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European Heart Journal (1997) 18, 1816-1822 Cardiopulmonary physiology after surgical closure of asymptomatic secundum atrial septal defects in childhood Exercise performance is unaffected by age at repair M. Rosenthal, A. Redington and A. Bush Departments of Paediatric Pulmonary and Cardiac medicine, The Royal Brompton Hospital, London, U.K. Aims Most secundum atrial septal defects, once diagnosed, are corrected at a young age. The evidence to justify early vs delayed or even non-closure is equivocal and little is known regarding long-term effects of later closure. This is particularly pertinent to those patients awaiting transcatheter closure of their defect for whom a device is only just becoming available. We examined the exercise cardiorespiratory physiology of children surgically treated for an isolated secundum defect. Methods and results One hundred and six healthy control children and 22 children more than 6 months after surgical repair for an isolated secundum atrial septal defect were studied. All were asymptomatic. Measurements of effective pulmonary blood flow, stroke volume, arteriovenous oxygen difference, minute ventilation, heart rate, oxygen consumption and carbon dioxide production were made using a quadrupole mass spectrometer during rest and graded exercise. Data from the normal children allowed calculation of z scores for the atrial septal defect group matched for age, sex, pubertal stage and surface area. Introduction 'It is widely but not universally accepted that atrial septal defects with a pulmonary to systemic flow ratio > 1-5:1 should be closed. The evidence to justify this policy is weak', ran a recent review1'1. The secundum atrial septal defect represents 10% of congenital heart defects at birth and 22% of those seen in adults. The long-term survival of those surgically closed before the Revision submitted 5 May 1997, and accepted 16 May 1997. Correspondence: Andrew Bush, Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London SW3 6NP. U.K This study was funded in part from a grant by Innovision PLC, Odense, Denmark. 0195-668X/97/111816+07 S18.00/0 Maximal exercise performance was equal between control and atrial septal defect groups, however, the atrial septal defect group had a significantly greater effective pulmonary blood flow and stroke volume but a lower heart rate than controls at a given exercise stage. Stroke volume abnormalities were most closely related to duration of follow-up (29% of the variance explained, /><001) rather than age at surgery. Conclusions We were unable to show a medium term benefit from early surgery for an asymptomatic secundum atrial septal defect during exercise. The clinical relevance of the haemodynamic differences that do exist remains unclear. (Eur Heart J 1997; 18: 1816-1822) Key Words: Atrial septal defect, physiology, children. cardiopulmonary age of 25 years is excellent'21. However, the long-term survival of those not surgically treated also appears good'31. Nevertheless, the practice of closing such defects at a progressively earlier age is widespread. This is supported by one study of unselected children which suggested that those operated <5 years of age have a superior cardiopulmonary exercise physiology on follow-up than those operated on later'41. There are relatively few data, however, and the optimal age at repair is yet to be determined. There are also an increasing number of children waiting for transcatheter closure of their defect and the effect of this delay is uncertain. We studied the rest and exercise cardiopulmonary physiology of children with isolated secundum atrial septal defects surgically closed at different ages using respiratory mass spectrometry. 4, 1997 The European Society of Cardiology A trial septal defects and age at repair Methods 1817 Table 1 Descriptive summary of test groups Control The study received local ethical committee approval and written informed consent from all the subject's parents was obtained. ASD Number Male Female 106 55 51 22 6 16 8-50-10-50 years 1051-12 60 years 12-61-14-50 years > 14-50 years PreEarly Late 23 24 37 22 30 36 40 4 7 7 4 11 4 7 Age at study The control group One hundred and six healthy children were recruited from three local London schools. The entry criteria were (i) at least 7-5 years old — the minimum age which ensured cooperation with the exercise protocol; (ii) at least 125 cm tall, the minimum height for using the exercise bicycle; (iii) no history of acute or chronic respiratory illness and receiving no medications. To ensure the control group was not biased towards more physically active children, volunteers were targeted to undertake studies on how the heart and lungs worked together rather than on the basis of testing their fitness; members of school athletic clubs were excluded. Puberty Age at surgery 0-4 years 4-1-8-0 