Ventilatory and Metabolic Changes as a Result of Exercise Training in COPD Patients

Ventilatory and Metabolic Changes as a Result of Exercise Training in COPO Patients· Antonio lbtessio, M.D.; Mauro Carone, M.D.; Francesco loli, M.D.; and Claudio Ferdinando Donner; M.D., F.C.C.R

Patients with COPD feel better and are able to sustain a given level of activity longer after a program of exercise training, but the underlying physiologic mechanisms have not been completely elucidated. Since the physical performance of patients with COPD is limited mainly by pathophysiologic derangements of the ventilatory system, the exercise performance can be ameliorated by increasing the level of ventilation that they can sustain or by reducing the ventilatory requirement for a given level of activity. Almost all studies have yielded negative results in patients with COPD in terms of exercise training having the ability to improve VEmu. The only way to reduce the ventilatory requirement is to reduce COl output. Lower levels oflactate result in less nonmetabolic COl produced by bicarbonate buffering and this is the likely mechanism responsible for a lower ventilatory requirement for work rates above the pretraining anaerobic threshold. We speci6cal1y wished to determine whether a program of intensity, frequency, and duration known capable of producing a physiologic training effect in healthy subjects would do so in patients with COPD. Further, we sought to determine whether exercise training at a work rate associated with lactic acidosis is more effective in inducing a training effect in patients with COPD than a work rate not associated with lactic acidosis. Nineteen patients with COPD were selected and performed an incremental test as well as 2 square wave tests at a low and a high work rate. Identical tests were performed after an 8-week program of cycle ergometer training either for 45 minlday at a high work rate or for a proportionally longer time at a low work rate. For the high work rate training group, identical work rates engendered less lactate (4.5 vs 7.2 mEqlL) and less VE (48 vs 55 Vmin) after training; the low work rate training group had significantly less lactate and VE decrease (p
*From the Division of Pulmonary Disease, Clinica del Lavoro Foundation, Medical Center of Rehabilitation, Veruno, Italy. Reprint requests: Dr. lbtessio, Divisione di Pneumologia, Centro Medico di Riabilitazione, Fondazione Clinica del Laooro, \eruno (Novara), Italy 28010 2748

evident that psychologic factors such as desensitization to dyspnea and gain of confidence play a role in improving exercise tolerance, the underlying physiologic mechanisms have not been completely elucidated. In normal subjects, endurance training increases the capacity for aerobic work by increasing capillary density, the number of mitochondria, the concentration ofthe oxidative enzymes, and the glycogen stores 1•2 specifically in the muscle groups participating in the training exercise. As a result, the oxygen uptake at which lactic acid begins to accumulate in the blood (the anaerobic threshold) can increase by 25% to 40% and the maximal oxygen uptake (V02max) by 5% to 20%. These changes would be advantageous in the patient with COPD whose physical performance is generally limited at inappropriately low work rates mainly by pathophysiologic derangements of the ventilatory system. 3 .f Increased airway resistance and reduced elastic recoil of the lung (expiratory flow during heavy exercise often impinges on the flowvolume loop recorded during a resting forced vital capacity maneuve~·6) limit the ventilatory capacity. Dynamic hyperinflation (ie, the increase in end expiratory volume over passive functional residual capacity) leads to a lower than expected ventilation for the same inspiratory activity and respiratory frequenc~ The higher the respiratory frequency, the higher the dynamic hyperinflation, which results in progressive truncation of the tidal volume and a marked impairment in the ability of the expiratory muscles to increase ventilation. 7 Because ofdynamic hyperinflation, the breathing strategy is very energetically expensive and the oxygen consumption of the respiratory muscle increases, 8 often to 35% to 40% of the whole body V02 at maximal exercise (vs 10% to 15% in healthy subjects), reducing the oxygen available for the exercising muscles. Ventilationperfusion inequality causes an increase in dead space to tidal volume ratio, which leads to a high ventilatory requirement. 9 •10 More ventilation is therefore necessary to maintain arterial blood gas and pH homeostasis. 11 Within this framework, 2 strategies can be identi6ed to increase the exercise performance of these patients: (1) increasing the level of ventilation that they can sustain, and (2) reducing the ventilatory requirement for a given level of activit~

We will examine previous reports that have used one or the other of these strategies and then discuss the results of a recent study from our laboratory. EFFECfS ON VENTILATORY CAPACITY

There are 2 theoretical possibilities to increase the ventilatory capacity: (1) changing resting lung mechanics, although it has been demonstrated that exercise training is not effective in this regard 12. 13; and (2) strengthening the muscles of respiration, which might allow the patient with Ventilatory and MetaboItc Changes after Exercise Training (Patessio et aI)

