Clinical Science (1973) 44, 113-128.
CARDIO-PULMONARY RESPONSES A N D G A S
E X C H A N G E D U R I N G EXERCISE I N A D U L T S WITH
HOMOZYGOUS SICKLE-CELL DISEASE (SICKLE-CELL
A NA E M I A )
G . J. M I L L E R , G. R. S E R J E A N T , S . SIVAPRAGASAM
M. C. P E T C H
AND
Medical Research Council Epidemiology Unit, Wellcome Sickle-Cell Anaemia Unit,
and University Hospital of the West Indies, Kingston, Jamaica
(Received 20 March 1972)
SUMMARY
1. Cardio-pulmonary responses and gas exchange during progressive exercise,
the ventilatory response to hypercapnia and anthropometric indices were measured
in twenty-two Jamaican adults with homozygous sickle-cell disease. Their anthropometric indices and exercise performances were compared with those observed in
healthy but sedentary adults in the Caribbean.
2. The patients had long lower limbs for their height; their body fat, proportion of
lean body mass as muscle and vital capacity were reduced. Haemoglobin concentrations ranged from 4 to 10 g/lOO ml. Heart rate and ventilation were normal at rest.
3. During exercise in the male patients haemoglobin concentrations below about
8 g/100 ml were associated with an increased demand for anaerobic metabolism. This
resulted in excessive lacticacidaemia and increased ventilation at standard oxygen
uptake (hyperpnoea). The ventilation-tidal volume relationship was normal. When
allowance was made for differences in body muscle, anaemia did not appear to affect
the heart-rate response to exercise.
4. Hyperventilation with respect to carbon dioxide output, increased alveolararterial oxygen-tension gradients and abnormal deadspace ventilation during exercise
indicated a pulmonary perfusion disturbance with mixed venous shunting. The most
likely basis for this disorder was considered to be the sickling phenomenon. Arterial
hypoxaemia produced by the pulmonary shunt probably accounted for some of the
exercise hyperpnoea, partly by increasing the chemoreceptor drive and partly by
encouraging lacticacidaemia.
5. Reduced arterial carbon dioxide tensions and bicarbonate concentrations had
lowered the threshold and increased the sensitivity of the ventilatory response to
Correspondence: Dr G . J. Miller, Medical Research Council, Pneumoconiosis Unit, Llandough Hospital,
Penarth, South Wales.
B
113
114
G.J. Miller et al.
carbon dioxide as measured by rebreathing. Increased chemosensitivity was not
thought to have contributed towards the exercise hyperpnoea since arterial carbon
dioxide tensions were below the threshold value for ventilatory drive.
6. Exertional dyspnoea in sickle-cell disease was attributed to the combination of
hyperpnoea and a reduced maximum breathing capacity (MBC) owing to small lungvolumes. The fraction of MBC used at standard work was therefore abnormally large,
and the increased ventilatory effort produced a sensation of breathlessness in some
patients.
Key words : sickle-cell anaemia, exercise studies, pulmonary gas exchange, chemosensitivity.
While moderate reductions in haemoglobin concentration do not appear to reduce exercise
performance (Rowell, Taylor & Wang, 1964; Cotes, Dabbs, Elwood, Hall, McDonald &
Saunders, 1972; Vellar & Hermansen, 1971) the effects of chronic severe anaemia are less well
defined. Sproule, Mitchell & Miller (1960) reported a marked reduction in maximal oxygen
uptake in severe anaemia but no allowances were made for age and body muscle and the study
was not repeated after correction of the anaemia.
Homozygous sickle-cell disease is characterized by a chronic severe anaemia and a tendency
to ischaemic episodes. Acute pulmonary infections and infarctive lesions are common and
chronic disturbances of lung function include reductions in vital capacity and ventilatory
capacity, a low diffusion capacity of the alveolar membrane (Miller & Serjeant, 1971) and
abnormal pulmonary mixed venous shunts (Bromberg & Jensen, 1967a). The effects of these
pulmonary changes and of the anaemia upon exercise performance in this disease are largely
unknown.
We report here the cardiopulmonary responses and pattern of gas exchange during progressive exercise on a cycle ergometer in twenty-two Jamaican men and women with sicklecell anaemia. Their exercise performance has been compared with that of healthy but sedentary
people in the Caribbean.
PATIENTS A N D METHODS
The patients attended the sickle-cell clinic of the University Hospital of the West Indies.
