Cystic fibrosis (CF) is the most common lifeshortening

Size: px

Start display at page:

Download "Cystic fibrosis (CF) is the most common lifeshortening"

Edwina Singleton
6 years ago
Views:

1 Prolonged Oxygen Kinetics During Early Recovery From Maximal Exercise in Adult Patients With Cystic Fibrosis* Eleni Pouliou, MD; Serafim Nanas, MD; Antonios Papamichalopoulos, MD; Theodoros Kyprianou, MD; Georgia Perpati, MD; Irini Mavrou, MD; and Charis Roussos, MD, MSc, PhD Study objectives: To explore the significance of oxygen kinetics during early recovery after maximal cardiopulmonary exercise testing (CPET) in the assessment of functional capacity and severity of the disease in cystic fibrosis (CF) patients. Participants: Eighteen patients with CF (9 male/9 female; mean SD age, years) and 11 healthy subjects (3 male/8 female; mean age, 29 4 years) underwent maximum CPET on a treadmill. Breath-by-breath analysis was used for measuring oxygen consumption (V O2 ), carbon dioxide production, and ventilation. Maximum V O2 (V O2 peak) and the first-degree slope of V O2 decline during early recovery (V O2 /t-slope) were calculated. To assess the severity of the disease, we used standard indexes like FEV 1 (% predicted), V O2 peak, and a widely accepted system of clinical evaluation, the Schwachman score (SS). Results: V O2 /t-slope was significantly lower in CF patients compared to healthy subjects ( L/min/min vs L/min/min; p < 0.01) and was closely correlated to FEV 1 (r 0.90, p < 0.001), V O2 peak (r 0.81, p < 0.001), and the SS (r 0.81, p < 0.001). The multivariate analysis showed that the only independent predictor of the SS is the V O2 /t-slope. Conclusion: We conclude that in CF patients, the prolonged oxygen kinetics during early recovery from maximal exercise is related to the disease severity. (CHEST 2001; 119: ) Key words: cystic fibrosis; exercise; recovery; Schwachman score Abbreviations: ATP adenosine triphosphate; CF cystic fibrosis; CFTR cystic fibrosis transmembrane conductance regulator; CPET cardiopulmonary exercise testing; SS Schwachman score; V co 2 carbon dioxide production; V e minute ventilation; V o 2 oxygen consumption; V o 2 peak maximum oxygen consumption; V o 2 /tslope first degree slope of oxygen consumption decline during early recovery Cystic fibrosis (CF) is the most common lifeshortening genetic disease among the white population. It is caused by mutations in a single gene on the long arm of chromosome 7, which encodes a protein, the cystic fibrosis transmembrane conductance regulator (CFTR). The CFTR functions as a chloride channel regulated by cyclic adenosine monophosphate-dependent protein kinase phosphorylation that requires binding of adenosine triphosphate (ATP) for channel opening. 1 Mutations in the CFTR cause abnormal chloride concentration *From the Adult Cystic Fibrosis Outpatient Clinic (Drs. Pouliou, Papamichalopoulos, and Perpati), Athens Chest Hospital; Department of Pulmonary and Critical Care Medicine (Drs. Nanas, Kyprianou, Mavrou, and Roussos), National and Kapodestrian University, Athens, Greece. Manuscript received March 22, 2000; revision accepted November 28, Correspondence to: Eleni Pouliou, MD, Pulmonary and Critical Care Medicine, National and Kapodestrian University, Evgenidio Hospital, Papadiamantopoulou 20, Athens, Greece; snanas@cc.uoa.gr across the apical membrane of epithelial cells, especially in the airways and pancreas, resulting in progressive lung disease and malnutrition. 2 FEV 1, 3 maximum oxygen consumption (V o 2 peak) during cardiopulmonary exercise testing (CPET), 4 and the Schwachman score (SS) 5 are commonly used to assess functional capacity and disease severity in CF patients. During the early (alactic) recovery period after CPET, oxygen is primarily required for the rephosphorylation of creatine in skeletal muscles, and the early rapid decline in oxygen consumption (V o 2 ) depends, at least in part, on the rate at which this process occurs. 6 Previous data 7 suggest a reduced efficiency of oxidative ATP synthesis in CF patients. We hypothesized that the recovery of the muscle energy stores, as reflected by V o 2 kinetics during early recovery, is an index of the efficiency of oxidative ATP resynthesis and therefore an index of disease severity. CHEST / 119 / 4/ APRIL,

