Exercise performance in tetralogy of Fallot after intracardiac repair

J

THoRAc CARDIOVASC SURG

80:582-593, 1980

Exercise performance in tetralogy of Fallot after intracardiac repair We evaluated 99 male and 36 female patients with tetralogy of Fallot I year or more after intracardiac repair (fCR) in 279 exercise studies between 1968 and 1979. Sixty tetralogy patients were studied serially two to nine times at 12 to 18 month intervals. Work performance and heart rate response to cycle exercise with stepwise loading (JOO kg-mlmin increments) were (1) related to clinical, pre- and post-1CR cardiac catheterization, surgical, and anatomic information and (2) compared to results obtained in 221 male and 157 female normal control volunteers. On the average, male tetralogy patients were shorter and weighed less than control subjects, but female tetralogy patients as a group showed no growth impairment. Many tetralogy patients had slower resting, submaximal, and final exercise heart rates than did control subjects. Work performance averaged 82% ± 21% of predicted in male patients and 86% ± 29% in female patients. Serial studies showed no significant changes in work performance in the majority of tetralogy patients for up to 10 years. Best work performance was found in nine varsity athletes (99% ± 22%) and 21 patients with primary 1CR (94% ± 23%). Statistical analysis demonstrated a significant relationship between reduced work performance and residual disease, notably cardiac enlargement. increased peak systolic right ventricular pressure. pulmonic valve incompetence (Pl ), residual ventricular septal defect (VSD). pulmonary hypertension, and cardiac rhythm disturbances. However, in individuals work performance cannot be predicted reliably from the presence of these lesions and should therefore be measured. We conclude that exercise testing is a useful adjunct to the clinical and hemodynamic evaluation of post-1CR tetralogy.

Hans U. Wessel, M.D., William J. Cunningham, M.D., Milton H. Paul, M.D., Christian K. Bastanier, M.D., Alexander J. Muster, M.D., and Farouk S. Idriss, M.D., Chicago, Ill.

T

he patient with surgically corrected tetralogy of Fallot anticipates a considerably improved or even normal life expectancy and exercise tolerance. However, the outcome of surgical correction is modified by a wide spectrum of residual disease that includes pulmonary outflow obstruction, pulmonic valve insufficiency (PI), persistent ventricular septal defect (VSD), pulmonary hypertension, impaired myocardial function, and cardiac arrhythmias. The quantitation of cardiovascular

From the Departments of Pediatrics and Surgery, Northwestern University Medical School, Willis J. Potts Children's Heart Center, The Children's Memorial Hospital, Chicago, Ill. 60614. This study was supported in part by National Institutes of Health Grants HL-17578 and GM-21293, by American Heart Association Research Grant 74-1028, by the Park Ridge Health Foundation, Inc., and by the Esper A. Peterson Foundation. Received for publication Dec. 21, 1979. Accepted for publication March 18, 1980. Address for reprints: Hans U. Wessel, M.D., The Children's Memorial Hospital, 2300 Children's Plaza, Chicago, Ill. 60614.

582

adjustments to exercise and the assessment of the capacity for physical work are potentially useful in the evaluation of this residuum of disease. Exercise performance after intracardiac repair (lCR) of tetralogy has been examined utilizing submaximalv ! or maximalv " work on the cycle ergometer or maximal treadmill exercise. 9- tI In general, these studies have demonstrated abnormal exercise hemodynamics even in the presence of normal hemodynamics at rest 9 - 11 and widely varying degrees of functional impairment as measured in maximal exercise tests by duration of exercise (DUR),IO, tI maximal oxygen uptake (Vo-max),» 5, 7.9 and work capacity.P- S The results between these individual studies have varied considerably; furthermore, these data have not permitted a close examination of the relationship of specific residual lesions to exercise performance because of the relatively small number of patients in each study. We have attempted a more detailed examination based on the study of a large number of patients followed at The Children's Memorial Hospital.

0022-5223/80/100582+12$01.2010 © 1980 The C. V. Mosby Co.

Volume80 Number 4 October, 1980

Patient data and methods One hundred thirty-five patients, 99 male and 36 female, were evaluated in 279 exercise studies between 1968 and 1979. There were only two selection criteria: The patient had to be at least 8 years old and I year post-ICR. The study group represents patients with a wide spectrum of surgical results and complications and lifestyles ranging from sedentary to participation in varsity athletics. Initially this group consisted of 91 patients who volunteered for exercise evaluation in 1968 and comprised 53% (91/173) of the 1968 eligible pool. Including the 44 patients added to the study since 1968, the entire group represents 37.7% (135/358) of the patients eligible for study between 1968 and 1979. Although this group represents a relatively large proportion of all patients and encompasses all levels of results, the data do not represent a population study. Seventy-five underwent palliation by shunt (BlalockTaussig [S-P], Potts, Waterston-Cooley) before ICR. In 84% (114/135), exercise data were matched to a data base of 140 variables related to clinical, pre-ICR and post-ICR cardiac catheterization, surgical, and anatomic information. Post-ICR cardiac catheterization data were available in 58 tetralogy patients. With few exceptions the reason for post-ICR catheterization was based on clinical indications, i.e., clinical evidence of persistent VSD, persistent cardiomegaly, or marked PI. Sixty tetralogy patients were exercised serially in two to nine studies at least I year apart. Maximal oxygen uptake (Vo.max) was measured in 40 patients (Table I). Exercise protocols. All patients were studied in the exercise laboratory, which is maintained at 20° C and ::;50% relative humidity. Control subjects were studied in their schools using the same exercise and measuring equipment. In all cases, informed consent was obtained from parents and subjects. No patient was studied until at least 1 year after ICR. All exercised upright on an electrically braked cycle ergometer (Quinton Instrument Co., Model 840), which is recalibrated at 3 to 6 month intervals. We utilized two exercise protocols: (1) stepwise loading at 1 minute intervals and (2) 4 minutes of work at both 1.5 and 3.0 watts/kg to determine Vo.max. With stepwise loading, work begins at 100 kg-m/min and is incremented by 100 kg-m/min after each minute until the patient is unable to continue to maintain the pedalling cadence of 60 to 70 rpm. The test is evaluated in terms of heart rate at rest and at each work rate, duration of exercise in minutes (DUR), and working capacity (W I 70 ) , based on linear regression of heart rate on work rate between the second and last minute of exercise. Results are expressed in absolute

Exercise performance in tetralogy of Fallot

583

Table I. Reference study of tetralogy study population _________1

No. of patients Primary ICR ICR after palliation Age at palliation (yr) Age at ICR (yr) Interval: Palliation-ICR Last exercise study: Age (yr) Years since ICR No. of exercise studies No. of patients with exercise study and complete CDB No. of patients with exercise study and post-ICR cath. and CDB No. of patients with serial exercise studies No. of patients with determination of Vo,max