The diagnosis of homozygous sickle-cell disease was based on the demonstration of only
haemoglobins S, F, and A, on starch-gel haemoglobin electrophoresis, normal HbA, values
on column chromatography, and characteristic erythrocyte morphology. There were thirteen
men and nine women with a mean age of 30 years. Each patient consented to the study after
its nature and the procedures involved had been explained to them by the clinic physician,
and they were free to withdraw at any stage. All were in a steady state when studied and exercise was not restricted by leg ulceration or bone and joint disease. Clinical details are summarized in Table 1. Fifteen patients admitted exertional dyspnoea on questioning and twelve
had had pulmonary complications in the past. The lung fields of all patients were clear at
the time of study, both clinically and radiographically. In twelve patients the chest radiograph
revealed cardiomegaly and enlarged main pulmonary arteries consistent with their chronic
severe anaemia.
Exercise responses in sickle-cell anaemia
115
Habitual physical activity was assessed by a standardized questionnaire which graded the
intensity of occupational activity, physical recreation and work involved in travel. Irregular
attendance at school and work was recorded. Standing and sitting height, weight, three limb
circumferences (upper arm, thigh and calf) and six skinfold thicknesses (biceps, triceps, subscapula, supra-iliac, anterior thigh and medial calf) were measured according to the recommendations of the Human Adaptability Sub-committee of the International Biological
Programme (Weiner & Lourie, 1969). Thigh measurements were taken at one third of the
sub-ischial height above the lower femoral condyles. Thigh muscle width (TMW) was assessed
from a soft-tissue radiograph as described for the Harpenden growth study (Tanner, 1964).
The gonads were protected from radiation with the appropriate lead-lined garments (Smith,
1971). Lean body mass (LBM) was estimated from the summed skinfold thickness at four
sites (EST) using the relationships of Durnin & Rahaman (1967) for young adults. TMW
and LBM were used as independent estimates of body muscle. Haemoglobin was estimated on
venous blood as cyanmethaemoglobin.
All measurements of lung function and exercise performance were made in an air-conditioned laboratory with ambient temperatures between 24 and 26°C and a relative humidity of
approximately 70%. Forced expiratory volume (FEV1.o) and forced vital capacity (FVC) were
measured by a standard technique (Cotes, 1968). Indirect maximum breathing capacity
(IMBC) was then calculated from FEVl.o using the chart published by Cotes (1968). The
ventilatory response to CO, was assessed using a rebreathing method (Read, 1967). For this
purpose ventilation and expired air carbon dioxide tension were recorded at half-minute
intervals, plotted as dependent and independent variable respectively and inspected by eye.
Data pertaining to the linear part of the relationship were then submitted to regression analysis.
The intercept of this relationship on the axis of abscissae (B of Lloyd & Cunningham, 1963)
was considered to be the threshold CO, tension for ventilatory response and the slope (D of
Lloyd & Cunningham, 1963) described the sensitivity of the response to changes in CO,
tension above the threshold value. The cardio-pulmonary responses to progressive exercise
were measured during the morning with the patient in the post-absorptive state and seated
on a cycle ergometer (Monark). After familiarization with the procedure, measurements of
gas exchange were made at rest, when the heart rate, breathing frequency and mixed expired
gas composition were stable. The patient then exercised while the work load was increased by
25 W (150 kpm min -') at 3-min intervals up to the limit of tolerance. Air was inhaled through
a dry-gas meter (Parkinson & Cowan CD4), mouthpiece (diameter 2.2 cm) and a low-resistance valve box (Bannister & Cormack, 1954), and exhaled to atmosphere through a gas
mixing chamber. Mixed expired gas was continuously drawn from the chamber through a
paramagnetic oxygen meter (Servomex OAl50) and an infra-red CO, analyser (Hartmann &
Braun). Accuracy of gas analysis was checked repeatedly with standard gas mixtures previously
analysed with a Scholander apparatus. Inspired minute volumes were converted into expired
volumes (VE)and the data for sub-maximal exercise were used to obtain the oxygen uptake
(Vo,) and carbon dioxide output ( VCO,) in each minute. The ventilation and cardiac frequency
at an oxygen uptake of 1.0 litre/min ( ~ ~ , 1 . 0 0and
, CF, .o respectively), ventilation at a carbon
dioxide output of 1.0 litre/min (VEy1'OCO2)and the tidal volume at a minute ventilation of
30 litres/min (Vt3J were then derived by interpolation or extrapolation and used to describe
the cardiac and pulmonary responses to progressive exercise. The justification for the use of
these indices foi this purpose is discussed by Cotes (1972). The dyspnoeic index was taken as
116
G. J. Miller et al.
the maximal ventilation reached during exercise (h,max) expressed as a fraction of the IMBC.
This index was used as an expression of the ventilatory effort made in exercise.
The control subjects (twelve men and twelve women) were healthy but sedentary adults
of the same ethnic origin in the Caribbean region (cf. Edwards, Miller, Hearn & Cotes, 1972;
Miller, Cotes, Hall, Salvosa & Ashworth, 1972). To compare the exercise responses of patients
and controls, linear regression analyses were performed within each group for each of the
various indices of exercise performance on the body muscle indices (LBM and TMW) and the
coefficients and constant terms were tested for differences. A common linear regression was
calculated whenever the relationships were similar. The 5% probability level was considered
significant.
