Cardiopulmonary exercise testing in patients with moderate-severe obesity: a clinical evaluation tool for OSA?

In this observational cross-sectional study, we evaluated 185 patients affected by moderate to severe obesity and suspected OSA, consecutively recruited within the Veneto Region diagnostic-therapeutic pathway for patients with obesity. These patients underwent cardiorespiratory sleep study analysis at University Hospital of Padova from February 2014 to January 2020 for suspicion of OSA based on clinical evaluation and a validated questionnaire (Epworth Sleepiness Scale). During the same period, these patients had been referred for functional evaluation to the Sport and Exercise Medicine Division. This study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee (99n/AO/21); all participants provided written informed consent. Inclusion criteria were age between 18 and 70 years, body mass index (BMI) > 35 kg/m², and suspected OSA. Exclusion criteria were significant heart, lung, or musculoskeletal disease that would impede maximal exercise testing. A subgroup of patients affected by OSA was treated with CPAP for at least 8 weeks before functional evaluation. The remaining patients with OSA were not receiving CPAP due to intolerance or were waiting to start therapy. Thus, the patients were divided in three groups:

The cardiorespiratory sleep study was performed using the SOMNOtouchTM® NIBP device (SOMNOmedics Italia), for at least 8 h per night. Peripheral oxygen saturation, respiratory flow in the upper airways, respiratory movements of the chest and abdomen, snoring phases, sleeping position, blood pressure levels, and ECG were recorded. These data were automatically analyzed by the DOMINO software® and subsequently validated by an expert operator according to the most recent American Academy of Sleep Medicine Reviewer criteria [11]. The polysomnographic data encompassed Apnea Hypopnea Index (AHI), minimum percentage oxyhemoglobin saturation (mSaO2%), mean percentage oxyhemoglobin saturation (meanSaO2%), percentage of time with oxyhemoglobin saturation percentage less than 90 (TS < 90%), and number of desaturations with oxyhemoglobin saturation < 90% (nSaO2 < 90%). We were unable to detect peripheral oxygen saturation of 13 participants. In this study, OSA was considered to be present in patients with an AHI of 15 or more events/h [11].

Each patient was subsequently evaluated with incremental, maximal, ECG-monitored CPET (Jaeger Masterscreen-CPX, Carefusion). All tests were performed on treadmill (T170 DE, Cosmed), using the modified Bruce protocol. Criteria of exhaustion were a Borg rating of perceived exertion ≥ 18/20 associated with a Respiratory Exchange Ratio (RER) > 1.10, and/or a peak heart rate (HR) ≥ 85% of predicted HR max, and/or the achievement of a plateau of oxygen uptake (VO₂). Arterial blood pressure and peripheral oxygen saturation were continuously monitored. Ventilatory and gas exchange measurements were sampled breath-by-breath to assess: VO₂, minute ventilation (VE), ventilatory equivalents for carbon dioxide (VE/VCO₂) and end-tidal pressures for oxygen and carbon dioxide (PETO₂ and PETCO₂). VE, VO₂ and PETCO₂ were determined also at the anaerobic threshold (AT) and respiratory compensation point (RCP) [12]. Differences between two PETCO₂ values were presented as ΔPETCO₂, i.e., the difference between the maximum PETCO₂ value reached during testing and PETCO₂ at peak exercise was defined as ΔPETCO₂ max-peak.

According to our data, Ob-OSA presented with lower cardiorespiratory fitness compared to Ob and Ob-CPAP. Different previous studies have evaluated exercise capacity in patients with OSA but only two of them analyzed patients with severe obesity [4, 5]. A recent systematic review and meta-analysis showed a reduced maximal aerobic capacity in patients with OSA, confirming its significant impact on patients’ cardiorespiratory fitness [3]. The reasons for these exercise limitations are not fully understood but different explanations have been proposed, suggesting a multifactorial impairment.

Patients with OSA present more frequently left and right ventricular diastolic dysfunction, respiratory alterations, restrictive pulmonary disease, and pulmonary hypertension, which may all contribute to a reduced maximal aerobic capacity [13, 14]. For this reason, patients affected by these diseases were excluded from this study. Indeed, lung function tests, breathing reserve, oxygen pulse at peak, and the absence of peripheral desaturation during exercise with normal VE/VCO₂ slope were not consistent with major pulmonary or cardiac limitations to exercise.