Males

I

Females

99 44 55 2.06 ± 1.49 7.91 ± 4.42 6.83 ± 4.24

36 16 20 2.38 ± 1.36 7.72 ± 4.23 6.79 ± 4.80

15.20 ± 4.08 7.61 ± 3.71 201

15.87 ± 4.58 7.93 ± 3.30 78

81 (81.8%)

33 (91.7%)

41 (41.4%)

17 (47.2%)

48 (48.5%)

12 (33.3%)

35 (35.3%)

5 (15.2%)

Legend: [CR, Intracardiac repair. COB, Clinical data base. Vo,max. Maximal oxygen uptake.

terms and as percent of predicted for age, height, and body surface area (BSA). Normal data were obtained in 221 male and 157 female normal volunteers who were recruited from a suburban school district. 12 In V02 max studies the patient works for 4 minutes at 1.5 watts/kg and then for 4 minutes at 3 watts/kg. For some patients the second work rate is adjusted to 2.0 to 2.5 watts/kg, if 3 watts/kg appears to be excessive. Some patients who work at 3 watts/kg are unable to complete 4 minutes of work; however, V0 2 max is always taken as the highest V0 2 achieved and is expressed as Llmin, L'min/rheight)", and ml/min/kg, absolute and in percent of predicted based on the standards of Mocellin and Bastanier. 13 Studies in our laboratory in 196 patients with a variety of cardiac defects indicate that the protocol for stepwise loading yields approximately 10% lower oxygen uptakes than the V02 max protocol. With stepwise loading, the final work rate and V02 averaged 13.7 ± 3.2 kg-m/min/kg and 30.7 ± 7.4 ml/min/kg, respectively, in 62 studies as compared to 15.3 ± 2.9 kg-m/min/kg and 33.8 ± 6.2 ml/min/kg in 134 studies with the V0 2 max protocol. Measurement techniques. A bipolar electrocardiographic (ECG) lead (CM 5) was monitored and recorded throughout each test. Heart rate was measured beat-by-beat with a highly accurate digital rate meter .14

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Wessel et al.

Thoracic and Cardiovascular Surgery

Table II. Average exercise performance of 99 male and 36 female patients with tetralogies for cycle ergometer work with stepwise increasing work rates ( 100 kg-m/min) in 279 studies

I ------DUR (min % predicted, age % predicted, height WI'" (kg-m/min) % predicted, age % predicted, height Heart rates/ min) Rest (silting) Fourth minute of exercise Final (exercise) Age (yr) Height (ern) No. of studies No. of patients

Males

6.80 82.1 91.3 760 97.0 112.7

± 2.50* ± 20.5 ± 19.3 ± 309

± 30.3 ± 28.3

83 ± 13.4 134 164 14.52 157.7 201 99

± 23.2

± 13.5 ± 3.57

± 17.3

I

Table III. Maximal oxygen uptake, ventilation, heart rate, and systemic blood pressure in 40 post-ICic tetralogy patients Maximal exercise data"

Females

5.74 86.2 88.4 614 107.4 112.6

1.74* 29.3 22.2 182 ± 34.2 ± 28.2

± ± ± ±

85 ± 12.0 144 164 14.69 153.0 78 36

± 20.5 ± 16.2 ± 3.87

± 13.13

Legend: OUR, Duration of exercise. W 170' Working capacity.

"Data represent mean ± I SO.

Range

Mean ± I SD Vo,max (L/min) % predicted

Vo,max/ht 2 % predicted Vo,max (ml/min/kg) % predicted Heart rate, (beats/min) Blood pressure (mm Hg) Systolic Diastolic v, (L'rnin, BTPS)

\;')\;0, Resp. exchange ratio Age (yr) Height (ern) Weight (kg) BSA (rn")

1.52 72.0 0.61 74.6 31.4 71.0 162.5 137.5 74.1 47.5 28.96 0.992 156.6 14.4 49.1 1.46

0.77-2.42 41-111 0.38-0.83 46-106 10.2-46.2 23-104 107-193

± 0.47 ± 18.0 ± 0.13 ± 16.9

± 7.5 ± 17.7

± 17.6 ± 18.0 ± 13.5 ± 12.2

± 4.57 ± 0.084

± 15.7 ± 3.7 ± 13.48 ± 0.27

115-175 55-107 27.3-71.5 19.06-41.02 0.840-1. 152 120-182 9.2-24.0 21.6-69.6 0.86-1.84

Legend: BSA, Body surface area. (CR, lntracardiac repair.

"Cycle ergometer work at work rates of I. 5 and 3 watts/kg.

Resting heart rate (sitting) was computed as the average rate during the 3 minute period before exercise. Exercise heart rates were averaged over the last 15 seconds at each work rate. Systemic blood pressure was obtained with an automatically inflatable cuff and measured from the analogue record of Korotkoff sounds superimposed on cuff pressure. Pulmonary ventilation and gas exchange were measured continuously and analyzed on a breath-by-breath basis by digital computer'<' t7 and averaged over I minute periods. Pertinent patient and control data were stored on disc files and analyzed with a statistical package which is part of the computerized exercise system developed in our laboratory .16 Male and female subjects were analyzed separately when appropriate and divided into age, height, weight, and BSA classes at I year, 10 em, 10 kg and 0.2 m 2 class intervals, respectively. Percents of predicted were computed as (patient result/class mean of controls) X 100. Subgroup mean differences were assessed by Student's t statistic. Simple linear and multiple stepwise linear regression analyses were used to compute the prediction of a dependent variable from one or more independent variables. Prediction of an event was evaluated by the standard equations for sensitivity, specificity, predictive value, and error. Antbropomorphic data. Male tetralogy patients of all age classes were shorter, weighed less, and therefore had lower BSAs than control subjects. For BSA these differences were significant (p < 0.05 to

< 0.001) for all age classes except 9, 12, and 18 year olds. Moreover, male tetralogy patients of a given height class had lower weights and BSAs than control subjects. These relationships did not change with increasing age and height. As a result of these size differences, mean age of tetralogy patients was significantly greater than that of control subjects of the same BSA class. Such marked differences were not observed in female patients, whose height and weight did not differ significantly from those of control volunteers of the same age class, with the exception of II and 12 year olds, who were shorter and weighed less (p < 0.02, P < 0.01). Work performance. In tetralogy patients the results of exercise testing ranged over a spectrum from normal work performance and heart rate response to grossly impaired exercise tolerance with an excessive or reduced heart rate response. The overall results of all studies including repeat tests are summarized in Table II. These results are not significantly altered if only the last study of each patient is considered. In both male and female tetralogy patients average duration of exercise (DUR) was significantly less than in control subjects (p < 0.001). This is due in part to the smaller size of the patients with tetralogy, but not entirely so, for DUR normalized for height was also less than predicted and the differences were significant for all height

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Exercise performance in tetralogy of Fallot

Number 4

585

October. 1980

Table IV. Results offirst and last exercise study in 60 post-ICk tetralogy patients who underwent from two to nine serial studies. First study Age (yr) OUR (min) % predicted age % predicted height W 170 (kg/m/min) % predicted age % predicted height Heart rate (beats/min) Rest Fourth minute of exercise Final

