Cardiopulmonary exercise testing in obstructive sleep apnea syndrome

Respiratory Physiology & Neurobiology 150 (2006) 27–34

Cardiopulmonary exercise testing in obstructive sleep apnea syndrome Ching-Chi Lin a, b, ∗ , Wen-Yeh Hsieh a , Chon-Shin Chou a , Shwu-Fang Liaw a a

Chest Division, Department of Internal Medicine, Department of Medical Research, Mackay Memorial Hospital, 92, Sec 2, Chung Shan North Road, Taipei, Taiwan b Mackay Medicine, Nursing and Management College, Taipei, Taiwan Accepted 20 January 2005

Abstract To investigate whether cardiac dysfunction or abnormal measurements on cardiopulmonary exercise testing (CPET) are present in patients with obstructive sleep apnea syndrome (OSAS) and what factors are responsible for exercise limitation in these patients. We enrolled 20 patients with moderate or severe OSAS in the OSA group and 20 subjects without OSAS in the control group. All subjects underwent a sleep study and cardiac evaluation by radionuclide scanning and CPET. There was no difference in left ventricular ejection fraction (VEF) between the two groups, but the OSA group had a lower right VEF. Patients in the OSA group had a lower VO2 peak , VO2 peak/kg and workpeak than the control group. The OSA group had a higher breathing reserve and a greater decrease in anaerobic threshold (AT) and oxygen pulse. In conclusion, patients with moderate to severe OSAS had abnormal CPET results. These abnormalities may be due to cardiac disease, pulmonary vascular disease, or possible lack of fitness. © 2005 Elsevier B.V. All rights reserved. Keywords: Obstructive sleep apnea syndrome; Tissue oxygenation; Cardiopulmonary exercise test

1. Introduction Obstructive sleep apnea syndrome (OSAS) is characterized by repetitive upper airway obstruction leading to a high negative intrathoracic pressure and alveolar hypoventilation (Guilleminault et al., 1976), resulting in abnormal gas exchange, arterial oxygen ∗ Corresponding author. Tel.: +886 2 25433535; fax: +886 2 25433642. E-mail address: [email protected] (C.-C. Lin).

1569-9048/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2005.01.008

desaturation, abnormal autonomic nerve function, acute and possibly chronic cardiac dysfunction, and hemodynamic impairment (Fletcher et al., 1987; Krieger et al., 1989; Hedner et al., 1995). Theoretically, OSAS patients may develop pulmonary hypertension and right ventricular failure due to hypoxic pulmonary vasoconstriction (Sforza et al., 1990; Sajkov et al., 1994) and increased right ventricular afterload related to exaggerated negative intrathoracic pressure swings during obstructive apnea (Sforza et al., 1990; Langanke et al., 1993; Sajkov et al.,

