Acta med. scand. Vol. 197, pp. 177-186, 1975
OXYGEN UPTAKE AND CARDIAC OUTPUT DURING SUBMAXIMAL AND MAXIMAL EXERCISE IN ADULT SUBJECTS WITH TOTALLY CORRECTED TETRALOGY OF FALLOT Bjorn Bjarke From the Department of Pediatrics, Karolinska Institutet. St. Goran’s Children’s Hospital, Stockholm, Sweden
Abstract. Ten female and eight male adults with tetralogy of Fallot, the majority totally corrected at adult age, have been studied at rest and during submaximal and maximal exercise on a bicycle ergometer. Oxygen uptake was determined by the Douglas bag technique and cardiac output by the dye-dilution method. Maximal oxygen uptake was reduced about 3 0 4 0 % from normal. Thus a complete normalization of the aerobic working capacity was not achieved in spite of an intracardiac repair that was considered surgically satisfactory. Cardiac output response to exercise was subnormal, mainly due to small stroke volumes and partly because of low heart rates. A fall in stroke volume of more than 10 ml was found in 8 of the patients during exercise. No correlation was found between stroke volume during maximal exercise, on the one hand, and the presence of a particular residual defect, anatomy of the right ventricular outflow tract prior to operation and the use of a right ventricular outflow patch on the other. However, too few patients were studied to allow any definite conclusions as to the possible influence of these variables. It remains to be shown whether the haemodynamic abnormalities will be less and the aerobic work capacity better if total correction is undertaken at an early age.
The first patient with tetralogy of Fallot (TOF) was totally corrected in 1955 (32). Thus the knowledge of the long-term results is incomplete. Total corrective operation has dramatically changed and improved the natural history for patients with TOF. Still, even a successful operation must be looked upon as an anatomical correction with some residua since the patients are left with a ventriculotomy scar, often with some degree of right ventricular outflow tract stenosis and a right bundle branch block (RBBB). The question is whether these residua will interfere with the normalization of the circulation which is aimed at when total correction is undertaken and whether the impact of these residua is 12 -752983
influenced by the age at which total correction is performed. Several authors (9, 17, 18, 33, 40) have found normal or near normal haemodynamics at rest and during mild exercise in patients with technically good operation results. However, this does not mean that they have a normal exercise tolerance and a normal haemodynamic response to heavy work. In the haemodynamic studies cited above, most patients were corrected before the age of 10. The aim of this study was therefore to study the haemodynamic response during submaximal and maximal exercise in a group of patients with TOF corrected at adult o r near adult age. The haemodynamic study presented in this article is part of a larger investigation comprising pulmonary and renal function as well as muscle metabolism in patients with TOF (5, 7,8). MATERIAL Eighteen adults, 10 females and 8 males, with totally corrected TOF took part in this study. All belonged to the material previously studied by Miiller (35) and all had undergone a palliative shunt operation between 1947 and 1955 at a mean age of 5 years. Total correction was undertaken at 19.5 years of age (range 11-27.5). Only 3 patients were less than I5 years old when intracardiac repair was performed. The mean age at the follow-up was 26 (range 19-35). Since total correction 6.5 years (range 2.5-10.5) had thus elapsed. The anatomy classification suggested by Hawe et al. (19) was used for the right ventricular (RV) outflow tract before operation. Eight patients had isolated infundibular stenosis (type I), 7 combined valvular and infundibular stenosis (type 11) and 3 diffuse hypoplasia of the outflow portion of the RV and the main pulmonary artery (type 111). Intracardiac repair was carried out in the Departments of Thomcic Surgery, Karolinska Sjukhuset, Stockholm (14 cases), and in the University Hospital, Acta med. scand. 197
178 B. Bjarke
(o),
Table I . Individual values for oxygen uptake (Voz),cardiac output heart rate ( H R ) , stroke volume (SV) and blood lactate concentration at rest ( R ) in supine position and during submaximal ( E l , Ez) and maximal exercise (Emax) in the sitting position ~
~
~~
Pat. no.
Age (y.)
Sex
Blood ExerHR Height Weight vol. cise Vo2 (beats/ (cm) (kg) (1) state (I/min) (l/min) min)
1
28.5
0
I70
2
25
P
164
73.5
55
4.7
4.1
R
0.25
El E2 Em,, R El
0.92 1.52 1.95 0.21 0.88 1.02
E2 3
4
5
22
22
27.5
P
0
0
167
167
163
60.3
48.4
62.7
4.4
4.7
4.5
Em,,
1.18
R
0.21 0.93 1.36 1.61 0.21 0.82 1.16
El E2 Em,, R El E2 Emax R El E2
&=
6
7
8
9
27
23.5
35
24
0
0
0
0
163
161
164
158
48.4
50.5
58
62
4.2
3.5
3.8
R El E2 Em,, R El E, Em,,
R El E2 Em,, R E, Ez
-
0.21 0.84 1.33 1.48 0.25 0.82 1.42 1.57 0.24 0.61 0.85 1.08
0.29 0.96 1.26 1.53 0.21
-
1.16
Em,, 1.53 10
21
0
165
65
3.8
R E, E2 Em,,
0.19 0.79 1.27 1.68
11
25
d
189
67.5
6.3
R
-
12
19
d
168
67
5.0
13
25
d
171
56. I
4.2
Acra med. wand. 197
E, El Em, R E, El
1.49 1.97 2.34 0.26 0.91 1.86 ‘Em,, 2.30 R 0.26 El 1.05 E2 1.44 Em,, 1.66
5.6 10.1 13.0 15.5
4.4 8.2 9.1 9.4 4.5 9.1 to. 1 13.4 3.9 6.3 6.7 8.9 3.9 7.3 8.5
9. I 4.3 6.3 10.0 11.4 4. I 6.5 7.3 7.9 5.4 10.7 11.0 10.9 4.6 7.3 9.0 9.7 4.4 7.2 9.5 11.7 6.3 10.5
12.5 13.4 5.3 9.2 12.3 14.1 5.1
8.7 11.4 12.4
85 1 I8
152 I 74 74 128 152 170 63 I17 156 173 66 124 I68 182 61 99 145 178 71 101
165 176 78 121 149 171 86 121 143 164
76 109 139 I74 83 109 143 186 79 121 150 177 66 104 155 187 78 129 168 185
~
~
SV (ml) 66 85 85 89
Lactate (mmol/l) Remark9 0.6 2.0 4.2
Type I VSD (minimal)’
11.1
0.5 4.8 7.0
Type I -
72 78 65 78 59
0.7 3.2 3.6 6.0
Type I1 PI
1.5
51
3.8 6.9 10.1 0.8 5.3 5.2 10.8 0.6 3.2 12. 1 15.7
Type I1 PI
60 64 60 55
40 49 63 73 58 51
61 63 61 65 53 53 49 46 63 88 77 66 61 67 65 56 53 66 66 63 80 87 83 76 81 89 79 76 66 67 68 67
1.1
3.0 4.8 9.7 0.7 3.2 5.9 9.7 0.9 5.0 7.3 15.6 0.8 2.0 3.1 7.9 1.0 3.3 5.8 12.8 1.1 3.7 10.0 0.5 3.1 6.0 14.0
Type I1 PI
Type I -
Type I1 PI Type 111 PI (pronounced) +PS Type I VSD+PS+PP
Type I1 PI* Type 111 PS+PI+VSD (minimaly Type 1 PS+VSI)b Type IIP PS+PI
Exercise in totally corrected tetralogy of Fallot
179
Table I (cont.) Pat. no.
Age (y.)
14
29
15
16
Blood ExerHR Height Weight vol. cise Voz (beats/ (cm) (kg) (I) state (I/min) (I/min) min)
Sex
180
25
162
31
192
79
61.2
106
3.5
3.8
6.4
R E, E, Em,, R E, Ez Em,, R
El 17
26.5
175
62
4.9
Ez Em,, R
E,
Ez Em,, I8
30.5
174
58.6
4.1
R E, Ez
Em,,
0.32 1.48 1.90 2.11 0.23 0.88 1.43 2.01 0.33 1.39 2.04 2.33 0.29 1.44 2.19 0.29 0.84 1.39 1.70
~
a
4.7 10.1 12.5 14. I 5.7 9.0 12.3 13.5 4.3 11.2 14.8 13.7 6.4 9.9 12.3 14.4 4.3 7.3 9.6 10.4
SV (ml)
55 123 I56 179 57
86 82 80 79 99 108 95 78 70 I06 I02 85
84
129 174 62 106 145 161 75 120 168 183 65
85 83 73 78 66 67 56 56
110
I72 I84 ~~
Lactate (mmol/l) Remarkso
-o.6 3.9 7.4 0.8 2.1 4. I 9.0 1.4 3.0 6.5 10.4
YeI Type 1 VSD (minimalp Type1 -
0.9 6.7 13.6
Type I1 -
1.0
Type I1 PI
3.9 9.8 14.4
~~~~
Type of anatomy in right ventricle outflow tract prior to operation and residual defects. Diagnosis established at cardiac catheterization.