13.06 5.60 81.90 89.20 605.0 100.8 113.1

± ± ± ± ± ± ±

3.01 1.90 19.20 16.20 263.0 31.9 30.8

86.9 ± 12.4 147.8 ± 21.1 166.2 ± 13.9

Last study

P

16.05 ± 3.40 7.1O±2.40 80.40 ± 24.30 90.10 ± 20.90 81O.0±311.0 99.7 ± 33.4 113.3 ± 27.7

<0.001 <0.001

79.7 ± 11.8 129.5 ± 23.6 162.5 ± 13.9

<0.001 <0.001

NS NS

<0.001

NS NS

NS

Legend: Cycle ergometer work with stepwise increasing work rates (100 kg/m/min increments). Data represent mean ± I SO. The p value refers to significance of

difference between first and second studies.

classes above 150 em in both male and female patients. On the average, male and female tetralogy patients had lower resting heart rates and achieved lower final heart rates (p < 0.01) than control subjects. Lower resting heart rates may be related to altered test conditions (prior activity, environmental temperature, and familiarity with the procedure), and lower final heart rates may reflect less vigorous exercise. To examine these possibilities we compared the heart rate response in 24 tetralogy studies with a final exercise heart rate of ::5150beats/min to 132 tetralogy studies with final rates in excess of 165 beats/min. These patients were all studied under the same standardized laboratory conditions by the same personnel, and there were no significant differences in age, height, weight, or BSA between groups. The patients with final exercise rates of ::5 150 beats/min had significantly lower resting rates but also significantly lower exercise rates at all subrnaximal work loads. Maximal oxygen uptake. The data are summarized (Table III) for males and females combined since all but five patients were male. Average age, height, and weight of these patients did not differ significantly from those of all tetralogy patients. V0 2max ranged from normal to grossly abnormal with low average values, absolute and normalized, for height or body weight. Despite exhortation, some patients did not achieve a maximal effort as indicated by a final respiratory exchange ratio of <1.000, a rise of oxygen ventilatory equivalent of <4 Llmin VE/L V02 , and respiratory frequencies of <40. Even if these patients are excluded, average V0 2max in the remaining 33 was 35 ml/min/kg-substantially below the predicted average of 45 ml/min/kg. Serial exercise studies. The serial studies in 60 te-

tralogy patients, 48 male and 12 female, are summarized in Table I V. Time between the first and last study varied between I and II years. On the average, OUR and W 170 were unchanged when expressed as percent of predicted for age or height. Gross deterioration was seen in only one patient with absent pulmonary valve, marked pulmonic regurgitation, and cardiomegaly. OUR was initially stable at 75% of predicted over a 2 year period but fell to 23% within 1 year, a course which paralleled progressive exertional dyspnea and a further increase in heart size. On the other hand, another patient with absent pulmonary valve but without cardiomegaly has shown no deterioration of performance in nine studies over an II year period, is now 23 years old, and has a V0 2max of 38 ml/min/kg. Work performance and surgical results of intracardiac repair. In control and tetralogy subjects, age and height are highly correlated with OUR and W 170 • OUR for stepwise loading is directly proportional to a near maximal work rate and therefore to a near maximal aerobic power. Multiple stepwise regression of the post-ICR exercise results in tetralogy patients identified the resting, peak systolic right ventricular pressure (PRV) and the degree of cardiac enlargement (cardiothoracic ratio, CTR) as significant predictors of OUR (multiple r 0.823). Since OUR normalized for age (OUR age) yielded the smallest standard error of the estimates and since we found no significant sex differences, we have used this index for pooled male and female data in the following evaluation of the data. The overall relationship of work performance to PRY and CTR is illustrated in Table V. It is apparent that on the average patients with large hearts or high PRY are capable of significantly less work than patients with normal-sized hearts or PRY' Moreover, the combination

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The Journal of Thoracic and Cardiovascular Surgery

Wessel et al.

Table V. Work performance in post-ICk tetralogy patients

I

CTR sO.52 CTR >0.52 P PH\' PH\'

s50 mm Hg >50 mm Hg

P CTR SO.52, CTR >0.52, P

PH\' PH\'

<50 >50

DUR (%. age)

I

PRV

CTR

(mm Hg)

n

85.7 ± 20.0 72.6 ± 26.7 <0.015

0.484 ± 0.03 0.584 ± 0.05 <0.0001

50.2 ± 17.8 51.1 ± 24.6

52 28

86.1 ± 20.7 69.5 ± 26.2 <0.015

0.523 ± 0.05 0.549 ± 0.08

38.5 ± 6.1 75.9 ± 24.1 <0.0001

26 15

89.3 ± 25.1 46.0 ± 20.3 <0.01

0.494 ± 0.03 0.610 ± 0.08 <0.001

38.5 ± 5.7 73.3 ± 26.4
15 13

NS

NS

Legend: Relationship of cardiothoracic ratio (CTR) and peak systolic right ventricular pressure (P HV) at rest to work performance in post-intracardiac repair tetralogy patients. All data represent group means ± I S.D. The p value refers to significance of difference between group means. OUR, Duration of exercise.

of cardiac enlargement with a high PRY results in extremely low work performance. The inverse relationship of work performance to severity of residual disease is magnified by a comparison of a subgroup of seven high performers in whom OUR (age) exceeded 100% (mean 117.3%, range 104% to 148%) with the 10 poorest performers in whom OUR (age) was below 60% (mean 42.8%, range 25% to 55%). In the 10 high performers CTR averaged 0.49 and did not exceed 0.52; PRY averaged 39 mm Hg and was :::;40 mm Hg in six of seven. By contrast, CTR averaged 0.58 (p < 0.001) in the low performers and was < 0.52 in only one of 10. Similarly PRY averaged 76.2 mm Hg (range 38 to 125 mm Hg) and was <40 mm Hg in only one (p < 0.001). These subgroups differed substantially in a number of other important aspects: In the high performers age at ICR averaged 5.83 years (range 1.9 to 10.0 years), but it averaged 10.7 years (p < 0.001) with a range from 4.9 to 19.4 years in the poorest performers. Five of seven (71.4%) high performers underwent primary ICR and none had had a Potts shunt. None had pulmonary artery branch stenosis and none had evidence of P.I by murmur or angiography. Only one (14.3 %) had evidence of differential pulmonary blood flow (radiography, angiography), only two of seven (28.6%) had evidence of residual pulmonary valvular obstruction, and only one had a small residual VSO (Qp/Qs < 1.4). By contrast, only three of 10 (30%) of the poorest performers underwent primary ICR and four of 10 had Potts shunts prior to ICR. Two had pulmonary artery branch stenosis, and all but two (80%) had a PI murmur and/or evidence of PI by angiography. In nine of 10 there was evidence of post-ICR valvular pulmonic stenosis, and in four of 10 (40%) a residual VSO was demonstrated by cardiac