In the patients but not the controls arterial blood was sampled at rest and over the final
minute at each level of work through a small polyethylene catheter inserted percutaneously.
Triplicate determinations of 0, (Payo,) and CO, (Pa,co,) tensions and pH were made on
each sample using Radiometer micro-electrodes which were calibrated before each set of
determinations with known buffer solutions in the case of the pH micro-electrode, and with
known gas mixtures in the case of the 0, and CO, micro-electrodes. In all but one man
whole blood lactate concentration was estimated by an ultra-violet spectrophotometric method.
Plasma bicarbonate concentration (HC03 -) was calculated from the Henderson-Hasselbalch
equation. Tidal volume (Vt), physiological deadspace (Vd) and the Vd/Vt ratio were calculated from Bohr’s formula after correcting for the valve box deadspace. The ‘ideal’ alveolar
oxygen tension (PA,o,) was calculated from the alveolar air equation (Fenn, Rahn & Otis,
1946) and the alveolar-arterial oxygen-tension gradient (A-aDo,) was then obtained by subtraction of the measured Payo,. Normal values for pulmonary ventilation, alveolar and arterial
blood gas tensions and other derived indices were those of Raine & Bishop (1963).
In a separate study, Payo, was measured in ten men with homozygous sickle-cell disease
while breathing room air and after breathing 100% 0, for 30 min. Adequate washout of
alveolar nitrogen after this time was assumed.
RESULTS
Habitual activity and anthropometry
Schooling and adult employment had been repeatedly interrupted by bone pains and leg
ulceration (Table 1). Many patients considered themselves handicapped and were less active
than the controls. Eight men and four women were unable to find employment because of their
medical history, and the remainder undertook light work. Very little effort was made in leisure
time.
Most patients had a severe anaemia, the mean haemoglobin concentration being 7.2 (range
4-3-9.5) g/lOO ml and 7.7 (range 5.3-10.1) g/lOO ml in men and women respectively.
Table 2 presents the anthropometry and shows that the patients were tall relative to body
weight. The increase in sub-ischial height and reduction in TMW indicated that the legs were
long and narrow. Fig. 1 shows that in the controls the relationship between LBM and TMW
was significant and similar to that found for English adults (J. E. Cotes, G. Berry & A. M.
Hall, unpublished work), LBM = 1-2 TMWl.’. In the patients, TMW was less than that for
the controls relative to estimated LBM. Patients had significantly smaller FEV,., and FVC
values (and therefore a smaller IMBC) than controls.
Exercise responses in sickle-cell anaemia
117
Exercise performance
The results of the progressive exercise tests are presented in Table 3. Heart rate and ventilation were significantly increased in the group of patients at the standard oxygen uptake of
TABLE1. A summary of relevant clinical details in the
patients
History
Men (1 3)
Women (9)
1
5
2
0
3
4
4
8
9
7
2
3
1
3
3
6
5
5
0
0
0
0
Dyspnoea* Grade 4
Grade 3
Grade 2
Grade 1
Chronic leg ulceration
Painful attacks
Pulmonary episodes
Duodenal ulcer
Apastic crisis
Congestivecardiac failure
Cigarette smoking
* The grading is that of Fletcher (1952).
TABLE2. Comparison of anthropometry of patients with homozygous sickle-cell disease and healthy
subjects
Women
Men
Sickle-cell
disease (13)
Health (12)
Sickle-cell
disease (9)
Health (12)
Index
Mean
Age (years)
Stature (m)
Sub-ischial height (m)
Weight (kg)
Lean body mass (LBM) (kg)
Thigh muscle width (TMW) (cm)
Haemoglobin (g/lOO ml)
Forced expiratory volume (litres, BTPS)
Forced vital capacity (litres, BTPS)
SD
30
13
1.75 0.07
0.89 0.04
56.7
8.4
51.2
6.7
0.8
10.4
7.2
2.8
3.2
1.7
0.7
0.6
Mean
SD
Mean
2
30
26
1-74 0.09 1.63
0*85* 0.05 0.82
66.8* 10.7 51.4
56.7
7.1 40.9
12*4* 0 7
9.9
14.8* 1.4
7.7
3-5* 0-5 2.2
06
2.5
4 1*
SD
Mean
7
0.06
0.05
5.1
3.5
1.2
1.7
0.4
05
27
1-63
0.79
596
43.7
11*3*
14*0*
2.8 *
3.1 *
SD
2
0.05
004
12.9
5.1
1-2
1-2
0.5
0.5
* Differences were statistically significant (P<0*05).
