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(Chest. 2001;119:1073-1078.)
© 2001 American College of Chest Physicians

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

* 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.

Correspondence to: Eleni Pouliou, MD, Pulmonary and Critical Care Medicine, National and Kapodestrian University, Evgenidio Hospital, Papadiamantopoulou 20, 11528 Athens, Greece; e-mail: snanas{at}cc.uoa.gr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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, 23 ± 13 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 (O2), carbon dioxide production, and ventilation. Maximum O2 (O2peak) and the first-degree slope of O2 decline during early recovery (O2/t-slope) were calculated. To assess the severity of the disease, we used standard indexes like FEV1 (% predicted), O2peak, and a widely accepted system of clinical evaluation, the Schwachman score (SS).

Results: O2/t-slope was significantly lower in CF patients compared to healthy subjects (0.61 ± 0.31 L/min/min vs 1.1 ± 0.13 L/min/min; p < 0.01) and was closely correlated to FEV1(r = 0.90, p < 0.001), O2peak (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 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.

Key Words: cystic fibrosis • exercise • recovery • Schwachman score


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cystic fibrosis (CF) is the most common life-shortening 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 across the apical membrane of epithelial cells, especially in the airways and pancreas, resulting in progressive lung disease and malnutrition.2

FEV1,3 maximum oxygen consumption (O2peak) 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 (O2) depends, at least in part, on the rate at which this process occurs.6 Previous data7 suggest a reduced efficiency of oxidative ATP synthesis in CF patients. We hypothesized that the recovery of the muscle energy stores, as reflected by O2 kinetics during early recovery, is an index of the efficiency of oxidative ATP resynthesis and therefore an index of disease severity.

The aim of this study was to explore the relationship of functional status and disease severity with early-recovery oxygen kinetics after CPET.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
This study involved 18 patients with CF (9 male and 9 female; mean ± SD age, 23 ± 13 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.


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  		Table 1.. Anthropometric, Clinical, and Lung Function Data of Patients With CF*

 
Assessment of Disease Severity
We used standard indexes like FEV1 (% predicted), O2peak, 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 FEV1 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. O2, carbon dioxide output (CO2), and air flow 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 O2 was calculated by averaging the measurements made for 2 min before the beginning of exercise. O2peak 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 [E]/O2) and carbon dioxide (E/CO2) were plotted simultaneously against time. In order to evaluate the O2 kinetics during recovery, the first-degree slope of O2 decline for the first minute of recovery period (O2/t-slope)9 was calculated by linear regression using an appropriate computerized statistical program, assuming that the fall in O2 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.



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  		Figure 1.. A representative diagram of changes in O2 during CPET (rest, exercise, and recovery) of a patient with CF. Anaerobic threshold and O2/t-slope are also depicted.

 
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 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
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The O2/t-slope was significantly lower in CF patients compared to healthy subjects (0.61 ± 0.31 L/min/min vs 1.1 ± 0.13 L/min/min; p < 0.01), and was closely correlated to FEV1(r = 0.90, p < 0.001; Fig 2 ), O2peak (r = 0.81, p < 0.001; Fig 3 ), and SS (r = 0.81, p < 0.001; Fig 4 ) in CF patients.



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  		Figure 2.. Scattergraph of FEV1 with the O2/t-slope in CF patients.

 


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  		Figure 3.. Scattergraph of O2peak with O2/t-slope in CF patients and in healthy subjects.

 


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  		Figure 4.. Scattergraph of the SS with O2/t-slope in CF patients.

 
The mean values of O2peak of the CF patients were also significantly lower than those of healthy subjects (24.8 ± 7.3 mL/kg/min vs 35.4 ± 7.3 mL/kg/min; p < 0.001). O2peak was closely correlated to FEV1 (r = 0.59, p < 0.009; Fig 5 ) and SS (r = 0.60, p < 0.009; Fig 6 ). The SS also correlated with FEV1 (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 O2/t-slope persisted (r = 0.69, p < 0.002) even after controlling for O2peak. In a multivariate analysis, we used the SS as a dependent variable while the independent variables were O2peak, FEV1, and early-recovery O2/t-slope. This analysis showed that the only variable independently associated with the SS was the O2/t-slope (F = 5.5, p < 0.001).



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  		Figure 5.. Scattergraph of O2peak with FEV1 in CF patients.

 


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  		Figure 6.. Scattergraph of the SS with O2peak in CF patients.

 


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  		Figure 7.. Scattergraph of the SS with FEV1 in CF patients.

 

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  		Table 2.. Exercise Test Indexes of Patients With CF*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results showed a significant correlation between the severity of CF and prolonged O2 kinetics during early recovery. The value of the O2/t-slope was significantly lower in CF patients and significantly correlated with FEV1, O2peak, and the SS. The O2peak 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. 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 O2peak and O2/t-slope would be expected. The multivariate analysis showed that the only independent predictor of disease severity as reflected by the SS was the O2/t-slope.

Prolonged O2 kinetics during recovery has been observed in various situations. O2 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 production14 may cause the increased O2. Using phosphorus-labeled nuclear magnetic resonance spectroscopy, de Meer et al7 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 muscle-fiber 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 recovery17 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 al19 observed a depletion of ATP and phosphocreatine content during exercise followed by delayed phosphocreatine recovery.

Another mechanism that should be considered in the prolonged O2 recovery is the oxygen cost of breathing.20 21 22 23 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 Horvath28 reported that the exercise cost in terms of E/O2 and E/CO2 correlated very well with the corresponding excess during recovery.

Another factor that might play a role in accounting for the prolonged O2 recovery in CF patients is deconditioning. O2 recovery is shortened by training29 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 al33 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 {Delta}F508 allele of CFTR may prevent the proper binding of ATP- required oxidative phosphorylation. These changes probably affect muscle oxidative metabolism and prolong the O2 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 O2/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, O2/t-slope is independent from effort and physical fitness34 35 36 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 reproducible37 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 O2/t-slope.


   Footnotes
 
Abbreviations: ATP = adenosine triphosphate; CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; CPET = cardiopulmonary exercise testing; SS = Schwachman score; CO2 = carbon dioxide production; E = minute ventilation; O2 = oxygen consumption; O2peak = maximum oxygen consumption; O2/t-slope = first degree slope of oxygen consumption decline during early recovery

Received for publication March 22, 2000. Accepted for publication November 28, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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