Exercise and cystic fibrosis

JOURNAL OF THE ROYAL SOCIETY OF MEDICINE Supplement No. 25 Volume 88 1995

Exercise and cystic fibrosisA K Webb FRCP M E Dodd MCSP J Moorcroft MRCP

J R Soc Med 1995;88(Suppl. 25):30-36 PAPER READ TO SECTION OF PAEDIATRICS, 25 OCTOBER 1994

Keywords: cystic fibrosis, exercise

INTRODUCTION

Physical exercise is recognized to have considerable clinicalbenefit for different disease processesl. Regular habitualactivity is cardioprotective and associated with a reducedmorbidity and mortality for established cardiovasculardisease2 3. Pulmonary rehabilitation programmes forpatients with chronic airways obstruction (COAD), ofwhich exercise is a core component, are beingenthusiastically researched for their potential therapeuticbenefit4. Although the short-term benefits of exercise havebeen established, whereby increased fitness improvesmorbidity and quality of lifes, there are no publishedprospective studies which report that regular exercisedecreases mortality for patients with pulmonary disease.Exercise has been studied intensively in patients with cysticfibrosis (CF), yet its value has not been established to thedegree that exercise must be adopted as an essentialcomponent of treatment. There needs to be scientificcertainty about the short- and long-term benefits of exercisebefore it is incorporated into the already demanding regimenof daily self care of CF patients.

This review considers the current knowledge and futuredirections for the role of exercise in the therapy of cysticfibrosis.

PULMONARY RESPONSES AND LIMITS TOEXERCISE IN CF PATIENTS

In health and disease, the ability to exercise is related to thecapacity of the cardiorespiratory system to deliver oxygen toworking muscles and the efficiency of those musdes toextract and utilize the oxygen. Training induces physiologicaladaptations which allow individuals to perform a level ofexercise more comfortably. Oxygen consumption (VO2) isthe most commonly used physiological measurement tomonitor the level of fitness in sickness and in healthfollowing exercise training.

It can be defined as follows:VO2max=stroke volume x heart rate x arteriovenous

oxygen differenceMaximum oxygen consumption (VO2max) is themeasurement made at an individual's peak work capacity(PWC) following a maximal exercise test. From this

equation, it is apparent that the maximal oxygenconsumption increases (improves) with training throughseveral physiological adaptations. Stroke volume can increasewith cardiac hypertrophy and chamber enlargement. Moreoxygen can be delivered to working muscles for a lowerheart rate. With training, skeletal muscle undergoesstructural and biochemical changes which permits a greaterextraction and more efficient usage of oxygen delivered bythe cardiorespiratory system.

During exercise ventilation increases from 5 1/min at restto 180 1/min in the trained athlete. This is achieved bychanges in tidal volume (VT) and breathing frequency (fb)and adjustments in the duty cycle of breathing (T,\Tt.t: theratio of inspiratory time (Ti) to total breath duration)resulting in alterations to inspiratory (VT\T,) expiratoryflow rates. During progressive exercise, tidal volume canincrease to 60% of the vital capacity; at this point the workof breathing increases disproportionately and subsequentlyminute ventilation increases by a rise in breathingfrequency6. Inspiratory and expiratory times are balancedto increase VT and allow the lungs to empty to maintain orreduce functional residual capacity. Consequently flow ismaintained to preserve alveolar ventilation. These areimportant determinants of diaphragmatic contraction andposition. Breathing patterns are adopted to minimize thesense of effort arising in the respiratory muscles in health anddisease.

Exercise in health is limited by the symptoms ofbreathlessness or muscle fatigue. These symptom limitsoccur when musde metabolism becomes oxygen depleted,enters the anaerobic phase and lactic acid accumulates. Lacticacidaemia stimulates a sharp increase in minute ventilationcausing breathlessness and oxygen deprived musdes tofatigue. The work of anaerobic exercise becomesuncomfortable and stops. Training delays the onset oflactic acid accumulation7 and increases the duration ofaerobic exercise. Normally exercise is not limited byventilation but patients with pulmonary disease (young andold) are ventilatory limited by the degree of severity of theirlung disease.