catheterization. It is apparent that multiple diverse factors contribute to impaired work performance and must be considered where work performance is examined in relationship to single specific parameters. Age at K'R. Linear regression of age at ICR on OUR (age) indicated a significant negative correlation (r - 0.484). However, scrutiny of the individual data suggests that this relationship was primarily determined by patients who underwent ICR in their late teens, all of whom had prior Potts shunts and were among the first patients treated surgically at the Children's Memorial Hospital. Since all patients with Potts shunts had lower average exercise scores than patients with primary ICR (p < 0.05), we excluded all shunt patients from subsequent analysis. For primary repairs alone (N = 65), there is only a weak correlation between exercise score and age at ICR (r - 0.200) for ages from 1.9 to 15.6 years; thus over this range the age at ICR in itself appears to have been of little consequence for the outcome. Number and type of corrective surgical procedures. Initial evaluation indicated that the patients with primary ICR had significantly better work performance (OUR age), 88.0% ± 21.7%, than patients who underwent palliation prior to ICR (OUR age), 76.5% ± 19.7%, p < 0.01. However, this latter group included most of the 25 patients with residual VSO. When these were excluded, OUR (age) did not differ significantly between primary ICR (89.2% ± 22.6%) and Blalock-Taussig (S-P) shunts (81.7% ± 23.3%), but was significantly lower in Potts shunts (78.7% ± 6.7%, p < 0.05). Eleven patients who required more than two surgical procedures, either two palliations plus ICR or palliation and two or more ICRs, had extremely low exercise scores (OUR, percent age 56.4% ± 13.9%),

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Exercise performance in tetralogy of Fallot

Table VI. Average work performance (DUR age), CTR, and PRV in post-fCR tetralogy patients with and without evidence of PI and with PRV ::;50 mm Hg or >50 mm Hg

I

PHI ";50, no PI P PHI' >50, no PI P

PI, PHI .,;50

p

PI, PHI >50

(~~:e)

I-----C-TR----~---------

98.2 ± 20.1

0.495 ± 0.071

NS

NS

87.7 ± 15.9 P <0.05

NS

P <0.02 74.7 ± 8.9 <0.001 51.0 ± 29.8

P <0.001

0.497 ± 0.04

NS 0.515 ± 0.02 <0.001 0.597 ± 0.04

_

PRV

(mm Hg)

NS

36.5 ± 4.41 <0.001 72 . 1 ± 18.5 NS <0.01 NS 39.3 ± 6.0 <0.0001 \ 74.0 ± 22.0

n

6

7

6 7

Legend: OUR, Duration of exercise. CTR, Cardiothoracic ratio. PH\" Peak systolic right ventricular pressure. PI, Pulmonary valve sufficiency. See text. Data represent mean ± I SO. The p value refers to significance of group mean differences as indicated.

indicating the overall poor surgical results in this group. These patients also had a significantly higher incidence of post-ICR scoliosis (35%) than the tetralogy population as a whole (9%). The effect of residual right ventricular outflow obstruction and PIon work performance. Multiple regression analysis and the data shown in Table Vestablish a direct relationship of elevated PRY to low exercise scores. Conversely, the fact that virtually all patients with the highest exercise scores had a low PRY suggests that residual right ventricular outflow tract obstruction contributes directly to impaired work performance. However, many patients with high PRY had also additional residual defects such as VSD, pulmonary hypertension, and PI, possibly to account for poor work performance. To examine the effect of right ventricular outflow obstruction per se on work performance, we compared patients with and without increased PRY but in the absence of any of these other defects (Table VI). This analysis indicates no significant difference of exercise scores even though PRY was low (36.5 ± 4.4 mm Hg) in one group and significantly higher (72.1 ± 18.5 mm Hg, p < 0.001) in the other. In lieu of a quantitative method, pulmonary regurgitatant flow (PI) was evaluated in terms of angiography, the presence or absence of a diastolic PI murmur, and by comparison of patients with and without a pulmonary outflow patch. Exercise scores were significantly higher in 17 patients without angiographic evidence of PI (DUR 82% ± 19%) than in 33 patients with definite PI by angiography (DUR 69 ± 22%, P < 0.02). Moreover, 29 patients without PI murmur had higher exercise scores than 26 patients with a Grade 2 to 4 murmur, although this difference was not significant. In order to assess the effect of PI alone, we have compared patients with or without evidence of PI whose PRY was <50 mm Hg or >50 mm Hg. All had

been catheterized post-ICR and none had evidence of residual VSD. As is evident (Table VI), exercise scores were significantly higher in patients without evidence of PI whether there was right ventricular hypertension or not. In the presence of definite PI, however, work performance was significantly better in the absence of an elevated PRY associated cardiac enlargement. The finding that PI results in low exercise scores especially when associated with cardiac enlargement is also substantiated by a review of the patients with transannular pulmonary outflow patch, a procedure which invariably resulted in some degree of pulmonic insufficiency. In II of these 26 patients, there was no clinical indication for post-ICR catheterization. In this subgroup, average CTR was 0.50 ± 0.06 and DUR (age) averaged 87.2% ± 24%. By contrast, in the 15 patients who underwent post-ICR cardiac catheterization, CTR averaged 0.57 ± 0.07 (p < 0.01) and DUR was only 71.3 ± 21.5 (p < 0.01). Altogether we examined the relationship of exercise performance to 68 different criteria for preoperative and postoperative anatomy, type of operation, and manifestations of residual disease. Table VII lists the two selection criteria associated with the highest average exercise scores, i.e., varsity athletes and primary ICR without postoperative cardiac catheterization, and the 13 criteria associated with the lowest average scores. Apart from PI, increased PRY' and CTR alone or in combination, these selection criteria include pulmonary arterial hypertension, residual VSD, pulmonary artery branch stenosis, post-ICR evidence of both infundibular and valvular residual pulmonic stenosis, differential pulmonapry blood flow, and palliation by Potts shunt. Excepting the residual VSD subgroup, the other subgroups do not include patients with residual VSD, since this lesion was associated with poor exercise performance irrespective of other residual defects.