Uppsala (4 cases), using a patch in the ventricular septa1 defect (VSD)in all cases. An RV outflow tract patch was used in 10 patients and in one of them it was extended into the main pulmonary artery. In 9 of the patients a postoperative haemodynamic assessment including cardiac catheterization had been performed elsewhere, usually within one year after the operation (range 1 month-3 years), whereas the remaining patients unwilling to undergo another cardiac catheterization were investigated only clinically. Five patients were found to have no residual lesion according to the criteria stated under Methods. Another 2 patients had a minimal VSD with no detectable shunt. Thus 7 patients could be regarded as having excellent operative results. Three patients had a VSD with a small left-to-right shunt. Pulmonary valve stenosis (PSI was present in 5 patients and pulmonary valve incompetence (PI) in 10. The operative results were considered acceptable in all patients. All subjects were in sinus rhythm and none received any medication at the time of the study. Individual anthropometric data are listed in Table I, as well as a detailed presentation of residual defects present.
PROCEDURE The investigation was carried out in St. Goran’s Children’s Hospital in March-Nov. 1972. The patients were hospitalized for 3 4 days during the study. On the second day they performed a preliminary test designed to evaluate their aerobic working capacity. The actual exercise study
was performed in the morning of the third or fourth day after a light meal. Polyethylene catheters, 10 cm long, were introduced percutaneously into a brachial artery and a cubital vein. Simultaneous determinations of cardiac output, oxgen uptake, ventilation and blood lactate concentrations were done at rest in the supine position and during exercise in the sitting position. The exercise was performed on an electrically braked bicyle ergometer (Elema) at a pedal rate of 60 revlmin. Two submaximal work loads corresponding to about 50 and 8 0 % of maximal oxygen uptake were performed. Maximal exercise was also done at the highest possible work load the patients could perform for 5-7 min as judged by the information obtained from the preliminary test. The patients were allowed a 5-10 min pause between the submaximal exercise and 15 min rest before maximal exercise. This was preceded by a 3 min “warming up” period corresponding to about 50% of maximal aerobic power. A blood volume determination preceded the exercise study. No adverse effects were noted in any patient during the study.
COMMENT The “levelling off” criterion (2) for maximal load on the oxygen transporting system was not strictly used in this study. However, in the test preceding the actual study, the intention was to establish the maximal load on which the subject worked to exhaustion in about 6 min. From this maximal load and a subjecActa med. scand. 197
180 B . Bjarke
Table 11. Oxygen uptake, ventilation, cardiac output, stroke volume, heart rate, haemoglobin and blood lactate concentrations at rest and during exercise in 10 female and 8 male corrected patients with TOF (means+S.D.) Submax. I, submax. I1 and maximal load averaged respectively 279,472 and 644 kpm/min for the female and 460,747 and 979 kpmlmin for the male subjects
Voo,(I/min STPD) v E
(I/min BTPS)
6 P 6 0
R
d 0
0 (I/min)
6 0 6 0 6 0
HR (beatslmin)
SV (ml) Hb (g/IOO ml)
d P
Lactate (mmol/l)
6
0
Rest
Submax. I
Submax. I1
Max. work
0.28f0.03 0.23f0.03 8.Of 1 * 1 7.6f1.9 0.76k0.02 0.81f0.08 5.3f0.8 4.5f0.6 67f 10 74f9 79f 12 61f6 l3.8f 1.2 12.8f1.0 0.9k0.3 0.8f0.3
1.18f0.29 0.84f0.11 29.3k6.2 25.0f3.6 0.8520.04 0.85k0.02 9.4+ I .4 7.9f1.7 112f16 113k9 86f 18 69f 13 14.5f1.6 13.6f0.9 3.1 k0.7 3.4k 1.1
1.72f0.28 1.24 +O. 20 43.9f6.6 36.9f6.0 0.91 f0.03 0.91f0.04 12.2f1.4 9.4f I .8 155f14 151f10 80k 15 62f13 15.4+.1.5 14.1f0.8 5.8f2.0 5.8f2.6
2.08k0.27 1.51k0.26 69. If 14.0 56.2f12.0 1 .Mf0.05 1.O 1f0.05 13.2f1.3 10.8f 2.3 179f8 175f6 74f9 62f13 15.9f1.8 14.5f0.9 11.4f2.6 10.3f3.2
tive evaluation by the investigator as to whether this load really represented the individual’s maximum, the load in the actual test was chosen. The lactate values obtained were >9 mmol/l in 14 of the 18 subjects investigated (1). It is therefore concluded that the mean deviation for maximal oxygen uptake from the “true” value is marginal.
.(e,
METHODS
Cardiac output I/min) was determined by the dyedilution technique using indocyanine-green (Cardiogreen? as the indicator substance and a Beckman densitometer as the recording unit. The amount of dye which was injected with a calibrated syringe into the cubital vein varied from 0.80 to 1.73 ml depending on the size of the patients and the work performed, the concentration being 10 mglml. Arterial blood was drawn through a cannula inserted in the brachial artery at a constant rate of 55 ml/min. The blood was kept sterile and reinfused after each determination. Duplicate 0 determinations were made at rest and on each exercise level. Blood for 4-point calibration curves was obtained during maximal exercise in all subjects. The dye-dilution curves were calculated according to the method of Kinsmann et al. (29), including manual semilogarithmic plotting, extrapolation and planimetry of the curve areas. The error of the method was calculated from the difference between two consecutive steady state determinations in which the mean difference in heart rate did not exceed 5 beatshin. Fifty-two pairs of observations were analysed, varying from 3.9 to 15.5 I/min, and the error was found to be 8.9%. Acta mcd. scand. 197
Heart rate (HR, beats/min) was calculated from continuous ECG tracings, counting over a period of 15 sec. HR,., is defined as the value obtained at exercise breaking point. Oxygen uptake #op, I/min STPD) was determined using the Douglas bag technique and the volume of expired air 1 BTPS/min) measured in a calibrated Tissot spirometer. Fractions of Opand Copin samples of expired air were analysed by the Micro-Scholander method (39). Arterial haemoglobin concentration (Hb, g/lOO ml) was measured by the cyanmethaemoglobin method, and haematocrit (Hct) with a high-speed centrifuge. Arterial lactate concentration (lactate, mmol/l) was measured enzymatically (1 1). Total blood volume (I) was measured by the 1*51albumin method (43). Values obtained were corrected for the difference between body Hct and central Hct. Heart volume (HV,ml) was Calculated according to Jonsell(25). The presence of residual heart lesions was established from previous postoperative catheterization (9 patients) and/or from physical examination. Significant residual PS was considered present if a peak-systolic gradient of 230 mmHg over the RV outflow tract and/or pressure in RV 250 mmHg was present at the follow-up catheterization. A PS was also said to be present if a 23/6 ejection systolic murmur was detected over the pulmonary valve area. A VSD was considered to be present either if proven at catheterization or if a pansystolic murmur (not due to tricuspidal insufficiency) was found. Pi was assessed by length and intensity of the diastolic regurgitant murmur. The Wilcoxon rank sum test was used to test the possible influence of a particular residual defect and of the use of a
(vE,
Exercise in totally corrected tetralogy of Fallot
181
Table 111. Correlation matrix for maximal oxygen uptake and some dimensions and functional capacities of the oxygen transport system in 18 totally corrected adubpatients with TOF n =no. of observations '02
max
(I/min/ kg b.wt.)
"S max
(I/min) .740*** n=17 .512* n=17 .486* n=17 -.038 n.s. n=16 .846** * n=17 0.816*** n=17 .I55 n.s. n=17
-.058 n.s. n=17 .567* n=17 -.019 n.s. n=17 .489 n.s. n=16 .553* n=17 .422 n.s. n=17 .517* n=17 .503* n=17
.84 1* **
n=17
right ventricular oufflow patch on stroke volume and VO, max. Otherwise current statistical methods were used (41). The degree of probability was designated as follows: O.OS 0.01, probably significant (*); 0.01~p>0.001,significant (**); O.O01~pp, highly significant (***).
