 0.004
to 0.018 anid from 0.002 to 0.008 in the 2
subjects.
Discussion
This study indicates that during sickle-cell
crisis arterialized blood is present in the
superficial veins of the forearm, as evidenced
by the oxygen content and pH values. In all
the determinations on patients with sicklecell disease who were not in crisis and in the
control patients who were febrile or anemic,
wide arteriovenous differences for oxygen and
pH were observed. The narrow arteriovenous
difference during crisis suggests an increase
in blood flow or a decrease in oxygeni uptake
by the tissue.
Fever or alneiimia, or both, during crisis
could account for arterialization of venous
blood on the basis of an inerease in peripheral blood flow. However, the 9 patients without sickle-cell disease but with fever or proCirculation, Volume XXII, October
1960
found anemia showed a normally wide
arteriovenous difference for oxygen. Furthermore, the appearance of the extremities of
these patients in crisis did not suggest dilated
vasculature or increased blood flow.
It is possible that the arterialization of
venous blood may be due to decreased oxygen
utilizationi by the tissues during crisis. However, in a group of 13 patients with sicklecell anemia, Leight et al.11 found an increase
in per cent oxygen utilization by the tissues.
In view of the lack of correlation between the
increase in cardiac index and the decrease in
hemoglobin level, they postulated the existeniee of a peripheral compensatory mechanisni
whereby the per cent of oxygen extraction in
the tissues is increased as the oxygen content
of arterial blood is lowered. Since most of our
patients had arterial oxygen unsaturation,
Leight's observation would suggest a low oxygen content in the returning superficial ve-
6MANFREDI, SPOTO, SALTZMAN, SIEKER
606
4
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Figure 3
Oxygen gradienzt between arterial and deep venous
system (superior venav cava and axillary vein), and
between arterial and superficial venous systemg
(superficial vein of the forearm) in 2 patients
wiiith sickle-cell disease during anl acute crisis.
blood. It must be emiphasized that the
patielnts reported by Leight were inot studied
during acute crisis. Moreover, it is possible
that the increased oxygen utilization by the
tissues demonstrated by these investigators
occurred in the deep muscles and not in the
cutaneous areas, since ill their study the arteriovenous differences referred to mixed venious blood samples from the pulimonary
nous
artery.
It may be postulated that arterialization of
superficial venlous blood duriiig sickle-cell crisis results fromn arteriovemmous shunts in the
superficial tissues of the hands. Arteriovenous
aniastomoses of considerable size have beenl
demoiistrated anatomnically in
the
skin.12
Moreover, even in the absence of anatomically
distiniet shunlts, the blood miay bypass the
inajor portion of the capillary mietwork where
oxygen is removed by the tissues. Neuroregulatory mimechanisms mnay conitrol the flow of
blood through the various pathways.'13 14 It is
well recognized that both vasodilator and
vasocolnstrictor nerves have a part in regulating the circulation through the skin of the
forearm.1'5 In sickle-cell disease, Kimmelstiel
observed ischemic niecrosis without vascular
thrombosis in various organs including the
lungs.16 He postulated that a neurogenie
mechanism affecting the capillaries is the factor initiatinig sickle-cell crisis. This nleurogenie mechanisnl could be responsible for diverting arterial blood to the cutaneous veins
through anatomnic or funetional bypasses, so
that oxygen could not be removed by the tissues. The widening of the arteriovenous differencee wheni a venous tourniquet was placed
at the wrist or when samples were drawn from
the deep veiious system v ia catheterization
indicates that only the superficial vasculature
is involved in this phenomenon.
Regardless of the mechanism involved, the
correlation betweeni a narrow arteriovenious
differenee anid sickle-eell crisis appears to be
consistenit. It is suggested that the finding of
arterialized venlous blood in patients with
sickle-cell anemia is an additional aid in the
differential diagnosis of sicklemic crisis.
Summary
In 18 Negro patienlts with sickle-cell aneniia
or sickle cell-hemoglobin C disease, gradients
of oxygeni and pH were mneasured between
brachial artery and superficial and deep venous systemn of the upper extremity. The results obtained during crisis were comnpared
with those obtained from asymuptomatic patients.
Arterial oxygen unsaturation, with normal
arteriovenous gradients for oxygen and pH
was observed in the 11 asyniptomatic patients.
Unusuallv low arteriov-enous gradients for
oxygen and pH, mainly due to abnormal venlOUs values, were found when blood draining
froml eutaneous areas was comnpared with arterial samples in the 7 patients studied during
acute crisis. The 5 patients restudied after
symptoms suibsided showed a return toward
normual of arteriovenous differences.
The evidence suggests that during crisis
arterialization of venous blood is the result of
anatomlie or funci,tional bypasses in the superficial eirculationl, so that oxygen is not removed by the tissues. It is postulated that a
Circulation, Volume XXII, October 1960
SICKLE-CELLI CRISIS
vascular neurogenic mechanism may be the
precipitating factor in sickle-cell crisis.
It is also suggested that a low arteriovenous
oxygen gradient or arterialization of superficial vein blood may be used as a laboratory
aid in establishing the diagnosis of sickle-cell
crisis in
uncertain
cases.
Summario in Interlingua
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In 18 patientes negre con anemia a cellulas falciforme o morbo drepanocytic a hemoglobina C, le
gradientes del oxygeino e del pH esseva determinate
inter le arteria brachial e le systema venose superficial e profunde in le extremitates superior. Le resultatos obtenite ab patientes in stato de crise esseva
comparate con illos ab patientes asymptomatic.
Dissaturation oxygenic arterial in le presentia de
normal gradientes arterio-venose pro oxygeno e pH
esseva observate in le 11 patientes asymptomatic.
Inusualmente hasse gradientes arterio-venose pro oxygeno e pH, principalmente in consequentia de anormal valores venose, esseva trovate in comparationes
de sanguine drainate ab areas cutanee con specimens
arterial in le 7 patientes studiate in stato de crise
acute. Le 5 patientes qui esseva restudiate post que
le symptomas subsideva monstrava un retorno verso
le norma con respecto al differentias arterio-venose.
Le observationes pare indicar que durante le crise
un arterialisation de sanguine venose es causate per
detornos anatomic o functional in le circulation superficial, de maniera que le oxygeno non es acceptate per
le tissus. Es postulate le possibilitate que un mechanismo vascular neurogenie es le factor precipitante
in le crise drepanocytic.
Es etiam suggerite que le constatation de un basse
gradiente arterio-venose de oxygeno o de arterialisation del sanguine venose superficial pote esser usate
como adjuta laboratorial in establir le diagnose de
crise drepanocytic in casos dubitose.
References
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2. BECKLAKE, M. R., GRIFFITHS, S. E., MCGREGOR,
M., GOLDMAN, H. I., AND SCHREVE, J. P.: Oxy-
Circulation, Volume XXII, October 1960
607
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RODMAN, T., CLOSE, H. P., FRAIMOW, W., CATHCART, R., AND PURCELL, M. K.: The oxygen
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FOWLER, N. O., SMITH, O., AND GREENFIELD, J.
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gen
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Studies of Peripheral Circulation during Sickle-Cell Crisis
FELICE MANFREDI, ANGELO P. SPOTO, HERBERT A. SALTZMAN and
HERBERT O. SIEKER
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Circulation. 1960;22:602-607
doi: 10.1161/01.CIR.22.4.602
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