2 Table 1 Anthropometric, Clinical, and Lung Function Data of Patients With CF* Variables CF Patients Healthy Subjects Age, yr (14 61) (22 36) Body mass index, kg/m Male/female gender, No. 9/9 3/8 SS (50 90) FEV 1, % predicted (23 128) ( ) FVC, % predicted (29 130) (97 128) FEV 1 /FVC, % (25 91) (80 97) *Data are presented as mean SD (range) unless otherwise indicated. The aim of this study was to explore the relationship of functional status and disease severity with early-recovery oxygen kinetics after CPET. Subjects Materials and Methods This study involved 18 patients with CF (9 male and 9 female; mean SD age, years) attending the outpatient CF clinic of Athens Chest Hospital and 11 healthy subjects (3 male/8 female; mean age, 29 4 years). All subjects were physically active but were not engaged in regular training. Table 1 lists the characteristics of both groups. All patients were in clinically stable condition and optimally treated at the time of the study. Those with recent pulmonary infection, respiratory failure, or other conditions affecting exercise capacity were excluded from the study. The diagnosis of CF was based on clinical evaluation and laboratory testing, including sweat testing and genotype analysis. Healthy subjects were volunteers in whom there was no evidence of cardiopulmonary disease according to medical history or physical findings. The Human Study Committee of our institution approved the study, and informed consent was formally obtained from each participant. were measured on a breath-by-breath basis using the Vmax 229 monitor for pulmonary and metabolic studies (Sensormedics; Yorba Linda, CA). The system was calibrated with standard gas of known concentration before each test. Measurements were obtained in the upright position before and during exercise, and during the first 10 min of recovery with the subject sitting in a chair. Baseline V o 2 was calculated by averaging the measurements made for 2 min before the beginning of exercise. V o 2 peak was calculated as the average of measurements made for 20 s before the end of exercise. Anaerobic threshold was determined using the V-slope technique, 8 and the result was confirmed by a graph on which respiratory equivalents for oxygen (minute ventilation [V e]/v o 2 ) and carbon dioxide (V e/v co 2 ) were plotted simultaneously against time. In order to evaluate the V o 2 kinetics during recovery, the first-degree slope of V o 2 decline for the first minute of recovery period (V o 2 /t-slope) 9 was calculated by linear regression using an appropriate computerized statistical program, assuming that the fall in V o 2 during early recovery is linear (Fig 1). The first minute was chosen to guarantee that the measurements reflected the fast component of the repayment of oxygen debt. 6,9 Patients and healthy control subjects were instructed to exercise until they could afford no more. Statistical Analysis Results are presented as mean SD. The unpaired Student s t test was used for the comparison of the CF patients with healthy Assessment of Disease Severity We used standard indexes like FEV 1 (% predicted), V o 2 peak, and the widely accepted system of clinical evaluation, the SS. The latter scores four separate aspects of the disease profile: (1) general activity, (2) physical findings, (3) nutritional status, and (4) chest radiographic findings. Each item is given equal weight, namely, 25 points. A total of 100 points represents a perfect score. 5 Pulmonary Function Assessment Each study participant underwent measurement of FVC and FEV 1 in the sitting position, before exercise. CPET CPET was performed on a treadmill (model 2000; Marquette Electronics; Milwaukee, WI) using the protocol of Bruce or modified Naughton. A 12-lead ECG was recorded every minute using the MAX 1 system (Marquette Electronics). BP measurements were obtained every 2 min using a standard-cuff mercury sphygmomanometer. A pulse oximeter was used for monitoring of pulse oximetric saturation. V o 2, carbon dioxide output (V co 2 ), and air flow Figure 1. A representative diagram of changes in V o 2 during CPET (rest, exercise, and recovery) of a patient with CF. Anaerobic threshold and V o 2 /t-slope are also depicted Clinical Investigations