years 8-1-12-0 years 121-160 years 6 9 4 3 0-2-5 years 2-6-5-0 years 5-1-7-5 years >7-5 years 3 6 6 7 Time from surgery ASD = atrial septal defect. The study group The entry criteria were the finding of an isolated secundum defect repaired at least 6 months prior to study and no pre- or post-operative complaints of symptoms referable to the defect. There was to be no residual interatrial shunt. In addition, the entry criteria for the control group were also applied. Children were excluded if there were associated defects such as atrioventricular valve anomalies, pulmonary outflow tract narrowing, right ventricular muscle bands or a patent arterial duct. Forty-four children were identified, 27 were traceable (15/44 lived abroad) and 22/27 agreed to participate. Subject details are summarized in Table 1. All children had their height, weight, two site skinfold thickness and pubertal stage assessed. Resting lung function (Compact Vitallograph, Lenexa, Kansas, U.S.A) was also measured according to American Thoracic Society standards'61. up and then forwards, at 25 W . m 2, increasing in 1 5 W . m ~ 2 increments every 3 min until exhaustion. During the last 20 s of each 3 min stage, children performed a 12 s rebreathing manoeuvre whilst continuing to pedal. At exhaustion, children stopped pedalling but remained on the bicycle for a further 9 min performing three further 12 s rebreathing manoeuvres. During the initial rest, exercise and recovery phases, continuous mixed expired gas analysis was undertaken when the subjects were not performing rebreathing manoeuvres. A typical study lasted 75 min during which the child performed 12-16 rebreathing manoeuvres. During the study the subject had continuous pulse rate and arterial saturation measured using a surface oximeter (Nellcor, Hayward Ca., U.S.A) placed over the right supraorbital artery. Respiratory mass spectrometry Protocol This has been fully described previously17'. Briefly, following a 1 h fast, anthropometric and spirometric measurements were obtained. The subjects then practised with the mass spectrometry equipment, rested for lOmin and then performed, seated, five 20 s rebreathing manoeuvres (bag volume: 40% of predicted vital capacity) from functional residual capacity, every 3 min for 15 min. After the resting measurements, the subject exercised using an electromagnetic bicycle (Seca 100, Birmingham, U.K.). After a 3 min rest, the subject performed a 12s rebreathing manoeuvre, and then began cycling, initially backwards at zero load to loosen An Innovision 2000 quadrupole mass spectrometer (Odense, Denmark) was used to sample the subjects ventilated gas and analyse it on the basis of its massxharge ratio. The hardware and physiological measurements are fully described elsewhere'710^16'. 0-3% acetylene was used to measure effective pulmonary blood flow and helium was the dilution gas used to measure the ventilatory parameters'15161. Analysis All traces were visually checked to ensure the correct point of complete mixing of the rebreathing and lung Eur Heart J, Vol. 18, November 1997 1818 M. Rosenthal et al. Workload (W.m" Figure 1 Effective pulmonary blood flow z score (mean; 95% confidence interval vs workload ( W . m ~ 2 ) for healthy children ( T ) and those after an atrial septal defect repair (A). gases, and to exclude pulmonary recirculation. Only the middle 40% of the exhaled breath was analysed as this best represents alveolar gas concentrations'71. The healthy controls were used to derive age, surface area and sex-determined mean results for all the parameters at rest and during each exercise stage. Resting values were the average of the last three rebreathing measurements'101. Children were divided into four age groups (8-10-5, 10-6-12-5, 12-6-14-5 and > 14-5 years) and three pubertal groups: pre, early and late puberty based on Tanner stages 1, 2-3 and 4-5, respectively. From these normal results, z scores were calculated such that for all control children taken together, their mean z score for any parameter during rest or any stage of exercise was 0 with an SD of 1. Thus, during exercise, even though all raw parameter values may increase in the control group, their mean z score remains zero. A deviation from mean zero in a patient group during exercise is interpreted as the patient group failing to match the changes expected rather than an absolute or fall in that parameter. This methodology allows comparison of the atrial septal defect group corrected for gender, age, surface area and pubertal stage. The maximum work performed by the patients was expressed as a percentage of the median maximum work performed by each control sex and age group. Z-score differences within each patient group were analysed using a two-way ANOVA with the subject as a blocking variable and Bonferroni's correction for multiple contrasts and / > <005 rejected the null