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Exercise Testing in Children with Lung Diseases
Paediatric Respiratory Reviews 10 (2009) 99–104
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Mini-symposium: The Clinical Applications of Exercise Testing in Children
Exercise Testing in Children with Lung Diseases Oon Hoe Teoh 1, Daniel Trachsel 2,a, Meir Mei-Zahav 3,b, Hiran Selvadurai 1,c,* 1
Department of Respiratory Medicine, Children’s Hospital at Westmead, Sydney Pediatric Intensive Care and Pulmonology, University Children’s Hospital Basel, Postal Box, 4005 Basel, Switzerland 3 Pulmonary Institute, Schneider Children’s Medical Center of Israel, Petach Tikwa, Israel 2
A R T I C L E I N F O
S U M M A R Y
Keywords: Cardiopulmonary exercise test exercise test field test child adolescent paediatric pulmonary disease lung disease asthma exercise induced asthma exercise induced bronchoconstriction cystic fibrosis bronchopulmonary dysplasia chronic lung disease
Exercise is an important aspect of health and development in children. By placing the pulmonary system under stress, exercise testing may reveal subtle dynamic abnormalities that are not apparent on conventional static pulmonary function tests. Furthermore, exercise testing assesses the functional impact of respiratory disease on children. Exercise testing has been used in children with a variety of respiratory diseases such as exercise induced bronchoconstriction, asthma, cystic fibrosis and bronchopulmonary dysplasia to assess the severity of disease as well as response to various interventions. Furthermore, there is good evidence that exercise testing is a useful tool to help determine prognosis in patients with cystic fibrosis. In addition to the clinical utility, exercise testing is also becoming an increasingly important outcome measure in research studies. ß 2009 Published by Elsevier Ltd.
INTRODUCTION Exercise is a complex activity which requires the integrative involvement of multiple organ systems - the pulmonary, cardiovascular, haematopoietic, musculoskeletal and neuropsychological systems.1 Exercise testing is an important diagnostic tool in the assessment of the cardiorespiratory status of the child. By placing the pulmonary system under the stress of exercise, subtle functional deficits in the lung may be identified that were not apparent during conventional static pulmonary function testing. Exercise testing is a dynamic assessment of pulmonary function and its utility in detecting early functional deficits due to early lung disease is gaining popularity. Exercise testing can not only help ascertain if exercise capacity is reduced but also define the aetiology of the reduced exercise capacity.
* Corresponding author. Tel.: +61 2 9845 3395; Fax: +61 2 98453396. E-mail addresses: [email protected] (O.H. Teoh), [email protected] (D. Trachsel), [email protected] (M. Mei-Zahav), [email protected] (H. Selvadurai). a Tel.: +41 61 685 6565; Fax: +41 61 685 5004. b Tel.: +972 3 9253654; Fax: +972 3 9253308. c Tel.: +61 2 9845 3395; Fax: +61 2 98453396. 1526-0542/$ – see front matter ß 2009 Published by Elsevier Ltd. doi:10.1016/j.prrv.2009.06.004
The importance of habitual activity and exercise in both healthy children and children with chronic diseases has been well documented in the literature. A systematic review by Strong et al.3 concluded that there was good evidence for the beneficial effects of habitual activity on musculoskeletal health, cardiovascular health, lipid and lipoprotein levels, self concept and academic performance in children.2 Strong et al.3 also demonstrated evidence for the beneficial effects of habitual activity on adiposity in overweight youth, blood pressure in mildly hypertensive adolescents, and in children with anxiety and depression.2 Children with lung diseases may theoretically have impaired habitual activity because of pulmonary limitation. Unless the pulmonary disease is severe, reduced habitual activity is unlikely to be due to respiratory limitation.3 Other co-existing factors such chronic deconditioning may be significant contributors to impaired habitual activity. Exercise limitation in these children may also be self-imposed or imposed upon them by care-givers because of misperceptions of physical fragility.4 Gender differences in habitual activity have been noted in children with chronic suppurative lung diseases such as cystic fibrosis.5,6 The aetiology of these gender differences is unclear. Regardless of the cause, regular exercise improves the sense of wellbeing of children and may reduce the rate of decline in lung function in children with cystic fibrosis.6 Physical inactivity is also a risk factor for obesity,2 a
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Table 1 Indications for exercise testing
Table 2 Utility of exercise testing in children
In clinical practice, exercise testing in children may be performed for one or more of the following indications: 1) Evaluation of overall fitness level. 2) Evaluation of undiagnosed exercise limitation. 3) Evaluation of exercise tolerance in a child with underlying respiratory or cardiovascular disease e.g. asthma, congenital heart disease. 4) Detection of exercise induced bronchoconstriction. 5) Detection of exercise induced arrhythmia. 6) Assessment for response to specific treatment, exercise prescription or rehabilitation programme. 7) Evaluation before specific treatment for baseline status or suitability for treatment e.g. chemotherapy, lung transplantation. 8) Assessment post specific treatment for potential complications e.g. drug induced lung injury from chemotherapy.
Diagnostic tool as to why a child cannot exercise like their peers * Physical fitness issues/ deconditioning * Respiratory limitation * Cardiac compromise Assessing response to therapy or intervention Prognostic aid (in cystic fibrosis)
condition associated with a myriad of co-morbidities, including insulin resistance, dyslipidaemia, hypertension and sleep disordered breathing.7 Obesity and its co-morbidities can also further contribute to exercise limitation in these children. In summary, children with respiratory disease may have reduced habitual activity either due to primary respiratory limitation or secondary causes. A negative feedback loop may be created where reduced habitual activity leads to deconditioning, prompting a further reduction in exercise capacity. This will impact on the child’s general health and well being, as well as self esteem. Formal exercise tests will help to determine if the aetiology of reduced exercise capacity in children with underlying respiratory disease is due to cardio-respiratory limitation or deconditioning. ROLE OF EXERCISE TESTING IN CHILDREN WITH LUNG DISEASE While spirometry and other pulmonary function tests have traditionally been useful in the diagnosis and guidance of management for children with lung disease, these tests measure only static or resting lung function indices and do not reliably predict functional and exercise capacity.1 Exercise testing provides a more accurate functional evaluation and serves as a useful adjunct in the management of children with lung diseases. Children with lung diseases may have exercise testing for any of the indications presented in Table 1. The results of the exercise test can be used as a guide to prescribing safe and individualised exercise programs and provide confidence to the child, their caregivers, physicians and teachers that it is safe for the child to exercise despite having a lung disease.8 PHYSIOLOGICAL RESPONSES TO EXERCISE A discussion of exercise testing in children requires a basic understanding of exercise physiology. For a detailed description of exercise physiology we refer the readers to the work of Wasserman et al.9 as it is beyond the scope of this review (Tables 2–4). During exercise, patients with mild lung disease achieve optimal alveolar ventilation by increasing tidal volume.10 However, as the severity of lung disease progresses and in children with restrictive lung disease (either chest wall restriction or parenchymal disease) there is a limited ability to increase the tidal volume (VT). Subsequent increases in minute ventilation (VE) are achieved through increases in the respiratory rate. Thus, in patients with moderate to severe lung disease, the respiratory rate is increased to higher levels to compensate for the inability to increase the tidal volume.11 In spite of the increased ventilatory rate, relative alveolar hypoventilation occurs due to an increased dead space.12 Thin et al.13 suggested that in moderate to severe cystic fibrosis (CF) lung disease that dynamic hyperinflation, limitation of tidal volume increase and compensatory high respiratory rate during
Table 3 ‘‘Field tests’’ versus ‘‘laboratory tests’’ of exercise capacity in children Field test
Laboratory test
Cheap to administer Expensive equipment necessary Easy access Specific expertise required to conduct Potentially less threatening Potentially more threatening to young children to children Useful in large population studiesDifficult to perform in large research studies Limited long term validity data Valid assessment short & long term Less useful diagnostically Useful diagnostic test Cannot measure ventilation Good physiological ventilation measures parameters
Table 4 Important parameters of assessment during exercise tests in children Heart rate (HR) Oximetry Blood pressure Tidal volume (VT) Peak oxygen uptake (VO2) Oxygen pulse (VO2/HR) Minute ventilation/carbon dioxide production (VE/VCO2) Minute ventilation/maximum voluntary ventilation (VE/MVV) Exercise flow volume loops Pre/post exercise forced expiratory volume in 1 second (FEV1) Physiological dead space (VD/VT) – usually derived value
exercise could explain the wasted ventilation on dead space previously observed.13 Moreover, Pianosi and Wolstein14 demonstrated that patients with CF have a decreased ventilatory response to carbon dioxide. The reduced chemosensitivity may further accentuate the relative alveolar hypoventilation during exercise in patients with CF.15 This relative alveolar hypoventilation has been shown to result in carbon dioxide retention in studies measuring end tidal carbon dioxide during exercise.10 In addition, Coates et al. demonstrated that patients with carbon dioxide retention had worse lung function than those who did not have carbon dioxide retention.16 In most situations, reduced oxygenation is not usually the limiting factor for exercise. There is a greater likelihood of oxygen desaturation in children whose forced expiratory volume in one second (FEV1) is <50% or DLCO<60%.17 End tidal carbon dioxide levels gradually increase with the onset of exercise, plateau and then begin to decrease by maximal exercise. It has been noted that in children with significant lung disease there is no decrease in carbon dioxide (CO2) levels after the plateau. Nixon et al.18 have demonstrated that in subjects with cystic fibrosis, an end tidal CO2 > 41 mm Hg at peak exercise is associated twice the mortality at 7 years compared to those who were able to defend their carbon dioxide levels with a peak exercise CO2 of <36 mm Hg.18 Patients with CF utilise a larger proportion of their total oxygen consumption on respiratory muscles when exercising than do controls.19 Thus, there is less reserve for use by the exercising peripheral muscles and therefore exercise tolerance may be limited. Further, exercise tolerance may also be limited by way of increased carbon dioxide production by peripheral muscles contributing to the ventilatory load of the respiratory system.20 Subjects who are aerobically fit have, however, a lower ventilatory
