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Hypoxemia and Hypercapnia During Exercise and Sleep in Patients With Cystic Fibrosis^*

^* From the Department of Respiratory Medicine and Monash University Medical School, Alfred Hospital, Prahran, Melbourne, Victoria, Australia.

Correspondence to: Matthew T. Naughton, MD, Department of Respiratory Medicine, Alfred Hospital, Commercial Road, Prahran, Victoria, 3181, Australia; e-mail: matthew.naughton{at}med.monash.edu.au

	Abstract

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Background: In patients with cystic fibrosis (CF), it has been proposed that hypoxemia and hypercapnia occur during episodes of stress, such as exercise and sleep, and that respiratory muscle weakness because of malnutrition may be responsible.

Methods: Pulmonary function, respiratory muscle strength, and nutrition were assessed and correlated with the degree of hypoxemia and hypercapnia during exercise and sleep in 14 patients with CF and 8 control subjects.

Results: Despite no differences in maximum static inspiratory pressure (PImax) between the two groups, the CF group developed more severe hypoxemia (minimum oxyhemoglobin saturation [SpO₂], 89 ± 5% vs 96 ± 2%; p < 0.001) and hypercapnia (maximum transcutaneous CO₂ tension [PtcCO₂], 43 ± 6 vs 33 ± 7 mm Hg; p < 0.01) during exercise. Similarly, during sleep, the CF group developed greater hypoxemia (minimum SpO₂, 82 ± 8% vs 91 ± 2%; p < 0.005), although CO₂ levels were not significantly different (maximum PtcCO₂, 48 ± 7 vs 50 ± 2 mm Hg). Within the CF group, exercise-related hypoxemia and hypercapnia did not correlate with FEV₁, residual volume/total lung capacity ratio (RV/TLC), PImax, or body mass index (BMI). Hypoxemia and hypercapnia during sleep correlated with markers of gas trapping (RV vs minimum arterial oxygen saturation [r = -0.654; p < 0.05]), RV vs maximum PtcCO₂ (r = 0.878; p < 0.001), and RV/TLC vs maximum PtcCO₂ (r = 0.790; p < 0.01) but not with PImax or BMI.

Conclusion: Patients with moderately severe CF develop hypoxemia and hypercapnia during exercise and sleep to a greater extent than healthy subjects with similar respiratory muscle strength and nutritional status. Neither respiratory muscle weakness nor malnutrition are necessary to develop hypoxemia or hypercapnia during exercise or sleep.

Key Words: cystic fibrosis • exercise • respiratory failure • sleep

	Introduction

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Cystic fibrosis (CF) results in progressive airflow obstruction because of chronic mucus hypersecretion, recurrent lower respiratory tract infection, and airway remodeling. This results in increased airflow resistance,¹ intrapulmonary gas trapping,² ventilation/perfusion (/) mismatching,³ and increased work of breathing (WOB).^{4 5}

Episodic hypoxemia and hypercapnia may occur during times of physiologic stress in CF, namely exercise and sleep. It has been proposed that, during exercise, moderate hypoxemia and hypercapnia occur because of wasted ventilation⁶ and expiratory flow limitation.^{6 7} It has also been proposed that exercise limitation in CF is greatest in those with the worst nutritional status.^{8 9}

During sleep, marked hypoxemia and hypercapnia^{10 11} may also occur and are thought to result from a reduction in respiratory drive and tidal volume (VT) and from a loss of functional residual capacity (FRC), particularly during rapid eye movement (REM) sleep^{12 13} in patients with CF.

The respiratory muscles in patients with CF are exposed repetitively to periods of increased work because of relative hyperinflation and alteration in the length-tension relationship¹⁴ during times of hypoxemia. Malabsorption-related malnutrition in patients with CF, and associated weight loss, may further aggravate respiratory muscle wasting,^{2 15 16 17 18} and thereby amplify hypoxemia and hypercapnia during exercise or sleep, in addition to leading to peripheral muscle weakness.^{18 19}

However, the relationship between respiratory muscle strength or nutritional status and the development of hypoxemia and hypercapnia during exercise or sleep has not previously been thoroughly investigated. Therefore, we undertook a study to determine (1) the severity of exercise- and sleep-related hypoxemia and hypercapnia in a group of stable, nonhypoxic patients with CF and a group of age- and weight-matched healthy subjects, and (2) whether episodic hypoxemia and hypercapnia could occur in patients with CF and relatively well-preserved muscle strength and nutritional status.