COPD to sustain a higher level ofventilation during exercise. In normal subjects14 and patients with cystic fibrosis, 15 exercise training has been shown to strengthen the respiratory muscles. On the contrary, almost all studies have yielded negative results in patients with COPD, both'in terms of exercise training baving the ability to improve the performance of respiratory muscles and to improve VEmax. 16-1O Only Christiel1 observed statistically significant increase in VEmax after physical training, but the change was very small (3.46 Umin). On the other hand, training the respiratory muscle through resistive breathing or hyperpnea can improve their strength and endurance. However, contradictory results have been obtained in improving exercise performance, which may be in part attributed to methodologic differences. Belman and Mittman, II Sonne and Davis, 23 and Hies and Moser'f were able to induce an increase in VEmax with a corresponding increase in exercise capacity by specifically training the respiratory muscles. The difference between specific training and whole body training may be attributed to the different intensity ofwork attained by the respiratory muscles. Noseda et al,15 Jones et al,· and Madsen et al27 concluded that exercise performance is not improved by respiratory muscle training. Pardy et al18 found an increased exercise tolerance only in 7 of 12 patients. It is very interesting to note that 6 of the 7 patients who improved showed electromyographic signs of inspiratory muscle fatigue during the pretraining exercise test. 18 Thus, it can be supposed that only patients whose exercise performance is limited by respiratory muscle fatigue can improve: the important question to be answered is whether respiratory muscle fatigue is the major limiting factor ofexercise capacity in an individual patient. VENTILATORY REQUIREMENT

The ventilatory requiremeItt for a given level of exercise is dictated by the following equation, which is an expression of the alveolar mass balance for CO2 : VE = K x Veo/paC02 x (1- VOIVT) where VE is the expired minute ventilation, Ve02 is the rate of carbon dioxide output, PaC02 is the arterial CO2 partial pressure, VolVT is a measure of inefficiency of pulmonary COl exchange, and k is 'a constant. Since exercise training does not improve the gas exchange efficiency of the lungs as indicated by a lack of change in arterial blood gaseS--3D or in alveo~arterial O 2 difference,29 the only way to reduce the ventilatory requirement is to reduce COl output. It has been demonstrated in normal subjects:U -33 that, after exercise training, the fall in ventilation is well-correlated with the fall in blood lactate level. Lower levels of lactate result in less nonmetabolic CO2 produced by bicarbonate buffering and this is the likely mechanism responsible for' a lower ventilatory requirement for work rates above the pretraining anaerobic threshold. A review of the literature reveals very poor effects of exercise training in decreasing the ventilatory requirement in patients with COPD. Vyas et al34 found a significant, but very small decrease in Ve (averaging 1.5 Umin) in 10 patients with COPD trained on average for 10 weeks, but no change in Vco. and heart rate. Alpert et al35 and Pierce et aP showed a decrease in VE and heart rate, but also in

VOl' which is more a result of an improved technique of performance of the exercise task, rather than a true physiologic training effect. A decrease in VE and respiratory frequenc~ but not in heart rate, was demonstrated by Alison et al,17 but the change in VOl was not mentioned. A small decrease in lactate for the same work rate was found by Mohsenifar et al,1O but the decrease was so small it is not surprising that no influence was observed on ventilation. These small effects might be explained by 2 factors: (1) the relatively small amount of work performed by these patients in comparison to programs that have been shown to be effective in normal subjects: a duration of 4 to 8 weeks, involving exercise for 30 to 45 min/day, 3 to 5 times per week, at a minimum intensity of roughly 60% of maximum heart rate or 50% ofVosmax; patients with COPD are likely to require training work rates that are a higher fraction of their maximum heart rate or maximum oxygen uptake to achieve a physiologic training effect; and (2) the fact that Qlany patients with COPD are so ventilatory limited that they cannot attain levels of work high enough to induce the onset of anaerobic metabolism. However, the latter factor has been challenged recently: a substantial portion of this patient population was able to develop lactic acidosis during exercise. In 1969, Shuey et al37 demonstrated that patients with COPD with a mean FEVI of 1.2 L reached higher values of lactate than normal subjects for the same VOl levels. Holle et al38 found a drop in bicarbonate greater than 5 mEq/L in 41 % of 68 patients with COPD (mean FEVI = 33% of predicted). Sue et al38 demonstrated a mean decrease in standard bicarbonate of 4.7 mEq/L in 14 of 22 patients (mean FEVI =1.2 L) and that the ability to sustain a metabolic acidosis is not related to the severity of the lung disease, judged by resting spirometric measurements. This is likely because the early onset of anaerobic metabolism is somewhat related to the presence of pulmonary vascular abnormalities that limit the oxygen supply to the exercising muscle than the reduction in lung volumes. PHYSIOLOGIC ApPROACH TO TRAINING

COPD PATIENTS We conducted a study to specifically apply the physiologic principles of exercise training to patients with COPD (for full details of this study see Casaburi et al40). We specifically wished to determine whether a program of intensi~ frequen~ and duration known capable of producing a physiologic training effect in healthy subjects would do so in patients with COPD. Further, we wished to determine whether exercise training at a work rate associated with lactic acidosis is more effective in inducing a training effect in COPD patients than a work rate not associated wi~ lactic acidosis. MATERIALS AND METHODS