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1994). Several recent studies indicate that intermittent apnea-related hypoxemia is not enough to explain sustained pulmonary hypertension. In contrast, diurnal hypoxemia or overlapping syndrome (OSAS + mild to moderate diffuse COPD) is essential for the development of pulmonary hypertension (Bradley et al., 1985; Weitzenblum et al., 1988; Marrone et al., 1989; Krieger et al., 1991). Many studies have also reported that OSAS can play a role in the pathogenesis of left ventricle (LV) heart failure through a combination of increased LV afterload related to obstructive-apneainduced negative intrathoracic pressure swings (Guz et al., 1987; Shiomi et al., 1991), intermittent hypoxia and chronically elevated sympathoadrenal activity (Jennum et al., 1989; Hedner et al., 1995). Cardiovascular disease remains the leading cause of death in developed countries. OSAS is also common, affecting about 2–5% of adult men (Young et al., 1993). Cardiovascular disturbances have been considered one of the most serious complications of OSAS (Pankow et al., 2000; Guidry et al., 2001; Shahar et al., 2001). Strong evidence suggests that snoring and sleep apnea significantly increase the relative risk of ischemic heart disease (Mooe et al., 2001). Substantial evidence has also shown that if OSAS is untreated it may lead to multiple organ-system dysfunction, including personality changes and intellectual impairment (Montplaisir et al., 1992). Untreated patients with OSAS also have increased mortality (He et al., 1988). Cardiopulmonary exercise testing (CPET) is used as a stress test to evaluate cardiac, pulmonary, and muscle function. It has also been used to differentiate whether the etiology of impairment of the cardiopulmonary exercise test is cardiac, pulmonary or muscle dysfunction. In otherwise healthy subjects, exercise limitation is due to heart disease. Patients with OSAS are frequently overweight and may exhibit lung function abnormalities related to their weight. These include a decrease in the functional residual capacity (FRC) due mainly to a decrease in the expiratory reserve volume (ERV) and a decrease in compliance of the respiratory system (Naimark and Cherniack, 1960; Ray et al., 1983). These functional abnormalities cause an increase in the energy cost of breathing. In addition, increased body mass is associated with greater metabolic energy requirements during muscular exercise, resulting in further ventilatory stress. There are reports demonstrating that there are discriminating

measurements during exercise in obesity, including a high O2 cost to perform external work, and upward displacement of the VO2 –WR relationship (Astrand et al., 1960; Whipp and Davis, 1984). OSAS patients have daytime hypersomnolence, decreased daily activity and tissue hypoxemia which may further impair muscle function and decrease exercise fitness. Recently, Peppard and Young (2004) found that, independent of body habitus, lack of exercise was associated with increased severity of sleep-disordered breathing. To our knowledge, CPET has never been studied in patients with OSAS, particularly looking at specific exercise limitations. The purpose of this study was to evaluate whether abnormalities of CPET are present in patients with OSAS and, if so, the factors responsible for exercise limitation, the abnormal patterns of response demonstrated, and clinical disorders that may result in these patterns of response.

2. Materials and methods 2.1. Selection of subjects Patients presenting to the Mackay Memorial Hospital Sleep Laboratory for sleep studies were considered for enrollment. They came either by referral from a physician who determined they had a clinical problem meriting overnight sleep polysomnographic evaluation or by their own request. All subjects underwent blood pressure, simple spirometric, and arterial blood gas (ABG) measurements; cardiac evaluation by radionuclide scanning; and an overnight polysomnography sleep study. We enrolled individuals consecutively presenting to the sleep clinic in one of two groups according to the sleep study results. The OSA group consisted of 20 patients with moderate or severe OSAS (respiratory disturbance index (RDI) > 30) as assessed by an overnight sleep study. They were all aged less than 55 and had a body mass index (BMI) less than 33. The control group consisted of 20 age-, sex- and weight-matched subjects without OSAS (RDI < 10, BMI > 25). All subjects in both groups had normal thyroid function and no evidence of cardiopulmonary failure, diabetes mellitus or other diseases which might affect energy expenditure (EE) (e.g. endocrine disease) as evaluated by clinical history, physical examination,