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load and use fat as a fuel (reducing the carbon dioxide by product) as well as metabolising lactate more efficiently. Cardiac output responses during exercise have been demonstrated to be normal until there is severe lung disease.21 Stroke volume is reduced in severe airflow limitation. Coates et al. have demonstrated that the reduced stroke volume in severe airflow limitation is due to the reduced inspiratory time to total respiratory time duty cycle ratio.16 MODALITIES, MEASUREMENTS AND PROTOCOLS IN EXERCISE TESTING FOR LUNG DISEASES Exercise testing in children can be done informally as a field test or formally as a cardiopulmonary exercise test (CPET) in a laboratory on a treadmill or cycle ergometer with metabolic measurements using breath by breath exhaled gas analysis. The main advantage of the formal test is that it measures airflow, peak oxygen consumption (VO2), carbon dioxide production (VCO2), and heart rate during exercise. Together with the measured or estimated work rate (WR) applied during the exercise test, numerous variables may be computed including maximal oxygen consumption (VO2max), anaerobic threshold (AT), minute ventilation (VE) and ventilatory reserve (VR). These indices may be useful in evaluation of the cause of the child’s exercise limitation. VO2max is the best index of aerobic fitness.1 Of note in children is that the VO2max criterion of VO2 plateau in spite of increasing WR may not always be evident at maximal exercise testing, in contrast to adult subjects.22 Therefore, the term peak VO2 (VO2peak) is preferred over VO2max because of this phenomenon in children. The ventilatory threshold is an estimate of the point at which CO2 production exceeds oxygen uptake.1 This indicates the upper limit of exercise intensity that can be achieved predominantly through the aerobic metabolic pathway. In reality, both the aerobic and anaerobic pathways of energy acquisition for skeletal muscle function run concurrently. Nevertheless, the ventilatory threshold is a useful point at which comparisons can be made within as well as between subjects. In healthy children and adolescents, the ventilatory threshold normally occurs at 55% to 65% of the VO2max. Because ventilatory threshold is a submaximal measurement, it is relatively independent of effort and may be useful in cases where the measurement of VO2max is difficult.9 The dyspnoea index is the ratio of peak VE during exercise to the maximal voluntary ventilation (MVV). MVV is determined using the 12 second sprint technique. Alternatively, MVV can be extrapolated in healthy children by multiplying the forced expiratory volume in the first second (FEV1) by 35. However, while this formula can be used to estimate the measured MVV in healthy children, it does not hold true for children with abnormal lung function.23 VR gives an indication of whether ventilatory limitation causes or contributes to the exercise intolerance. In addition to the usual indices, simultaneous assessment of exercise tidal breathing flow-volume loops (extFVLs) in relation to the maximal flow-volume loop (MFVL) may be done with a formal exercise test to provide information on operating lung volumes and flows during exercise. Field tests are exercise tests that can be performed without the need for specialised exercise equipment or gas analysis. The main advantages of field tests are that they require inexpensive and portable equipment and that they are simple to perform. They are often used in the evaluation of responses to treatment or intervention, or for the diagnosis of exercise induced asthma in young children who are not able to do a formal exercise test. The measurements taken during field tests include baseline and highest pulse rate, baseline and lowest oxygen saturation, subjective and objective measures of breathlessness before and after the test, distance or steps achieved, and muscle fatigue. Field tests that have been validated in children with lung diseases
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include the 6-minute walk test (6MWT)24 and the 3-minute step test (3MST).25 A maximal field test that has been validated in children with cystic fibrosis is the modified shuttle test (MST).26 The choice of a formal or field test, treadmill or cycle ergometer, and exercise test protocol is largely dependent on the availability of equipment and expertise at the centre, the age and underlying medical condition that the child has, and the specific objectives of the test. For example, it would be more practical to utilise a field test for large population studies. However, a diagnostic study that requires an answer as to the aetiology of reduced exercise tolerance in a particular child would require a formal CPET in an accredited exercise laboratory. ASTHMA & EXERCISE INDUCED BRONCHOCONSTRICTION Exercise induced bronchoconstriction is the transient airway narrowing brought on by exercise or physical activity.28,29 In most cases, EIB reflects airway inflammation and bronchial hyperreactivity from an underlying respiratory disease such as asthma. In the presence of symptoms or known diagnosis of asthma, the term ‘‘exercise induced asthma’’ is often used interchangeably with EIB.30 However, EIB is not limited to those with asthma, and can also be present in elite athletes in the range of 10 to 50%. Current literature suggests that the prevalence of EIB is higher in the elite athlete population than in the nonathlete population; whether this is related to some degree of underlying asthma in these athletes, or to lung injury from inhalation of cold dry air, high emission pollutants and chloramine associated with the sports activity remains unclear.31 Asthma is a common chronic respiratory condition affecting children worldwide. The prevalence of asthma symptoms in the 13- to 14-year-old age group is as high as 37%, and 32% in the 6- to 7-year old age group.32 Children with asthma may have exercise limitation. Up to 30% of asthmatic children experience exercise limitation with reduced daily physical activity.33 EIB characteristically appears after the cessation of physical activity, usually resolving within 20–40 minutes. However, a late bronchoconstrictive response may occur. Besides suboptimal asthma control resulting in EIB, deconditioning or restriction by self or caregivers can also contribute to exercise limitation in children.34 In a study of urban school-aged children, those with asthma were less likely to be active compared to their peers. Among this group, those with moderate to severe asthma were more likely to be inactive. Children whose parents believed that exercise could improve asthma control were more likely to be highly active.4 Exercise limitation affects the quality of life in asthma.35 The association between asthma and obesity is inconclusive at the moment.36 In a classic dilemma of the ‘‘chicken or the egg’’, it is unclear if they independently reduce physical activity or if reduced physical activity is the common pathway that results in both asthma and obesity. This is a focus of much ongoing research.36 Exercise tests have contributed to our knowledge on the effect of asthma on exercise and its non-pharmacological management. For example, the evaluation of an asthmatic adolescent with exercise limitation despite being on adequate controller treatment should be done with a formal exercise test on a treadmill with spirometry before and after exercise and with extFVLs assessment in relation to the MFVL during the test. Free unencumbered running, more so than treadmill, has been found to be a more potent bronchoconstrictor compared to cycling.37 Difficulties in standardising test conditions and motivating children to high levels of exertion are recognised weaknesses of this type of provocation test. Some exercise test studies, have found decreased aerobic and anaerobic fitness in youths with asthma.2 The Cochrane review on physical training programs in asthma found that the training improves cardiovascular fitness but does not
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affect resting lung function in children.38 The effect of physical training on reducing EIB is less clear, but a recent randomised controlled trial by Fanelli et al.39 has found decreased severity of EIB with exercise training and improved quality of life scores.39 The most important role of exercise testing in children with asthma is in the assessment of EIB. It is often difficult for the children to differentiate between self-perceived symptoms of EIB and shortness of breath from mere deconditioning. In a study by Joyner et al.40, of 42 asthmatic children who attributed exercise symptoms to asthma despite daily controller therapy, only 24% had proven EIB on CPET.40 Exercise limitation from deconditioning, without EIB, was found in the remaining children, both obese and non-obese. As a majority of children have normal resting lung function during the asymptomatic intervals, spirometry at rest alone is often not predictive of exercise limitation in children with asthma.41,42 In most children with known asthma, exercise tests are not usually necessary; however in children with exercise limitation despite being compliant on controller treatment, exercise tests may be helpful in differentiating between deconditioning and EIB as the dominant factor. This prevents unnecessary ‘‘stepping up’’ of the inhaled corticosteroid treatment in these children and allows management to be targeted at the aetiology of the symptoms. In some cases, a normal exercise test other than decreased cardiorespiratory fitness gives the child, care-givers and teachers confidence that the child can exercise and guides the physician in exercise prescription for the child. In children with exercise symptoms without other typical symptoms of asthma, exercise tests can help to exclude EIB as a cause and direct management accordingly. In less commonly encountered cases, upper airway abnormalities masquerading as EIB, such as vocal cord dysfunction, examination of the flow-volume loop may help in differentiating the conditions as both will show a positive response in FEV1 after exercise.43 The assessment for EIB can be done with an exercise challenge test in the laboratory or as an informal field test, together with serial spirometry before and after the exercise challenge. The treadmill protocol recommended by American Thoracic Society (ATS) is 4 to 6 minutes of exercise at 80 to 90% of the maximum predicted heart rate, with a total duration of exercise of 6 to 8 minutes. The treadmill is started at a low speed and grade, progressively advanced within 2 to 3 minutes to achieve the target heart rate, and maintained for the rest of the test. For children older than 12 years of age the exercise duration is usually about 8 minutes whereas younger children may exercise typically for 6 minutes. Spirometry is performed before exercise and serially at close intervals for up to 30 minutes after exercise. The test can also be done on a cycle ergometer using a target work rate instead of heart rate, and the VE and VO2 are measured to help assess adequacy of airway stimulus and exercise intensity.43 As outlined earlier, simultaneous assessment of the extFVLs in relation to the MFVL may be done with a formal CPET if the setup in the laboratory allows this.1 In young children who are not able to perform the test on a treadmill, free range running may be considered.43 Both the ATS and European Respiratory Society recommend taking a decrease in FEV1 of 10% or more as a criterion for EIB, although some have suggested that a decrease of 15% or more is more diagnostic of EIB, particularly if the exercise is performed in the field.43 CYSTIC FIBROSIS LUNG DISEASE Cystic fibrosis is a disease affecting multiple organ systems, with the greatest morbidity and mortality arising from the respiratory component of the disease. Lung disease in CF is characterised by viscid mucous production leading to bronchiolar obstruction and infection, and progressive deterioration in pulmonary function.44