hypothesis. Z-score differences between patient groups at each rest and exercise stage were analysed using the unpaired student t-test and /><0-05 rejected the null hypothesis. This methodology was used to strike a balance between the effects of multiple contrasts and the maximum reduction in the residual variance. Eur Heart J, Vol. 18, November 1997 Results There was no differences in height z score (control: mean 0-43, 95% confidence interval 0-24 to 0-63; atrial septal defect: - 0 0 9 , -0-55 to 0-36) or mean skinfold thickness z score (control: mean 0-73, 95% confidence interval 0-58 to 0-89; atrial septal defect: 0-40, 0-1 to 0-7) between controls and the disease group. This suggests that their lean body mass is similar. In children with a surgically corrected atrial septal defect, the effective pulmonary flow (Fig. 1), similar to controls at rest, was higher than controls at all stages of exercise. At rest this blood flow difference amounted to approximately 0-2 1. min" ' . m~ 2 2 and rising to 0-61 min ' . m by 55 W . m " at 70 W . m . In addition, there 111. min" m was a significant positive relationship between blood flow z score and length of follow up (/><003, 23% explained variance) but not with age at surgery. Heart rate (Fig. 2), initially marginally higher at rest, demonstrates mild chronotropic incompetence with exercise, at 55 W. m~ 2 the discrepancy being 12 beats. min~'. As a result, the stroke volume (Fig. 3) in these atrial septal defect treated children deviated progressively from normal such that at 55 W . m ~ 2 their stroke volume was 4-5ml" ' . beat. m~ 2 greater than controls. Time from surgery contributed 29% of the variance of stroke volume (P<001, Fig. 4) thus, the greater the time from surgery, the greater the stroke volume. There was no relationship between the degree of chronotropic incompetence and length of follow-up, age at testing or age at repair. As oxygen consumption mirrored the change in effective pulmonary blood flow (Fig. 5), there was no difference in arteriovenous oxygen difference between the groups (Fig. 6). There was no significant difference in the anaerobic threshold z score (control: mean 000, 95% Atrial septal defects and age at repair 1819 0.8 0.6 — 0.4 - o 0.2 - T- 0.0 -0.2 - x 1 -0.4 - 1 -0.6 -0.8 N= 1 102 22 Rest 1 103 22 103 22 25 40 Workload 1 96 20 55 1 70 13 70 Figure 2 Heart rate z score (mean; 95% confidence interval vs workload (W. m"2) for healthy children (T) and those after an atrial septal defect repair (A). 1.5 £ 1.0 d 2 0.5 1 s B £ o.o 1 N = 103 22 Rest 1 1 103 21 103 22 96 20 25 40 55 Workload (W.nT2) 1 70 13 70 Figure 3 Effective stroke volume z score (mean; 95% confidence interval vs workload (W.m~ 2 ) for healthy children (T) and those after an atrial septal defect repair (A). confidence interval — 0-2 to 0-2; atrial septal defect: 0-43, - 0 1 7 to 104, P=00S) though the trend was for post-atrial septal defect children to have a higher threshold. There was a significant relationship between anaerobic threshold z score and age at testing (Fig. 7) but not age at or time from surgery. The equation: z score = 5-36-0-39 (age at testing, years) explained 43% of the variance (P<00006). Maximum exercise performance was no different to controls and bore no relation to either age at or time from surgery. Discussion This study is the first systematic investigation of cardiopulmonary haemodynamics in patients after closure of an atrial septal defect. We used mass spectrometry to assess effective pulmonary blood flow during graded exercise and our results show important differences to previously published data obtained using different techniques. In this study, maximum exercise performance was indistinguishable from normal regardless of age at surgery or duration of follow-up. In addition, age at Eur Heart J, Vol. 18, November 1997 1820 M. Rosenthal et al. 4 6 Follow-up (years) 10 12 Figure 4 The relationship of effective stroke volume z score to duration of follow-up after correction of a secundum atrial septal defect. This relationship is after completing 3 min of exercise at 40 W . m ~ 2 (9 min exercise in total). /><001; r2 = 0-2886. -0.5 N= 103 22 Rest Workload (W.irf) Figure 5 Oxygen consumption z score (mean; 95% confidence interval vs workload ( W . m ~ 2 ) for healthy children ( • ) and those after an atrial septal defect repair ( • ) . surgery could not be shown to affect any haemodynamic parameter of performance, rather it was follow-up and age at testing that influenced haemodynamics. This does not confirm the findings of Reybrouck et a/.