RESULTS
SVmax (ml)
HRmax (beatslmin)
.606** n=l8 .403 n.s. n=18 .267 n.s. n=18 .274 n.s. n=17 -
.677** n=18 ,334 n.s. n=18 .322 n.s. n=l8 -.319 n.s. n=17 .974*** n=18
0.974*** n=18 .057 n.s. n=18 .866*** n=18
-
-.289 n.s. n=18 .169 n.s. n=18 -.254 n.s. n=l8 .260 n.s. n=17 .057 n.s. n=18 -.I67 n.s. n=18
Qmax
(I/min)
-.I67 n.s. n=18 .834*** n=l8
0.87 n.s. n=18
was found to be normal in both the male and the female group (l), the mean being 22.9+1.4% at submaximal load 11. Cardiac output was low when related to 00,both during submaximal and maximal work (Fig. 1). Half of the observations were below -2 S.D. of the. regression line for young males found by Ekblom et al. (12), using techniques similar to those in the
Individual and mean values are given in Tables I and
I1 and a correlation matrix in Table 111. The mean maximal oxygen uptake (Vo2-,,,=)was 2.08 l/min for the males and 1.51 I/min for the females. This corresponds to a value of 30.5 ml/min/kg and 25.5 ml/min/kg for the males and females, respectively, when related to body weight and to values of 1.13 I/min/m2, 0.92 I/min/m2 when related toBSA. Both the absolute and relative values for Vo2 are lower than normal for Swedish males and females of corresponding ages (1, 2). Individual values were all below -2 S.D. The correlation between VozmW, on the one hand, and and SVmax on the other was highly significant. No correlation was found with blood volume or HR,,,. Mechanical eficiency /mechanical work performed (kpm/min)x loO\
emax
\
Fig. 1 . Cardiac output in relation to oxygen uptake at rest in the supine position and during exercise in the sitting position in 18 totally corrected adult patients with TOF. The regression line @=5.72~+5.13;S.D.f1.44)is calculated from data of Ekblom et al. (12). The present regression equation: y=4.56r+3.8; S.D.kl.39. Siflficance of difference between lines 0.052p>O.01. Acta med. s c a d . 197
182 B. Bjarke
BSA. Ip the female subjects the values were 714+ 136 ml and 439f85 ml/m*, respectively. Values for Hb and lactate concentrations as well as ventilation are summarized in Table 111. A detailed statement of spirometric data, pulmonary ventilation, gas exchange and acid-base balance has been given in an earlier publication (7).
DISCUSSION 5
bz 1/.h Fig. 2. Individual values for stroke volume in relation to oxygen uptake at rest in the supine position and during exercise in the sitting position in 18 totally corrected adult patients with TOF.
present investigation. Only one observation was above this regression line., was 13.2 l/min for the males and 10.8 l/min for the females, corresponding to cardiac indices of 7.2 and 6.6 llminl m2 for males and females, respectively. No correlation was found between and HV, blood volume or HR,,,. Stroke volumes (SV, ml) at rest in the supine position were small when compared with normal volumes (3,6,28). The mean value for males was 79 ml (range 66-99) and forfemales 61 ml (range 52-72). Corresponding values for stroke index were 43.4 and 37.6, respectively. SVs at submaximal exercise I were slightly but significantly higher (0.01 a p >0.001) than at rest in the supine position. During exercise there was a fall in SV with increasing work loads, mean SV being 76 ml during submaximal exercise I, 70 ml during submaximal exercise I1 and 67 ml during maximal exercise (Fig. 2). The difference between SV during exercise I and maximal exercise was highly significant (0.001zy). In 8 patients the fall in SV was > 10 ml. The fall in SV and the size of SV,,, could not be correlated to any particular residual lesion. No correlation existed between SV,,, and blood volume, HV or HR,,,. Mean maximal heart rate was 184f9 beatslminfor the male group and 17957 beatslmin for the female. HR related to relative work is illustrated in Fig. 3. Total blood volume was 4.78f1.10 1 or 71f15 ml/kg b.wt. in the male group and 4.20f0.43 1 or 73 f 13 ml/kg b.wt. in the female. Heart volumes were larger than normal. In the male group a mean value of 8645 150 ml was found, corresponding to 465+36 ml/m2 when related to
em,,
em,,
Acta med. scond. 197
1
The values obtained for maximal oxygen uptake are low for both sexes. They are almost identical with the figures found in totally corrected TOF patients by Epstein et al. in a recently published investigation (14) and represent a reduction of 3040% compared with normal figures ( I , 2). These findings show that in spite of a successful anatomic repair, no true normalization of the aerobic work capacity occurs. However, in a study from this department of 16 only shunt-operated TOF patients of comparable age, the Vo2,,, was found to be only 18.0 mllkglmin. Thus about 60% higher values were found in the totally corrected subjects. This corresponded well with the subjective evaluation made by the patients themselves who felt that their exercise tolerance had increased considerably after intracardiac repair. Values for cardiac output related to oxygen uptake were lower than in normal subjects (Fig. 1). This finding is contrary to earlier reports (9,17,18,33,40)
Y 1.
0 0
* , , 40
t a ' h ' i Yo H ~ 912 I
Fig. 3 . Individual values for heart rate (beatslmin) during submaximal work in the sitting position in relation to oxygen uptake expressed as percentage of the maximal oxygen uptake in 18 totally corrected adult patients with TOF. Regression line with S.D. calculated from data of Astrand (2).
Exercise in totally corrected tetralogy of Fullot
8i
.
F
Fig. 4. Arteriovenous oxygen difference in relation to oxygen uptake expressed as percentage of maximal oxygen uptake in 18 totally corrected adult patients with TOF. The regression lines, females y=0.07&+6.40 and males y=0.072x+9.61, are calculated from data of Astrand et al. (3). The present regression equations, males y=0.087x+7.11 and females y=0.067x+7.36,
were not significantly different from those of Astrand.
which state that anormal increase i n 0 occurred with exercise. In the latter studies, however, haemodynamic evaluations were performed with the patients working at low exercise loads. The finding of an altered relationship between 30, and 8 is, however, in agreement with Epstein’s results from 10 corrected patients with TOF without significant residual lesion. The same situation has been found to exist in other types of congenital heart disease, e.g. atrial septa1 defect, pulmonary valvular stenosis, mitral stenosis, aortic insufficiency (4, 13, 14,22,26, 371, both before and after total correction. In the present series no correlation was found between the decrease i n 0 relative to Vozand the type of anatomy in the RV outflow tract, the use of outflow patch or the presence of a particular residual lesion. It is thus likely that the “inadequacy” of the Q response to exercise is less related to the type of congenital heart malformation than to the myocardial function itself. The low 0 relative to 30, led to a higher-thannormal AV oxygen difference. This does not reflect a more effective oxygen extraction and/or a changed distribution of the left ventricular (LV) output, e.g. from visceral organs to working muscles, since the AV oxygen difference was found to be normal when relative work was used as frame of reference (Fig. 4). Furthermore the AV oxygen difference ’during maximal exercise expressed as percentage of oxygen binding capacity of the blood was found to be normal (73 %). An analysis of the subfunctions of the cardiac
183