The role of exercise in maintaining lung function in children with CF has been studied in detail. Most studies are of short term duration and last less than 3 months. Training programs (e,g. swimming, cycling) have been shown to improve aerobic capacity and pulmonary function.45 However, the effect on pulmonary function was temporary, disappearing when exercise was terminated. Aerobic as well as anaerobic training has been proven to be beneficial in patients hospitalized with CF pulmonary exacerbations.46 A randomised controlled trial of a 3 year home-based aerobic exercise program in children and adolescents with mild to moderate CF lung disease by Schneiderman-Walker et al.47 showed a significant slowing of the decline in forced vital capacity (FVC), a similar but non-significant trend in FEV1, and improved the sense of well being.47 Moorcroft studied 42 adult CF patients for a year and found that a training effect could be achieved with unsupervised individualized home exercise. A benefit to pulmonary function was also observed.48 Notably, no single resting pulmonary function test index or combination of indices predicts oxygen saturation changes with exercise.49 Besides respiratory limitations, other factors like nutrition and peripheral muscle dysfunction and CF genotype may also influence exercise capacity in CF.50–52 The value of exercise testing for prognostication of survival in CF has also been documented by previous cross-sectional studies. Nixon et al.18 found in a group of children and adults with CF that those with higher VO2peak (ie VO2 82% predicted normal) more than three times more likely to survive for 8 years than those with low VO2peak,(VO2 less than 58% predicted).53 Of note, the study suggested that conventional FEV1 was not independently correlated with survival. Moorcroft et al.48 however, found in a group of adults with CF that while VO2peak correlates with survival, it was not better than FEV1 as prognostic indicator.48 More recently, Pianosi et al.54 studied the relationship between FEV1 and VO2peak in a group of children with CF over 5 years and found a high correlation between these measurements, particularly in children with FEV1 less than 80% predicted.54 Pianosi et al.54 found a significant decline in VO2peak over time at an average of 1.9 ml/ min/kg annually, commencing around the time FEV1 fell below 80% predicted, particularly in adolescent patients. When they looked at mortality rate in the same series, the first, last and rate of decline in FEV1 over time were significant predictors of mortality. Initial VO2peak was not predictive of mortality but the rate of decline and final peak VO2peak were significant predictors. Those with VO2peak less than 32 ml/min/kg in their series had a dramatic increase in mortality, while none of those with VO2peak above 45 ml/min/kg died during the period of the study.55 In a retrospective study, Javadpour et al.56 demonstrated that children with CF with similar FEV1, if found to have CO2 retention during exercise testing, had a significantly greater decline in FEV1 compared to their counterparts who did not retain CO2.56 The presence of CO2 retention during exercise may be an additional prognostic marker of disease progression in CF. The breathing reserve index at ventilatory threshold is considered a more pure index of pulmonary mechanics. This index was studied by Tantisira et al.57 in patients with CF awaiting lung transplantation. This index was found to be the best estimate of risk for mortality in these patients.57 Besides being a reflection of disease severity, exercise limitation affects the quality of life in CF.45 Despite evidence of the value of exercise testing in the management of children with CF, it may still be a tool that is under utilised. In a questionnaire survey of exercise testing and training in German CF centres, it was found that only 60% of the specialised centres which responded performed some sort of exercise testing, at an average frequency of 1 in 2.3 years for patients aged 8 and above.58 Protocols and indication criteria were often not standardised or not specified at all.58 While laboratory based CPET is of value to CF management in children, and is the
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‘‘gold standard’’ of exercise testing, it is not without disadvantages. The equipment is expensive, it requires technical expertise, and young children may not be able to perform the test. Maximal field tests like the MST have been validated in children with cystic fibrosis, and can serve as an alternative when a formal CPET cannot be performed, or as a complementary tool in CF management together with the formal CPET. The assessment of clinical response to antibiotic treatment for pulmonary exacerbations in children with CF has been reported using a ‘‘field test’.59 This is an important finding as even clinicians without access to a formal exercise laboratory may assess the response to an intervention using a simple ‘‘field test’’. Therefore, both formal and informal field exercise tests can be used in exercise prescription, and monitoring of disease progress and response to treatment. BRONCHOPULMONARY DYSPLASIA Bronchopulmonary dysplasia (BPD) was well described in 1967 in prematurely born infants with severe respiratory distress syndrome (RDS) who developed a form of chronic lung disease after receiving positive pressure mechanical ventilation and oxygen supplementation.60 With the use of antenatal steroids, surfactant replacement and gentler mechanical ventilation strategies over the past 3 decades, the ‘‘classic’’ form of BPD with markedly hyperinflated cystic radiographic appearance of the lung is now rarely seen, and has been replaced with a ‘‘new’’ BPD which is characterized by more subtle radiographic findings of bilateral, diffuse, hazy lungs and interstitial thickening and normal to increased expansion of the lung with little change over time.61 The pathophysiology of the new BPD is extreme lung prematurity with hypoalveolarization. These changes and the decreased incidence of BPD in infants with birth weight above 1000 g in which the condition was originally described have lead to the common use of the term chronic lung disease to describe the form of BPD seen in very-low-birth-weight, premature infants.62 Although BPD is uncommon now in infants of birth weight more than 1200 grams and more than 30 weeks of gestation, it is still the most common cause of chronic lung disease in infants.63 The long term studies of lung function in BPD show normalisation of lung volumes over time as somatic and lung growth occur, but persistence of small airway function abnormality.63 Parat et al.64 have reported persistence of reduced dynamic compliance in children 8 years of age with BPD and CLD.64 The general trend of the findings of numerous studies performed on school age children with a history of BPD showed lower FEV1, FVC and FEV1/FVC ratio, and higher residual volume/total lung volume (RV/TLC) ratio than children born at term, but no significant difference in total lung volume (TLC) or functional residual capacity (FRC).65 Much less data is available on BPD survivors in adulthood, but the observations in childhood seem to persist into adulthood.66 Airway hyper-reactivity was detected in 40 % of children with BPD, children who were preterm with RDS and children who were preterm without RDS, in contrast to 5% in children born full term.65 Studies on the exercise capacity of children with BPD shave demonstrated varied results. Bader et al.67 found that although the VO2peak in children with BPD was similar to healthy children who were born at term, the former were more likely to show evidence of pulmonary limitation to exercise with a fall in arterial oxygen saturation and rise in transcutaneous carbon dioxide tension.67 Parat et al.64 did not find significant difference in the VO2peak between children with BPD and those born preterm without lung disease or those born at term, but found decreased VR in children with BPD.64 Similarly, Jacob et al.68 did not find any difference in the exercise capacity between children with BPD, children born preterm with RDS but no BPD and children born at term, but found
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reduced VR in children with BPD at maximal exercise.68 Santuz et al.69 found that at rest, arterial oxygen saturation was 98% or more in all BPD children, but at peak exercise, some had a fall of 4% or more. Maximum VO2 and VE were significantly lower in BPD children with respect to the control group of children born at term.69 Also, at submaximal levels of exercise dynamic, VO2 and VE responses were significantly lower in the BPD group, with a ventilatory pattern characterized by lower tidal volumes.70 Pianosi and Fisk71 found lower VO2peak that was within normal range in children born preterm with BPD or with hyaline membrane disease only without BPD, compared to children born at term.71 These children also tend to increase their respiratory rate rather than their tidal volume during exercise compared to children born at term. They postulated that the lower VO2peak may have been due to less metabolically active muscle in these children rather than cardiorespiratory limitation. Although these studies do not report consistent findings on the exercise capacity of children with BPD, all of them did report some degree of respiratory abnormalities, including airway hyperreactivity, associated with exercise. EXERCISE TESTING AS AN OUTCOME MEASURE Exercise testing is an important tool in assessing the response to a given intervention, and as an outcome measure in clinical trials.72 The intervention may be a therapy for exercise induced asthma or weight control or treatment of arthritis.73,74 CONCLUSION Exercise testing plays an important role in children with respiratory diseases. Together with resting pulmonary function tests, exercise tests help us understand how specific respiratory diseases affect exercise capacity in children. This knowledge can be applied in the optimal management of the diseases in terms of treatment, assessment of response to treatment and prognosis. REFERENCES 1. American Thoracic Society/American College of Chest Physicians. ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003; 167: 211– 277. 2. Strong W, Malina R, Blimkie C, Daniels S, Dishman R, Gutin B et al. Evidenced based physical activity for school-age youth. J Pediatr 2005; 145: 732–737. 3. Orenstein DM, Franklin BA, Doershuk CF, Hellerstein HK, Germann KJ, Horowitz JG. Exercise conditioning and cardiopulmonary fitness in Cystic Fibrosis. Chest 1981; 80: 392–398. 4. Lang DM, Butz AM, Duggan AK, Serwint JR. Physical activity in urban school-aged children with asthma. Pediatrics 2004; 113: e341–e346. 5. Selvadurai HC, Blimkie CJ, Cooper PJ, Mellis CM, Van Asperen PP. Gender differences in habitual activity in children with cystic fibrosis. Arch Dis Child 2004; 89: 928–933. 6. Schneiderman Walker J, Wilkes D, Corey M, Hay J, Lands L, Selvadurai H. Gender differences in habitual physical activity and lung function decline in children with cystic fibrosis. J Pediatrics 2005; 147: 321–326. 7. Daniels SR. The consequences of overweight and obesity. Future Child 2006; 16: 47– 67. 8. Nixon PA, Orenstein DM. Exercise testing in children. Pediatr Pulmonol 1988; 5: 107– 122. 9. Wasserman K, Hansen JE, Sue DY, Whipp BJ, Casaburi R. Principles of Exercise Testing and Interpretation. 4th Ed.. Philadelphia: Lea & Febiger, 2004. 10. Cerny FJ, Pullano TP, Cropp GJ. Cardiorespiratory adaptations to exercise in cystic fibosis. Am Rev Respir Dis 1982; 126: 217–220. 11. Levison H, Cherniack RM. Ventilatory cost of exercise in chronic obstructive pulmonary disease. J Appl Physiol 1968; 25: 21–27. 12. Godfrey S, Mearns M. Pulmonary function and response to exercise in Cystic Fibrosis. Arch Dis Child 1971; 46: 144–151. 13. Thin AG, Dodd JD, Gallagher CG et al. Effect of respiratory rate on airway deadspace ventilation during exercise in cystic fibrosis. Respir Med 2004; 98: 1063–1070. 14. Pianosi P, Wolstein R. Carbon dioxide chemosensitivity and exercise ventilation in healthy children and in children with cystic fibrosis. Pediatr Res 1996; 40: 508– 513. 15. Germann K, Orenstein DM. Pulmonary adjustments to exercise in cystic fibrosis. Med Sci Sports Exerc 1981; 13: 120–124.