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Table VII. Work performance in post-ICk tetralogy patients Criteria

1. Varsity athletes 2. Primary ICR without post-ICR cardiac catheterization 3. CTR >0.52, PRv>50 4. PI(angio), PRv>50 5. Pltrnurmurj, PRY >50 6. PR1-(Syst) >40 mm Hg 7. Residual VSD 8. PA branch stenosis 9. PRv>50 10. CTR >0.52 II. Post-ICR, infundibular + valvular stenosis 12. Differential pulmonary blood flow 13. Pulmonary gradient >50 mm Hg 14. PI murmur >Grade 2 15. All AP shunts

I

n

9 21 6 7 II

7 25 4 15 28 14 19 9 26 10

I

DUR (% age)

p

p'

98.8 ± 21.6 94.1 ± 22.7

NS

NS

± ± ± ± ± ±

<0.001 <0.001 <0.001 <0.001 <0.001 NS <0.01 <0.01 <0.01 <0.02 <0.05 <0.01 <0.05

<0.001 <0.001 <0.001 <0.01 <0.01 NS <0.02 <0.0001 <0.05 <0.05 <0.01 <0.02 NS

46.0 51.0 55.9 55.9 67.3 68.3 69.5 72.6 72.8 74.9 75.3 75.4 78.7

± ± ±

± ± ± ±

20.3 29.8 24.4 19.6 19.8 28.4 26.2 26.7 17.2 22.7 20.3 21.7 6.7

Legend: Work performance in post-intracardiac repair tetralogy patients. Average OUR (age) in the two groups (I and 2) with the best and the 13 groups (3 to 15) with the poorest performance is given. Selection criteria shown on the left were the only criteria used for inclusion in each group. The significance evaluates difference of individual group mean to mean of Group 2, where p refers to significance of duration of exercise (OUR) and p' to significance of cardiothoracic ratio (CTR). Differential pulmonary blood flow refers to patients with definite differences in pulmonary perfusion between right and left lung as indicated by chest roentgenogram, angiography or radioisotope scan. AP shunt, Aortopulmonary (Potts) anastomosis. PA, Pulmonary artery.

Despite the large standard deviation about the mean exercise scores, average DUR (age) was significantly less when compared to the primary ICR subgroup for all 13 subgroups. In all but two, average CTR was significantly greater as well (p', Table VII). Work performance and dysrhythmic events. The relationship of work performance to dysrhythmic events and atrioventricular conduction defects, noted either on routine ECG before or after ICR or during exercise testing, was evaluated in 81 of 115 patients with complete ECG data. In this group we reviewed 950 routine ECG tracings spanning 1,121 patient-years an all ECG records obtained in 198 admissions for exercise evaluation. In 39 patients (48.1 %) no dysrhythmic events were detected during exercise testing or on routine ECG. In 28 (34.6%), dysrhythmic activity was observed during exercise testing, and in six of them, dysrhythmic events were also noted on at least one routine ECG. In 14 patients (17.3%) dysrhythmic activity was seen only on routine ECG either before or after ICR but excluding the immediate postoperative period. Of the 42 patients with dysrhythmia, 57% (24/42) had premature ventricular contractions, 55% (23/42) had other premature beats, 21% (9/42) had intermittent atrioventricular junctional rhythm, and one each had second- and third-degree atrioventricular block and an episode of ventricular tachycardia. There were three patients with trifascicular block.

The 39 patients without dysrhythmia comprised predominantly patients with excellent surgical results as indicated by mean DUR (age) of 89.9% ± 21%, CTR of 0.50 ± 0.05, and PRY of 57 ± 21.6 mm Hg. By contrast, the dysrhythmia group included mostly patients with poor results: mean DUR 66.4 ± 19.4 (p < 0.001), CTR 0.54 ± 0.07 (p < O.OI), and PRY 71.3 ± 30.2 mm Hg. Among the patients with dysrhythmia, the poorest results were obtained in the six patients with dysrhythmic activity both on routine ECG and with exercise (DUR 53.5 ± 25.2%, CTR 0.584 ± 0.07, PRY 90 ± 27.5 mm Hg), followed by patients (N = 14) with dysrhythmic events on routine ECG but not during exercise (DUR 65.5 ± 25.5, CTR 0.56 ± 0.06, PRY 81.6 ± 34.3 mm Hg) and patients (N = 22) with dysrhythmia on exercise testing only (DUR 70.5 ± 12%, CTR 0.52 ± 0.07, PRY 59 ± 23.3 mm Hg). Prediction of a low exercise score (DUR [age] 75% of predicted) from any dysrhythmic activity (rest and/or exercise) was found to have a sensitivity of 76.3%, a predictive value of 72.5%, and a predictive error of 24.3%, and a specificity of 71.8%. Discussion The primary purpose of this study was to determine the utility of exercise data in the evaluation of the surgical results of intracardiac repair (lCR) in tetralogy of Fallot. The study group was sufficiently large and unselected to encompass poor as well as excellent results,

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it included the entire range of varied residual disease, and it also reflected the continuum of progress over the years toward perfection of the surgical management. At the outset, we decided to exercise our patients on the cycle ergometer since the pediatric exercise literature was based primarily on cycle ergometer studies, most of our children are familiar with bicycles, and the cycle erometer requires less space and personnel for operation than the treadmill. Initial experience in children with congenital heart disease suggested that routine exercise testing would be optimized and repeat voluntary participation ensured by a single session test, noninvasive study methods, and minimal demands on patient cooperation. The exercise protocol with stepwise loading" and the methodology developed for measurement of ventilation and gas exchange'P"!? meet these criteria. The protocol is similar to that of Balke and Ware." for treadmill exercise and to the protocol of continuously increasing work loads (60 kg-m/min) employed by Rutenfranz and co-workers'v " in their extensive studies in normal children and patients. In our experience the protocol has been reproducible with respect to the end point (duration of exercise) and response of heart rate, ventilation, and gas exchange for individual normal subjects or patients. In contrast to some studies," 8 many of our patients, in particular males, had evidence of growth retardation. Preoperatively, the short stature and low weight may result from the effects of hypoxemia on the growth process and feeding. It is worthy of note that our data indicate no significant catch-up growth after intracardiac repair as evidenced by the regression slopes for height and weight on age and the unchanged relative height and weight of the serially studied patients. Exercise studies have provided evidence that patients who undergo ICR at an early age have better functional results than those operated upon at an older age. In the series of James and associates, 6 exercise capacities were not significantly different from normal in patients who underwent ICR at 10 years of age or less, but they were significantly below normal in those operated upon beyond this age. James' group found an inverse linear relationship between age at ICR and working capacity for patients with or without palliation prior to ICR. Similar results were reported by Strieder and associates." Moreover, the patients studied by Cumming'? (N = 29, mean age at exercise testing 11.3 years) and Mocellin and colleagues? (N =21, mean age at ICR 8.5 ± 2.1 years) had clearly higher functional capacities and Vo 2 max than did those in the series of Bjarke" (N = 10, mean age at ICR 20 years) and Epstein and associates" whose 10 patients were studied at a mean