3 Figure 2. Scattergraph of FEV 1 with the V o 2 /t-slope in CF patients. Figure 4. Scattergraph of the SS with V o 2 /t-slope in CF patients. subjects. The Pearson correlation was used to assess the association between parameters of severity and oxygen kinetics indexes. A stepwise linear multivariate regression analysis was applied to assess the independent relationship of oxygen kinetics indexes with the severity of CF. Results The V o 2 /t-slope was significantly lower in CF patients compared to healthy subjects ( L/min/min vs L/min/min; p 0.01), and was closely correlated to FEV 1 (r 0.90, p 0.001; Fig 2), V o 2 peak (r 0.81, p 0.001; Fig 3), and SS (r 0.81, p 0.001; Fig 4) in CF patients. The mean values of V o 2 peak of the CF patients were also significantly lower than those of healthy subjects ( ml/kg/min vs ml/ kg/min; p 0.001). V o 2 peak was closely correlated to FEV 1 (r 0.59, p 0.009; Fig 5) and SS (r 0.60, p 0.009; Fig 6). The SS also correlated with FEV 1 (r 0.75, p 0.001; Fig 7). Table 2 shows the results of the CPET parameters. Partial correlation analysis showed that the correlation of the SS with early-recovery V o 2 /t-slope persisted (r 0.69, p 0.002) even after controlling for V o 2 peak. In a multivariate analysis, we used the SS as a dependent variable while the independent variables were V o 2 peak, FEV 1, and early-recovery V o 2 / t-slope. This analysis showed that the only variable Figure 3. Scattergraph of V o 2 peak with V o 2 /t-slope in CF patients and in healthy subjects. Figure 5. Scattergraph of V o 2 peak with FEV 1 in CF patients. CHEST / 119 / 4/ APRIL,

4 Table 2 Exercise Test Indexes of Patients With CF* Indexes CF Patients Healthy Subjects Figure 6. Scattergraph of the SS with V o 2 peak in CF patients. V o 2 peak, % predicted 63 (13) 91 (15) V o 2 peak, ml/kg/min 24.8 (7.3) 35.4 (7.3) Anaerobic threshold, % predicted 40 (14) 69 (16) Anaerobic threshold, ml/kg/min 20.5 (5) 24.7 (5.3) V o 2 /t-slope, L/min/min 0.61 (0.31) 1.1 (0.13) Exercise time, min 8.5 (2.4) 8.8 (2.2) Heart rate, beats/min 172 (14) 187 (13) METS 8.7 (2.9) 13.3 (2.4) Breathing frequency peak, 37 (5) 44 (7) breaths/min Breathing reserve, % predicted 24 (22) 31 (12) V e peak, L/min 62.7 (19.2) 83.9 (15.0) V e/v o 2 slope 24.3 (4.8) 17.3 (3.2) V e/v co 2 slope 28.4 (5.9) 26.6 (3.1) Heart rate/v o 2 slope, beats/l/min 3.1 (1.4) 2.8 (0.9) *Data are presented as mean (SD). METS multiple of the resting metabolic oxygen requirements. independently associated with the SS was the V o 2 /tslope (F 5.5, p 0.001). Discussion Our results showed a significant correlation between the severity of CF and prolonged V o 2 kinetics during early recovery. The value of the V o 2 /t-slope was significantly lower in CF patients and significantly correlated with FEV 1,V o 2 peak, and the SS. The V o 2 peak value of CF patients was also significantly lower than that of healthy subjects. The sample of patients included a 61-year-old woman; there was no difference in the result when the analysis was performed with or without this patient. Figure 7. Scattergraph of the SS with FEV 1 in CF patients. The fact that the patients were younger than the healthy control subjects is in favor of our findings, because in younger subjects, higher values of V o 2 peak and V o 2 /t-slope would be expected. The multivariate analysis showed that the only independent predictor of disease severity as reflected by the SS was the V o 2 /t-slope. Prolonged V o 2 kinetics during recovery has been observed in various situations. V o 2 recovery is prolonged by deconditioning, 10 in chronic heart failure, 11 and in COPD. 12 This phenomenon is not completely understood, and it is considered to be related in part to a slow recovery of energy stores of the peripheral skeletal muscles. 13 In principle, an increased ATP utilization or a reduced efficiency of ATP production 14 may cause the increased V o 2. Using phosphorus-labeled nuclear magnetic resonance spectroscopy, de Meer et al 7 found changes in inorganic phosphate and phosphocreatine levels and reduced efficiency of oxidative ATP synthesis in exercising forearm muscles in patients with CF. An increased ATP utilization could result from altered recruitment patterns of two different musclefiber types, 14 ie, type I oxidative and type II glycolytic, each with different metabolic properties. 15,16 Glycolytic fibers carry out anaerobic glycolysis, and consequently their content of ATP and phosphocreatine is readily depleted during exercise, 15 followed by delayed phosphocreatine recovery 17 that is proportional to the oxidative capacity. 18 In a phosphorus-labeled nuclear magnetic resonance study of skeletal muscle metabolism in patients with chronic respiratory impairment, Kutsuzawa et al 19 observed a depletion of ATP and phosphocreatine content during exercise followed by delayed phosphocreatine recovery Clinical Investigations