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16. Coates AL, Canny G, Zimmerman R. The effects of chronic airflow limitation, increased dead space and the pattern of ventilation on gas exchange during maximal exercise in advanced cystic fibrosis. Am Rev Respir Dis 1988; 138: 1524–1531. 17. Cropp GJ, Pullano TP, Cerny FJ, Nathanson IT. Exercise tolerance and cardiorespiratory adjustments at peak work capacity in cystic fibrosis. Am Rev Respir Dis 1982; 126: 211–216. 18. Nixon P, Orenstein D, Kelsey S, Doershuk C. The prognostic value of exercise testing in patients with Cystic Fibrosis. N Engl J Med 1992; 327: 1785–1788. 19. Katsardis CV, Desmond KJ, Coates AL. Measuring the oxygen cost of breathing in normal adults and patients with Cystic Fibrosis. Respir Physiol 1986; 65: 257–266. 20. Lands LC, Heigenshauser GJ, Jones NO. Analysis of factors limiting exercise performance in cystic fibrosis. Clin Sci 1992; 83: 391–397. 21. Marcotte JE, Grisdale R, Levison H, Coates AL, Canny G. Multiple factors limit exercise capacity in cystic fibrosis. Pediatr Pulmonol 1986; 2: 274–281. 22. Rowland TW. Does peak VO2 reflect VO2max in Children?: Evidence from supramaximal testing. Med Sci Sports Exerc 1993; 25: 689–693. 23. Stein R, Selvadurai HC, Schneiderman- Walker J, Wilkes D, Corey M, Coates A. Determination of maximal voluntary ventilation in children with cystic fibrosis. Pediatr Pulomonol 2002; 35: 265–271. 24. Nixon PA, Joswiak ML, Fricker FJ. A six-minute walk test for assessing exercise tolerance in severely ill children. J Pediatr 1996; 129: 362–366. 25. Narang I, Pike S, Rosenthal M, Balfour-Lynn IM, Bush A. Three –minute step test to assess exercise capacity in children with cystic fibrosis with mild lung disease. Pediatr Pulmonol 2003; 35: 108–113 Cumming GR, Everatt D, Hastman L. Bruce treadmill in children: Nomal values in a clinic population. Am J Cardio 1978; 41: 69–75. 26. Selvadurai HC, Cooper PJ, Meyers N et al. Validation of shuttle tests in children with cystic fibrosis. Pediatr Pulmonol 2003; 35: 133–138. 28. 1362–1367. 29. Beck KC, Offord KP, Scanlon PD. Bronchoconstriction occurring during exercise in asthmatic subjects. Am J Respir Crit Care Med 1994; 149: 352–357. 30. Carlsen KH, Carlsen KCL. Exercise-induced asthma. Paediatric Respiratory Reviews 2002; 3: 154–160. 31. Rundell KW, Slee JB. Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes. J Allergy Clin Immunol 2008; 122: 238–246. 32. Beasley R, Ellwood, Asher I. International patterns of the prevalence of paediatric asthma. The ISAAC program. Pediatr Clin N Am 2003; 50: 539–553. 33. Taylor WR, Newacheck PW. Impact of childhood asthma upon health. Pediatrics 1992; 90: 657–662. 34. Fink G, Kaye C, Blau H, Spitzer SA. Assessment of exercise capacity in asthmatic children with various degrees of acivity. Pediatr Pulmonol 1993; 15: 41–43. 35. Gibson PG, Henry RL, Vimpani GV, Halliday J. Asthma knowledge, attitudes, and quality of life in adolescents. Arch Dis Child 1995; 73: 321–326. 36. Story RE. Asthma and obesity in children. Curr Opin Pediatr 2007; 19: 680–684. 37. Anderson SD, Connolly NM, Godfrey S. Comparison of bronchoconstriction induced by cycling and running. Thorax 1971; 26: 396–401. 38. Ram FSF, Robinson SM, Black PN, Picot J. Physical training for asthma. Cochrane Database of Systematic Reviews 2005; Issue 4. 39. Fanelli A, Cabral ALB, Neder JA, Martins MA, Carvalho CRF. Exercise training on disease control and quality of life in asthmatic children. Med Sci Sports Exerc 2007; 39: 1474–1480. 40. Joyner BL, Fiorino EK, Matta-Arroyo E, Needleman JP. Cardiopulmonary exercise testing in children and adolescents with asthma who report symptoms of exerciseinduced bronchoconstriction. J Asthma 2006; 43: 675–678. 41. Lex C, Dymek S, Heyin R, Kovacevic A, Kramm CM, Schuster A. Value of surrogate tests to predict exercise-induced bronchoconstriction in atopic childhood asthma. Pediatr Pulmonol 2007; 42: 225–230. 42. Fonseca-Guedes CHF, Cabral ALB, Martins MA. Exercise-induced bronchospasm in children: Comparison of FEV1 and FEF25-75% responses. Pediatr Pulmonol 2003; 36: 49–54. 43. Crapo RO, Casaburi R, Coates AL et al. Guidelines for methacholine and exercise challenge testing – 1999. Am J Respir Crit Care Med 2000; 161: 309–329. 44. Wood RE, Boat TF, Doershuk CF. Cystic Fibrosis. Am Rev Respir Dis 1976; 133: 833– 878. 45. de Jong W, Kaptein AA, van der Schans CP et al. Quality of life in patients with cystic fibrosis. Ped Pulmonol 1997; 2: 95–100. 46. Selvadurai HC, Blimkie CJ, Mellis CM, Cooper PC, Van Asperen PP. Randomised controlled study of in hospital training programs in children with cystic fibrosis. Pediatr Pulmonol 2002; 34: 278–284.
47. Schneiderman-Walker J, Pollock SL, Corey M et al. A randomised controlled trial of a 3-year exercise program in cystic fibrosis. Journal of Pediatrics 2000; 136: 304–310. 48. Moorcroft AJ, Dodd ME, Webb AK. Exercise testing and prognosis in adults with cystic fibrosis. Thorax 1997; 52: 291–293. 49. Henke KG, Orenstein DM. Oxygen saturation during exercise in cystic fibrosis. Am Rev Respir Dis 1984; 129: 708–711. 50. Boucher GP, Lands LC, Hay JA, Hornby L. Activity levels and the relationship to lung function and nutritional status in children with cystic fibrosis. Am J Phys Med Rehabil 1997; 76: 311–315. 51. de Meer K, Gulmans VA, van Der Laag J. Peripheral muscle weakness and exercise capacity in children with cystic fibrosis. Am J Respir Crit Care Med 1999; 159: 748– 754. 52. Selvadurai HC, McKay KO, Blimkie CJ et al. The relationship between genotype and exercise tolerance in children with cystic fibrosis. Am J Respir Crit Care Med 2002; 165: 762–765. 53. Nixon PA, Orenstein DM, Kelsey SF, Doershuk CF. The prognostic value of exercise testing in patients with cystic fibrosis. N Engl J Med 1992; 327: 1785–1788. 54. Pianosi P, LeBlanc J, Almudevar A. Relationship between FEV1 and peak oxygen uptake in children with cystic fibrosis. Pediatr Pulmonol 2005; 40: 324–329. 55. Pianosi P, LeBlanc J, Almudevar A. Peak oxygen uptake and mortality in children with cystic fibrosis. Thorax 2005; 60: 50–54. 56. Javadpour SM, Selvadurai H, Wilkes DL, Schneiderman-Walker J, Coates AL. Does carbon dioxide retention during exercise predict a more rapid decline in FEV1 in cystic fibrosis? Arch Dis Child 2005; 90: 792–795. 57. Tantisira KG, Systrom D, Ginns L. An elevated breathing reserve index at lactatce threshold is a predictor of mortality in patient with CF awaiting lung transplantation. Am JResp Crit Care Med 2002; 165: 1629. 58. Barker M, Hebestreit A, Gruber W, Hebestreit H. Exercise testing and training in German CF centers. Pediatr Pulmonol 2004; 37: 351–355. 59. Cox NS, Follett J, Mckay K. Modified shuttle test performance in hospitalized childreb abd adolescents with CF. J Cys Fibrosis 2006; 5: 165–170. 60. 357–368. 61. 5–7. 62. Bland RD, Coalson JJ (eds). Chronic lung disease in early infancy. : Marcel Dekker, Inc, 2000; p. 1062. 63. Bhandari A, Panitch HB. Pulmonary outcomes in bronchopulmonary dysplasia. Semin Perinatol 2006; 30: 219–226. 64. Parat S, Moriette G, Delaperche MF, Escourrou P, Denjean A, Gaultier C. Long-term pulmonary functional outcome of bronchopulmonary dysplasia and premature birth. Pediatr Pulmonol 1995; 20: 289–296. 65. Allen JL, Panitch HB. Lung function testing: chronic lung disease of infancy. Pediatr Pulmonol Suppl 2001; 23: 138–140. 66. 1793–1799. 67. Bader D, RamosAD, Lew CD, Platzker ACG, Stabile MW, Keens TG. Childhood sequelae of infant lung disease: Exercise and pulmonary function abnormalities after bronchopulmonary dysplasia. J Pediatr 1987; 110: 693–699. 68. Jacob SV, Coates AL, Lands LC et al. Exercise ability in survivors of severe bronchopulmonary dysplasia. Am J Respir Crit Care Med 1997; 155: 1925–1929. 69. Santuz P, Baraldi E, Zaramella P, Filippone M, Zacchello F. Factors limiting exercise performance in long-term survivors of bronchopulmonary dysplasia. Am J Respir Crit Care Med 1995; 152: 1284–1289. 70. Palange P, Ward SA, Carlsen KH et al. Recommendations on the use of exercise testing in clinical practice. Eur Respir J 2007; 29: 185–209. 71. Pianosi PT, Fisk M. Cardiopulmonary exercise performance in prematurely born children. Pediatr Res 2000; 47: 653–658 Global Initiative for Asthma. Global strategy for asthma management and prevention. Global Initiative for Asthma 2007.. 72. Ramsey B, Boat T, for the Consensus Group. Outcome measures for clinical trials in Cystic Fibrosis. Summary of Cystic Fibrosis Foundation Consensus Conference. J Pediatr 1994; 124: 177–193. 73. Singh-Grewal D, Schneiderman-Walker J, Selvadurai HC, Wright V, Bar-Or O, Beyene J, Cameron B, Laxer RM, Schneider R, Silverman ED, Spiegel L, Tse S, Leblanc C, Wong J, Stephens S, Feldman BM. The effects of vigorous exercise training on physical function in children with arthritis: a randomized, controlled, single-blinded trial. Arthritis & Rheumatism 2007 Oct 15; 57: 1202–1210. 74. Stephens S, Singh-Grewal D, Selvadurai HC, Bar-Or O, Beyene J, Cameron B, Leblanc CM, Schneider R, Schneiderman-Walker J, Silverman E, Spiegel L, Tse SM, Wright V, Feldman BM. Reliability of exercise testing and functional activity questionnaires in children with juvenile arthritis. Arthritis & Rheumatism 2007 Dec 15; 57: 1446–1452.