Nineteen patients were selected on the basis of the following: (I) clinical history consistent with COPD; (2) evidence of airway obstruction (FEV.<8O% predicted with a reduced FEV/FVC); and (3) ability to elevate blood lactate >3 mEqIL at the end of an incremental exercise test. Exercise testing was preceded by percutaneous placement of a radial artery catheter. Exercise testing was performed on a cycle ergometer. Minute ventilation (VE), oxygen uptake (VoJ, and carbon dioxide output (Vco,J were measured every 30 s. Heart rate was CHEST I 101 151 MA'f, 1992 I Supplement

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measured from the electrocardiogram. Arterial blood pressure was measured by sphygmomanometer. Blood samples were taken every 1 to 2 min to measure blood lactate, pH, PaOlh and PaC02 • An incremental test with an increase in work rate of 10 WImin was first performed and from the VoI - Veo2 relationship, the anaerobic threshold (AT) was determined. 4 • After 90 min of rest, a square wave test was carried out at a work rate of 90% of the AT work rate. After another 60 min, a second square wave test was perfonned at a work rate of 60% of the difference between AT and maximal work rate. After a program of exercise training, a series of tests identical to the pretraining assessments was carried out. The training program consisted ofdaily sessions ofcycling, 5 days a week for 8 weeks. The patients were randomly allocated to 1 of2 groups. Group A (11 patients) perfonned 45 min of daily exercise at the high work rate chosen in the preliminary test, whereas group 8 (8 patients) was trained at the low work rate for a total amount of work calculated according the following fonnula: 45 min X high work ratellow work rate. RESULTS

There were no significant differences in age (49± 11 years and 54 ± 8 years; mean ± SD), FEV! (56% ± 14% and 56 ± 12% of predicted), resting Pa02 (84 ± 9 mm Hg and 81 ± 11 mm Hg), and resting PaC02 (41 ±5 mm Hg and 39 ± 4 mm Hg) between the 2 groups. In group A, lactate threshold increased by 24% (p
2785

FIGURE 1. Changes in blood lactate, ventilation, O. uptake, CO. output, ventilatory equivalent for 0., and heart rate after training at a high work rate (left panel; 11 patients) and low work Tate (right panel; 8 patients). Percent change is calculated £rom the average change in response at the time the pretraining study ended. Vertical lines represent 1 SEM (from Casaburi et aI,40 with pe~~sion).

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The major findings of this study are that patients with COPD who experience lactic acidosis during exercise c~ achieve physiologic training responses from a program of endurance training and that training work rates engendering high levels of blood lactate are more effective than wor~ rates eliciting low lac~te levels. The major physiologic benefit is the fall in the ventilatory requirement for a given level of exercise, likely D}ediated through the reduction in blood lactate levels. Previous s~dies demonstrating reductions in the ventilatory requirement have shown also substantial decrease in oxygen uptake, likely reflecting a learning effect in the efficiency ofperformance. Our patients were trained and performed the tests on a cycle ergometer. Cycling is les~ prone to learning effects than Qther modes of exercise and the observation that the ~up B had a smaller response, despite the same p~tice Ventilatory and Metabolic Changes after Exercise li'aining (PaIes8Io et aJ)

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considered ventilatory limited. Omitting the data of these patients, the statistical comparisons between the groups did not change. It is certainly true that patients with COPD do not fonn a homogeneous population. The degree of IUDg function impairment interacts with factors such as duration of illness, cardiac function, and bronchoreactivity to determine the potential to achieve a physiologic training response. It seems that the degree of airway obstruction is only one of the criteria for selecting patients suitable for exercise training. This study suggests that the ability to develop lactic acidosis during exercise could be a selection criterion. In fact, we found that the greater the lactic acidosis, the greater was the physiologic training effect. These changes were associated with a substantial increase in tolerance for heavy exercise.

REFERENCES

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FIGURE 2. Relation between the % of predicted FEV. with lactate panel) and the arterial lactate level at the highest tolerated work rate (bottom ,.nel). Neither correlation is significant: r = 0.39 and 0.26, reSpectivel}'. Open triangles = patients in the low work rate training group; closed triangles = patients in the high work rate training group (from Casaburi et al,4O with permission). threshol~ (tOp

as group A, is consistent with a training effect rather than a learning phenomenon. Our patients had a range of lung function impairment, ranging from severe to mild. It may be objected that some of these patients were not ventilatory limited, but resting spirometric measurements and maximal voluntary ventilation maneuvers are not completely satisfactory in defining whether an individual patient is ventilatory limited. 4t Adopting a criterion suggested by Zavala43 (breathing reserve below 30%), only 6 of our patients could not be

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'if Decrease (L/min)

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Lactate Decrease (mEq I L)

FIGURE 3. Relation between the decrease in blood lactate and the decrease in ventiiation in response to identical exercise tasks as a result of a program of exercise training in patients with COPD. Closed triangles = high work rate training group; open triangles=low work rate training group; r=0.73; p
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Ventilatory and Metabole Changes after exercise TraInklg (PafeeaIo at aI)