1.0litrelmin. Tidal volumes (Vt,,) were normal relative to exercise ventilation. At maximal
exercise oxygen uptake (vo,,max), ventilation (Ih,max) and heart rate (CF,max) were lower
in patients than controls but the dyspnoeic index was comparable in the two groups.
118
G. J. Miller et al.
Thigh muscle width (TMW) correlated significantly with CF1.o in the male patients and
female controls. Statistically there were no differences in CF1.o between sexes or between
patients and controls when TMW was allowed for (Fig. 2).
Lean body mass (LBM) correlated significantly with CF, .o in female patients and controls.
In patients and controls the data for men and women could be combined, but the relationships
differed between patients and controls such that CF, .o was significantly higher (Table 4) in
the patients when estimated LBM was allowed for.
rn
n
yt0
rn
o
0
0
gt
0
0
0
I
I
I
I
I
I
40
45
50
55
60
65
LEM (kg)
FIG.1. Comparison of relationships between thigh muscle width (TMW, cm) and estimated lean
body mass (LBM, kg) in healthy men (m) and women (o), and in men ( 0 )and women (0)with
homozygous sickle-cell disease. The regression line describes the relationship for young English
adults (J. E. Cotes, G. Berry & A. M. Hall, unpublished work).
When standardized for oxygen uptake sub-maximal ventilation correlated with body
muscle in the controls and the data could be combined for men and women. Fig. 3 presents
these results and also shows that no similar correlation was apparent for the patients, most of
whom hyperventilated in exercise even when allowance was made for body muscle. In looking
for reasons for this difference between patients and controls it was found that the degree of
anaemia correlated with exercise ventilation in the men and that when this was taken into
account the partial regression coefficients of ventilation on haemoglobin and on body muscle
were significant and of the expected sign:
v~,l.00, (litre/min)
=
142.0-5.9 TMW-5.4 Hb (SD 7.8, coefficient of variation 19.6%)
The female patients behaved differently from the males in that submaximal ventilation did
not correlate with either body muscle or haemoglobin concentration. The main reason for this
1.59-3.25
157-209
570-1070
41-102
071-1.55
24.7-30.0
91-134
20G-41.0
Health
(12)
Range
046
13
178
19
024
2.0
14
6.1
SD
* Significant differences between patients and controls.
030 244
10
188
128
88.3
15
72
020
1.12
271
30.5-461
36.7*
5.2
1M-210 32
114
25.5-69.00 13.2 272
Mean
Men
140*
40.0*
At maximal exercise
1.28* 065-1.73
Oxygen uptake (Voa, max) (litreslmin)
166*
151-186
Heart rate (CF,max) (min-1)
55.88
320-73.0
Ventilation (VE.
. .max), flitreslmin)
,
. ,
?E, maxx 100+indirect maximum breathing capacity (%) 62
32-86
Tidal volume at an exercise ventilation of 30 litreslmin (Vtao) 1.08
083-1.50
At an oxygen uptake of 1.0 litre/min
Heart rate (C.F 1.0) (min-l)
Ventilation (Ve,l*Ooa)(litrelmin)
At a carbon diqxide output of 1.0 litrelmin
Ventilation (W,l.Ocoa)(litreslmin)
Sickle-cell disease
(13)
SD
Mean
Range
TABLE
3. Indices of exercise performance
28.2
5.6
38.88 329-48.0
090. 062-1-21 019
145-177
11
157*
400* 270-602 11.3
31-85
19
52
098 079-1.20
017
254-33.0
109-164
260-34.5
1.53 1.13-234
173
147-190
53.9 38.0-93.0
55
32-87
1.06 068-1.43
137
295
24
10.2
4&1*
121-194
34M6.0
164*
Health
(12)
Mean
Range
Women
Sickle-celldisease
(9)
Mean
Range
SD
19
0.20
161
036
12
28
16
3.4
SD
2
0
Ei'
8
?
%
5.
3
2
2G
3
Y
E'
cb
G. J. Miller et al.
120
discrepancy appeared to be that two women with large body muscle (represented as the outlying points in Fig. 3) and only moderate anaemia (Hb 9.0 and 10-1g/100 ml) had unusually
high rates of ventilation.
0
/
0
180
--.-
160
0
-
I
E
0
*
Y
b
140-
120
-
100 -
I
I
I
I
I
9
10
II
12
BI
13
TMW (crn)
FIG.2. Relationship between heart rate at an oxygen uptake of 1.0 litre/min (CFl.,, min-') and
thigh muscle width (TMW, cm) in healthy men (a) and women (a), and in men ( 0 ) and women
( 0 ) with homozygous sickle-cell disease. The regression curve describes the relationship for young
English adults (J. E. Cotes, G . Berry & A. M. Hall, unpublished work).