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
Mini-symposium: The Clinical Applications of Exercise Testing in Children
Exercise Testing in Children with Lung Diseases Oon Hoe Teoh 1, Daniel Trachsel 2,a, Meir Mei-Zahav 3,b, Hiran Selvadurai 1,c,* 1
Department of Respiratory Medicine, Children’s Hospital at Westmead, Sydney Pediatric Intensive Care and Pulmonology, University Children’s Hospital Basel, Postal Box, 4005 Basel, Switzerland 3 Pulmonary Institute, Schneider Children’s Medical Center of Israel, Petach Tikwa, Israel 2
A R T I C L E I N F O
S U M M A R Y
Keywords: Cardiopulmonary exercise test exercise test field test child adolescent paediatric pulmonary disease lung disease asthma exercise induced asthma exercise induced bronchoconstriction cystic fibrosis bronchopulmonary dysplasia chronic lung disease
Exercise is an important aspect of health and development in children. By placing the pulmonary system under stress, exercise testing may reveal subtle dynamic abnormalities that are not apparent on conventional static pulmonary function tests. Furthermore, exercise testing assesses the functional impact of respiratory disease on children. Exercise testing has been used in children with a variety of respiratory diseases such as exercise induced bronchoconstriction, asthma, cystic fibrosis and bronchopulmonary dysplasia to assess the severity of disease as well as response to various interventions. Furthermore, there is good evidence that exercise testing is a useful tool to help determine prognosis in patients with cystic fibrosis. In addition to the clinical utility, exercise testing is also becoming an increasingly important outcome measure in research studies. ß 2009 Published by Elsevier Ltd.
INTRODUCTION Exercise is a complex activity which requires the integrative involvement of multiple organ systems - the pulmonary, cardiovascular, haematopoietic, musculoskeletal and neuropsychological systems.1 Exercise testing is an important diagnostic tool in the assessment of the cardiorespiratory status of the child. By placing the pulmonary system under the stress of exercise, subtle functional deficits in the lung may be identified that were not apparent during conventional static pulmonary function testing. Exercise testing is a dynamic assessment of pulmonary function and its utility in detecting early functional deficits due to early lung disease is gaining popularity. Exercise testing can not only help ascertain if exercise capacity is reduced but also define the aetiology of the reduced exercise capacity.
* Corresponding author. Tel.: +61 2 9845 3395; Fax: +61 2 98453396. E-mail addresses: [email protected] (O.H. Teoh), [email protected] (D. Trachsel), [email protected] (M. Mei-Zahav), [email protected] (H. Selvadurai). a Tel.: +41 61 685 6565; Fax: +41 61 685 5004. b Tel.: +972 3 9253654; Fax: +972 3 9253308. c Tel.: +61 2 9845 3395; Fax: +61 2 98453396. 1526-0542/$ – see front matter ß 2009 Published by Elsevier Ltd. doi:10.1016/j.prrv.2009.06.004
The importance of habitual activity and exercise in both healthy children and children with chronic diseases has been well documented in the literature. A systematic review by Strong et al.3 concluded that there was good evidence for the beneficial effects of habitual activity on musculoskeletal health, cardiovascular health, lipid and lipoprotein levels, self concept and academic performance in children.2 Strong et al.3 also demonstrated evidence for the beneficial effects of habitual activity on adiposity in overweight youth, blood pressure in mildly hypertensive adolescents, and in children with anxiety and depression.2 Children with lung diseases may theoretically have impaired habitual activity because of pulmonary limitation. Unless the pulmonary disease is severe, reduced habitual activity is unlikely to be due to respiratory limitation.3 Other co-existing factors such chronic deconditioning may be significant contributors to impaired habitual activity. Exercise limitation in these children may also be self-imposed or imposed upon them by care-givers because of misperceptions of physical fragility.4 Gender differences in habitual activity have been noted in children with chronic suppurative lung diseases such as cystic fibrosis.5,6 The aetiology of these gender differences is unclear. Regardless of the cause, regular exercise improves the sense of wellbeing of children and may reduce the rate of decline in lung function in children with cystic fibrosis.6 Physical inactivity is also a risk factor for obesity,2 a
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Table 1 Indications for exercise testing
Table 2 Utility of exercise testing in children
In clinical practice, exercise testing in children may be performed for one or more of the following indications: 1) Evaluation of overall fitness level. 2) Evaluation of undiagnosed exercise limitation. 3) Evaluation of exercise tolerance in a child with underlying respiratory or cardiovascular disease e.g. asthma, congenital heart disease. 4) Detection of exercise induced bronchoconstriction. 5) Detection of exercise induced arrhythmia. 6) Assessment for response to specific treatment, exercise prescription or rehabilitation programme. 7) Evaluation before specific treatment for baseline status or suitability for treatment e.g. chemotherapy, lung transplantation. 8) Assessment post specific treatment for potential complications e.g. drug induced lung injury from chemotherapy.
Diagnostic tool as to why a child cannot exercise like their peers * Physical fitness issues/ deconditioning * Respiratory limitation * Cardiac compromise Assessing response to therapy or intervention Prognostic aid (in cystic fibrosis)
condition associated with a myriad of co-morbidities, including insulin resistance, dyslipidaemia, hypertension and sleep disordered breathing.7 Obesity and its co-morbidities can also further contribute to exercise limitation in these children. In summary, children with respiratory disease may have reduced habitual activity either due to primary respiratory limitation or secondary causes. A negative feedback loop may be created where reduced habitual activity leads to deconditioning, prompting a further reduction in exercise capacity. This will impact on the child’s general health and well being, as well as self esteem. Formal exercise tests will help to determine if the aetiology of reduced exercise capacity in children with underlying respiratory disease is due to cardio-respiratory limitation or deconditioning. ROLE OF EXERCISE TESTING IN CHILDREN WITH LUNG DISEASE While spirometry and other pulmonary function tests have traditionally been useful in the diagnosis and guidance of management for children with lung disease, these tests measure only static or resting lung function indices and do not reliably predict functional and exercise capacity.1 Exercise testing provides a more accurate functional evaluation and serves as a useful adjunct in the management of children with lung diseases. Children with lung diseases may have exercise testing for any of the indications presented in Table 1. The results of the exercise test can be used as a guide to prescribing safe and individualised exercise programs and provide confidence to the child, their caregivers, physicians and teachers that it is safe for the child to exercise despite having a lung disease.8 PHYSIOLOGICAL RESPONSES TO EXERCISE A discussion of exercise testing in children requires a basic understanding of exercise physiology. For a detailed description of exercise physiology we refer the readers to the work of Wasserman et al.9 as it is beyond the scope of this review (Tables 2–4). During exercise, patients with mild lung disease achieve optimal alveolar ventilation by increasing tidal volume.10 However, as the severity of lung disease progresses and in children with restrictive lung disease (either chest wall restriction or parenchymal disease) there is a limited ability to increase the tidal volume (VT). Subsequent increases in minute ventilation (VE) are achieved through increases in the respiratory rate. Thus, in patients with moderate to severe lung disease, the respiratory rate is increased to higher levels to compensate for the inability to increase the tidal volume.11 In spite of the increased ventilatory rate, relative alveolar hypoventilation occurs due to an increased dead space.12 Thin et al.13 suggested that in moderate to severe cystic fibrosis (CF) lung disease that dynamic hyperinflation, limitation of tidal volume increase and compensatory high respiratory rate during
Table 3 ‘‘Field tests’’ versus ‘‘laboratory tests’’ of exercise capacity in children Field test
Laboratory test
Cheap to administer Expensive equipment necessary Easy access Specific expertise required to conduct Potentially less threatening Potentially more threatening to young children to children Useful in large population studiesDifficult to perform in large research studies Limited long term validity data Valid assessment short & long term Less useful diagnostically Useful diagnostic test Cannot measure ventilation Good physiological ventilation measures parameters
Table 4 Important parameters of assessment during exercise tests in children Heart rate (HR) Oximetry Blood pressure Tidal volume (VT) Peak oxygen uptake (VO2) Oxygen pulse (VO2/HR) Minute ventilation/carbon dioxide production (VE/VCO2) Minute ventilation/maximum voluntary ventilation (VE/MVV) Exercise flow volume loops Pre/post exercise forced expiratory volume in 1 second (FEV1) Physiological dead space (VD/VT) – usually derived value
exercise could explain the wasted ventilation on dead space previously observed.13 Moreover, Pianosi and Wolstein14 demonstrated that patients with CF have a decreased ventilatory response to carbon dioxide. The reduced chemosensitivity may further accentuate the relative alveolar hypoventilation during exercise in patients with CF.15 This relative alveolar hypoventilation has been shown to result in carbon dioxide retention in studies measuring end tidal carbon dioxide during exercise.10 In addition, Coates et al. demonstrated that patients with carbon dioxide retention had worse lung function than those who did not have carbon dioxide retention.16 In most situations, reduced oxygenation is not usually the limiting factor for exercise. There is a greater likelihood of oxygen desaturation in children whose forced expiratory volume in one second (FEV1) is <50% or DLCO<60%.17 End tidal carbon dioxide levels gradually increase with the onset of exercise, plateau and then begin to decrease by maximal exercise. It has been noted that in children with significant lung disease there is no decrease in carbon dioxide (CO2) levels after the plateau. Nixon et al.18 have demonstrated that in subjects with cystic fibrosis, an end tidal CO2 > 41 mm Hg at peak exercise is associated twice the mortality at 7 years compared to those who were able to defend their carbon dioxide levels with a peak exercise CO2 of <36 mm Hg.18 Patients with CF utilise a larger proportion of their total oxygen consumption on respiratory muscles when exercising than do controls.19 Thus, there is less reserve for use by the exercising peripheral muscles and therefore exercise tolerance may be limited. Further, exercise tolerance may also be limited by way of increased carbon dioxide production by peripheral muscles contributing to the ventilatory load of the respiratory system.20 Subjects who are aerobically fit have, however, a lower ventilatory