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chest X-ray, electrocardiogram and biochemistry examinations (including free T4, T3 resin uptake, AC and PC blood sugar). Patients were excluded if there was any history or clinical evidence of primary central nervous system, systemic or neuromuscular diseases, or if they had evidence of acute infection within one month prior to the study. Alcohol or sedatives were avoided for at least one week prior to the overnight sleep study. Drugs or substances that alter metabolism (e.g. caffeine, tea, nicotine and theophylline) were avoided for at least 2 days. 2.2. Sleep studies Overnight sleep studies were performed with complete polysomnography. An electroencephalogram (EEG) (C4/A1, C3/A2), EOG, and submental EMG for sleep staging were recorded according to standard criteria. Respiratory movement was monitored by inductance plethysmography. Nasal and oral air flow were monitored by a thermocouple. Arterial oxygen saturation and heart rate were continuously measured by an Omheda pulse oximeter. Bilateral tibial EMG and ECG were also monitored from surface electrodes (American Thoracic Society, 1989). Sleep was staged by the method of Rechtschaffen and Kales (1968) on the basis of 30-s epochs. 2.3. Sleep variables Apnea/hypopnea event was defined by a clear decrease (>50%) from baseline in the amplitude of ventilation (summation of chest and abdominal excursion) for longer than 10 s as measured by calibrated inductive plethysmography during sleep (American Academy of Sleep Medicine, 1999). The baseline was defined as the mean amplitude of stable breathing and oxygenation in the 2 min preceding onset of the event (in individuals who had a stable breathing pattern during sleep) or the mean amplitude of the three largest breaths in the 2 min preceding onset of the event (in individuals without a stable breathing pattern). Apnea/hypopnea events also included a clear amplitude of ventilation reduction during sleep that did not reach the above criterion but was associated with either oxygen desaturation of >3% or arousal. The RDI was defined as the mean number episodes of hypopnea and apnea per hour of sleep. Desaturation event frequency (DEF) was defined as the

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mean number of oxygen desaturation episodes per hour of sleep (American Thoracic Society, 1989). Sleep apnea syndrome (SAS) was diagnosed as a RDI equal to or greater than 10 during overnight polysomnography. Moderately severe or severe SAS was defined as an RDI equal to or greater than 30. Central apnea was defined as the cessation of nasal and oral airflow with the cessation of respiratory effort, which was appreciated by both inductive plethysmography and diaphragm EMG from a surface electrode. Obstructive apnea was defined as the absence of nasal and oral airflow despite continuing respiratory effort. Mixed apnea had both central and obstructive components, the obstructive part usually following the central. OSAS was diagnosed when obstructive and mixed apneas represented more than 80% of all apneic episodes. Arousal was defined as a minimum of 10 continuous seconds in any stage of sleep before a minimum 10 s period of return of ␣ or ␪ waves with or without an increase in submental EMG measurements in non-REM sleep or with an increase in EMG tone in REM sleep. The arousal index was defined as the mean number of arousals per hour of sleep (EEG Arousals, 1992). Sleep efficiency was the percentage of total sleep time divided by total bed time. 2.4. Daytime sleepiness evaluation The level of daytime sleepiness was assessed using the Epworth sleepiness scale (ESS) on the morning after nocturnal polysomnography. The ESS is a validated questionnaire containing eight items that asks about the self-reported probability of dozing in a variety of situations. The dozing probability ranges from 0 (never) to 3 (high probability). Normal values range from 2 to 10, with scores >10 indicating daytime sleepiness (Johns, 1991). 2.5. Pulmonary function tests Pulmonary function tests (PFT) were performed prior to entry into the study, using a Gould 5000 CPI computerized spirometer with the subjects in a sitting position. The loop with the highest sum of FEV1 and FVC was analyzed. The FEV1, FVC and FEV1/FVC ratio were recorded. The maximal minute ventilation (MVV, L/min, BTPS) was measured directly. When MVV was

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measured, patients were asked to sit up very straight and make sure nothing was restricting chest movement or airflow (such as tie, coat, belt, chewing gum, etc.). Obese adults stood rather than sat for the test and began by breathing normally through the mouthpiece, followed by breathing as deeply (recommended depth: 1/2–3/4 of the patient’s vital capacity) and rapidly (recommended rate: 70–150 breaths/min) as possible. At the end of the measurement interval, they were told to resume normal breathing and remove the mouthpiece. At least two trials were done showing consistent effort with reproducible results. 2.6. Cardiac function evaluation Cardiac function was evaluated by a radionuclide method to determine the left and right ventricular ejection fractions (LVEF, RVEF).