TABLE
4. Comparison of heart rates at 1.0 litre/min oxygenuptake, adjusted for estimated
lean body mass, in patients with homozygous sickle-cell disease and control subjects
Patients
Group
Men
Women
Controls
No.
Mean
SD
No.
Mean
SD
t
P
13
134.4
28.4
12
114.1
11.3
2.3
<0.05
9
156.4
18.0
12
138.1
12.4
3.8
<0.01
Table 3 also shows that patients hyperventilated with respect to carbon dioxide output.
At a standard carbon dioxide output of 1.0 litre/min, ventilation (h,l.0c02) was on average
about 10 litres greater in patients compared with that for controls. No correlation was found
between V E , *Oco2
~
and the body-muscle indices.
Exercise responses in sickle-cell anaemia
121
The relationship between oxygen uptake and blood lactate was curvilinear. In the men
the data permitted a reasonable estimate (within 0.1 litrelmin) of the oxygen uptake when the
~ ) . the resting blood lactate concentrations
blood lactate was 30 mg/100 ml ( V O ~ , L A ~Since
(mean 10.6 mg/100 ml, SD 2.4) and oxygen uptakes (mean 0-32 litrelmin, SD 0-08) were
~ ~ used as an approximate index of the demand for anaerobism
similar in the men, V O Z , L Awas
during exercise. This index correlated with haemoglobin concentration (Y, 0.76; P< 0-01) and
thigh muscle width (r, 0.76; Pc0.01) (Fig. 4), and also with exercise ventilation (Y, -0.78:
0
.f
30.
20 '
9
I
I
I
I
10
II
12
13
I
14
TMW (cm)
FIG.3. Relationship between ventilation at an oxygen uptake of 1.0litre/min (VE,1.0litre/min)
and thigh muscle width (TMW, cm) in healthymen(.) and women(.), and in men(o) and women
homozygous sickle-cell disease.
( 0 ) with
P < 0.01). Haemoglobin concentration was not correlated with thigh muscle width. Similar
relationships were not shown for the women, partly because the two patients with moderate
anaemia, referred to earlier, had a very rapid rise in blood lactate on exercise, and partly
A four
~ ~ patients.
because the data did not permit a reliable estimate of V O ~ , L in
A group of two men and four women is presented in Table 5 because they had the most
distinctive pattern of exercise response with the highest rates of lactate accumulation, marked
hyperventilation (with one exception) and high heart rates (again with one exception).
Gas exchange
After correcting for the apparatus deadspace, the mean resting minute ventilation was
8.5 (SD 1.8) and 7-3 (SD 1-7)litreslmin in male and female patients respectively. Resting oxygen
consumption was 0.32 (SD 0.08) litrelmin for the men and 0.28 (SD 0.05) litrelmin for women.
These values are very similar to those described by Raine & Bishop (1963) for healthy subjects.
G. J. Miller et al.
122
Respiratory quotient, physiological deadspace and deadspaceltidal volume (Vd/Vt) ratio were
also normal when the patients were at rest. The resting plasma bicarbonate concentration
0
1.4
-
-
0
1.2
0
-
-
0
0
0
“7
4.
0
0
C
-
0
0
-._
,E
c
.-
0
-
1.6 -
I.0 -
-
0
.f
0
0
0
0
0
0
-
0.8 -
0
0
0
0
U
0.6
0
I
I
I
I
TMW (cm)
I
I
I
I
L
Hb (g/IOO mll
FIG.4. Relationship of oxygen uptake at a bloodlactateconcentration of 30 mg/100 ml ( V O ~ , L A ~ , ,
litre/min) to thigh muscle width (TMW, cm) and haemoglobin concentration (Hb, g/lOO ml)
respectively in men with homozygous sickle-cell disease.
TABLE
5. Summary of results in the group of six patients with the most distinctive pattern of
cardio-pulmonary exercise response
Patient
Index
G.M.
A.R.
M
Sex
60
Age (years)
Haemoglobin (g/lOO ml)
5.9
At an oxygen uptake of 1.0 (litre/min)
Heart rate (CF,.,)(min -’)
210
Ventilation ( V ~ ~ 1 . 0(litrelmin)
0~)
69
Oxygen uptake at a blood lactate of 30
mg/IOO ml (V O ~ , L A (Iitre/min)
~,)
0.65
M
22
5.8
180
60
0.73
C.L.
N.P.
E.B.
D.S.
F
F
F
F
34
7.3
35
5.3
40
9.0
39
10.1
194
44
0.68
191
50
067
187
66
068
121
54
071
(mean 22.3 mM, range 17-7-32.4) and Pa,co, level (mean 34 mmHg, range 27-45) were reduced
in the majority of patients. Mild to moderate reductions in Pa,02 were found in six men and
three women. The mean Payo, and A-aDo, for all patients was 80.5 mmHg (range 56-95)
Exercise responses in sickle-cell anaemia
123
and 25 mmHg (range 13-41) respectively. In four men and one woman resting arterial pH
was greater than 7.45.