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load and use fat as a fuel (reducing the carbon dioxide by product) as well as metabolising lactate more efficiently. Cardiac output responses during exercise have been demonstrated to be normal until there is severe lung disease.21 Stroke volume is reduced in severe airflow limitation. Coates et al. have demonstrated that the reduced stroke volume in severe airflow limitation is due to the reduced inspiratory time to total respiratory time duty cycle ratio.16 MODALITIES, MEASUREMENTS AND PROTOCOLS IN EXERCISE TESTING FOR LUNG DISEASES Exercise testing in children can be done informally as a field test or formally as a cardiopulmonary exercise test (CPET) in a laboratory on a treadmill or cycle ergometer with metabolic measurements using breath by breath exhaled gas analysis. The main advantage of the formal test is that it measures airflow, peak oxygen consumption (VO2), carbon dioxide production (VCO2), and heart rate during exercise. Together with the measured or estimated work rate (WR) applied during the exercise test, numerous variables may be computed including maximal oxygen consumption (VO2max), anaerobic threshold (AT), minute ventilation (VE) and ventilatory reserve (VR). These indices may be useful in evaluation of the cause of the child’s exercise limitation. VO2max is the best index of aerobic fitness.1 Of note in children is that the VO2max criterion of VO2 plateau in spite of increasing WR may not always be evident at maximal exercise testing, in contrast to adult subjects.22 Therefore, the term peak VO2 (VO2peak) is preferred over VO2max because of this phenomenon in children. The ventilatory threshold is an estimate of the point at which CO2 production exceeds oxygen uptake.1 This indicates the upper limit of exercise intensity that can be achieved predominantly through the aerobic metabolic pathway. In reality, both the aerobic and anaerobic pathways of energy acquisition for skeletal muscle function run concurrently. Nevertheless, the ventilatory threshold is a useful point at which comparisons can be made within as well as between subjects. In healthy children and adolescents, the ventilatory threshold normally occurs at 55% to 65% of the VO2max. Because ventilatory threshold is a submaximal measurement, it is relatively independent of effort and may be useful in cases where the measurement of VO2max is difficult.9 The dyspnoea index is the ratio of peak VE during exercise to the maximal voluntary ventilation (MVV). MVV is determined using the 12 second sprint technique. Alternatively, MVV can be extrapolated in healthy children by multiplying the forced expiratory volume in the first second (FEV1) by 35. However, while this formula can be used to estimate the measured MVV in healthy children, it does not hold true for children with abnormal lung function.23 VR gives an indication of whether ventilatory limitation causes or contributes to the exercise intolerance. In addition to the usual indices, simultaneous assessment of exercise tidal breathing flow-volume loops (extFVLs) in relation to the maximal flow-volume loop (MFVL) may be done with a formal exercise test to provide information on operating lung volumes and flows during exercise. Field tests are exercise tests that can be performed without the need for specialised exercise equipment or gas analysis. The main advantages of field tests are that they require inexpensive and portable equipment and that they are simple to perform. They are often used in the evaluation of responses to treatment or intervention, or for the diagnosis of exercise induced asthma in young children who are not able to do a formal exercise test. The measurements taken during field tests include baseline and highest pulse rate, baseline and lowest oxygen saturation, subjective and objective measures of breathlessness before and after the test, distance or steps achieved, and muscle fatigue. Field tests that have been validated in children with lung diseases
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include the 6-minute walk test (6MWT)24 and the 3-minute step test (3MST).25 A maximal field test that has been validated in children with cystic fibrosis is the modified shuttle test (MST).26 The choice of a formal or field test, treadmill or cycle ergometer, and exercise test protocol is largely dependent on the availability of equipment and expertise at the centre, the age and underlying medical condition that the child has, and the specific objectives of the test. For example, it would be more practical to utilise a field test for large population studies. However, a diagnostic study that requires an answer as to the aetiology of reduced exercise tolerance in a particular child would require a formal CPET in an accredited exercise laboratory. ASTHMA & EXERCISE INDUCED BRONCHOCONSTRICTION Exercise induced bronchoconstriction is the transient airway narrowing brought on by exercise or physical activity.28,29 In most cases, EIB reflects airway inflammation and bronchial hyperreactivity from an underlying respiratory disease such as asthma. In the presence of symptoms or known diagnosis of asthma, the term ‘‘exercise induced asthma’’ is often used interchangeably with EIB.30 However, EIB is not limited to those with asthma, and can also be present in elite athletes in the range of 10 to 50%. Current literature suggests that the prevalence of EIB is higher in the elite athlete population than in the nonathlete population; whether this is related to some degree of underlying asthma in these athletes, or to lung injury from inhalation of cold dry air, high emission pollutants and chloramine associated with the sports activity remains unclear.31 Asthma is a common chronic respiratory condition affecting children worldwide. The prevalence of asthma symptoms in the 13- to 14-year-old age group is as high as 37%, and 32% in the 6- to 7-year old age group.32 Children with asthma may have exercise limitation. Up to 30% of asthmatic children experience exercise limitation with reduced daily physical activity.33 EIB characteristically appears after the cessation of physical activity, usually resolving within 20–40 minutes. However, a late bronchoconstrictive response may occur. Besides suboptimal asthma control resulting in EIB, deconditioning or restriction by self or caregivers can also contribute to exercise limitation in children.34 In a study of urban school-aged children, those with asthma were less likely to be active compared to their peers. Among this group, those with moderate to severe asthma were more likely to be inactive. Children whose parents believed that exercise could improve asthma control were more likely to be highly active.4 Exercise limitation affects the quality of life in asthma.35 The association between asthma and obesity is inconclusive at the moment.36 In a classic dilemma of the ‘‘chicken or the egg’’, it is unclear if they independently reduce physical activity or if reduced physical activity is the common pathway that results in both asthma and obesity. This is a focus of much ongoing research.36 Exercise tests have contributed to our knowledge on the effect of asthma on exercise and its non-pharmacological management. For example, the evaluation of an asthmatic adolescent with exercise limitation despite being on adequate controller treatment should be done with a formal exercise test on a treadmill with spirometry before and after exercise and with extFVLs assessment in relation to the MFVL during the test. Free unencumbered running, more so than treadmill, has been found to be a more potent bronchoconstrictor compared to cycling.37 Difficulties in standardising test conditions and motivating children to high levels of exertion are recognised weaknesses of this type of provocation test. Some exercise test studies, have found decreased aerobic and anaerobic fitness in youths with asthma.2 The Cochrane review on physical training programs in asthma found that the training improves cardiovascular fitness but does not
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affect resting lung function in children.38 The effect of physical training on reducing EIB is less clear, but a recent randomised controlled trial by Fanelli et al.39 has found decreased severity of EIB with exercise training and improved quality of life scores.39 The most important role of exercise testing in children with asthma is in the assessment of EIB. It is often difficult for the children to differentiate between self-perceived symptoms of EIB and shortness of breath from mere deconditioning. In a study by Joyner et al.40, of 42 asthmatic children who attributed exercise symptoms to asthma despite daily controller therapy, only 24% had proven EIB on CPET.40 Exercise limitation from deconditioning, without EIB, was found in the remaining children, both obese and non-obese. As a majority of children have normal resting lung function during the asymptomatic intervals, spirometry at rest alone is often not predictive of exercise limitation in children with asthma.41,42 In most children with known asthma, exercise tests are not usually necessary; however in children with exercise limitation despite being compliant on controller treatment, exercise tests may be helpful in differentiating between deconditioning and EIB as the dominant factor. This prevents unnecessary ‘‘stepping up’’ of the inhaled corticosteroid treatment in these children and allows management to be targeted at the aetiology of the symptoms. In some cases, a normal exercise test other than decreased cardiorespiratory fitness gives the child, care-givers and teachers confidence that the child can exercise and guides the physician in exercise prescription for the child. In children with exercise symptoms without other typical symptoms of asthma, exercise tests can help to exclude EIB as a cause and direct management accordingly. In less commonly encountered cases, upper airway abnormalities masquerading as EIB, such as vocal cord dysfunction, examination of the flow-volume loop may help in differentiating the conditions as both will show a positive response in FEV1 after exercise.43 The assessment for EIB can be done with an exercise challenge test in the laboratory or as an informal field test, together with serial spirometry before and after the exercise challenge. The treadmill protocol recommended by American Thoracic Society (ATS) is 4 to 6 minutes of exercise at 80 to 90% of the maximum predicted heart rate, with a total duration of exercise of 6 to 8 minutes. The treadmill is started at a low speed and grade, progressively advanced within 2 to 3 minutes to achieve the target heart rate, and maintained for the rest of the test. For children older than 12 years of age the exercise duration is usually about 8 minutes whereas younger children may exercise typically for 6 minutes. Spirometry is performed before exercise and serially at close intervals for up to 30 minutes after exercise. The test can also be done on a cycle ergometer using a target work rate instead of heart rate, and the VE and VO2 are measured to help assess adequacy of airway stimulus and exercise intensity.43 As outlined earlier, simultaneous assessment of the extFVLs in relation to the MFVL may be done with a formal CPET if the setup in the laboratory allows this.1 In young children who are not able to perform the test on a treadmill, free range running may be considered.43 Both the ATS and European Respiratory Society recommend taking a decrease in FEV1 of 10% or more as a criterion for EIB, although some have suggested that a decrease of 15% or more is more diagnostic of EIB, particularly if the exercise is performed in the field.43 CYSTIC FIBROSIS LUNG DISEASE Cystic fibrosis is a disease affecting multiple organ systems, with the greatest morbidity and mortality arising from the respiratory component of the disease. Lung disease in CF is characterised by viscid mucous production leading to bronchiolar obstruction and infection, and progressive deterioration in pulmonary function.44