[4' who demonstrated a lower ventilatory threshold (a difficult parameter to obtain in children) in those operated after the age of 5 years. In contrast to Reybrouck et al's study, the anaerobic threshold, which precedes the ventilatory threshold demonstrated a trend to be greater than normal and there was a relationship between anaerobic threshold and age at testing rather than age at, or time from surgery. Furthermore, children with treated atrial septal defects in our study had a higher effective pulmonary blood flow both at rest and during exercise. We, like Reybrouck et al., found mild chronotropic incompetence, however, and so there was a markedly increased effective stroke volume after atrial septal defect repair. As the chronotropic incompetence did not Eur Heart J, Vol. 18, November 1997 significantly vary with follow up, the rise in pulmonary blood flow for a given exercise load is therefore due to an increasing stroke volume. Epstein et a/.[l8], studying healthy corrected atrial septal defect patients (youngest 14 years) demonstrated a reduction in the rise in cardiac output (measured using peripheral arterial and pulmonary arterial oxygen concentrations) during exercise due mainly to a failure to augment the stroke volume. PeterssonII9) reported that although cardiac output was low normal at rest, it rose in proportion to exercise and therefore remained low normal with a raised arteriovenous oxygen difference. The results of this study are difficult to interpret however as the author did not compare their results with contemporary normal data obtained with the same technique. The mechanism for the findings in our study are unclear. One important possibility are problems with the Atrial septal defects and age at repair 1821 -0.1 N = 103 22 Rest Workload (W.nT Figure 6 Arteriovenous oxygen difference z score (mean; 95% confidence interval vs workload (W . m ~ 2 ) for healthy children ( T ) and those after an atrial septal defect repair (A). 10 12 14 Age at testing (years) 16 18 Figure 7 Relationship of anaerobic threshold z score to age at testing in 22 children following repair of a secundum atrial septal defect. /»<00006; r 2 =0-456. matching of the control and atrial septal defect children, i.e. atrial septal defect children may be more sedentary and thus require a higher oxygen consumption and effective pulmonary blood flow at a given exercise load. Control children were recruited 'for a study examining the way the heart and lungs work together' and not to assess athleticism, and we avoided recruits from athletic clubs. Not all control children (15%) owned a bicycle and all lived in inner London which may bias the control population towards sedentary behaviour. In contrast, the atrial septal defect children all owned bicycles and most lived outside London in more rural areas which may bias this group towards athleticism or at least counteract the negative psychological effects of having congenital heart disease. Age at detection of an atrial septal defect murmur is influenced by many factors other than the presence of symptoms. It is also possible that the children treated at a young age had more symptoms or had easier access to better health care services and it was not possible to match patients so that left to right shunts were equal. All studies were performed under identical conditions by a single investigator (M.R.) in an albeit non-formal random order. We therefore believe that the observed differences are not due to experimental error. The finding of a trend towards a raised anaerobic threshold in atrial septal defect children points towards superior athleticism in atrial septal defect children, but is at odds with the increased oxygen requirement, increased pulmonary blood flow but similar arteriovenous oxygen differences to controls at a given workload. This combination points to an increased oxygen requirement by skeletal muscle in atrial septal defect children, which is serviced by a raised pulmonary blood Eur Heart J, Vol. 18, November 1997 1822 M. Rosenthal et al. flow. That no differences in arteriovenous oxygen difference occurs implies that the circulation is better able to supply oxygen to the skeletal muscle in atrial septal defect than control children, again going along with superior cardiovascular fitness. This may be a legacy of the pre-operative abnormal circulation. The reduced pre-operative systemic circulation may alter skeletal muscle metabolism to improve oxygen extraction. Postoperatively these mechanisms may persist in a setting where the systemic circulation is now near normal. The ability of the circulation to now supply the muscle's increased oxygen needs is now met by persisting changes in right ventricular performance and size rather than increased oxygen extraction. In the early follow-up period, this superior supply is sufficient to keep the anaerobic threshold higher than normal but with increasing follow-up this benefit is progressively lost (Fig. 7) and with this falling anaerobic threshold, the stroke volume and pulmonary blood flow rise in compensation to maintain skeletal muscle oxygen supply. This mechanism must remain speculative, however; nonetheless, indirect evidence in support of this comes from Meyer et al.