5 Another mechanism that should be considered in the prolonged V o 2 recovery is the oxygen cost of breathing In CF patients, there is a basic physiologic defect, which appears as an enlargement of dead space, and it is present even in the most mildly affected patients. 24 This increase in dead space would necessitate an increase in total ventilation in order to keep alveolar ventilation constant. 25,26,27 Williams and Horvath 28 reported that the exercise cost in terms of V e/v o 2 and V e/v co 2 correlated very well with the corresponding excess during recovery. Another factor that might play a role in accounting for the prolonged V o 2 recovery in CF patients is deconditioning. V o 2 recovery is shortened by training 29 and prolonged by bed rest-induced deconditioning. 10 Our patients were physically active and occasionally exercised. An increased rate of ATP turnover could be the result of biochemical processes not related to the contraction process or even the working muscle. 14 Studies of fibroblasts and leukocytes from CF patients have shown mitochondria abnormalities such as increased calcium concentration, 30 lower nicotinamide adenine dinucleotide dehydrogenase activity, 31 and higher ph optimum of nicotinamide adenine dinucleotide dehydrogenase. 32 O Rawe et al 33 reported an association between the main CF gene mutation and raised energy expenditure in CF patients. They speculated that the effect of an abnormal ATP binding domain in the F 508 allele of CFTR may prevent the proper binding of ATPrequired oxidative phosphorylation. These changes probably affect muscle oxidative metabolism and prolong the V o 2 recovery after exercise. We conclude that prolonged oxygen kinetics during early recovery from maximal CPET in CF patients is related to the disease severity. The V o 2 /t-slope appears to be the only independent predictor of the SS. Pathophysiologic mechanisms affecting muscle oxidative metabolism could partially explain this observation. Thus, oxygen kinetics during early recovery from CPET offers a useful approach to the understanding of the pathophysiologic mechanisms of exercise limitation in CF patients. From the clinical point of view, V o 2 /tslope is independent from effort and physical fitness and it can be used even with submaximal exercise, which is of paramount importance for debilitated CF patients who cannot sustain a maximum exercise session. Furthermore, data obtained at maximal exercise may not be reproducible 37 because of factors such as the patient s motivation and the criteria used by the physician to terminate CPET. Further prospective studies are needed to explore the clinical significance and prognostic value of the V o 2 /t-slope. References 1 Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science 1992; 159: Welsh M, Anderson M, Rich DP, et al. Cystic fibrosis, CFTR, and abnormal electrolyte transport. In: Davis PB, ed. Cystic fibrosis (vol 64). New York, NY: Marcel Dekker, 1993; Kerem E, Reisman J, Corey M, et al. Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992; 326: Webb AK, Dodd ME. Exercise and cystic fibrosis. JRSoc Med 1995; 88(suppl 25): Shcwachman H, Kulczycki L. Long-term study of one hundred five patients with cystic fibrosis. Am J Dis Child 1958; 96: Margaria R, Edwards HT, Dill DB. The possible mechanisms of contracting and paying the oxygen debt and the role of lactic acid in muscular contraction. Am J Physiol 1933; 106: de Meer K, Jeneson JAL, Gulmans VAM, et al. Efficiency of oxidative work performance of skeletal muscles in patients with cystic fibrosis. Thorax 1995; 50: Beaver WL, Wasserman K, Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 1986; 60: Nanas S, Nanas J, Kassiotis CH, et al. Respiratory muscles performance is related to oxygen kinetics during maximal exercise and early recovery in patients with congestive heart failure. Circulation 1999; 100: Convertino VA, Goldwater DJ, Sandder H. V o 2 kinetics of constant-load exercise after bed-rest-induced deconditioning. J Appl Physiol 1984; 57: Cohen-Solal A, Laperche T, Morvan D, et al. Prolonged kinetics of recovery of V o 2 after maximal graded exercise in patients with chronic heart failure. Circulation 1995; 91: Chick TW, Cagle TG, Vegas FA, et al. Recovery of gas exchange variables and heart rate after maximal exercise in COPD. Chest 1990; 97: Harris RC, Edwards RHT, Hultman E, et al. The time course of phosphoryl-creatine resynthesis during recovery of the quadriceps muscle in man. Pflugers Arch 1976; 367: Bahr R, Opstad PK, Medbo JI, et al. Strenuous prolonged exercise elevates resting metabolic rate and causes reduced mechanical efficiency. Acta Physiol Scand 1991; 141: Achten E, van Cauteren M, Willem R, et al. 31 P-NMR spectroscopy and metabolic properties of different muscle fibers. J Appl Physiol 1990; 68: Park JH, Brown RL, Park CR, et al. Functional pools of oxidative and glycolytic fibers in human muscle observed by 31 P magnetic resonance spectroscopy during exercise. Proc Natl Acad Sci USA 1987; 84: Tesh PA, Thorsson A, Fujitsuka N. Creatine phosphate in fiber types of skeletal muscle before and after exhaustive exercise. J Appl Physiol 1989; 66: Taylor DJ, Bore PJ, Styles P, et al. Bioenergetics of intact human muscle: a 31 P nuclear magnetic resonance study. Mol Biol Med 1983; 1: Kutsuzawa T, Shioya S, Kurita D, et al. 31 P-NMR study of skeletal muscle metabolism in patients with chronic respiratory impairment. Am Rev Respir Dis 1992; 146: Bye PTP, Farkas GA, Roussos C. Respiratory factors limiting exercise. Ann Rev Physiol 1983; 45: Field S, Kelly SM, Macklem PT. The oxygen cost of breathing in patients with cardiorespiratory disease. Am Rev Respir Dis 1982; 126: Katsardis C, Desmond KJ, Coates AL. Measuring the oxygen CHEST / 119 / 4/ APRIL,