The most striking changes in gas exchange on exercise were an increase in the A-aDo,
and Vd/Vt ratio in many patients. On exercise, A-aDo, was normal in only one of eighteen
patients, and Vd/Vt failed to fall below resting values in ten of twenty patients. (The detailed
results of these gas-exchange studies, together with the lactate measurements, have been
deposited as Clinical Science Tables 42/57 and 42/58 with the Librarian, Royal Society of
Medicine, from whom copies may be obtained on request.)
Chemosensitivity: ventilatory response to hypercapnia
There was a good inverse correlation between resting Pa,co, and the sensitivity of the ventilatory response to carbon dioxide (D of Lloyd & Cunningham, 1963). This relationship was
described by the equation:
D(l min-l mmHg-')
=
6.24-0-12 Pa,co, mmHg (SD, 0.74) (r, - 0-61; P<O*Ol)
The mean D for patients with resting Pa,co, values of 36 mmHg or above was 1.49 (SD,
0.48) litre min-l mmHg-', whereas for those with values less than 36 mmHg it was 2.62
(SD, 0.85) litre min-l mmHg-l.
The mean threshold of ventilatory response to CO, (B of Lloyd & Cunningham, 1963) was
36.7 (SD, 3.6) mmHg and B was positively correlated with the resting arterial bicarbonate
concentration (r, 0-55; P<0.02).
Fifteen patients had no effective respiratory drive from CO, when this was considered to be
(Pa,co,-B). The overall mean drive was negative during rest, -2.3 (SD, 4.1) mmCO,, and
in exercise -3.2 (SD, 4.6) mmCO,. During the rebreathing procedure there was often a lag
in measurable ventilatory response of up to 1 min even though the rise in Pa,coZwith time was
linear.
Oxygen breathing
When 100% 0, was breathed for 30 min the Payo, increased to between 300 and 400 mmHg
in four men, between 400 and 500 mmHg in five, and to above 500 mmHg in one.
DISCUSSION
The anthropometric disproportion in these patients was similar to that previously described
in homozygous sickle-cell disease (Winsor & Burch, 1945; Ashcroft & Serjeant, 1972), and
characterized by an increased stature relative to body weight with long legs. The pathogenesis
of this growth disorder is not understood,
The cardio-pulmonary responses to exercise are to some extent determined by the mass of
working muscle. During cycling, oxygen uptake is mainly that of the thighs and calves (Houtz
& Fischer, 1959). Previous comparisons of exercise responses in healthy subjects gave similar
results when heart rate was related either to lean body mass or thigh muscle width (cf. Cotes,
Davies, Edholm, Healy & Tanner, 1969; Edwards et al., 1972; Miller et al., 1972). In this study
the patients' heart rate response appeared to be increased when related with lean body mass,
but not when related with thigh muscle width. This suggested that one of the body muscle
indices was invalid for this purpose.
124
G . J. Miller et al.
Lean body mass was an indirect estimate of body muscle derived from empirical relationships between skinfold thickness and body fat described for young healthy European adults
by Durnin & Rahaman (1967). These relationships differ with sex and age, and probably also
with disease. The estimated lean body mass of patients will have been incorrect if the distribution of body fat is altered in sickle-cell anaemia. More important, Fig. 1 shows that the thigh
muscle width was reduced in the patients relative to lean body mass. This suggested that the
proportion of lean body mass as body muscle differed between patients and controls, the
patients carrying less muscle on their skeletal frame. In contrast, thigh muscle width was a
direct measurement of the working body muscle which has been shown to be highly correlated
with body total potassium (Cotes et al., 1969), most of which is in muscle. For these reasons
we considered thigh muscle width a more valid index of body muscle than the estimate of lean
body mass in our patients.
The anaemia of sickle-cell disease appeared to have had no significant effect upon the heartrate response to exercise, which agreed well with the findings of studies cited in the introduction.
Six men and three women had normal heart rates relative to body muscle even though their
haemoglobin levels were less than 8 g/100 ml. This suggested that the high heart rates shown by
five of the patients in Table 5 were unlikely to have been caused by the anaemia.
In contrast, the increased ventilatory response to exercise (hyperpnoea) was clearly related
with the degree of anaemia and rate of lactate production in the male patients. The multilinear
regression equation relating exercise ventilation with body muscle and haemoglobin in this
group showed that hyperpnoea lessened as the anaemia decreased until ventilation was within
the normal range at haemoglobin concentrations of about 8 g/lOO ml. J. E. Cotes, G. Berry &
A. M. Hall (unpublished work) found that in iron-deficiency anaemia sub-maximal exercise
ventilation was uninfluenced by a reduction in the haemoglobin concentration to 8 g/lOO ml.