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age of 26 years, 0.5 to 4 years after ICR. Cumming, II James' group," and Mocellin and associates? have stressed the importance of physical training as one possible explanation for the better functional capacities in the patients with ICR at an earlier age, since these patients had the opportunity and motivation to be more normally active. This argument is strengthened by the observation of James and associates" that four of their patients who had participated actively in sports had normal functional capacities despite intracardiac repair at an older age. There were nine varsity athletes with normal functional capacities in our series. All had excellent surgical results as indicated by normal heart size, low systolic PRY' and absence of pulmonic regurgitation or residual YSD. One may argue that these individuals became athletes not simply because they were inclined to be physically more active than others, but because their surgical result permitted them to do so in the first place. Our own data suggest that the relationship of age at ICR to functional capacity may in part be due to an overall poorer surgical result in the patients operated upon at an older age: (I) In the past, older patients in general were at risk to sustain more severe impairment of myocardial function due to longer early intervals of hypoxemia and right ventricular hypertension continuing throughout most of their formative years. (2) It may be deduced from the elegant studies of De Troyer and associates" in isolated pulmonic stenosis that the tetralogy patients who were older at ICR have smaller lungs than those operated upon earlier. (3) Perhaps most significant is the factor that patients who were older at ICR often represent some of the earliest surgical candidates, whereas the more recent and younger candidates have benefitted from the many advances in surgical technique. These factors were certainly observed in our study group. A new and important subset of tetralogy subjects is being provided with the recent adoption by some groups of essentially routine primary repair at a young age, i.e., < 1 or 2 years of age. 23 - 25 The increased surgical risk of young age and small size and the early hemodynamic results are being assessed.P- 24 and it is anticipated that eventually exercise performance, late arrhythmia incidence, and clinical follow-up studies will support early primary repair. Our overall exercise results are in general similar to other studies employing different protocols, i.e., the average exercise scores of postoperative tetralogy patients are lower than normal, but there is a wide range of individual scores even for the patients with seemingly similar surgical results. II The low Vo 2 max is due to a reduced maximal stroke volume resulting in a low

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maximal cardiac output, since maximal exercise heart rates are either normal or decreased.': 6. 7. 11 A wider arteriovenous oxygen difference partially compensates for the hypodynamic circulation." 7. 9 Stroke volume is also reduced at submaximal levels of exercise"; however, the normal relationship between submaximal exercise \'0 2 and cardiac output could be preserved presumably by a compensatory increase in heart rate. 2. 7 If submaximal exercise heart rates cannot increase appropriately or are in fact reduced, the increased arteriovenous oxygen difference must lead to a higher \'0 2 in relation to cardiac output, as was demonstrated in the series of Bjarke." Reduced submaximal exercise heart rates were also observed in over half of our patient studies. We attribute this finding in part to impaired autonomic nervous system function, which has been documented in heart disease for both the adrenergic and vagal components.P?: 27 In our patients, the magnitude of the initial heart rate transient during the first 5 seconds of exercise was not different from that of the normal control subjects. Since this early response represents primarily vagal release, the finding suggests normal vagal tone and implicates a reduced adrenergic drive as the mechanism. Furthermore, the submaximal exercise heart rates tend to be disproportionately lower in relation to body size as compared to age." if the patients are small for their age, as was the case in many of our subjects. These two mechanisms combine to make the relationship between heart rate and work rate more variable in tetralogy patients than normal subjects. For example, in 53 normal 13-year-old children heart rate at a moderate work rate of 400 kg-m/min averaged 148 ± 12.3 beats/min with 95% confidence limits between 144 and 152 beats/min. In 23 13-year-old children with tetralogy, this rate averaged 146 ± 27 beats/min with confidence limits between 126 and 166 beats/min, a five times greater range. In postoperative tetralogy patients, exercise performance is thus modified by varying degrees of impaired chronotropy and reduced stroke volume. The latter has been attributed to a multiplicity of factors which more often than not operate in concert. These include residual outflow obstruction at various levels, PI, generalized myocardial fibrosis, regional akinetic right ventricular myocardium, impaired coronary blood supply;" impaired left ventricular function, 29. 30 and others. In addition, exercise performance varies, as in normal subjects, as a function of genetic determinants, body build, physical training, and motivation. Apart from the question of the optimal age at ICR, much of the debate concerning the surgical manage-

The Journal of Thoracic and Cardiovascular Surgery

ment of tetralogy has centered on the question of the long-term relative importance of residual outflow obstruction versus pulmonic valve insufficiency (PI). Results of exercise studies have been inconclusive in this regard and the clinical and surgical literature is divided on this point. 31-37 Bjarke ," examining the cardiac output response to exercise, found no correlation with the type of right ventricular outflow tract anatomy, patch, or particular lesion. It thus appears that the cardiac output response was not related to the type of congenital cardiac defect but rather reflected myocardial function in a general way. His patients were palliated at an average age of about 15 years and underwent ICR approximately at age 20; therefore, impaired myocardial function may well have been the most important determinant of impaired function, since these patients remained hypoxic during most of their growth. Hirschfeld and colleagues" found that working capacity decreased as the average resting PRY increased, but the results were inconclusive because of a large variance about the subgroup means and the small number of individuals. In Cumming's series;'! the mean group centile exercise capacities (Bruce treadmill protocol) were better in patients with good repair and low resting PRY than in patients with poor repair and higher average PRY' The latter also had greater increases of PRY with exercise, but most patients, even those with normal resting pressures in the right ventricle, had abnormally high exercise pressures.": 11 Despite the large variance introduced by noncardiac factors as emphasized by Cumming;" our data clearly revealed significant relationships between exercise scores and manifestations of residual disease, notably elevated PRY at rest and an increased heart size (CTR). On the basis of regression analysis and group comparisons, the data may be interpreted as follows: Patient subgroups with normal exercise scores, i.e., close to 100% of predicted, in general have little evidence of residual outflow obstruction, normal heart size, and no pulmonary hypertension, residual VSD, or significant PI. Residual outflow obstruction is tolerated well only if it is isolated, i.e., in the absence of pulmonary arterial hypertension, VSD, PI, or myocardial factors. In our series however, isolated residual outflow obstruction is uncommon (Table VI). In the majority of patients it exists in conjunction with one or more of the residual lesions, and there is a tendency for heart size to increase and exercise scores to decrease as resting PRY is further elevated. Moreover, at a given level of increased resting PRY, exercise scores tended to be lowest in the subgroup with the largest average heart size.

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In a number of exercise studies, the relationship of working capacity to PI was not explored.v'" Others suggested that PI is tolerated rather well in postoperative tetralogy either because cardiac function did not differ between patients with or without PP or because of unchanged hemodynamics in the presence of Plover periods as long as 10 years." Similar conclusions were reached on the basis of large clinical reviews. 30. 31. 36 In an extensive review of 221 patients, with an overall 70% incidence of PI, Ruzyllo and associates-" found that PI was well tolerated clinically and hemodynamically unless there was distal pulmonary artery or branch stenosis. This view is consistent with the analysis of postoperative results in infants with tetralogy reported by Calder and associates.:" Kinsley and colleagues'" reviewed 61 tetralogy patients with pulmonary artery hypertension and found no significant difference in the clinical outcome between those with and without PI. Chiariello and co-workers;" in a review of 403 tetralogy patients, stated that: " ... pulmonary regurgitation is preferable to residual stenosis." It has been shown in experimental animals'" and in clinical studies'": 40 that pulmonary incompetence as an isolated lesion is well tolerated over a number of years. However, our data and other series suggest that isolated postoperative PI must be relatively uncommon in tetralogy, and it seems therefore unwarranted to broadly infer the benign nature of PI. Vliers and associates," for example, reported cardiomegaly in 19 of 20 patients with PI postoperatively (without residual VSD). Idriss and co-workers:" described seven patients who required valve replacement for massive residual PI following intracardiac repair. Miller's group" reported on 22 symptomatic post-ICR patients who underwent a total of 28 reoperative procedures including ten pulmonary and four tricuspid valve replacements; they concluded that valve replacement can provide some degree of protection against recurrent symptomatic deterioration. Recent reports caution against the liberal use of transannular outflow patch prostheses,": 32 which almost invariably result in pp3 and produce a greater degree of PI than valvotomy alone.V Specifically, Blackstone, Kirklin, and Pacifico" recommend limiting the use of such prostheses to situations in which they are truly necessary. They recommend primary insertion of a trans annular patch only if the predicted intraoperative ratio PRy/PLY exceeds 0.85 (equivalent to a late postoperative PRy/PLY >0.75), where the prediction is based on the intraoperative measurement of the internal diameter at the narrowest point in the pulmonary outflow tract. Furthermore, transannular patching appears to have an incremental risk effect on hospital