6 cost of breathing in normal adults and patients with cystic fibrosis. Respir Physiol 1986; 65: Welch HG, Faulkner JA, Barclay JK, et al. Ventilatory response during recovery from muscular work and its relation with O 2 debt. Med Sci Sports 1970; 2: Godfrey S, Mearns M. Pulmonary function and response to exercise in cystic fibrosis. Arch Dis Child 1971; 46: Cerny FJ, Pullano TP, Cropp GJ. Cardiorespiratory adaptations to exercise in cystic fibrosis. Am Rev Respir Dis 1982; 126: Hirsch JA, Zhang Shao-Ping, Rudnick MP, et al. Resting V o 2 and ventilation in cystic fibrosis. Pediatr Pulmonol 1989; 6: Coates AL, Canny G, Zinman R, et al. 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: Williams RE, Horvath SM. Recovery from dynamic exercise. Am J Physiol 1995; 268:H2311 H Hagberg JM, Hickson RC, Ehsani AA, et al. Faster adjustment to and recovery from submaximal exercise in the trained state. J Appl Physiol 1980; 48: Shapiro BL. Evidence for a mitochondrial lesion in cystic fibrosis. Life Sci 1989; 44: Dechecchi MC, Girella E, Cabrini G, et al. The Km of NADH dehydrogenase is decreased in mitochondria of cystic fibrosis cells. Enzyme 1988; 40: Shapiro BL, Feigal RJ, Lam LFH. Mitochondrial NADH dehydrogenase in cystic fibrosis. Proc Natl Acad Sci USA 1979; 76: O Rawe A, Dodge JA, Redmond AOB, et al. Gene/energy interaction in cystic fibrosis. Lancet 1990; 3: Henry FM. Aerobic V o 2 and alactic dept in muscular work. J Appl Physiol 1951; 3: Piiper J, Spiller P. Repayment of O 2 debt and resynthesis of high-energy phosphates in gastrocnemius muscle of the dog. J Appl Physiol 1970; 28: Mancini DM, Henson D, LaManca, et al. Respiratory muscle function and dyspnea in patients with chronic congestive heart failure. Circulation 1992; 86: Janicki JS, Cupta S, Ferris ST, et al. Long-term reproducibility of respiratory gas exchange measurements during exercise in patients with cardiac failure. Chest 1990; 97: Clinical Investigations

Key words: exercise capacity; heart failure; hemodynamics; inspiratory capacity; lung function; peak oxygen uptake

Key words: exercise capacity; heart failure; hemodynamics; inspiratory capacity; lung function; peak oxygen uptake Resting Lung Function and Hemodynamic Parameters as Predictors of Exercise Capacity in Patients With Chronic Heart Failure* Serafim Nanas, MD; John Nanas, MD, PhD; Ourania Papazachou, MD; Christos Kassiotis,