Thus, in moderate anaemia oxygen delivery appeared to be maintained by increased oxygen
extraction at the capillary level, aided in sickle-cell anaemia by the reduced affinity of
haemoglobin S for oxygen (Bromberg & Jensen, 1967b), a raised total blood volume (Erlandson, Schulman & Smith, 1960) and an increased cardiac output (Leight, Sneider, Clifford
& Hellems, 1954). These adjustments were unable to fully compensate when the reduction in haemoglobin concentration was below 8 g/100 ml, and thereafter the dependence on
anaerobic metabolism during exercise increased progressively. Premature lacticacidaemia
caused hyperpnoea, and, although some of the reduction in haemoglobin and bicarbonate
concentration may have been a dilution effect (cf. Manfredi, 1965), a low blood buffer capacity may also have contributed towards the increased ventilation during exercise. A similar
ventilatory response probably occurs in other forms of severe anaemia since these are also
associated with a reduced oxygen affinity of haemoglobin (Mulhausen, Astrup & Kjeldsen,
1967), and a low blood bicarbonate concentration (Manfredi, 1965).
The absence of any demonstrable correlation of exercise hyperpnoea and lacticacidaemia
with the haemoglobin concentration in the female patients implied that anaemia was not the
only cause of hyperventilation in sickle-cell disease. The results suggested that the most likely
additional stimulus to ventilation during exercise was a reduced Pa ,o,.
Hypoxaemia with an increased A-aDo, has been reported previously in sickle-cell disease
by Fowler, Smith & Greenfield (1957) and Bromberg & Jensen (1967a). In this study, these
changes were not accompanied by any abnormality in the total minute ventilation or deadspace
ventilation at rest. In fact Vd was less in our patients than in the Europeans reported by Raine &
Exercise responses in sickle-cell anaemia
125
Bishop (1963), probably as a result of the small lung volumes in this condition (Miller &
Serjeant, 1971). Since the hypoxaemia was likely to have been longstanding, the normal
resting ventilation may have represented a diminished chemoreceptor drive as an adaptive
response similar to that found in other chronic hypoxic states (Edelman, Lahiri, Braudo,
Cherniack & Fishman, 1970).
During exercise, the triad of an increased A-aDo,, failure of the Vd/Vt ratio to fall (in ten
patients) and hyperventilation with respect to carbon dioxide output closely resembled that
found by Jones & Goodwin (1965) in patients with pulmonary thrombo-embolic disease and
venous shunts. A similar pathology probably accounted for these findings in our patients,
since the sickling phenomenon predisposes to vascular obstruction through its effects on blood
viscosity and the tendency for sickle-cell aggregates to occlude small blood vessels. Organized
thrombo-emboli have been found at autopsy in sickle-cell disease (Diggs & Barreras, 1967)
and cor pulmonale is an unusual but well-documented complication (Moser & Shea, 1957;
Sproule, Halden & Miller, 1958).
Apart from a reduction in the diffusion capacity of the alveolar capillary membrane (cf.
Miller & Serjeant, 1971) there was no other evidence for pulmonary vascular obstruction in
these patients. Chest radiography was of little value in this respect, since the hyperdynamic
circulation in sickle-cell anaemia frequently results in predominantly left-sided ventricular
hypertrophy and prominence of the main pulmonary arteries. Catheter techniques were not
available to us and in any case we would be reluctant to employ them in a study of this nature.
There was no clinical evidence of right ventricular hypertrophy or pulmonary hypertension
and conventional twelve lead electrocardiographywith, in addition, lead V,R showed no evidence of right ventricular hypertrophy or strain. It may be, therefore, that gas-exchange studies
in exercise may be more sensitive indicators of thrombo-embolic pulmonary vascular occlusion
than radiography or electrocardiography. Jones & Goodwin (1965) considered the exercise
technique to be more sensitive than cardiac catheterization and angiography for this purpose.
Hypoxaemia will have placed further stress on an embarrassed oxygen transport system
and increased demand for anaerobic metabolism during work. In addition a reduced Payo,
probably accounted for part of the hyperventilation during exercise by increasing the chemoreceptor drive even though in its presence ventilation was normal at rest. A similar pattern of
ventilation has been described in the chronic hypoxia of high altitude by Weil, Byrne-Quinn,
Sodal, Filley & Grover (1971). Thus, both anaemia and hypoxaemia probably contributed
towards exercise hyperpnoea in these patients.