	Materials and Methods

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Subjects
Patients attending the Alfred Hospital Adult Cystic Fibrosis Service and healthy control subjects were invited to participate in the study. Patients with CF of either sex were eligible for inclusion in the study if they were 18 years of age, with FEV₁ < 60% of predicted normal, PaO₂ > 55 mm Hg at rest, not receiving domiciliary oxygen, and in a clinically stable condition as indicated by no hospital admission or change in medications for 4 weeks. The healthy subjects recruited were matched for age, sex, height, and weight. All subjects gave written informed consent. The study was approved by the Ethics Committee of The Alfred Healthcare Group.

Investigations
Spirometry and carbon monoxide diffusing capacity (DLCO; Jaeger Master Lab; Wuerburg, Germany), alveolar volume (VA) measured by helium dilution, and plethysmographic lung volumes (total lung capacity [TLC], residual volume [RV], and FRC [PK Morgan; Kent, UK]) were measured according to the criteria of the American Thoracic Society²⁰ while patients were awake and in the seated position. An arterial blood sample was taken from the radial artery using a 25-gauge needle, and blood gases and pH were determined (ABL 500 Radiometer; Radiometer-Copenhagen; Copenhagen, Denmark) before exercise and sleep studies.

Inspiratory and expiratory respiratory muscle strength were measured using maximal static respiratory pressures produced at the mouth (Micro Mouth Pressure Meter; Micromedical; Rochester, Kent, UK) with a nose clip in place and a small leak in the circuit during both maneuvers to ensure prevention of glottic closure and minimize artifact caused by cheek muscles. While subjects were seated, maximal static inspiratory pressure (PImax) was measured at RV, and maximal static expiratory pressure (PEmax) was measured at TLC. Each pressure was measured at 1-min intervals a minimum of four times until there was < 10 cm H₂O between the two higher values. The highest values obtained for PImax and PEmax were recorded and expressed in absolute values.

The sum of nine skinfold thicknesses was measured as an indicator of body fat composition and nutritional status as previously described,²¹ and lean body mass (LBM) was calculated according to the methods described by Slaughter et al.²¹

Peripheral muscle strength (PMS) was estimated from the maximum voluntary concentric torque generated by the knee extensors and flexors of the right leg with an isokinetic dynamometer (Kin-Com; Med-Ex Diagnostics of Canada; Coquitlam, British Columbia, Canada).²² Average PMS represented the mean of six extension and flexion torque values and was expressed in newton meters.

An incremental cycle exercise test was used to measure maximal work capacity, maximum oxygen consumption (O₂max), heart rate, VT, oxyhemoglobin saturation (SpO₂; Biox 3700 Pulse Oximeter; Ohmeda; Louisville, CO), and transcutaneous CO₂ (PtcCO₂; FasTrac; SensorMedics; Anaheim, CA). After a 2-min period of baseline data collection, exercise was initiated at 16.3 W and increased by 16.3 W with each subsequent workload every minute, until continuation of the test was prevented by fatigue or at the physician's discretion. Throughout exercise, PtcCO₂ and SpO₂ were continuously measured. Symptoms of dyspnea and chest and leg discomfort were assessed at the completion of the test with the 0 to 10 Borg scale.²³

Standard cardiopulmonary sleep studies were conducted and recorded onto a computerized recording system (Somnostar; SensorMedics). Surface electrodes were used to record the EEG, electrooculogram (EOG), submental electromyogram, ECG, and anterior tibial electromyogram. Standard techniques and scoring criteria were used for the manual determination of sleep stages.²⁴ SpO₂ was measured by ear oximetry, and PtcCO₂ was measured by a capnograph placed on the anterior chest wall. Chest and abdominal movements were monitored using respiratory effort bands (Resp-ez; EPM Systems; Midlothian, VA). Oronasal airflow was monitored by thermocouples (Pro-Tech Services; Woodinville, WA). Time in bed was defined as time from lights out to lights on; total sleep time was the sum of non-REM and REM sleep epochs. Sleep efficiency was defined as total sleep time as a percentage of the total time in bed.