a number from 0 to 10; the numbers were tagged to simple descriptive terms such as slight, moderate and severe (Borg scale). After completion they were asked why they stopped the exercise. Symptoms attributed to the leg muscles (leg effort or fatigue) were limiting in all subjects. Maximal power output (MPO) was defined as the highest power output maintained for at least 30 s. The breathing reserve = 1 − [VEmax /MVV], where VEmax is the maximal minute ventilation (L/min, BTPS) at maximal exercise. The anaerobic threshold (AT) was determined by using the following criteria: (1) inflection point in the minute ventilation (VE) and/or VCO2 versus VO2 diagram; (2) point of increase in end-tidal PO2 (PETO2 ); and (3) point of increase in the ventilatory equivalent of O2 (VE/VO2 ) without a concomitant reduction of end tidal PCO2 (PETCO2 ) (Marcus et al., 1971; Wasserman, 1988; ERS Task Force on Standardization of Clinical Exercise Testing, 1997).

2.7. Cardiopulmonary exercise test 2.8. Data analysis On arrival in the exercise laboratory, the procedure and attendant risks were explained, and written informed consent was obtained. Height, weight, and spirometry (FVC, FEV1) were measured. Exercise tests were performed on an electrically braked cycle ergometer with electrocardiographic monitoring under the supervision of a physician, and with defined criteria for stopping such as serious cardiac arrhythmias, hypotension, and electrocardiographic changes. Termination of exercise by the supervising physician according to those criteria was not required in any subject. Before exercise, while seated comfortably on the cycle ergometer (Erich Jaeger GmbH, Germany), subjects breathed for 1 min through a unidirectional valve (Hans Rudollph, Kansas City, MO, USA) with the expired air going to a universal exercise testing system (Vmax series/6200 autobox DL metabolic cart, Sensor Medics, Anaheim, California, USA). After 1 min of loadless pedaling, subjects cycled at 60 rpm at an initial power output of 100 kpm/min. At the end of each minute the power output was increased by 100 kpm/min. Heart rate, blood pressure, ventilation, respiratory rate and tidal volume were measured. Patients were encouraged to continue exercise until exhaustion. They were asked to estimate the intensity of discomfort of breathing and the intensity of leg effort every minute by matching their subjective estimate to

Student’s t-test was used for statistical analysis. All values were expressed as the mean ± standard deviation, with significance accepted when p < 0.05. 3. Results 3.1. Patient data and baseline measurements These are summarized in Table 1. There were no significant differences in age, hematocrit, FEV1, FVC, FEV1/FVC or baseline PaO2 between the OSA and control groups. There was also no significant difference in BMI between the two groups. The OSA group had higher Epworth sleepiness scale scores than the control group. While the LVEF did not differ significantly, the OSA group had a lower RVEF. 3.2. Sleep measurements The OSA group had a higher RDI and DEF than the control group and a lower lowest SpO2 during sleep. The OSA group had a more abnormal sleep architecture characterized by a higher percentage of stage I sleep but a lower percentage of stage II and REM stage sleep and a higher arousal index (Table 2).

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Table 1 Patient characteristics and baseline measurements

Age (years) Sex (male/female) BMI (kg/m2 ; male) LVEF (%) RVEF (%) Epworth sleepiness scale FEV1 (% predicted) FVC (% predicted) FEV1/FVC Hematocrit pH Baseline PaO2 (mmHg) Baseline PaCO2 (mmHg)

OSA group (n = 20)

Control group (n = 20)

47 ± 7 18/2 28.3 ± 2.6 57.70 ± 4.82 38.05 ± 4.08* 16.4 ± 3.1* 89.58 ± 5.63 88.25 ± 5.34 82.92 ± 4.50 40.17 ± 1.36 7.40 ± 0.03 96.18 ± 2.55 39.61 ± 1.70

44 ± 7 18/2 27.6 ± 2.7 62.15 ± 4.20 44.20 ± 3.36 6.4 ± 2.3 90.29 ± 5.97 89.59 ± 5.86 83.26 ± 4.75 39.65 ± 1.31 7.40 ± 0.03 97.15 ± 1.64 39.48 ± 1.48

BMI: body mass index; LVEF: left ventricular ejection fraction; RVEF: right ventricular ejection fraction; FVC: forced vital capacity. The Student’s t-test was used. * p < 0.05 comparison between OSA group and control group.