output, i.e. heart rate and stroke volume, reveals that the main cause of the low 0 was the small SVs found, 74 ml in the male and 62 ml in the female group during maximal exercise in the sitting position. A highly significant correlation existed between SV,,, and The reason for the small SVs found cannot be fully elucidated from the results of this study. However, some conclusions could be drawn from the findings in the postoperative catheterizations performed on some of our patients and from previous investigations. The S V depends not only on the anatomical size of the ventricles, but also on the venous return to the heart, the resistance to emptying of the ventricles, and the contractibility characteristics of the heart muscle. Some controversy exists concerning the size of the LV in TOF. Some investigators have found the LV to be normal or slightly small (3 1,34), and an underdevelopment of this chamber severe enough to be of haemodynamic significance is said to be present in less than I % of the patients (36). However, Jamarkaqi et al. (23) convincingly showed that cyanotic patients with TOF, more than 2 years of age, had smaller left HV than normal. With successful shunt operation or total correction an increase in LV end-diastolic volume as well as LV mass occurred to values significantly higher than normal. In spite of this the LV ejection fraction remained subnormal. This latter finding was attributed to a depressed LV function and consequently not to small left HV. It is well documented that stroke volume is influenced by the degree of physical activity and that it can be increased by physical training (12,15,28,38). Our patients were definitely more inactive than normal during their childhood and they are probably less active physically also after total correction. In the present study only 2 patients stated that they regularly participated in strenuous physical activities. The vast majority of our patients have an occupation which could classify them as white-collar workers. The reduction in S V might therefore theoretically be explained by small circulatory dimensions secondary to prolonged physical inactivity. It has been shown that a high degree of interdependence exists between different components of the oxygen transport system and the degree of physical activity or VoZmax(20). The correlation matrix (Table 111) shows that this was the case in our subjects too, with one exception, namely the dimensions of the cardiovascular system. Though the SV was correActa med. scand. 197
184 B. Bjarke higher HR,a longer duration of systole results in a shorter diastole. This may hamper ventricular filling when an increased filling pressure is needed and the ejection time is prolonged. One may speculate whether this causes the fall in SV during exercise in some of our patients. Support for this theory may be the observed negative correlation between the enddiastolic pressure in R V and the size of SV,,, (0.01~p>0.001)and SV/BSA (0.053p>0.01) found MI in our seriers (Fig. 5 ) . However, this latter finding ss , O , * ; must be viewed with caution due to the small 5 10 15 number of observations and the fact that data of p t d m RV,rnHO enddiastolic pressure and SV were obtained on Fig. 5 . Individual values for stroke volume during maximal exercise in relation to end-diastolic pressure in the right different occasions. ventricle at rest in 9 subjects with totally corrected The slightly low maximal heart rate agrees with TOF. findings of Hurvitz and Goldberg (21) that the HR,,, was lower than normal, not only before, lated to v02max, this was not the case with blood but also after operative correction of different volume or heart volume. Neither was there any cardiac lesions. Similar or related observations intercorrelation between stroke volume, blood vol- have been reported by others (16, 26, 27, 42). The in cardiac ume and heart size. If the reduction in SV were to be reason for the subnormal HR,,, explained by low physical activity alone, one would patients is not fully understood. One possible exhave expected such correlations to exist. However, planation is that the subjects stop exercising for it cannot be excluded that physical inactivity was a other reasons than circulatory, such as e.g. contributory cause of the reduction of the SVs. It dysponea or hypoxaemia (26). This might be the would therefore have been of interest to see whether explanation in uncorrected but hardly in totally our patients' SV would have increased after or- corrected TOF patients, since their ventilatory response to exercise is normal and since ganized physical training. they do not have hypoxaemia (7). Another exOne explanation of the small SVs may be an abnormal contractile response of the ventricles and planation may be that the lower maximal cardiac altered compliance characteristics of the ventricular frequency represents a physiological adaptation to myocardium (14, 23). Several factors such as the the haemodynamic situation. A lower-than-normal myocardial changes in the right ventricle, secondary heart rate may be needed to allow optimal diastolic to the long-standing muscular hypothropy, non- filling. If this explanation is valid, one would expect contractile parts of the myocardium, corresponding not only the HR,,, to be lower than normal, but also to the'ventriculotomyscar, the patch in the ventricu- the HR at submaximal loads. That this is the case is lar septum and the R V outflow tract have to be shown in Fig. 3. Other possible explanations may be considered as well as the RBBB that is usually pres- related to muscular ventricular hypertrophy or to the presence of conduction disturbances, e.g. RBBB. It ent. An R V outflow tract gradient is usually present should, however, be noted that in the series of even in successfully operated TOF patients (9, 14, Hurvitz and Goldberg (21) patients with conduction 30,40). This gradient increases during exercise (14, disturbances were excluded. In the present study the decrease in aerobic capac40). To maintain an adequate SV in this situation there are three possibilities: to increase the RV ity could not be correlated to the anatomy of the RV systolic pressure, to prolong the ejection time and to outflow tract or to the use of an outflow patch. increase the diastolic filling (22). Each of these Though the number of patients studied was small, compensatory mechanisms has been found in TOF (9, this tends to substantiate the findings of others (9,18, 14,23,40). However, SV decreased during exercise 24,331 that TOF patients tolerate PI reasonably well. in the present group. If the R V is the limiting factor This seems to be the case also when correction is for maintenance of the SV, this indicates that the undertaken at adult age. above mentioned mechanisms are not sufficient. At There was no complete normalization of physical
i
Acto med. scond. 197
Exercise
work capacity in our patients, the majority of whom werecorrectedat adult age. Future studies will show whether a better normalization is achieved if total correction is undertaken in early life. This might perhaps be expected if the TOF patients perform a normal degree of physical activity during the years when growth of circulatory dimensions takes place. The reduction in Vjo2maxwas moderate and did not interfere with everyday activities. However, it means that at a certain degree of activity our subjects utilized agreater portion of their aerobic work capacity. A greater portion of the cardiac reserve was mobilized. This may prove to be a disadvantage as the patients grow older and are subjected to the ageing processes in the heart and to ischaemic heart disease. ACKNOWLEDGEMENT This study was supported by grants from the Swedish National Association against Heart and Chest Diseases.
REFERENCES 1. Astrand, I.: Aerobic work capacity in men and women
with special reference to age. Acta physiol. scand., Suppl. 169, 1%0. 2. Astrand, P.-0.: Experimental studies of physical working capacity in relation to sex and age. Munksgaard, Copenhagen 1952. 3. Astrand, P.-O., Cuddy, T. E., Saltin, B. & Stenberg, J.: Cardiac output during submaximal and maximal work. J. appl. Physiol. 19: 268, 1964. 4. Astrom, H.: Effect of posture on circulation and respiration at rest and during exercise in heart disease. Acta physiol. scand., Suppl. 347, 1970. 5. Aperia, A., Bjarke, B., Broberger, 0. & Thoren, C.: Renal function in Fallot’s tetralogy. Acta paediat. scand. 63: 398, 1974. 6. Bevegkrd, S ., Holmgren, A. & Jonsson, B.: The effect of body position on the circulation at rest and during exercise, with special reference to the influence on the stroke volume. Acta physiol. scand. 49: 279, 1960. 7. Bjarke, B.: Spirometnc data, pulmonary ventilation and gas exchange at rest and during exercise in adult patients with tetralogy of Fallot. Scand. J. resp. Dis. 55: 47, 1974. 8. Bjarke, B., Eriksson, B. 0. & Saltin, B.: ATP, CPand lactate concentrations in muscle tissue during exercise in male patients with tetralogy of Fallot. Scand. J. clin. Lab. Invest. 33: 255, 1974. 9. Bristow, D., Kloster, F., Lees, M., Menashe, V., Griswold, H. & Stan-, A.: Serial cardiac catheterizations and exercise hemodynamics after correction of tetralogy of Fallot. Circulation 41: 1057, 1970. 10. Burnell, R. H., Woodson, D., Lees, M. H.,Bristow, J. D. & Starr, A.: Result of correction of tetralogy of Fallot in children under four years of age. J. thorac. cardiovasc. Surg. 51: 153, 1969.