Lung disease in cystic fibrosis is initiated by mucusplugging of the small airways. Bacterial infection of themucus causes chronic inflammatory damage to thebronchioles. The early radiological changes indicatingdisease are hyperinflation and areas of atelectasis. These30

Cystic Fibrosis Unit, Wythenshawe Hospital, Southmoor Road, ManchesterM23 9LT


changes are parallelled by the earliest observed abnormalityof pulmonary function in CF; an increase in the physiologicaldead space which increases with disease severity8.Ventilation is therefore higher for a given workload andthe majority of CF patients with mild to moderate lungdisease (FEV1% predicted >60%) can exercise and trainsafely with the same intensity as their healthy peers, butsimilar levels of maximal oxygen consumption and peakwork capacity may not be achieved. In cystic fibrosis,progressive airways obstruction reduces the vital capacity,limiting the compensatory increase in tidal volume duringexercise with a resulting increase in the physiological deadspace. The pulmonary pathology which disorders therelationship between gas exchange and ventilation incystic fibrosis can be measured during exercise testing bythe changing ratio of the physiological dead space (VD) andtidal volume (VT). In health and patients with mild lungdisease, the VD/VT ratio which at rest is 25-35%, fallsduring exercise. In CF patients with severe disease this ratiois high at rest and increases with exercise due to poormatching of ventilation and perfusion and a limited tidalvolume.

During exercise minute ventilation must be maintainedto preserve the inspiratory and expiratory flow rates. Thisis achieved by two compensatory mechanisms; an increasein end-expiratory lung volume (EELV) and a decrease ininspiratory time (TI)9"10. Airways obstruction causesprolongation of expiratory flow and in association withan increased breathing frequency results in air trapping.The consequence of the air trapping is to compromiseeffective functioning of the inspiratory muscles byflattening of the diaphragm and shortening the accessoryand intercostal muscles. The compensatory mechanismexaggerates this situation. The work and oxygen cost ofbreathing are increased. It is the work of breathing athigh lung volumes rather than changes in breathingpatterns which increase the oxygen cost of breathing'1.During maximal exercise the respiratory muscles mayutilize 35-40% (normal 10-15%) of whole body oxygenconsumption'2. More respiratory work is performedduring inspiration. If the inspiratory muscles aredisadvantaged or overworked they will fatigueprematurely during progressive exercise.

As respiration during exercise becomes ventilatorylimited, breathing patterns vary in order to maintain thecontinuation of comfortable breathing'3. Coates et al. havestudied this timing component of ventilation duringprogressive exercise in CF patients with severe airflowlimitation14. In their study, the inspiratory time of somepatients was reduced with an associated reduction in tidalvolume. Although there was an increase in carbon dioxidethis only occurred during the initial stages of exercise and didnot imply the onset of respiratory failure. The adoption of

this comfortable breathing pattern has also been described inolder patients with chronic airflow limitation15'16.

The duty cycle of breathing (Tj/Ttot) should also berelated to the mouth pressure (Pm) required to sustaininspiratory flow. This can be expressed as the ratio of theinspiratory pressure for a given breath to maximalinspiratory pressure (MIP) reflecting the relative forcerequired for inspiration. It follows if tidal volume is reducedby shortening the inspiratory time, the required pressuregenerated at the mouth (Pm) to sustain inspiration islessened and consequently the oxygen cost of breathing.Altering breathing patterns in this manner may forestallmuscle fatigue and permit more comfortable breathing'5.

An increased alveolar-arterial oxygen gradient is one ofthe early pathological changes to occur in cystic fibrosis17.An increase in ventilation-perfusion mismatch parallelsdisease severity and can result in oxygen desaturationduring exercise. Although arterial oxygen desaturationoccurs with severe disease during exercise (FEV, <35%predicted18, resting oxygen saturation is a less predictablefactor of oxygen desaturation during exercise for themajority of patients'9. In patients with severe disease' anincrease or no change in oxygen saturation were morecommon than a decrease during exercise.

Pulmonary disease is the main contributing factor toexercise limitation in cystic fibrosis but poor nutritionalstatus is also considered to be an independent contributoryfactor20. Although muscle strength has been reported asnormal in CF patients21'22, decreased muscle mass in thelegs can reduce aerobic exercise performance on a cycleergometer23 suggesting that adequate nutrition may improvemuscle mass and exercise performance. A recent study ofdiaphragmatic power in CF patients showed that strengthdecreased with disease severity and hyperinflation butmalnutrition was the strongest indicator of diaphragmaticweakness24. No studies have been performed as to whetherexercise training will delay respiratory muscle fatigue.