A change in blood viscosity and propensity for pulmonary vascular obstruction similar to
that found in sickle-cell disease also occurs in polycythaemia rubra Vera (Burgess & Bishop,
1963; Bland, 1963). In addition, there are similar disturbances in pulmonary diffusion, deadspace-tidal volume relationships and the alveolar-arterial oxygen-tension gradient (Burgess &
Bishop, 1963). This suggests that a change in blood viscosity is the basis of the lung disorder
in both diseases.
The cause of the exertional dyspnoea mentioned by fifteen patients appeared complex.
Small lung volumes which were the result of anthropometric disproportion (Miller & Serjeant,
1971) had reduced maximum breathing capacity. In addition, anaemia and hypoxaemia were
responsible for hyperpnoea. The result was that the fraction of the maximum available ventilation used at any level of work was considerablylarger than normal. This need for increased
ventilatory effort was the probable source of the sensation of breathlessness in this disorder.
126
G. J. Miller et al.
Since oxygen breathing abolishes the effect of underventilation on the A-aDo, but not
that of blood flow through non-ventilated lung (the anatomical shunt) (Berggren, 1942),
failure of this procedure to raise the arterial oxygen tension above 500 mmHg in most patients
indicated a moderate anatomical shunt. This confirmed the findings of Sproule et al. (1958)
and Bromberg & Jensen (1967a). Had we known the exact position of the in vivo oxyhaemoglobin dissociation curve it would have been possible to estimate the fraction of the cardiac
output which had been shunted through the lungs (cf. Cotes, 1968). Unfortunately, however,
changes in blood pH and carbon dioxide tension, together with differences in the amount of
foetal haemoglobin present in the erythrocyte (Bromberg & Jensen, 1967b), cause considerable
individual variability in the position of the dissociation curve in sickle-cell disease.
The size of the A-aDo, is unlikely to correlate closely with the extent of the pulmonary
perfusion disturbance in sickle-cell disease. This is because the A-aDo, gradient for any shunt
increases with anaemia (Brody & Coburn, 1969) and decreases with a reduction in the oxygen
affinity of the circulating haemoglobin (Riley & Cournand, 1951). Nevertheless, since the
A-aDo, gradients in this study were larger than those reported by Housley (1967) in other
types of severe anaemia they were evidence for abnormal pulmonary venous shunting in sicklecell disease.
When calculating Vd with Bohr’s formula it is standard practice to equate alveolar with
arterial carbon dioxide tension. This will be in error in the presence of pulmonary veno-arterial
shunts when arterial tension will be higher than alveolar end capillary tension by the contribution from shunted mixed venous blood. Since the change in A-aDo, indicated that a larger
fraction of the cardiac output was shunted during exercise than at rest in our patients, at least
part of the concurrent increase in Vd/Vt will have been apparent rather than real. However,
the absence of any correlation between the change in Vd/Vt and A-aDo, during exercise
suggested that some other factor had also contributed to the increased deadspace estimate.
As indicated earlier, this was most likely to have been mismatching of ventilation with perfusion secondary to pulmonary vascular obstruction.
The increased chemosensitivity to carbon dioxide in the presence of a low Pa,coz and HCO, agreed with the findings of Tenney (1954) and King & Yu (1970). This was not considered to
have affected exercise ventilation, since for most patients Pa,co, in exercise was below the
threshold of ventilatory response measured by the rebreathing procedure. While it was true
that the rebreathing procedure had been performed during hyperoxaemia whereas exercise
was accompanied by hypoxaemia, this discrepancy did not invalidate the foregoing since
Lloyd & Cunningham (1963) have shown the threshold of CO, response to be independent of
Payo,. The delay in ventilatory response during rebreathing presumably indicated the time
required for this method to raise Pa,coz to the threshold level for ventilatory stimulation.
We believe this study has demonstrated the usefulness of measurements made in submaximal exercise for purposes of clinical investigation. Comparisons can be made when the
responses are related to gas exchange (oxygen uptake and carbon dioxide output) and allowances are made for differences in body muscle. In patients, thigh muscle width is probably a
more reliable index of body muscle than lean body mass, but more simple and accurate
indices may be found in the future. Much information will be overlooked if the results
of sub-maximal exercise are used only for the indirect assessment of maximal oxygen uptake
(cf. World Health Organization, 1971).
Exercise responses in sickle-cell anaemia
127
ACKNOWLEDGMENTS
This study was supported by the Medical Research Council and the Wellcome Trust, London.
We are grateful to Dr M. T. Ashcroft for help with the anthropometric measurements, Miss
Joyce Harris and Mr Graham Johnson for the assessment of thigh muscle width, Mrs L. Clarke,
Miss C. Innis and Mr H. Rogers for assistance with the exercise tests, Miss Rose Coates for
the blood lactate determinations and Mrs Ann Hall-Jones for the statistical analysis.
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