in totally corrected
tetralogy of Fallot
185
11. Cramp, D. G.: Automated enzymatic fluorometric method for the determination of pyruvic and lactic acids in blood. J. clin. Path. 21: 171, 1968. 12. Ekblom, B., Astrand, P.-0.. Saltin, B., Stenberg, J. & Wallstrom, B.: Effect of training on circulatory response to exercise. J. appl. Physiol. 24: 518, 1%8. 13. Enghoff, E.: Aortic incompetence. Acta med. scand., Suppl. 538, 1972. 14. Epstein, S., Beiser, D., Goldstein, R., Rosing, D., Redwood, D. & Morrow, A.: Hemodynamic abnormalities in response to mild and intense upright exercise following operative correction of an atrial septa1 defect or tetralogy of Fallot. Circulation 47: 1065, 1973. IS. Eriksson, B. 0.& Koch, G.: Effect of physical training on hemodynamic response during submaximal and maximal exercise in 11-13 year old boys. Actaphysiol. scand. 87: 27, 1973. 16. Goldberg, S. J., Weiss, R. & Adams, F. H.: A comparison of the maximal endurance of normal children and patients with congenital cardiac disease. Pediatrics 69:46, 1966. 17. Gotsman, M. S.: Haemodynamic and cineangiocardiographic findings after one stage repair of Fallot’s tetralogy. Brit. Heart J. 28: 448, 1966. 18. Gotsman, M. S., Beck, W., Barnard, C. N., O’Donovan, T. G. & Schrire, V.: Results of repair of tetralogy of Fallot. Circulation 40:803, 1%9. 19. Hawe, A., Rastelli, G. C., Ritter, D. G., DuShane, J. W. & McGoon, D. C.: Management of the right ventricular outflow tract in severe tetralogy of Fallot. J . thorac. cardiovasc. Surg. 60:131, 1970. 20. Holmgren, A. &Astrand,P.-0.: 0,and thedimensions and functional capacities of the O2transport system in humans. J. appl. Physiol. 21: 1463, 1966. 21. Hurvitz, R. & Goldberg, S.: Maximal cardiac rate before and following repair of cardiac lesions. J. Sport Med. 10 165, 1970. 22. Ikkos, D., Jonsson, B. & Linderholm, H.: Effect of exercise in pulmonary stenosis with intact ventricular septum. Brit. Heart J. 28: 316, 1966. 23. Jarmakani, J., Graham, T., Jr, Canent, R. & Jewett, P.: Left heart function in children with tetralogy of Fallot before and after palliative or corrective surgery. Circulation 46: 478, 1972. 24. Jones, E. L., Conti, R. C., Neill, C. A., Gott, V. L., Brawley, R. K. & Hailer, A. J.: Long-term evaluation of tetralogy patients with pulmonary valvular insufficiency resulting from outflow-patch correction across the pulmonicannulus. Circulation, Suppl. 3: 1 I , 1973. 25. Jonsell, S.: A method for the determination ofthe heart size by teleroentgenography. Acta radiol. 20: 325, 1939. 26. Jonsson, B.: Circulatory adaptation to exercise in congenital heart disease. Proc. Ass. Europ. Paediat. Cardiol. 9: 2, 1973. 27. Jose, A. D. & Taylor, R. R.: Autonomic blockade by propranolol and atropine to study intrinsic myocardial function in man. J. clin. Invest. 48: 2019, 1969. 28. Kilbom, A. & Astrand, I.: Physical training with submaximal intensities in women. 11. Effect on cardiac output. Scand. J. clin. Lab. Invest. 28: 163. 1971. Acla med. scand. 197
186 B . Bjarke 29. Kinsman, J. M., Moore, J. W. & Hamilton, W. F.: Studies on the circulation. I. Injection method: Physical and mathematical considerations. Amer. J. Physiol. 89: 322, 1929. 30. Kirklin. J. & Karp, R.: The tetralogy of Fallot. Saunders, Toronto 1970. 31. Lew, M., Rimoldi, H. J. A. & Rowlatt, U.: The quantitative anatomy of cyanotic tetralogy of Fallot. Circulation 3 0 53 I , 1%4. 32. Lillehei, C. W., Cohen, M., Warden, H. E., Read, R. C., Aust, J. B., DeWall, R. A. & Varco, R. L.: Direct vision intracardiac surgical correction of the tetralogy of Fallot, pentalogy of Fallot, and pulmonary atresia defects; report of first ten cases. Ann. Surg. 142: 418, 1955. 33. Malm, J. R. ,Blumenthal, S., Bowman, F. O., Ellis, K., Jameson, A. G., Jesse, M. J. & Yeoh, C. B.: Factors that modify hemodynamic results in total correction of tetralogy ofFallot. J. thorac. cardiovasc. Surg. 52: 502, 1966. 34. Miller, G., Kirklin, J., Rahimtoola, S. & Swan, H.: Volume of left ventricle in tetralogy of Fallot. Amer. J. Cardiol. 16: 488, 1965. 35. Moller, T.: Shunt operations in morbus Caerules. Acta paediat. scand., Suppl. 134, 1%2. 36. Nagao, G. I., Daoud, G. I., McAdams, A. J.,
Acta med. scand. 197
37.
38.
39. 40.
41. 42. 43.
Schwartz, D. C. & Kaplan, S.: Cardiovascular anomalies associated with tetralogy of Fallot. Amer. J. Cardiol. 2 0 206, 1%7. Petersson, P. 0.:Atrial septa1 defect of secundum type: A clinical study before and after operation with special reference to haemodynamic function. Acta paediat. scand., Suppl. 174, 1%7. Saltin, B., Blomqvist, G., Mitchell, J. H., Johnson, R. L., Jr, Wildenthal, K. BC Chapman, B.: Response to exercise after bed rest and after training. Circulation, Suppl. 7, 1%8. Scholander, P. F.: Analyzer for accurate estimation of respiratory gases in one-halfcubic centimeter samples. J. biol. Chem. 167: 235, 1947. Shah, P. & Kidd, L.: Hemodynamic responses to exercise and to isoproterenol followingtotal correction of Fallot’s tetralogy. J. thorac. cardiovasc. Surg. 52: 138, 1966. Snedecor, G. W.: Statistical methods, 6th ed. The Iowa State University Press, Iowa 1%7. Vatner, S. & Braunwald, E.: Cardiac frequency: control and adjustments to alterations. Progr. cardiovasc. Dis. 14: 431, 1972. Williams, J. A. & Fine, J.: Measurement of blood volume with a new apparatus. New Engl. J. Med. 264: 842, 1961.
OXYGEN UPTAKE AND CARDIAC OUTPUT DURING SUBMAXIMAL AND MAXIMAL EXERCISE IN ADULT SUBJECTS WITH TOTALLY CORRECTED TETRALOGY OF FALLOT Bjorn Bjarke From the Department of Pediatrics, Karolinska Institutet. St. Goran’s Children’s Hospital, Stockholm, Sweden
Abstract. Ten female and eight male adults with tetralogy of Fallot, the majority totally corrected at adult age, have been studied at rest and during submaximal and maximal exercise on a bicycle ergometer. Oxygen uptake was determined by the Douglas bag technique and cardiac output by the dye-dilution method. Maximal oxygen uptake was reduced about 3 0 4 0 % from normal. Thus a complete normalization of the aerobic working capacity was not achieved in spite of an intracardiac repair that was considered surgically satisfactory. Cardiac output response to exercise was subnormal, mainly due to small stroke volumes and partly because of low heart rates. A fall in stroke volume of more than 10 ml was found in 8 of the patients during exercise. No correlation was found between stroke volume during maximal exercise, on the one hand, and the presence of a particular residual defect, anatomy of the right ventricular outflow tract prior to operation and the use of a right ventricular outflow patch on the other. However, too few patients were studied to allow any definite conclusions as to the possible influence of these variables. It remains to be shown whether the haemodynamic abnormalities will be less and the aerobic work capacity better if total correction is undertaken at an early age.
The first patient with tetralogy of Fallot (TOF) was totally corrected in 1955 (32). Thus the knowledge of the long-term results is incomplete. Total corrective operation has dramatically changed and improved the natural history for patients with TOF. Still, even a successful operation must be looked upon as an anatomical correction with some residua since the patients are left with a ventriculotomy scar, often with some degree of right ventricular outflow tract stenosis and a right bundle branch block (RBBB). The question is whether these residua will interfere with the normalization of the circulation which is aimed at when total correction is undertaken and whether the impact of these residua is 12 -752983
influenced by the age at which total correction is performed. Several authors (9, 17, 18, 33, 40) have found normal or near normal haemodynamics at rest and during mild exercise in patients with technically good operation results. However, this does not mean that they have a normal exercise tolerance and a normal haemodynamic response to heavy work. In the haemodynamic studies cited above, most patients were corrected before the age of 10. The aim of this study was therefore to study the haemodynamic response during submaximal and maximal exercise in a group of patients with TOF corrected at adult o r near adult age. The haemodynamic study presented in this article is part of a larger investigation comprising pulmonary and renal function as well as muscle metabolism in patients with TOF (5, 7,8). MATERIAL Eighteen adults, 10 females and 8 males, with totally corrected TOF took part in this study. All belonged to the material previously studied by Miiller (35) and all had undergone a palliative shunt operation between 1947 and 1955 at a mean age of 5 years. Total correction was undertaken at 19.5 years of age (range 11-27.5). Only 3 patients were less than I5 years old when intracardiac repair was performed. The mean age at the follow-up was 26 (range 19-35). Since total correction 6.5 years (range 2.5-10.5) had thus elapsed. The anatomy classification suggested by Hawe et al. (19) was used for the right ventricular (RV) outflow tract before operation. Eight patients had isolated infundibular stenosis (type I), 7 combined valvular and infundibular stenosis (type 11) and 3 diffuse hypoplasia of the outflow portion of the RV and the main pulmonary artery (type 111). Intracardiac repair was carried out in the Departments of Thomcic Surgery, Karolinska Sjukhuset, Stockholm (14 cases), and in the University Hospital, Acta med. scand. 197
178 B. Bjarke
(o),
Table I . Individual values for oxygen uptake (Voz),cardiac output heart rate ( H R ) , stroke volume (SV) and blood lactate concentration at rest ( R ) in supine position and during submaximal ( E l , Ez) and maximal exercise (Emax) in the sitting position ~
~
~~
Pat. no.
Age (y.)