Although attention has focused on the progression oflung disease causing pulmonary hypertension, two-dimensional echocardiography has demonstrated anenlarged right ventricle compressing the left ventricle25.The result is a decreased left ventricular filling and adiminished stroke volume at rest which is exaggerated byexercise.

RECOGNIZED BENEFITS OF EXERCISE TRAININGIN CYSTIC FIBROSIS

The ability to sustain exercise comfortably is defined asfitness and the purpose of training is to increase the length oftime during which comfortable exercise can be undertaken(endurance). It is with this intention that extensive researchhas been undertaken to assess the value of training and 31

JOURNAL OF THE ROYAL SOCIETY OF MEDICINE

exercise in CF patients. Although considerable usefulinformation has resulted and been put into practice fromthese studies many questions remain. There is no publishedevidence in pulmonary disease as to whether long-termexercise influences mortality. More specifically, what is themost appropriate form of exercise and will patients remainsufficiently motivated to include it in their daily self care?Before considering the future directions which exerciseprogrammes should assess, it is appropriate to evaluatecurrent knowledge.

Two early studies reviewed the cardiorespiratoryadjustments that take place during progressive exercise inCF patients with a spectrum of disease severity26'27. Patientswith mild to moderate disease could exercise almost to thesame level as controls in terms of peak minute ventilation,peak work rate and oxygen consumption, but patients withsevere disease had a reduced work capacity, an exercise-induced arterial oxygen desaturation and an increase in endtidal carbon dioxide. Over the last decade, severalsupervised studies of general exercise training (running orcycling) have confirmed that CF patients with a range ofdisease severity can improve their exercise tolerance2-32.Specific features highlighted in these studies were an increasein respiratory muscle endurance28, overall endurance32, areduction in residual volume29, an increase in sputumexpectoration associated with exercise training30 andmaintenance of pulmonary function31.

The purpose of supervised training is to transfer thisactivity from the hospital to home. Two short studies havereported mixed results in successfully achieving this goal.Although an early study reported a decline in compliancewith home exercise33, a later study demonstrated animprovement in the activities of daily living throughincreased fitness34. One study has recorded a reduction inbreathlessness following training which was independent ofventilation but associated with a reduction in residualvolume as the only change in static lung function35.

Athletes adopt specific training programmes to acquirefitness for their chosen discipline. The five elements offitness consist of strength, endurance, flexibility, speed andskill. For respiratory disease, the most important componentof fitness is to improve endurance. The ability to sustaincomfortable exercise is more practically related to fulfillingthe activities of daily living and therefore the quality of life.In a similar manner, flexibility and speed can be equated toincreasing the mobility of the breathless unfit patient. Therole of training muscles purely for strength in CF patients isunclear.

Training studies for CF patients initially evaluatedgeneral exercise programmes, but similar to athletes whoseek to achieve fitness for a specific sport, research hasscrutinized specific training of (i) the upper body musclesand (ii) the inspiratory muscles. The upper body muscles and

arms are used for many activities of daily living. Patientswith airflow obstruction may develop severe breathlessnessand dyssynchronous movements of abdomen and chest wallwhen using their upper limbs but can perform more exercisewhen using only their lower limbs36. The majority of studiesof upper and lower limb training have been undertaken inpatients with chronic airflow limitation37-40. The overallresults demonstrated that improvement was specific to thosemuscles undergoing training with no associatedimprovement in respiratory muscle strength or endurance.Conversely, if only upper extremity exercise wasundertaken there was no increase in general exercisetolerance although breathlessness and fatigue decreased38.

The only published weight training study in CF patientsresulted in an increase in muscle strength, size and gain inbody weight41. As in other studies with different exercisetraining programmes there was a reduction in residualvolume which was attributed to increased elasticity andmobility of the chest wall.