To ensure optimal accuracy of the transcutaneous capnograph during exercise and sleep, the following was completed: (1) a new sensor membrane was installed before each recording; (2) a two-point calibration was undertaken with 5% and 10% CO₂ gas mixtures; and (3) capnograph readings had to be within 3 mm Hg of a PaCO₂ level, taken simultaneously at the commencement of either the exercise or sleep studies, as previously described.²⁵

Statistical Analysis
All values were expressed as mean ± SD. Error bars in the figures represent mean ± SEM. Except where indicated, all values were compared using a two-tailed unpaired t test. Pearson's correlation coefficient was used to determine the relationship between variables. Primary variables of baseline lung function (FEV₁, DLCO, RV, RV/TLC), respiratory muscle strength (PImax), and nutrition (body mass index [BMI], sum of skinfold thickness, LBM, and PMS) were correlated with primary variables of ventilatory capacity during exercise (maximum workload, VO₂max, minimum SpO₂, and maximum PtcCO₂) and sleep (minimum SpO₂ and maximum PtcCO₂). A p value of < 0.05 was taken as significant.

	Results

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Subject Characteristics
Fourteen patients with CF (9 men and 5 women), and 8 control subjects (4 men and 4 women) participated in the study (Table 1 ). PaO₂ was significantly lower in the CF group (67 ± 8 vs 99 ± 4 mm Hg; p < 0.0001); however, there were no significant differences in PaCO₂ or pH (Table 1) . Compared with control subjects, the patients with CF had significantly lower FEV₁, FVC, and FEV₁/FVC, and significantly greater RV (Table 1) . Neither TLC nor DLCO were significantly different between groups. The degree of gas trapping was significantly greater in the CF group, as indicated by the significantly larger RV/TLC ratio and the significantly greater difference between TLC and VA compared with the control group.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Relationship between percentage of maximal work capacity (individual subject's progressive work capacity as a percent of individual maximum work capacity) and respiratory rate for normal (open boxes and dashed line) and CF (solid boxes and continuous line) groups. Data are expressed as mean ± SE.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Relationship between percentage of maximal work capacity and relative VT (as percentage of FEV1) for normal (open boxes and dashed line) and CF (solid boxes and continuous line) groups. Data are expressed as mean ± SE.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Relationship between percentage of maximal work capacity and E/FEV1 for normal (open boxes and dashed line) and CF (solid boxes and continuous line) groups. Data are expressed as mean ± SE.

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Relationship between percentage of maximal work capacity and E/O2 for normal (open boxes and dashed line) and CF (solid boxes and continuous line) groups. Data are expressed as mean ± SE.

In the CF group, hypoxemia occurred to a greater degree during sleep compared with exercise, as indicated by a lower minimum SpO₂ (82 ± 8% vs 89 ± 5%; p < 0.0005) and a greater fall in SpO₂ (11 ± 7% vs 6 ± 3%; p < 0.005). The maximum PtcCO₂ tended to be greater during sleep than exercise (48 ± 7 vs 43 ± 6 mm Hg), but this difference failed to reach statistical significance.

	Discussion

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The major findings of the current study were fourfold. First, hypoxemia and hypercapnia occurred during exercise and sleep to a greater degree in stable, nonhypoxic adult patients with CF, despite normal respiratory muscle strength, than in control subjects. Second, in the CF group, pulmonary function, respiratory muscle strength, and nutritional status correlated with maximum workload during exercise but not with levels of hypoxemia or hypercapnia that occurred during exercise. Third, in the CF group, markers of airflow obstruction, but not respiratory muscle strength or nutritional status, correlated with sleep-related hypoxemia and hypercapnia. Finally, in the CF group, hypoxemia and hypercapnia occurred to a greater degree during sleep than during exercise.