The role of exercise in maintaining lung function in children with CF has been studied in detail. Most studies are of short term duration and last less than 3 months. Training programs (e,g. swimming, cycling) have been shown to improve aerobic capacity and pulmonary function.45 However, the effect on pulmonary function was temporary, disappearing when exercise was terminated. Aerobic as well as anaerobic training has been proven to be beneficial in patients hospitalized with CF pulmonary exacerbations.46 A randomised controlled trial of a 3 year home-based aerobic exercise program in children and adolescents with mild to moderate CF lung disease by Schneiderman-Walker et al.47 showed a significant slowing of the decline in forced vital capacity (FVC), a similar but non-significant trend in FEV1, and improved the sense of well being.47 Moorcroft studied 42 adult CF patients for a year and found that a training effect could be achieved with unsupervised individualized home exercise. A benefit to pulmonary function was also observed.48 Notably, no single resting pulmonary function test index or combination of indices predicts oxygen saturation changes with exercise.49 Besides respiratory limitations, other factors like nutrition and peripheral muscle dysfunction and CF genotype may also influence exercise capacity in CF.50–52 The value of exercise testing for prognostication of survival in CF has also been documented by previous cross-sectional studies. Nixon et al.18 found in a group of children and adults with CF that those with higher VO2peak (ie VO2 82% predicted normal) more than three times more likely to survive for 8 years than those with low VO2peak,(VO2 less than 58% predicted).53 Of note, the study suggested that conventional FEV1 was not independently correlated with survival. Moorcroft et al.48 however, found in a group of adults with CF that while VO2peak correlates with survival, it was not better than FEV1 as prognostic indicator.48 More recently, Pianosi et al.54 studied the relationship between FEV1 and VO2peak in a group of children with CF over 5 years and found a high correlation between these measurements, particularly in children with FEV1 less than 80% predicted.54 Pianosi et al.54 found a significant decline in VO2peak over time at an average of 1.9 ml/ min/kg annually, commencing around the time FEV1 fell below 80% predicted, particularly in adolescent patients. When they looked at mortality rate in the same series, the first, last and rate of decline in FEV1 over time were significant predictors of mortality. Initial VO2peak was not predictive of mortality but the rate of decline and final peak VO2peak were significant predictors. Those with VO2peak less than 32 ml/min/kg in their series had a dramatic increase in mortality, while none of those with VO2peak above 45 ml/min/kg died during the period of the study.55 In a retrospective study, Javadpour et al.56 demonstrated that children with CF with similar FEV1, if found to have CO2 retention during exercise testing, had a significantly greater decline in FEV1 compared to their counterparts who did not retain CO2.56 The presence of CO2 retention during exercise may be an additional prognostic marker of disease progression in CF. The breathing reserve index at ventilatory threshold is considered a more pure index of pulmonary mechanics. This index was studied by Tantisira et al.57 in patients with CF awaiting lung transplantation. This index was found to be the best estimate of risk for mortality in these patients.57 Besides being a reflection of disease severity, exercise limitation affects the quality of life in CF.45 Despite evidence of the value of exercise testing in the management of children with CF, it may still be a tool that is under utilised. In a questionnaire survey of exercise testing and training in German CF centres, it was found that only 60% of the specialised centres which responded performed some sort of exercise testing, at an average frequency of 1 in 2.3 years for patients aged 8 and above.58 Protocols and indication criteria were often not standardised or not specified at all.58 While laboratory based CPET is of value to CF management in children, and is the
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‘‘gold standard’’ of exercise testing, it is not without disadvantages. The equipment is expensive, it requires technical expertise, and young children may not be able to perform the test. Maximal field tests like the MST have been validated in children with cystic fibrosis, and can serve as an alternative when a formal CPET cannot be performed, or as a complementary tool in CF management together with the formal CPET. The assessment of clinical response to antibiotic treatment for pulmonary exacerbations in children with CF has been reported using a ‘‘field test’.59 This is an important finding as even clinicians without access to a formal exercise laboratory may assess the response to an intervention using a simple ‘‘field test’’. Therefore, both formal and informal field exercise tests can be used in exercise prescription, and monitoring of disease progress and response to treatment. BRONCHOPULMONARY DYSPLASIA Bronchopulmonary dysplasia (BPD) was well described in 1967 in prematurely born infants with severe respiratory distress syndrome (RDS) who developed a form of chronic lung disease after receiving positive pressure mechanical ventilation and oxygen supplementation.60 With the use of antenatal steroids, surfactant replacement and gentler mechanical ventilation strategies over the past 3 decades, the ‘‘classic’’ form of BPD with markedly hyperinflated cystic radiographic appearance of the lung is now rarely seen, and has been replaced with a ‘‘new’’ BPD which is characterized by more subtle radiographic findings of bilateral, diffuse, hazy lungs and interstitial thickening and normal to increased expansion of the lung with little change over time.61 The pathophysiology of the new BPD is extreme lung prematurity with hypoalveolarization. These changes and the decreased incidence of BPD in infants with birth weight above 1000 g in which the condition was originally described have lead to the common use of the term chronic lung disease to describe the form of BPD seen in very-low-birth-weight, premature infants.62 Although BPD is uncommon now in infants of birth weight more than 1200 grams and more than 30 weeks of gestation, it is still the most common cause of chronic lung disease in infants.63 The long term studies of lung function in BPD show normalisation of lung volumes over time as somatic and lung growth occur, but persistence of small airway function abnormality.63 Parat et al.64 have reported persistence of reduced dynamic compliance in children 8 years of age with BPD and CLD.64 The general trend of the findings of numerous studies performed on school age children with a history of BPD showed lower FEV1, FVC and FEV1/FVC ratio, and higher residual volume/total lung volume (RV/TLC) ratio than children born at term, but no significant difference in total lung volume (TLC) or functional residual capacity (FRC).65 Much less data is available on BPD survivors in adulthood, but the observations in childhood seem to persist into adulthood.66 Airway hyper-reactivity was detected in 40 % of children with BPD, children who were preterm with RDS and children who were preterm without RDS, in contrast to 5% in children born full term.65 Studies on the exercise capacity of children with BPD shave demonstrated varied results. Bader et al.67 found that although the VO2peak in children with BPD was similar to healthy children who were born at term, the former were more likely to show evidence of pulmonary limitation to exercise with a fall in arterial oxygen saturation and rise in transcutaneous carbon dioxide tension.67 Parat et al.64 did not find significant difference in the VO2peak between children with BPD and those born preterm without lung disease or those born at term, but found decreased VR in children with BPD.64 Similarly, Jacob et al.68 did not find any difference in the exercise capacity between children with BPD, children born preterm with RDS but no BPD and children born at term, but found
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reduced VR in children with BPD at maximal exercise.68 Santuz et al.69 found that at rest, arterial oxygen saturation was 98% or more in all BPD children, but at peak exercise, some had a fall of 4% or more. Maximum VO2 and VE were significantly lower in BPD children with respect to the control group of children born at term.69 Also, at submaximal levels of exercise dynamic, VO2 and VE responses were significantly lower in the BPD group, with a ventilatory pattern characterized by lower tidal volumes.70 Pianosi and Fisk71 found lower VO2peak that was within normal range in children born preterm with BPD or with hyaline membrane disease only without BPD, compared to children born at term.71 These children also tend to increase their respiratory rate rather than their tidal volume during exercise compared to children born at term. They postulated that the lower VO2peak may have been due to less metabolically active muscle in these children rather than cardiorespiratory limitation. Although these studies do not report consistent findings on the exercise capacity of children with BPD, all of them did report some degree of respiratory abnormalities, including airway hyperreactivity, associated with exercise. EXERCISE TESTING AS AN OUTCOME MEASURE Exercise testing is an important tool in assessing the response to a given intervention, and as an outcome measure in clinical trials.72 The intervention may be a therapy for exercise induced asthma or weight control or treatment of arthritis.73,74 CONCLUSION Exercise testing plays an important role in children with respiratory diseases. Together with resting pulmonary function tests, exercise tests help us understand how specific respiratory diseases affect exercise capacity in children. This knowledge can be applied in the optimal management of the diseases in terms of treatment, assessment of response to treatment and prognosis. REFERENCES 1. American Thoracic Society/American College of Chest Physicians. ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003; 167: 211– 277. 2. Strong W, Malina R, Blimkie C, Daniels S, Dishman R, Gutin B et al. Evidenced based physical activity for school-age youth. J Pediatr 2005; 145: 732–737. 3. Orenstein DM, Franklin BA, Doershuk CF, Hellerstein HK, Germann KJ, Horowitz JG. Exercise conditioning and cardiopulmonary fitness in Cystic Fibrosis. Chest 1981; 80: 392–398. 4. Lang DM, Butz AM, Duggan AK, Serwint JR. Physical activity in urban school-aged children with asthma. Pediatrics 2004; 113: e341–e346. 5. Selvadurai HC, Blimkie CJ, Cooper PJ, Mellis CM, Van Asperen PP. Gender differences in habitual activity in children with cystic fibrosis. Arch Dis Child 2004; 89: 928–933. 6. Schneiderman Walker J, Wilkes D, Corey M, Hay J, Lands L, Selvadurai H. Gender differences in habitual physical activity and lung function decline in children with cystic fibrosis. J Pediatrics 2005; 147: 321–326. 7. Daniels SR. The consequences of overweight and obesity. Future Child 2006; 16: 47– 67. 8. Nixon PA, Orenstein DM. Exercise testing in children. Pediatr Pulmonol 1988; 5: 107– 122. 9. Wasserman K, Hansen JE, Sue DY, Whipp BJ, Casaburi R. Principles of Exercise Testing and Interpretation. 4th Ed.. Philadelphia: Lea & Febiger, 2004. 10. Cerny FJ, Pullano TP, Cropp GJ. Cardiorespiratory adaptations to exercise in cystic fibosis. Am Rev Respir Dis 1982; 126: 217–220. 11. Levison H, Cherniack RM. Ventilatory cost of exercise in chronic obstructive pulmonary disease. J Appl Physiol 1968; 25: 21–27. 12. Godfrey S, Mearns M. Pulmonary function and response to exercise in Cystic Fibrosis. Arch Dis Child 1971; 46: 144–151. 13. Thin AG, Dodd JD, Gallagher CG et al. Effect of respiratory rate on airway deadspace ventilation during exercise in cystic fibrosis. Respir Med 2004; 98: 1063–1070. 14. Pianosi P, Wolstein R. Carbon dioxide chemosensitivity and exercise ventilation in healthy children and in children with cystic fibrosis. Pediatr Res 1996; 40: 508– 513. 15. Germann K, Orenstein DM. Pulmonary adjustments to exercise in cystic fibrosis. Med Sci Sports Exerc 1981; 13: 120–124.