Sex
Blood ExerHR Height Weight vol. cise Vo2 (beats/ (cm) (kg) (1) state (I/min) (l/min) min)
1
28.5
0
I70
2
25
P
164
73.5
55
4.7
4.1
R
0.25
El E2 Em,, R El
0.92 1.52 1.95 0.21 0.88 1.02
E2 3
4
5
22
22
27.5
P
0
0
167
167
163
60.3
48.4
62.7
4.4
4.7
4.5
Em,,
1.18
R
0.21 0.93 1.36 1.61 0.21 0.82 1.16
El E2 Em,, R El E2 Emax R El E2
&=
6
7
8
9
27
23.5
35
24
0
0
0
0
163
161
164
158
48.4
50.5
58
62
4.2
3.5
3.8
R El E2 Em,, R El E, Em,,
R El E2 Em,, R E, Ez
-
0.21 0.84 1.33 1.48 0.25 0.82 1.42 1.57 0.24 0.61 0.85 1.08
0.29 0.96 1.26 1.53 0.21
-
1.16
Em,, 1.53 10
21
0
165
65
3.8
R E, E2 Em,,
0.19 0.79 1.27 1.68
11
25
d
189
67.5
6.3
R
-
12
19
d
168
67
5.0
13
25
d
171
56. I
4.2
Acra med. wand. 197
E, El Em, R E, El
1.49 1.97 2.34 0.26 0.91 1.86 ‘Em,, 2.30 R 0.26 El 1.05 E2 1.44 Em,, 1.66
5.6 10.1 13.0 15.5
4.4 8.2 9.1 9.4 4.5 9.1 to. 1 13.4 3.9 6.3 6.7 8.9 3.9 7.3 8.5
9. I 4.3 6.3 10.0 11.4 4. I 6.5 7.3 7.9 5.4 10.7 11.0 10.9 4.6 7.3 9.0 9.7 4.4 7.2 9.5 11.7 6.3 10.5
12.5 13.4 5.3 9.2 12.3 14.1 5.1
8.7 11.4 12.4
85 1 I8
152 I 74 74 128 152 170 63 I17 156 173 66 124 I68 182 61 99 145 178 71 101
165 176 78 121 149 171 86 121 143 164
76 109 139 I74 83 109 143 186 79 121 150 177 66 104 155 187 78 129 168 185
~
~
SV (ml) 66 85 85 89
Lactate (mmol/l) Remark9 0.6 2.0 4.2
Type I VSD (minimal)’
11.1
0.5 4.8 7.0
Type I -
72 78 65 78 59
0.7 3.2 3.6 6.0
Type I1 PI
1.5
51
3.8 6.9 10.1 0.8 5.3 5.2 10.8 0.6 3.2 12. 1 15.7
Type I1 PI
60 64 60 55
40 49 63 73 58 51
61 63 61 65 53 53 49 46 63 88 77 66 61 67 65 56 53 66 66 63 80 87 83 76 81 89 79 76 66 67 68 67
1.1
3.0 4.8 9.7 0.7 3.2 5.9 9.7 0.9 5.0 7.3 15.6 0.8 2.0 3.1 7.9 1.0 3.3 5.8 12.8 1.1 3.7 10.0 0.5 3.1 6.0 14.0
Type I1 PI
Type I -
Type I1 PI Type 111 PI (pronounced) +PS Type I VSD+PS+PP
Type I1 PI* Type 111 PS+PI+VSD (minimaly Type 1 PS+VSI)b Type IIP PS+PI
Exercise in totally corrected tetralogy of Fallot
179
Table I (cont.) Pat. no.
Age (y.)
14
29
15
16
Blood ExerHR Height Weight vol. cise Voz (beats/ (cm) (kg) (I) state (I/min) (I/min) min)
Sex
180
25
162
31
192
79
61.2
106
3.5
3.8
6.4
R E, E, Em,, R E, Ez Em,, R
El 17
26.5
175
62
4.9
Ez Em,, R
E,
Ez Em,, I8
30.5
174
58.6
4.1
R E, Ez
Em,,
0.32 1.48 1.90 2.11 0.23 0.88 1.43 2.01 0.33 1.39 2.04 2.33 0.29 1.44 2.19 0.29 0.84 1.39 1.70
~
a
4.7 10.1 12.5 14. I 5.7 9.0 12.3 13.5 4.3 11.2 14.8 13.7 6.4 9.9 12.3 14.4 4.3 7.3 9.6 10.4
SV (ml)
55 123 I56 179 57
86 82 80 79 99 108 95 78 70 I06 I02 85
84
129 174 62 106 145 161 75 120 168 183 65
85 83 73 78 66 67 56 56
110
I72 I84 ~~
Lactate (mmol/l) Remarkso
-o.6 3.9 7.4 0.8 2.1 4. I 9.0 1.4 3.0 6.5 10.4
YeI Type 1 VSD (minimalp Type1 -
0.9 6.7 13.6
Type I1 -
1.0
Type I1 PI
3.9 9.8 14.4
~~~~
Type of anatomy in right ventricle outflow tract prior to operation and residual defects. Diagnosis established at cardiac catheterization.
Uppsala (4 cases), using a patch in the ventricular septa1 defect (VSD)in all cases. An RV outflow tract patch was used in 10 patients and in one of them it was extended into the main pulmonary artery. In 9 of the patients a postoperative haemodynamic assessment including cardiac catheterization had been performed elsewhere, usually within one year after the operation (range 1 month-3 years), whereas the remaining patients unwilling to undergo another cardiac catheterization were investigated only clinically. Five patients were found to have no residual lesion according to the criteria stated under Methods. Another 2 patients had a minimal VSD with no detectable shunt. Thus 7 patients could be regarded as having excellent operative results. Three patients had a VSD with a small left-to-right shunt. Pulmonary valve stenosis (PSI was present in 5 patients and pulmonary valve incompetence (PI) in 10. The operative results were considered acceptable in all patients. All subjects were in sinus rhythm and none received any medication at the time of the study. Individual anthropometric data are listed in Table I, as well as a detailed presentation of residual defects present.
PROCEDURE The investigation was carried out in St. Goran’s Children’s Hospital in March-Nov. 1972. The patients were hospitalized for 3 4 days during the study. On the second day they performed a preliminary test designed to evaluate their aerobic working capacity. The actual exercise study
was performed in the morning of the third or fourth day after a light meal. Polyethylene catheters, 10 cm long, were introduced percutaneously into a brachial artery and a cubital vein. Simultaneous determinations of cardiac output, oxgen uptake, ventilation and blood lactate concentrations were done at rest in the supine position and during exercise in the sitting position. The exercise was performed on an electrically braked bicyle ergometer (Elema) at a pedal rate of 60 revlmin. Two submaximal work loads corresponding to about 50 and 8 0 % of maximal oxygen uptake were performed. Maximal exercise was also done at the highest possible work load the patients could perform for 5-7 min as judged by the information obtained from the preliminary test. The patients were allowed a 5-10 min pause between the submaximal exercise and 15 min rest before maximal exercise. This was preceded by a 3 min “warming up” period corresponding to about 50% of maximal aerobic power. A blood volume determination preceded the exercise study. No adverse effects were noted in any patient during the study.
COMMENT The “levelling off” criterion (2) for maximal load on the oxygen transporting system was not strictly used in this study. However, in the test preceding the actual study, the intention was to establish the maximal load on which the subject worked to exhaustion in about 6 min. From this maximal load and a subjecActa med. scand. 197
180 B . Bjarke
Table 11. Oxygen uptake, ventilation, cardiac output, stroke volume, heart rate, haemoglobin and blood lactate concentrations at rest and during exercise in 10 female and 8 male corrected patients with TOF (means+S.D.) Submax. I, submax. I1 and maximal load averaged respectively 279,472 and 644 kpm/min for the female and 460,747 and 979 kpmlmin for the male subjects
Voo,(I/min STPD) v E
(I/min BTPS)
6 P 6 0
R
d 0
0 (I/min)
6 0 6 0 6 0
HR (beatslmin)
SV (ml) Hb (g/IOO ml)
d P
Lactate (mmol/l)
6
0
Rest
Submax. I
Submax. I1
Max. work
0.28f0.03 0.23f0.03 8.Of 1 * 1 7.6f1.9 0.76k0.02 0.81f0.08 5.3f0.8 4.5f0.6 67f 10 74f9 79f 12 61f6 l3.8f 1.2 12.8f1.0 0.9k0.3 0.8f0.3
1.18f0.29 0.84f0.11 29.3k6.2 25.0f3.6 0.8520.04 0.85k0.02 9.4+ I .4 7.9f1.7 112f16 113k9 86f 18 69f 13 14.5f1.6 13.6f0.9 3.1 k0.7 3.4k 1.1
1.72f0.28 1.24 +O. 20 43.9f6.6 36.9f6.0 0.91 f0.03 0.91f0.04 12.2f1.4 9.4f I .8 155f14 151f10 80k 15 62f13 15.4+.1.5 14.1f0.8 5.8f2.0 5.8f2.6
2.08k0.27 1.51k0.26 69. If 14.0 56.2f12.0 1 .Mf0.05 1.O 1f0.05 13.2f1.3 10.8f 2.3 179f8 175f6 74f9 62f13 15.9f1.8 14.5f0.9 11.4f2.6 10.3f3.2
tive evaluation by the investigator as to whether this load really represented the individual’s maximum, the load in the actual test was chosen. The lactate values obtained were >9 mmol/l in 14 of the 18 subjects investigated (1). It is therefore concluded that the mean deviation for maximal oxygen uptake from the “true” value is marginal.