The inspiratory muscles sustain the workload ofbreathing and fatigue when breathing becomes anaerobic.In the early 1960s, it was suggested that breathlessness as arespiratory sensation was related to 'lengh-tensioninappropriateness' of the respiratory muscles42. A recentstudy has shown that breathlessness may be correlated withinspiratory flow in exercising patients with airflowobstruction43. The perception that mechanicallydisadvantaged respiratory musdes may fatigue prematurelyas breathing becomes more loaded with severe disease andexercise, has resulted in specific training of these muscles.Early studies of specific inspiratory muscle training in CFpatients using normocapnic hyperpnoea or inspiratoryresistances, demonstrated an improvement in respiratorymuscle strength and endurance44'45. There was noimprovement in general exercise capacity and evaluation ofdelay in muscle fatigue was inconclusive. The patients alsofound breathing through inspiratory resistances tedious. Amore recent study evaluated inspiratory musde training inyoung children46. The study group showed an improvementin inspiratory musde strengt, pulmonary function andexercise tolerance. The increased exercise tolerance has notbeen observed in previous studies and was related to thelength of the study and the increase in total lung capacity.However, Lands et al. also found that the strength ofinspiratory muscles of CF patients was preserved and fatiguepatterns were normal. They questioned the value of trainingthese muscles further47. As noted, some CF patients withsevere disease who retain CO2 during exercise alter theirbreathing into a more comfortable pattern as acompensatory mechanism to the increased work ofbreathing but do not develop muscle fatigue14. Chronichypercapnia appears to be associated with better survival inCOAD: a distinction is necessary between permissive32

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Table 1 Some questions for the future directions of cystic fibrosis

Does exercise reduce mortality?

Does the intensity of exercise matter for respiratory and skeletalmuscles?

Does the type of training matter?

Does exercise induced oxygen desaturation matter?

Do the components of ventilation change with training?Can breathing patterns be changed to relieve dysponea?

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Figure 1 Cardiorespiratory fitness for males and femalesaftending the Manchester adult CF unit. V02 max% predictedmean (SE). Reproduced with the permission of Chapman Hall

hypercapnia and progressive hypercapnia leading torespiratory failure48.

FUTURE DIRECTIONS OF EXERCISE INCYSTIC FIBROSIS

Considerable knowledge has been acquired from (i) thestudy of the cardiorespiratory responses to exercise in CFpatients and (ii) the benefit from short-term exercise studies.This information has provided the basis for the prescriptionof safe and effective training programmes. However, manyquestions regarding the value of exercise in pulmonaryrehabilitation remain unanswered (Table 1). The mostpertinent question is whether regular exercise will improvesurvival in CF patients? It has been shown that higher levelsof aerobic fitness in CF patients is associated with asignificantly decreased risk of dying49'50. However, noinformation was available from these studies about the

Figure 2 The relationship between oxygen consumption andspirometry for males and females. There Is a wide scatter foroxygen consumption for patients with mild lung disease reflectinga range of fitness levels. For those patients with severe lungdisease oxygen consumption is less and approximates tightly withthe regression line. Reproduced with the permission of ChapmanHall

habitual exercise of the fitter patients and whether they wereself-selected by virtue of less severe disease. In our unit98 unselected CF adults (56 M and 39 F) had their fitnessassessed with a maximal exercise test (Figure 1). Levelsof fitness as reflected by their habitual activity showed a largevariation in patients with mild-moderate disease(Figure 2)s1.

There is no evidence that exercise improves lungfunction in terms of spirometry but if exercise preservedor delayed decline in pulmonary function this would besufficient to improve survival. Wegener et al. showed thatexercise capacity corresponded better with clinical ratings ofdyspnoea and quality of life than lung function52. Severity oflung disease can be used as a predictor of mortality ; patientswith an FEVy of <30% predicted have a 50%/c chance ofdying within two years53. In association with infectiveexacerbations there may be a decline in FEV, ofapproximately 112ml/yr54. Those exercise studies whichhave shown either a reduction in residual volume29,35S41 oran increase in sputum dearance30S55 with training provide acollective due as to how exercise may preserve pulmonaryfunction. Exercise improves sputum dearance whichmaintains collateral ventilation by preventing air trappingand the physiological dead space is minimized. As aconsequence, the pathophysiological compensatory changesassociated with disease progression, described in the firstsection, are delayed. The adoption of breathing patternswhich are ultimately disadvantageous to the workingcapacity of the respiratory musdes are forestalled.Currently there are no published prospective long-termstudies showing that regular exercise decreases mortality incystic fibrosis.