Malnourished adults, without pulmonary disease, have decreased respiratory muscle mass and strength as assessed by PImax and PEmax.^{15 26} Because CF disease progression is associated with weight loss because of exocrine pancreatic insufficiency and toxemia, respiratory muscle strength has been reported to be reduced in advanced disease by some authors,¹⁹ particularly in those patients who were significantly malnourished or who demonstrated chest hyperinflation.² A relative "steal" of cardiac output by the respiratory muscles²⁷ and detrimental effects of drugs may also contribute to respiratory myopathy and weakness.²⁸

On the other hand, other authors have reported respiratory muscle strength to be normal,^{16 17 18 29} possibly because of an intrinsic training effect of the increased WOB.¹⁸ The discrepancy between these reports, which have been confined mainly to young patients (9 to 24 years old), may relate to the lack of BMI-matched control subjects^{16 17} or studies that relied on age and height rather than body weight for comparison.²¹ The findings of the current study, albeit in an older group of subjects, would suggest that the respiratory muscle strength is well maintained compared with age- and BMI-matched controls.

Whether respiratory muscle strength and PMS are similarly impaired in patients with CF is unclear. Lands et al¹⁸ proposed that leg strength is impaired to a greater degree than that seen with respiratory muscles, and speculated that the respiratory strength is relatively well maintained because of the intrinsic training effect of the increased WOB.^{4 5 18} Others^{19 30} have reported respiratory muscle strength and PMS to be similarly reduced in compromised respiratory patients when compared with healthy controls. The discrepancy may be related to inadequate control groups and differences in severity of lung disease or nutritional status. Our results suggest the respiratory muscle strength is maintained within normal limits within the CF group, and, although PMS had a tendency to be impaired in the CF group compared with the control group, this reached statistical significance only in the male patients with CF.

The lack of relationship between respiratory muscle strength and exercise capacity is consistent with current concepts of exercise limitation in CF.³¹ During exercise, normal subjects recruit inspiratory and expiratory reserve volumes to increase VT early in exercise, and, toward the later part of exercise, they increase respiratory rate. In contrast, patients with chest hyperinflation, such as those with CF, are unable to recruit significant inspiratory or expiratory reserve volumes and therefore have a relatively greater respiratory rate throughout exercise, as observed in the current study.³² Tachypnea would result in a relative increase in WOB and therefore an increased requirement for cardiac output.²⁷

The rise in PtcCO₂ in patients with CF during exercise would suggest that much of the increased ventilation is wasted and likely to result in increased dead space ventilation, as previously suggested.³¹ Factors that may counteract the ventilatory limitation to exercise include upright posture and increased cardiac output with secondary improvement in / matching. In the current study, although the absolute E was lower in the CF group compared with the control group, the E expressed per FEV₁ was 60% greater in the CF group. Therefore, the subjective reports of dyspnea in the CF group are likely to be indicative of the inability of respiratory muscles to overcome the severe airflow limitation rather than respiratory muscle weakness per se. Our findings would suggest that hypercapnia during exercise in the CF group is likely to be related to increased dead space ventilation as indicated by greater E/O₂ ratio rather than respiratory muscle weakness.

It has been proposed that nocturnal hypoxemia contributes to the development of pulmonary hypertension and ultimately cor pulmonale.^{33 34} Cor pulmonale is now recognized as a feature of end-stage CF and is associated with poor survival.³⁵ In patients with CF, the supine position is associated with increased perfusion of the apical, scarred, and poorly ventilated zones,⁵ thereby worsening / matching. Moreover, non-REM sleep is associated with reduced E (because of a reduction in VT rather than a fall in respiratory rate), respiratory neuromuscular activation, and increased gas trapping, without any significant increase in upper or lower airway resistance.^{12 13 36} In addition, FRC has been shown to fall during REM sleep, because of the decrease in activity of the intercostal muscles,^{10 12 37} and may approach or fall below closing volume, resulting in airway narrowing and closure and nonventilation of lung regions,³⁸ which would further aggravate / mismatch. Results from the current study suggest that hypoxemia and hypercapnia can occur during sleep despite normal respiratory muscle strength and in the absence of marked malnutrition in the CF group. Moreover, the CF group had a respiratory rate nearly twice that of the control group, suggestive of increased WOB during sleep and cardiac output requirements. This may be one factor responsible for the relative tachycardia we observed within the CF group.