3.3. Response to the cardio-pulmonary exercise test

4. Discussion

Results of the CPET study are shown in Table 3. The intensity of dyspnea (median rating 7, very severe) and leg effort (median rating 7, very severe) were the same in both groups. However, patients in the OSA group had a lower VO2 peak , VO2 peak/kg and workpeak than controls, and a greater decrease in anaerobic threshold and oxygen pulse (Table 3). The OSA group had a higher breathing reserve and a lower VEmax . There was no difference in respiratory quotient, VD/VT, SpO2 , heart rate and heart rate reserve between the groups (Table 3). Table 2 Results of sleep study OSA group RDI, times (h) DEF, times (h) Baseline SpO2 (%) Lowest SpO2 (%)

44.01 31.17 97.10 65.50

± ± 7.35* ± 0.79 ± 7.96* 8.16*

Percent of total sleep time at each sleep stage Stage 1 (%) 32.61 ± 9.16* Stage 2 (%) 46.58 ± 7.66* Stage 3 + 4 (%) 3.06 ± 1.56* REM (%) 17.75 ± 3.98* Sleep efficiency (%) 76.45 ± 6.74* AI, times (h) 37.46 ± 13.01*

Control group 5.14 2.41 97.20 91.85

± ± ± ±

1.60 1.15 0.70 1.66

11.25 56.28 10.65 21.82 86.37 4.38

± ± ± ± ± ±

2.70 1.38 1.10 2.12 2.61 1.41

RDI: respiratory disturbance index; DEF: desaturation event frequency; REM: rapid eye movement; AI: arousal index; data are presented as mean ± S.D. The Student’s t-test was used. * p < 0.05 comparison between OSA group and control group.

In this study of cardiopulmonary function in patients with OSA, we found on CPET that those in the OSA group had a lower VO2 peak , VO2 peak/kg and workpeak than did the control group. The reasons for the exercise limitations are not well understood. Factors that may

Table 3 Cardio-pulmonary exercise test results OSA group Intensity of dyspnea Intensity of leg effort VO2 peak (L/min) VO2 peak/kg (mL/kg/min) Workpeak (W) Anaerobic threshold (L/min) Heart rate (bpm) Heart rate reserve (bpm) VEmax (L/min) BTPS Breathing reserve (%) O2 pulse (mL/beat) PETO2 PETCO2 VE/VO2 VE/VCO2 Respiratory quotient VD/VT (%) SpO2 (%)

6.75 7.05 1.69 21.64 119.9 0.84 156.7 8.3 74.72 39.2 9.40 114.63 39.73 33.83 34.50 1.21 17.15 94.15

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

1.33 1.54 0.21* 3.27* 14.9* 0.10* 7.5 4.4 9.43* 3.2* 1.81* 4.79 4.30 5.04 4.38 0.06 3.86 2.08

Control group 6.70 7.10 2.34 30.1 154.85 1.26 161.1 6.4 95.5 29.1 12.61 116.42 37.73 31.35 32.50 1.23 15.20 95.40

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

1.38 1.52 0.20 3.35 14.1 0.09 6.9 3.4 9.72 2.5 1.37 4.38 4.53 4.82 4.80 0.06 3.29 1.27

IBW: ideal body weight; data are presented as mean ± S.D. The Student’s t-test was used. * p < 0.05 comparison between OSA group and control group.