If the premise is accepted that exercise is essentialtherapy, how should exercise be prescribed. In order toacquire fitness, the principles of training dictate exerciseshould comprise a defined frequency, duration andintensity56. Cessation of exercise results in a rapid loss of 33

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all the benefits acquired from training57. The progess offitness training can be monitored by repeat measurements ofventilation and oxygen consumption for a given work rate.Measuring blood lactate levels during exercise of differentintensity provides another objective measurement of theprogress of training58. It is apparent that if exercise has long-term benefits, it should commence during childhood andcontinue through adulthood. At school participation in sportis usually compulsory but during adulthood this activitydeclines due to other demands on lifestyle. Encouragementshould be given to return to a habitual activity of choice. Thepatient may ask for advice. From the present evidence, theaim of exercise training should be for endurance rather thanstrength as this equates better to daily living activities. Thereshould be a general component such as running or cyclingand a specific component such as upper body training withweights. How much daily exercise can be achieved willdepend upon the motivation and compliance of the individualpatient59.

It is essential that exercise should be recommended forall CF patients. No patient should be excluded fromparticipating in exercise because of disease severity. Theseverity of lung disease can be defined by a graded exercisetest. On the basis of this assessment carefully tailoredtraining programmes can be provided for all patients.Patients with mild to moderate disease can safely beprescribed levels of exercise similar to healthy controlsalthough the maximum work rate and oxygen consumptionachieved may be less26,27. The objective in patients withmild to moderate disease is to institute and maintain exercisethrough childhood and adult life and prevent progression ofpulmonary disease.

The goals of exercise for patients with severe disease maybe different. As their lungs deteriorate they becomeincreasingly breathless, immobilized and quality of lifedeclines. The sensation of breathlessness is modulated bymultiple factors but during exercise, thresholds of dyspnoeamay be specifically related to the ventilatory patterns ofbreathing; tidal peak inspiratory flow and breathingfrequency. Flow is identified as the most relevantcomponent of the relationship between ventilation todyspnoea43. If breathlessness can be diminished byencouraging exercise then quality of life can be improved.

Several approaches can be adopted to training thebreathless patient. It has been shown that by reducing theintensity of exercise but increasing the duration, themuscular effort of breathing and associated dyspnoea arereduced to less than a third60. However, if the training isdirected specifically at the inspiratory musdes in COADpatients, dyspnoea is reduced and power increased but thepattern of breathing is altered to cope better with anincreasing load (exercise or infection) so forestalling musdiefatigue61 .

The oxygen cost of the respiratory musdes is high for CFpatients with severe disease. Supplemental oxygen has beenshown to lower the cost of ventilation in CF patients byminimizing oxygen desaturation62 and enabling a longerduration of exercise63. The provision of oxygen will increasepatient mobility. For those patients awaiting transplantationthe ability to increase mobility will make them fitter for therigours of surgery. Another mechanism for alleviating therespiratory work of breathing during exercise is theapplication of continuous positive airway pressure(CPAP)64. The benefits of CPAP were specific to CFpatients with severe disease and resulted in a reduced oxygenconsumption, dyspnoea and transdiaphragmatic pressurewith an increase in exercise tolerance.

CONCLUSION

The continuing vigorous research into exercise demonstrateshow many questions both physiological and medical stillneed evaluating. Short-term trials over the last decade haveclearly established that fitness through training can beachieved for motivated patients with all levels of diseaseseverity. Care must be taken that by adding anotherdiscipline to the treatment of CF patients the burden doesnot become too onerous and create resentment. Althoughthe object of a novel treatment for cystic fibrosis is toincrease survival, it is equally important to improvemorbidity for a disease where median survival is only intothe third decade of life. The quality of well being scale(QWB) has been previously validated65 and usedsubsequently to measure the quality of life in CF patientsaccording to mobility, physical activity and social activity66.Although the QWB scale correlated significantly withpulmonary function and exercise tolerance it alsoincorporated other non-pulmonary dimensions just asimportant to the quality of life of CF patients. It isimportant to understand that quality of life may not dependupon increasing functional activity. Some patients choosedeliberately not to participate in physical activity and aretotally content.

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Exercise and cystic fibrosis

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