.(e,
METHODS
Cardiac output I/min) was determined by the dyedilution technique using indocyanine-green (Cardiogreen? as the indicator substance and a Beckman densitometer as the recording unit. The amount of dye which was injected with a calibrated syringe into the cubital vein varied from 0.80 to 1.73 ml depending on the size of the patients and the work performed, the concentration being 10 mglml. Arterial blood was drawn through a cannula inserted in the brachial artery at a constant rate of 55 ml/min. The blood was kept sterile and reinfused after each determination. Duplicate 0 determinations were made at rest and on each exercise level. Blood for 4-point calibration curves was obtained during maximal exercise in all subjects. The dye-dilution curves were calculated according to the method of Kinsmann et al. (29), including manual semilogarithmic plotting, extrapolation and planimetry of the curve areas. The error of the method was calculated from the difference between two consecutive steady state determinations in which the mean difference in heart rate did not exceed 5 beatshin. Fifty-two pairs of observations were analysed, varying from 3.9 to 15.5 I/min, and the error was found to be 8.9%. Acta mcd. scand. 197
Heart rate (HR, beats/min) was calculated from continuous ECG tracings, counting over a period of 15 sec. HR,., is defined as the value obtained at exercise breaking point. Oxygen uptake #op, I/min STPD) was determined using the Douglas bag technique and the volume of expired air 1 BTPS/min) measured in a calibrated Tissot spirometer. Fractions of Opand Copin samples of expired air were analysed by the Micro-Scholander method (39). Arterial haemoglobin concentration (Hb, g/lOO ml) was measured by the cyanmethaemoglobin method, and haematocrit (Hct) with a high-speed centrifuge. Arterial lactate concentration (lactate, mmol/l) was measured enzymatically (1 1). Total blood volume (I) was measured by the 1*51albumin method (43). Values obtained were corrected for the difference between body Hct and central Hct. Heart volume (HV,ml) was Calculated according to Jonsell(25). The presence of residual heart lesions was established from previous postoperative catheterization (9 patients) and/or from physical examination. Significant residual PS was considered present if a peak-systolic gradient of 230 mmHg over the RV outflow tract and/or pressure in RV 250 mmHg was present at the follow-up catheterization. A PS was also said to be present if a 23/6 ejection systolic murmur was detected over the pulmonary valve area. A VSD was considered to be present either if proven at catheterization or if a pansystolic murmur (not due to tricuspidal insufficiency) was found. Pi was assessed by length and intensity of the diastolic regurgitant murmur. The Wilcoxon rank sum test was used to test the possible influence of a particular residual defect and of the use of a
(vE,
Exercise in totally corrected tetralogy of Fallot
181
Table 111. Correlation matrix for maximal oxygen uptake and some dimensions and functional capacities of the oxygen transport system in 18 totally corrected adubpatients with TOF n =no. of observations '02
max
(I/min/ kg b.wt.)
"S max
(I/min) .740*** n=17 .512* n=17 .486* n=17 -.038 n.s. n=16 .846** * n=17 0.816*** n=17 .I55 n.s. n=17
-.058 n.s. n=17 .567* n=17 -.019 n.s. n=17 .489 n.s. n=16 .553* n=17 .422 n.s. n=17 .517* n=17 .503* n=17
.84 1* **
n=17
right ventricular oufflow patch on stroke volume and VO, max. Otherwise current statistical methods were used (41). The degree of probability was designated as follows: O.OS 0.01, probably significant (*); 0.01~p>0.001,significant (**); O.O01~pp, highly significant (***).
RESULTS
SVmax (ml)
HRmax (beatslmin)
.606** n=l8 .403 n.s. n=18 .267 n.s. n=18 .274 n.s. n=17 -
.677** n=18 ,334 n.s. n=18 .322 n.s. n=l8 -.319 n.s. n=17 .974*** n=18
0.974*** n=18 .057 n.s. n=18 .866*** n=18
-
-.289 n.s. n=18 .169 n.s. n=18 -.254 n.s. n=l8 .260 n.s. n=17 .057 n.s. n=18 -.I67 n.s. n=18
Qmax
(I/min)
-.I67 n.s. n=18 .834*** n=l8
0.87 n.s. n=18
was found to be normal in both the male and the female group (l), the mean being 22.9+1.4% at submaximal load 11. Cardiac output was low when related to 00,both during submaximal and maximal work (Fig. 1). Half of the observations were below -2 S.D. of the. regression line for young males found by Ekblom et al. (12), using techniques similar to those in the
Individual and mean values are given in Tables I and
I1 and a correlation matrix in Table 111. The mean maximal oxygen uptake (Vo2-,,,=)was 2.08 l/min for the males and 1.51 I/min for the females. This corresponds to a value of 30.5 ml/min/kg and 25.5 ml/min/kg for the males and females, respectively, when related to body weight and to values of 1.13 I/min/m2, 0.92 I/min/m2 when related toBSA. Both the absolute and relative values for Vo2 are lower than normal for Swedish males and females of corresponding ages (1, 2). Individual values were all below -2 S.D. The correlation between VozmW, on the one hand, and and SVmax on the other was highly significant. No correlation was found with blood volume or HR,,,. Mechanical eficiency /mechanical work performed (kpm/min)x loO\
emax
\
Fig. 1 . Cardiac output in relation to oxygen uptake at rest in the supine position and during exercise in the sitting position in 18 totally corrected adult patients with TOF. The regression line @=5.72~+5.13;S.D.f1.44)is calculated from data of Ekblom et al. (12). The present regression equation: y=4.56r+3.8; S.D.kl.39. Siflficance of difference between lines 0.052p>O.01. Acta med. s c a d . 197
182 B. Bjarke
BSA. Ip the female subjects the values were 714+ 136 ml and 439f85 ml/m*, respectively. Values for Hb and lactate concentrations as well as ventilation are summarized in Table 111. A detailed statement of spirometric data, pulmonary ventilation, gas exchange and acid-base balance has been given in an earlier publication (7).
DISCUSSION 5
bz 1/.h Fig. 2. Individual values for stroke volume in relation to oxygen uptake at rest in the supine position and during exercise in the sitting position in 18 totally corrected adult patients with TOF.
present investigation. Only one observation was above this regression line., was 13.2 l/min for the males and 10.8 l/min for the females, corresponding to cardiac indices of 7.2 and 6.6 llminl m2 for males and females, respectively. No correlation was found between and HV, blood volume or HR,,,. Stroke volumes (SV, ml) at rest in the supine position were small when compared with normal volumes (3,6,28). The mean value for males was 79 ml (range 66-99) and forfemales 61 ml (range 52-72). Corresponding values for stroke index were 43.4 and 37.6, respectively. SVs at submaximal exercise I were slightly but significantly higher (0.01 a p >0.001) than at rest in the supine position. During exercise there was a fall in SV with increasing work loads, mean SV being 76 ml during submaximal exercise I, 70 ml during submaximal exercise I1 and 67 ml during maximal exercise (Fig. 2). The difference between SV during exercise I and maximal exercise was highly significant (0.001zy). In 8 patients the fall in SV was > 10 ml. The fall in SV and the size of SV,,, could not be correlated to any particular residual lesion. No correlation existed between SV,,, and blood volume, HV or HR,,,. Mean maximal heart rate was 184f9 beatslminfor the male group and 17957 beatslmin for the female. HR related to relative work is illustrated in Fig. 3. Total blood volume was 4.78f1.10 1 or 71f15 ml/kg b.wt. in the male group and 4.20f0.43 1 or 73 f 13 ml/kg b.wt. in the female. Heart volumes were larger than normal. In the male group a mean value of 8645 150 ml was found, corresponding to 465+36 ml/m2 when related to
em,,
em,,
Acta med. scond. 197
1
The values obtained for maximal oxygen uptake are low for both sexes. They are almost identical with the figures found in totally corrected TOF patients by Epstein et al. in a recently published investigation (14) and represent a reduction of 3040% compared with normal figures ( I , 2). These findings show that in spite of a successful anatomic repair, no true normalization of the aerobic work capacity occurs. However, in a study from this department of 16 only shunt-operated TOF patients of comparable age, the Vo2,,, was found to be only 18.0 mllkglmin. Thus about 60% higher values were found in the totally corrected subjects. This corresponded well with the subjective evaluation made by the patients themselves who felt that their exercise tolerance had increased considerably after intracardiac repair. Values for cardiac output related to oxygen uptake were lower than in normal subjects (Fig. 1). This finding is contrary to earlier reports (9,17,18,33,40)
Y 1.