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contribute to exercise limitation in patients with OSAS include dyspnea or leg weakness, cardiac dysfunction, abnormalities of respiratory mechanics or respiratory muscle dysfunction, arterial hypoxemia, lack of fitness, and other factors, such as motivation and peripheral vascular disease. The most common symptoms limiting the CPET were shortness of breath (SOB) and leg muscle weakness. SOB and leg effort are different sensations, and either one or both can limit CPET (el-Manshawi et al., 1986). Most subjects in the present study stopped exercise at submaximal ventilation and submaximal symptom intensities, making it difficult to isolate the true limiting factor. One possibility is that symptoms alone are limiting. We believe that some subjects tolerate only a little discomfort (somewhat severe), while the average individual tolerates a greater degree of discomfort (very severe). Most subjects stopped exercise when the symptom intensity of leg effort and/or dyspnea reached 7, i.e., very severe, and few subjects were willing to exercise to maximal symptom intensity. Individual motivation and symptom tolerance are also related factors. Some subjects have low tolerance and stop when symptoms are rated somewhat severe, and others exercise to maximal intensity. The symptom score is also very subjective. Overrating and underrating by individual subjects is another factor. In this study, there was no difference in dyspnea and leg effort scores at the level of peak exercise between the OSA and control groups. There was no significant difference in baseline FVC, FEV1, FEV1/FVC and baseline PaO2 , PaCO2 between OSA and control groups. We did demonstrate that there was a lower VE peak but higher breathing reserve in the OSA group. There was no difference in VD/VT and SpO2 between the two groups during exercise, proving that exercise limitation is not due to pulmonary factors. There was no difference in heart rate reserve between the two groups (Table 3), but the OSA group had a greater decrease in anaerobic threshold and oxygen pulse. Both anaerobic threshold and oxygen pulse have been considered related to cardiac function (Wasserman, 1988; Weisman and Zeballos, 1994; Zeballos et al., 1998). In addition, the RVEF is significantly lower in the OSA group than the control group at rest. Therefore, cardiac impairment may contribute to exercise limitation in patients with OSAS.

Lack of fitness is another possible reason for exercise limitation in patients with OSAS. They stopped exercising at submaximal levels and preserved a higher breathing reserve than normal. The reason for lack of fitness is poorly understood. We found that there was a significantly higher RDI and DEF and a greater decrease in the mean and lowest SpO2 in the OSA group than in the control groups, as well as a lower sleep efficiency, more abnormal sleep architecture, and a greater arousal index during sleep. These findings suggest that poor sleep quality leads to daytime hypersomnolence and decreased daily activity. Both may result in the lack of fitness observed in OSAS patients (Laaban et al., 1998). We found that the sleep efficiency and sleep architecture were better in the control group than the OSA group and that the RDI and DEF were lower in the control group than the OSA group. The level of daytime sleepiness was lower in the control group than in the OSA group. Sleep deprivation can impair ventilatory response to hypoxia and carbon dioxide. Conversely, sleep restores cellular aerobic enzyme activity and cellular function, especially in the brain and in the muscles that increase the VO2 max during exercise. Better daytime alertness in the control group may also contribute to improved motivation and performance of CPET, with an accompanying increase in VO2 max (Vondra et al., 1981; White et al., 1983). Therefore, poor sleep efficiency and sleep architecture may contribute to exercise limitation in patients with OSAS. Many factors have been reported which could affect the results of CPET. These include age, weight, and hematocrit. To control for age, we chose only subjects between 25 and 55 years old. We excluded subjects with a BMI greater than 33 kg/m2 , and in the control group we only chose subjects with a BMI higher than 25. There was no difference in the mean age and BMI between the two groups, nor there was a significant difference in the baseline hematocrit. In conclusion, patients with OSAS had abnormal CPET results as reflected by low VO2 peak/kg , workpeak, anaerobic threshold, and oxygen pulse. Cardiac dysfunction, lack of fitness, and poor sleep efficiency and abnormal sleep architecture may all contribute to the frequent complaint of these individuals that they cannot exercise vigorously.

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Acknowledgment This research was supported by NSC 89-2314-B195-005.

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