mortality rate, and the younger the patient the higher the proportion receiving transannular patches. Group comparisons indicated lower exercise scores for our patients with PI as compared to those without PI, whether PI was evaluated by murmur intensity or angiography. The data (Table VI) further suggest that isolated PI is less well tolerated than isolated residual obstruction. However, the significance of this finding could not be substantiated statistically because of the small number of cases and remains to be documented more fully. Patients with PI and outflow obstruction including pulmonary artery branch stenosis had significantly reduced exercise scores, and this finding is in agreement with conclusions based on clinical and resting cardiac catheterization evaluation. 33 It is noteworthy that the only patient who showed marked deterioration by serial exercise evaluation had severe PI and cardiomegaly. If a distal pulmonary stenosis cannot be adequately relieved and transannular patching with attendant extensive pulmonary valve insufficiency is anticipated, it may be important for the long-term integrity of right ventricular function if primary placement of a prosthetic pulmonary valve is also considered. In the 81 patients in whom complete ECG data were reviewed, the overall incidence of dysrhythmic activity was 51 %. Ventricular ectopy during exercise testing was present in 23.5% (19/81), an incidence similar to that reported by Garson and associates" in 104 patients and by Issenberg, Freed, and Nadasv' in 45 tetralogy patients. In contrast to the latter study, we did not observe severe ventricular ectopy with exercise when ectopy was present at rest. In the majority of patients ectopy was suppressed when the sinus rate approached or exceeded the rate of the ectopic pacemaker. There were no tachyarrhythmias induced and couplets occurred in only two patients. Consistent with the data of Garson and associates, 43 the patients in this series with dysrhythmic activity had low exercise scores and poor surgical results. These findings suggest that dysrhythmic activity, particularly when seen at rest, represents a nonspecific expression of significant residual disease. Although age at ICR, presence of dysrhythmia, resting PRY and CTR were clearly related to exercise scores in this series, the individual correlations are relatively low (r 0.4 to 0.5). Therefore, even the best joint predictions of DUR from these or many of the other variables tested have standard errors of the estimate of ±15% or larger. Similarly, a low exercise score (DUR s 75%) was only moderately sensitive in predicting a PRY of >40 mm Hg (Sn 86%) and highly nonspecific (S, 36%). Thus, given a low exercise score, there is a

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high chance of PRV >40 mm Hg with few false negatives, i.e., patients with low scores and pressures <40 mm Hg. On the other hand, there are many false positives, i.e., patients with normal exercise scores but high PRV ' It is apparent, therefore, that exercise performance should be measured and cannot be predicted sufficiently reliably for individual patients. This is understandable considering that indices such as DUR or V0 2 max represent the integrated global adaptation to all cardiac as well as noncardiac factors, such as genetics, body build, physical training, and motivation. 7. 11 However, the results of our exercise studies were highly reproducible, as indicated by the serial studies in a large number of patients. The lack of change in relative work performance during periods of significant growth and development up to 11 years following intracardiac repair attest to the general stability of postoperative anatomy in tetralogy. Our experience during the past 11 years suggests that exercise testing in post-ICR tetralogy is a valuable adjunct to clinical evaluation and the study of hemodynamics at rest. Exercise studies provide accurate and reproducible quantitative information about the cardiovascular and pulmonary responses to exercise and the ability to do physical work. We currently recommend exercise testing in all post-ICR tetralogy patients. These studies include complete pulmonary function studies and measurement of the ECG, heart rate, systemic blood pressure, and ventilation and pulmonary gas exchange throughout the test. Repeat studies are recommended at 12 to 18 month intervals if the heart rate response to exercise is abnormal, there is evidence of arrhythmia, a significantly reduced exercise tolerance and/or aerobic capacity, significant cardiomegaly, or post-ICR anatomy to suggest the possibility of future deterioration. REFERENCES

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Shah P, Kidd L: Hemodynamic responses to exercise and to isoproterenol following total correction of Pallor's tetralogy. J THoRAc CARDIOVASC SURG 64:495, 1972 Bristow OJ, Kloster FE, Lees MH, Menashe VD, Griswold HE, Starr A: Serial cardiac catheterizations and exercise hemodynamics after correction of tetralogy of Fallot. Circulation 41: 1057, 1970 Finnegan P, Haider R, Patel RG, Abrams LD, Singh SP: Results of total correction of the tetralogy of Fallot. Br Heart J 38:934, 1976 Bjarke B: Oxygen uptake and cardiac output during submaximal and maximal exercise in adult subjects with totally corrected tetralogy of Fallot. Scand J Thorac Cardiovasc Surg (Suppl) 16:9, 1974 Strieder OJ, Aziz KU, Zaver AG, Fellows KE: Exercise