0 0
* , , 40
t a ' h ' i Yo H ~ 912 I
Fig. 3 . Individual values for heart rate (beatslmin) during submaximal work in the sitting position in relation to oxygen uptake expressed as percentage of the maximal oxygen uptake in 18 totally corrected adult patients with TOF. Regression line with S.D. calculated from data of Astrand (2).
Exercise in totally corrected tetralogy of Fullot
8i
.
F
Fig. 4. Arteriovenous oxygen difference in relation to oxygen uptake expressed as percentage of maximal oxygen uptake in 18 totally corrected adult patients with TOF. The regression lines, females y=0.07&+6.40 and males y=0.072x+9.61, are calculated from data of Astrand et al. (3). The present regression equations, males y=0.087x+7.11 and females y=0.067x+7.36,
were not significantly different from those of Astrand.
which state that anormal increase i n 0 occurred with exercise. In the latter studies, however, haemodynamic evaluations were performed with the patients working at low exercise loads. The finding of an altered relationship between 30, and 8 is, however, in agreement with Epstein’s results from 10 corrected patients with TOF without significant residual lesion. The same situation has been found to exist in other types of congenital heart disease, e.g. atrial septa1 defect, pulmonary valvular stenosis, mitral stenosis, aortic insufficiency (4, 13, 14,22,26, 371, both before and after total correction. In the present series no correlation was found between the decrease i n 0 relative to Vozand the type of anatomy in the RV outflow tract, the use of outflow patch or the presence of a particular residual lesion. It is thus likely that the “inadequacy” of the Q response to exercise is less related to the type of congenital heart malformation than to the myocardial function itself. The low 0 relative to 30, led to a higher-thannormal AV oxygen difference. This does not reflect a more effective oxygen extraction and/or a changed distribution of the left ventricular (LV) output, e.g. from visceral organs to working muscles, since the AV oxygen difference was found to be normal when relative work was used as frame of reference (Fig. 4). Furthermore the AV oxygen difference ’during maximal exercise expressed as percentage of oxygen binding capacity of the blood was found to be normal (73 %). An analysis of the subfunctions of the cardiac
183
output, i.e. heart rate and stroke volume, reveals that the main cause of the low 0 was the small SVs found, 74 ml in the male and 62 ml in the female group during maximal exercise in the sitting position. A highly significant correlation existed between SV,,, and The reason for the small SVs found cannot be fully elucidated from the results of this study. However, some conclusions could be drawn from the findings in the postoperative catheterizations performed on some of our patients and from previous investigations. The S V depends not only on the anatomical size of the ventricles, but also on the venous return to the heart, the resistance to emptying of the ventricles, and the contractibility characteristics of the heart muscle. Some controversy exists concerning the size of the LV in TOF. Some investigators have found the LV to be normal or slightly small (3 1,34), and an underdevelopment of this chamber severe enough to be of haemodynamic significance is said to be present in less than I % of the patients (36). However, Jamarkaqi et al. (23) convincingly showed that cyanotic patients with TOF, more than 2 years of age, had smaller left HV than normal. With successful shunt operation or total correction an increase in LV end-diastolic volume as well as LV mass occurred to values significantly higher than normal. In spite of this the LV ejection fraction remained subnormal. This latter finding was attributed to a depressed LV function and consequently not to small left HV. It is well documented that stroke volume is influenced by the degree of physical activity and that it can be increased by physical training (12,15,28,38). Our patients were definitely more inactive than normal during their childhood and they are probably less active physically also after total correction. In the present study only 2 patients stated that they regularly participated in strenuous physical activities. The vast majority of our patients have an occupation which could classify them as white-collar workers. The reduction in S V might therefore theoretically be explained by small circulatory dimensions secondary to prolonged physical inactivity. It has been shown that a high degree of interdependence exists between different components of the oxygen transport system and the degree of physical activity or VoZmax(20). The correlation matrix (Table 111) shows that this was the case in our subjects too, with one exception, namely the dimensions of the cardiovascular system. Though the SV was correActa med. scand. 197
184 B. Bjarke higher HR,a longer duration of systole results in a shorter diastole. This may hamper ventricular filling when an increased filling pressure is needed and the ejection time is prolonged. One may speculate whether this causes the fall in SV during exercise in some of our patients. Support for this theory may be the observed negative correlation between the enddiastolic pressure in R V and the size of SV,,, (0.01~p>0.001)and SV/BSA (0.053p>0.01) found MI in our seriers (Fig. 5 ) . However, this latter finding ss , O , * ; must be viewed with caution due to the small 5 10 15 number of observations and the fact that data of p t d m RV,rnHO enddiastolic pressure and SV were obtained on Fig. 5 . Individual values for stroke volume during maximal exercise in relation to end-diastolic pressure in the right different occasions. ventricle at rest in 9 subjects with totally corrected The slightly low maximal heart rate agrees with TOF. findings of Hurvitz and Goldberg (21) that the HR,,, was lower than normal, not only before, lated to v02max, this was not the case with blood but also after operative correction of different volume or heart volume. Neither was there any cardiac lesions. Similar or related observations intercorrelation between stroke volume, blood vol- have been reported by others (16, 26, 27, 42). The in cardiac ume and heart size. If the reduction in SV were to be reason for the subnormal HR,,, explained by low physical activity alone, one would patients is not fully understood. One possible exhave expected such correlations to exist. However, planation is that the subjects stop exercising for it cannot be excluded that physical inactivity was a other reasons than circulatory, such as e.g. contributory cause of the reduction of the SVs. It dysponea or hypoxaemia (26). This might be the would therefore have been of interest to see whether explanation in uncorrected but hardly in totally our patients' SV would have increased after or- corrected TOF patients, since their ventilatory response to exercise is normal and since ganized physical training. they do not have hypoxaemia (7). Another exOne explanation of the small SVs may be an abnormal contractile response of the ventricles and planation may be that the lower maximal cardiac altered compliance characteristics of the ventricular frequency represents a physiological adaptation to myocardium (14, 23). Several factors such as the the haemodynamic situation. A lower-than-normal myocardial changes in the right ventricle, secondary heart rate may be needed to allow optimal diastolic to the long-standing muscular hypothropy, non- filling. If this explanation is valid, one would expect contractile parts of the myocardium, corresponding not only the HR,,, to be lower than normal, but also to the'ventriculotomyscar, the patch in the ventricu- the HR at submaximal loads. That this is the case is lar septum and the R V outflow tract have to be shown in Fig. 3. Other possible explanations may be considered as well as the RBBB that is usually pres- related to muscular ventricular hypertrophy or to the presence of conduction disturbances, e.g. RBBB. It ent. An R V outflow tract gradient is usually present should, however, be noted that in the series of even in successfully operated TOF patients (9, 14, Hurvitz and Goldberg (21) patients with conduction 30,40). This gradient increases during exercise (14, disturbances were excluded. In the present study the decrease in aerobic capac40). To maintain an adequate SV in this situation there are three possibilities: to increase the RV ity could not be correlated to the anatomy of the RV systolic pressure, to prolong the ejection time and to outflow tract or to the use of an outflow patch. increase the diastolic filling (22). Each of these Though the number of patients studied was small, compensatory mechanisms has been found in TOF (9, this tends to substantiate the findings of others (9,18, 14,23,40). However, SV decreased during exercise 24,331 that TOF patients tolerate PI reasonably well. in the present group. If the R V is the limiting factor This seems to be the case also when correction is for maintenance of the SV, this indicates that the undertaken at adult age. above mentioned mechanisms are not sufficient. At There was no complete normalization of physical
i
Acto med. scond. 197
Exercise
work capacity in our patients, the majority of whom werecorrectedat adult age. Future studies will show whether a better normalization is achieved if total correction is undertaken in early life. This might perhaps be expected if the TOF patients perform a normal degree of physical activity during the years when growth of circulatory dimensions takes place. The reduction in Vjo2maxwas moderate and did not interfere with everyday activities. However, it means that at a certain degree of activity our subjects utilized agreater portion of their aerobic work capacity. A greater portion of the cardiac reserve was mobilized. This may prove to be a disadvantage as the patients grow older and are subjected to the ageing processes in the heart and to ischaemic heart disease. ACKNOWLEDGEMENT This study was supported by grants from the Swedish National Association against Heart and Chest Diseases.
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