[20] who demonstrated increased right ventricular dimensions and abnormal septal motion in >90% of patients preoperatively. Post-operatively, their children showed an early reduction in right ventricular size although not to normal, and it remained increased 5 years post-operatively as did the left ventricular shortening fraction. Indeed there was a trend for both parameters to return to pre-operative values by 5 years follow-up. Haemodynamic changes may even begin before birth. Wagenvoort et al.[2X] in support of this, reported that the medial surface area index (ratio of the pulmonary arterial medial smooth muscle surface area to the lung parenchymal surface area) was markedly raised in fetuses found to have atrial septal defects although it is difficult to envisage the fetal haemodynamic differences of a patent foramen ovale and secundum atrial septal defect as being more than minor. Whatever the mechanism, the clinical importance of our data is clear; correction of an asymptomatic secundum atrial septal defect before the age of 5 years confers no medium term physiological advantage with regard to exercise although the psychological effects of delay and the risks of late arrhythmias are factors in considering the timing of closure. With these caveats, our findings are reassuring for atrial septal defect patients who may already have been waiting several years for transcatheter closure. References [1] Ward C. Secundum atrial septal defect: routine surgical treatment is not of proven benefit. Br Heart J 1994; 71: 219-23. Eur Heart J. Vol. 18. November 1997 [2] Murphy JG, Gersh BJ. Mcgoon MD et al. Long term outcome after surgical repair of isolated atrial septal defect. New Eng J Med 1990; 323: 1645-1650. [3] Shah D, Azhar M, Oakley CM, Cleleand JGF, Nihoyannopoulas P. Natural history of secundum atrial septal defects in adults after medical or surgical treatment: a historical prospective study. Br Heart J 1994; 71: 224-8. [4] Reybrouck T, Bisschop A, Dumoulin M, van der Hauwaert LG. Cardiorespiratory exercise capacity after surgical closure of atrial septal defect is influenced by the age at surgery. Am Heart J 1991; 122: 1073-8. [5] Tanner JM, Growth at adolescence, 2nd edn OxfordBlackwell Scientific Publications 1962. [6] Standardisation of Spirometry-1987 update. Am Rev Respir Dis 1991; 143: 1215-23. [7] Rosenthal M, Deanfield JE, Bush A, Redington A. A comparison of cardiopulmonary function in children undergoing the atriopulmonary or total cavopulmonary connection Fontan procedure. Circulation 1995; 91: 372-78. [8] Nielson OW, Hanson S, Christensen P, Gronlund J. Repeatability of the acetylene rebreathing method in measuring cardiac output: influence of acetylene concentration. Acta Anaesthesiol Scand 1990; 34: 354-7. [9] Schied P. Respiratory mass spectroscopy. In: Laszlo G, Sudlow MF (eds). Measurement in clinical respiratory physiology. London: Academic Press, 1983: 163-90. [10] Bush A, Busst C, Johnson S, Denison DM. Rebreathing method for the simultaneous measurement of oxygen consumption and effective pulmonary blood flow during exercise. Thorax 1988; 43: 268-75. [11] Cander L, Forster RE. Determination of pulmonary parenchymal tissue volume and pulmonary capillary flow in man. J Appl Physiol 1959; 14: 541-51. [12] Petrini MF, Peterson BT, Hyde RW. Lung tissue volume and blood flow by rebreathing: theory. J Appl Physiol 1978; 44: 795-802. [13] Bowyer JJ, Warner JO and Denison DM. Effective pulmonary blood flow in normal children at rest. Thorax 1988; 43: 972-7. [14] Sackner MA, Greeneltch D, Heiman MS, Epstein S, Atkins N. Diffusing capacity, membrane diffusing capacity, capillary blood volume, pulmonary tissue volume, and cardiac output measured by a rebreathing technique. Am Rev Respir Dis 1975; 111: 157-65. [15] Davis NJH, Denison DM. The measurement of metabolic gas exchange and minute volume by mass spectroscopy alone. Respir Physiol 1979; 36: 261-7. [16] Beaver WL, Wasserman BJ and Whipp A. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 1986; 60. 2020-7. [17] Gardner MJ, Altman DG. Confidence intervals rather than P values: estimation rather than hypothesis testing. Br Med J 1986; 292: 746-50. [18] Epstein SE, Beiser GD, Goldstein RE, Rosing DR, Redwood DR, Morrow AG. Haemodynamic abnormalities in response to mild and intense upright exercise following operative correction of an atrial septal defect or tetralogy of Fallot. Circulation 1973; 47: 1065-75. [19] Pedersson PO. Atrial septal defect of the secundum type. Acta Paed Scand 1967; Suppl 174: 5-96. [20] Meyer RA, Korhagen JC. Covitz W, Kaplan S. Long term follow up study after closure of secundum atrial septal defect in children: an echocardiographic study. Am J Cardiol 1982; 50: 143-8. [21] Wagenvoort CA, Neufeld HN, DuShane JW, Edwards JE. The pulmonary artery tree in atrial septal defect. Circulation 1961; 23: 733-9.