Comparisons of hypoxemia and hypercapnia during exercise and sleep have been sparingly reported, yet are important in providing perspective on areas in which therapies could be targeted. Coffey et al⁷ reported that patients with CF exhibit greater hypoxemia during sleep than exercise. However, the exercise regimen used by Coffey et al⁷ was submaximal and as such may not have reflected the full potential for these patients to desaturate during exercise, nor was sleep stage or overnight PtcCO₂ reported. The current study, however, does confirm that hypoxemia and hypercapnia occur to a greater degree during sleep than during exercise.

A potential limitation of our study was the accuracy of PtcCO₂ as a measurement of PaCO₂. Although simultaneous measurements of PaCO₂ and PtcCO₂ were taken at the beginning of each test and were not significantly different and calibration of PtcCO₂ at the beginning and end of each study was performed, we could have underestimated the change in CO₂ levels with sleep and exercise. Despite these technical limitations, our PtcCO₂ findings are consistent with previous reports. Comparing wakefulness with sleep, Gozal ³⁹ reported a rise in PtcCO₂ from 46 to 62 mm Hg (two patients who were hypercapnic were awake), and Ballard and colleagues³⁶ observed a small fall in E from 11 to 9.2 L/min in nonhypoxic patients with CF. During exercise, other reports showed CO₂ to rise by < 4 mm Hg⁴⁰ in nonhypercapnic patients and by only 6.7 mm Hg in hypercapnic patients⁴¹ with CF, consistent with our observations.

In summary, stable, nonhypoxic adult patients with CF experience hypoxemia and hypercapnia to a greater degree during sleep than during exercise in the absence of significant respiratory muscle weakness or malnutrition. In the current study, exercise-related hypoxemia and hypercapnia, albeit mild, was unrelated to markers of airflow obstruction, respiratory muscle weakness, or nutritional status. Sleep-related hypoxemia and hypercapnia were dependent on degree of hyperinflation, but not respiratory muscle strength or nutritional status. Whether treatment of hypoxemia and hypercapnia during sleep and/or exercise in these nonhypoxic patients with CF will have a prognostic benefit remains to be determined.

	Acknowledgements

 
ACKNOWLEDGMENT: Thanks are extended to Ms. Teanau Roebuck, Dr. Judy Morton, and the staff of the sleep and respiratory function laboratories. The efforts of Ms. Libby Francis are also appreciated for assisting in the recruitment of subjects. Finally, gratitude is extended to the patients with CF and control subjects who gave up their time so generously.

	Footnotes

 
Abbreviations:BMI = body mass index; CF = cystic fibrosis; DLCO = carbon monoxide diffusing capacity of the lung; FRC = functional residual capacity; LBM = lean body mass; PEmax = maximal static expiratory pressure; PImax = maximal static inspiratory pressure; PMS = peripheral muscle strength; REM = rapid eye movement; RV = residual volume; SpO₂ = oxyhemoglobin saturation; PtcCO₂ = transcutaneous CO₂ tension; TLC = total lung capacity; VA = alveolar volume; E = minute ventilation; O₂max = maximal O₂ consumption; / = ventilation/perfusion ratio; VT = tidal volume; WOB = work of breathing

Dr. Solin is a recipient of an Australian National Health and Medical Research Council scholarship. Matthew Naughton is a recipient of an Astra/Australian Lung Foundation Career Development Award and Viertal Clinical Investigatorship.

Received for publication January 28, 1999. Accepted for publication April 15, 1999.

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