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tolerance after repair of tetralogy of Fallot. Ann Thorac Surg 19:397, 1975 6 James FW, Kaplan S, Schwartz DC, Chow TC, Sandker MJ, Naylor V: Response to exercise in patients after total surgical correction of tetralogy of Fallot. Circulation 54:671, 1976 7 Mocellin R, Bastanier CK, Hofacher K. Biihlmeyer K: Exercise performance in children and adolescents after surgical repair of tetralogy of Fallot. Eur J Cardiol 413:367, 1976 8 Hirschfeld S, Tuboku-Metzger AJ, Borkat G, Ankeney J, Clayman J, Liebman J: Comparison of exercise and catheterization results following total surgical correction of tetralogy of Fallot. J THoRAc CARDIOVASC SURG 75:446, 1978 9 Epstein SE, Beiser GO, Goldstein RE, Rosing DR, Redwood DR, Morrow AG: Hemodynamic abnormalities in response to mild and intense upright exercise following operative correction of an atrial septal defect of tetralogy of Fallot. Circulation 47: 1065, 1973 10 Cumming GR: Maximal exercise capacity of children with heart defects. Am J Cardiol 42:613, 1978 I I Cumming GR: Maximal supine exercise hemodynamics after open heart surgery for Fallot's tetralogy. Br Heart J 41:683, 1979 12 Wessel HU, Stout RL, Guerrero L, Paul MH: Postoperative exercise studies in tetralogy of Fallot, The Child With Congenital Heart Disease Following Surgery, BSL Kidd, RD Rowe, eds, New York, 1976, Futura Publishing Company, p 7 I 13 Mocellin R, Bastanier CK: Zur Frage der Zuverliissigkeit der W 170 als Mass der korperlichen Leistungsfahigkeit bei der Beurteilung von Kindem mit Herzkrankheiten. Eur J Pediatr 122:223, 1976 14 James GW, Paul MH, Wessel HU: Precision digital heart rate meter. J Appl Physiol 32:718, 1972 15 Wessel HU, Stout RL, Paul MH: Minicomputer based system for breath-by-breath analysis of ventilation and pulmonary gas exchange. Proceedings of the Fifth American Conference, Computers in Cardiology, Long Beach, Calif., 1979, JR Cox, PG Hugenholtz, eds., IEEE Computer Soc Publisher, p 97 16 Wessel HU, Stout RL, Paul MH: The effect of breathby-breath variations of FRC on the measurement of O 2 and CO 2 gas exchange at the mouth. Biomed Tech 24:(Suppl), 48, 1979 17 Wessel HU, Stout RL, Bastanier CK, Paul MH: Breathby-breath variation of FRC: Effect on V0 2 and VC02 measured at the mouth. J Appl Physiol 46:1122, 1979 18 Balke B, Ware RW: An experimental study of physical fitness of Air Force personnel. U S Armed Forces Med J 10:675, 1959 19 Rutenfranz J, Hettinger TH: Untersuchungen iiber die Abhangigkeit der korperliche Leistungsfahigkeit von Lebensalter, Geschlecht und Korperlicher Enrwicklung. Z Kinderheilk 83:65, 1959

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20 Rutenfranz 1, Mocellin R: Untersuchungen iiber die korperliche Leistungsfahigkeit gesunder und kranker Heranwachsender. I Bezugsgrossen und Normwerte. Z Kinderheilk 103: 109, 1968 21 Rutenfranz 1, Mocellin R, Bauer 1, Hertig W: Untersuchungen iiber die korperliche Leistungsfahigkeit gesunder und kranker Heranwachsender, II. Die Leistungsfahigkeit von Kindem und lugendlichen mit Diabetes Mellitus. Z Kinderheilk 103: 133, 1968 22 De Troyer A, Yernault lC, Englert M: Lung hypoplasia in congenital pulmonary valve stenosis. Circulation 56: 647, 1977 23 Barratt-Boyes BG, Neutze 1M: Primary repair of tetralogy of Fallot in infancy using profound hypothermia with circulatory arrest and limited cardiopulmonary bypass. Ann Surg 178:406, 1973 24 Castaneda AR, Freed MD, Williams RG, Harwood WI: Repair of tetralogy of Fallot in infancy. Early and late results. 1 THORAC CARDIOVASC SURG 74:380, 1977 25 Kirklin rw, Blackstone EH, Pacifico AD, Brown RN, Bargeron LM lr: Routine primary repair vs two stage repair of tetralogy of Fallot. Circulation 60:373, 1979 26 Goldstein RE, Beiser GO, Stampfer M, Epstein SE: Impairment of autonomically mediated heart rate control in patients with cardiac dysfunction. Circ Res 36:571, 1975 27 Eckberg DL, Drabinsky M, Braunwald E: Defective cardiac parasympathetic control in patients with heart disease. New Engl 1 Med 285:877, 1971 28 Fixler DE, Archie lP, Ullyot Dl, Buckberg GD, Hoffman HE: Effects of acute right ventricular systolic hypertension on regional myocardial blood flow in anesthetized dogs. Am Heart 1 85:491, 1973 29 larmakani 1, Graham T Jr, Caneut R, lewett P: Left heart function in children with tetralogy of Fallot before and after palliative or corrective surgery. Circulation 46:478, 1972 30 Green LH, Keane IF: Age at repair of tetralogy of Fallot. Effects on postoperative left ventricular function. (abstr). Pediatr Res 13:341, 1979 31 Calder LA, Barratt-Boyes BG, Brandt PWT, Neutze 1M: Postoperative evaluation of patients with tetralogy of Fallot repaired in infancy. 1 THORAC CARDIOVASC SURG 77:704, 1979 32 Blackstone EH, Kirklin lW, Pacifico AD: Decision-

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making in repair of tetralogy of Fallot based on intraoperative measurements of pulmonary arterial outflow tract. 1 THORAC CARDIOVASC SURG 77:526, 1979 Ruzyllo W, Hill MR, Mulling CE, McNamara DG: Hemodynamic evaluation of 221 patients after intracardiac repair of tetralogy of Fallot. Am 1 Cardiol 34:565, 1974 Chiariello L, Meyer 1, Wukasch DC, Halloran GL, Cooley DA: Intracardiac repair of tetralogy of Fallot. 1 THORAC CARDIOVASC SURG 70:529, 1975 Vliers A, Jaumin P, Stijns M, Trernouroux-Wattiez M, Raveau A, Ponlot R, Chalant CH: Hemodynamic studies after total correction of tetralogy of Fallot. 1 Cardiovasc Surg (Torino) Spec No:768-77I , 1973 Kinsley RH, McGoon DC, Danielson GK, Wallace RC, Mair DD: Pulmonary arterial hypertension after repair of tetralogy of Fallot. 1 THORAC CARDIOV ASC SURG 67: 110, 1974 Idriss FS, Markowitz A, Nikaidoh H, Muster Al, Paul MH: Insertion of Hancock valve for pulmonary valve insufficiency in previously repaired tetralogy of Fallot (abstr). Circulation 53,54:Suppl 2: 100, 1976 Ellison RG, Brown wr, Yeh TJ, Harrington WF: Surgical significance of acute and chronic pulmonary valvular insufficiency. 1 THORAC CARDIOVASC SURG 60:549, 1970 Holmes lC, Fowler NI, Kaplan S: Pulmonary valvular insufficiency. Am 1 Med 44:851, 1968 Reid 1M, Coleman EN, Stevenson lG, Inall lA, Doig WD: Long term results of surgical treatment for pulmonary valve stenosis. Arch Dis Child 51:79, 1976 Miller DC, Rossiter si, Stinson EB, Oyer PE, Reitz BA, Shumway NE: Late right heart reconstruction followup repair of tetralogy of Fallot. Ann Thorac Surg 28:239249, 1979 Rohmer 1, Van der Mark F, Ziptra WG: Pulmonary valve incompetence. II. Application of electromagnetic flow velocity catheters in children. Cardiovasc Res 10:46-55, 1977 Garson A Jr, Gillette PC, Gutgesell HP, McNamara DG: Stress-induced ventricular ectopy after tetralogy of Fallot repair (abstr). Pediatr Res 13:344, 1979 Issenberg Hl, Freed MD, Nadas A: Exercise-induced ventricular ectopy after surgical repair of tetralogy of Fallot (abstr). Pediatr Res 13:346, 1979