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16. Coates AL, Canny G, Zimmerman R. The effects of chronic airflow limitation, increased dead space and the pattern of ventilation on gas exchange during maximal exercise in advanced cystic fibrosis. Am Rev Respir Dis 1988; 138: 1524–1531. 17. Cropp GJ, Pullano TP, Cerny FJ, Nathanson IT. Exercise tolerance and cardiorespiratory adjustments at peak work capacity in cystic fibrosis. Am Rev Respir Dis 1982; 126: 211–216. 18. Nixon P, Orenstein D, Kelsey S, Doershuk C. The prognostic value of exercise testing in patients with Cystic Fibrosis. N Engl J Med 1992; 327: 1785–1788. 19. Katsardis CV, Desmond KJ, Coates AL. Measuring the oxygen cost of breathing in normal adults and patients with Cystic Fibrosis. Respir Physiol 1986; 65: 257–266. 20. Lands LC, Heigenshauser GJ, Jones NO. Analysis of factors limiting exercise performance in cystic fibrosis. Clin Sci 1992; 83: 391–397. 21. Marcotte JE, Grisdale R, Levison H, Coates AL, Canny G. Multiple factors limit exercise capacity in cystic fibrosis. Pediatr Pulmonol 1986; 2: 274–281. 22. Rowland TW. Does peak VO2 reflect VO2max in Children?: Evidence from supramaximal testing. Med Sci Sports Exerc 1993; 25: 689–693. 23. Stein R, Selvadurai HC, Schneiderman- Walker J, Wilkes D, Corey M, Coates A. Determination of maximal voluntary ventilation in children with cystic fibrosis. Pediatr Pulomonol 2002; 35: 265–271. 24. Nixon PA, Joswiak ML, Fricker FJ. A six-minute walk test for assessing exercise tolerance in severely ill children. J Pediatr 1996; 129: 362–366. 25. Narang I, Pike S, Rosenthal M, Balfour-Lynn IM, Bush A. Three –minute step test to assess exercise capacity in children with cystic fibrosis with mild lung disease. Pediatr Pulmonol 2003; 35: 108–113 Cumming GR, Everatt D, Hastman L. Bruce treadmill in children: Nomal values in a clinic population. Am J Cardio 1978; 41: 69–75. 26. Selvadurai HC, Cooper PJ, Meyers N et al. Validation of shuttle tests in children with cystic fibrosis. Pediatr Pulmonol 2003; 35: 133–138. 28. 1362–1367. 29. Beck KC, Offord KP, Scanlon PD. Bronchoconstriction occurring during exercise in asthmatic subjects. Am J Respir Crit Care Med 1994; 149: 352–357. 30. Carlsen KH, Carlsen KCL. Exercise-induced asthma. Paediatric Respiratory Reviews 2002; 3: 154–160. 31. Rundell KW, Slee JB. Exercise and other indirect challenges to demonstrate asthma or exercise-induced bronchoconstriction in athletes. J Allergy Clin Immunol 2008; 122: 238–246. 32. Beasley R, Ellwood, Asher I. International patterns of the prevalence of paediatric asthma. The ISAAC program. Pediatr Clin N Am 2003; 50: 539–553. 33. Taylor WR, Newacheck PW. Impact of childhood asthma upon health. Pediatrics 1992; 90: 657–662. 34. Fink G, Kaye C, Blau H, Spitzer SA. Assessment of exercise capacity in asthmatic children with various degrees of acivity. Pediatr Pulmonol 1993; 15: 41–43. 35. Gibson PG, Henry RL, Vimpani GV, Halliday J. Asthma knowledge, attitudes, and quality of life in adolescents. Arch Dis Child 1995; 73: 321–326. 36. Story RE. Asthma and obesity in children. Curr Opin Pediatr 2007; 19: 680–684. 37. Anderson SD, Connolly NM, Godfrey S. Comparison of bronchoconstriction induced by cycling and running. Thorax 1971; 26: 396–401. 38. Ram FSF, Robinson SM, Black PN, Picot J. Physical training for asthma. Cochrane Database of Systematic Reviews 2005; Issue 4. 39. Fanelli A, Cabral ALB, Neder JA, Martins MA, Carvalho CRF. Exercise training on disease control and quality of life in asthmatic children. Med Sci Sports Exerc 2007; 39: 1474–1480. 40. Joyner BL, Fiorino EK, Matta-Arroyo E, Needleman JP. Cardiopulmonary exercise testing in children and adolescents with asthma who report symptoms of exerciseinduced bronchoconstriction. J Asthma 2006; 43: 675–678. 41. Lex C, Dymek S, Heyin R, Kovacevic A, Kramm CM, Schuster A. Value of surrogate tests to predict exercise-induced bronchoconstriction in atopic childhood asthma. Pediatr Pulmonol 2007; 42: 225–230. 42. Fonseca-Guedes CHF, Cabral ALB, Martins MA. Exercise-induced bronchospasm in children: Comparison of FEV1 and FEF25-75% responses. Pediatr Pulmonol 2003; 36: 49–54. 43. Crapo RO, Casaburi R, Coates AL et al. Guidelines for methacholine and exercise challenge testing – 1999. Am J Respir Crit Care Med 2000; 161: 309–329. 44. Wood RE, Boat TF, Doershuk CF. Cystic Fibrosis. Am Rev Respir Dis 1976; 133: 833– 878. 45. de Jong W, Kaptein AA, van der Schans CP et al. Quality of life in patients with cystic fibrosis. Ped Pulmonol 1997; 2: 95–100. 46. Selvadurai HC, Blimkie CJ, Mellis CM, Cooper PC, Van Asperen PP. Randomised controlled study of in hospital training programs in children with cystic fibrosis. Pediatr Pulmonol 2002; 34: 278–284.
47. Schneiderman-Walker J, Pollock SL, Corey M et al. A randomised controlled trial of a 3-year exercise program in cystic fibrosis. Journal of Pediatrics 2000; 136: 304–310. 48. Moorcroft AJ, Dodd ME, Webb AK. Exercise testing and prognosis in adults with cystic fibrosis. Thorax 1997; 52: 291–293. 49. Henke KG, Orenstein DM. Oxygen saturation during exercise in cystic fibrosis. Am Rev Respir Dis 1984; 129: 708–711. 50. Boucher GP, Lands LC, Hay JA, Hornby L. Activity levels and the relationship to lung function and nutritional status in children with cystic fibrosis. Am J Phys Med Rehabil 1997; 76: 311–315. 51. de Meer K, Gulmans VA, van Der Laag J. Peripheral muscle weakness and exercise capacity in children with cystic fibrosis. Am J Respir Crit Care Med 1999; 159: 748– 754. 52. Selvadurai HC, McKay KO, Blimkie CJ et al. The relationship between genotype and exercise tolerance in children with cystic fibrosis. Am J Respir Crit Care Med 2002; 165: 762–765. 53. Nixon PA, Orenstein DM, Kelsey SF, Doershuk CF. The prognostic value of exercise testing in patients with cystic fibrosis. N Engl J Med 1992; 327: 1785–1788. 54. Pianosi P, LeBlanc J, Almudevar A. Relationship between FEV1 and peak oxygen uptake in children with cystic fibrosis. Pediatr Pulmonol 2005; 40: 324–329. 55. Pianosi P, LeBlanc J, Almudevar A. Peak oxygen uptake and mortality in children with cystic fibrosis. Thorax 2005; 60: 50–54. 56. Javadpour SM, Selvadurai H, Wilkes DL, Schneiderman-Walker J, Coates AL. Does carbon dioxide retention during exercise predict a more rapid decline in FEV1 in cystic fibrosis? Arch Dis Child 2005; 90: 792–795. 57. Tantisira KG, Systrom D, Ginns L. An elevated breathing reserve index at lactatce threshold is a predictor of mortality in patient with CF awaiting lung transplantation. Am JResp Crit Care Med 2002; 165: 1629. 58. Barker M, Hebestreit A, Gruber W, Hebestreit H. Exercise testing and training in German CF centers. Pediatr Pulmonol 2004; 37: 351–355. 59. Cox NS, Follett J, Mckay K. Modified shuttle test performance in hospitalized childreb abd adolescents with CF. J Cys Fibrosis 2006; 5: 165–170. 60. 357–368. 61. 5–7. 62. Bland RD, Coalson JJ (eds). Chronic lung disease in early infancy. : Marcel Dekker, Inc, 2000; p. 1062. 63. Bhandari A, Panitch HB. Pulmonary outcomes in bronchopulmonary dysplasia. Semin Perinatol 2006; 30: 219–226. 64. Parat S, Moriette G, Delaperche MF, Escourrou P, Denjean A, Gaultier C. Long-term pulmonary functional outcome of bronchopulmonary dysplasia and premature birth. Pediatr Pulmonol 1995; 20: 289–296. 65. Allen JL, Panitch HB. Lung function testing: chronic lung disease of infancy. Pediatr Pulmonol Suppl 2001; 23: 138–140. 66. 1793–1799. 67. Bader D, RamosAD, Lew CD, Platzker ACG, Stabile MW, Keens TG. Childhood sequelae of infant lung disease: Exercise and pulmonary function abnormalities after bronchopulmonary dysplasia. J Pediatr 1987; 110: 693–699. 68. Jacob SV, Coates AL, Lands LC et al. Exercise ability in survivors of severe bronchopulmonary dysplasia. Am J Respir Crit Care Med 1997; 155: 1925–1929. 69. Santuz P, Baraldi E, Zaramella P, Filippone M, Zacchello F. Factors limiting exercise performance in long-term survivors of bronchopulmonary dysplasia. Am J Respir Crit Care Med 1995; 152: 1284–1289. 70. Palange P, Ward SA, Carlsen KH et al. Recommendations on the use of exercise testing in clinical practice. Eur Respir J 2007; 29: 185–209. 71. Pianosi PT, Fisk M. Cardiopulmonary exercise performance in prematurely born children. Pediatr Res 2000; 47: 653–658 Global Initiative for Asthma. Global strategy for asthma management and prevention. Global Initiative for Asthma 2007.. 72. Ramsey B, Boat T, for the Consensus Group. Outcome measures for clinical trials in Cystic Fibrosis. Summary of Cystic Fibrosis Foundation Consensus Conference. J Pediatr 1994; 124: 177–193. 73. Singh-Grewal D, Schneiderman-Walker J, Selvadurai HC, Wright V, Bar-Or O, Beyene J, Cameron B, Laxer RM, Schneider R, Silverman ED, Spiegel L, Tse S, Leblanc C, Wong J, Stephens S, Feldman BM. The effects of vigorous exercise training on physical function in children with arthritis: a randomized, controlled, single-blinded trial. Arthritis & Rheumatism 2007 Oct 15; 57: 1202–1210. 74. Stephens S, Singh-Grewal D, Selvadurai HC, Bar-Or O, Beyene J, Cameron B, Leblanc CM, Schneider R, Schneiderman-Walker J, Silverman E, Spiegel L, Tse SM, Wright V, Feldman BM. Reliability of exercise testing and functional activity questionnaires in children with juvenile arthritis. Arthritis & Rheumatism 2007 Dec 15; 57: 1446–1452.