Furthermore, a decreased maximal lactate concentration and its delayed elimination has been observed in patients with OSA during exercise when compared to age and BMI matched controls and this may indicate impaired glycolytic metabolism and reduced exercise tolerance [15].

Also, musculoskeletal damage has been proposed as possible cause of exercise impairment. Indeed, muscular biopsies have demonstrated structural and bio-energetic changes in skeletal muscle fibers, probably due to continuous or intermittent hypoxia [16].

Sleep-related hypopnea leads to excessive daytime sleepiness, which may affect the ability to achieve maximum exercise workload. Sleep deprivation has already been identified as a limiting factor in exercise time because it seems to increase perceived maximal effort [17]. Moreover, aerobic capacity is influenced by physical activity level, which is known to be lower in patients with OSA [18, 19].

Ob-CPAP exhibited higher aerobic capacity than Ob-OSA, comparable with controls. The continuous CPAP treatment effect on aerobic capacity in patients with OSA has been already described [2]. In fact, CPAP therapy for at least eight consecutive weeks was predominantly associated with significant improvements in VO₂ max [8, 9, 20, 21]. CPAP therapy may normalize gas exchanges during sleep and contribute to structural and bio-energetic changes in skeletal muscles. Furthermore, CPAP associated reduction of sleep deprivation and better daytime alertness may help to increase motivation and performance during CPET, consequently leading to higher maximal aerobic capacity. Indeed, though CPAP therapy does not seem to improve quality of life scores, it has been shown to increase physical domains and vitality of patients with OSA patients [22].

The reduced aerobic capacity found in Ob-OSA may at least in part be due to a lower HR response during exercise [4, 23]. Indeed, several other studies have reported a chronotropic impairment at peak exercise in patients with OSA suggesting a downregulation of beta-adrenergic receptors consequent to sympathetic hyperactivity [24].

The cardiovascular response to exercise was also characterized by a higher DBP at peak exercise in Ob-OSA, which is in line with results of previous studies [15, 25]. However, the Ob-CPAP group showed a similar DBP response during exercise compared to Ob. Indeed, CPAP therapy has been associated with a decrease in sympathetic hyperactivity as assessed by HR variability [20]. Excessive sympathetic activity may contribute to limit maximal aerobic capacity through peripheral vasoconstriction probably due to the activation of excitatory chemoreflex afferents.

OSA is characterized by recurrent upper airway collapse during sleep which may cause CO₂ retention leading to the onset of respiratory acidosis, resulting in compensatory renal retention of bicarbonate ions. This condition leads to a subsequent reduced respiratory frequency and daily ventilation. Although resting ventilation was similar between the three study groups, data showed a reduced ventilatory response to exercise in Ob-OSA. The continuous stimulus by chronic CO₂ retention might cause a dysregulation of the metabolic set point that affects the ventilatory drive, causing it to be less sensitive to CO₂ levels [26]. Moreover, a reduced ventilatory response at high exercise intensities may reduce patients’ exercise tolerance due to limited metabolic buffering and directly influence their maximal aerobic capacity. Indeed, the blunted respiratory drive cannot compensate for the increased respiratory demand during exercise and thus patients with OSA cannot eliminate the extra amount of CO₂ produced during exercise, causing increased levels of PETCO₂ at elevated intensities [27].

PETCO₂ presents a specific pattern during exercise, which is mainly influenced by progressive accumulation of lactic acid during incremental exercise, the subsequent metabolic buffering, and the associated ventilatory response. PETCO₂ rises until reaching the AT, remaining constant during isocapnic buffering until the RCP is reached. Afterwards, a further ventilatory surge exceeds the increase in the respiratory elimination of CO₂ causing a physiological reduction in PETCO₂. The trend of PETCO₂ during the exercise phases seems similar in the different study groups until reaching the RCP, when Ob-OSA showed a lower decreasing trend in PETCO₂ up to peak exercise. Indeed, 16 patients presented a PETCO₂ peak higher than PETCO₂ at the RCP and 15 of them belonged to Ob-OSA group. This is further supported by the positive correlation between PETCO₂ peak and the severity of OSA. Despite the role of PETCO₂ has already been evaluated during sleep in patients with OSA [28], there are only few published data investigating its behavior during exercise, and no information is currently available during CPET in patients with moderate-severe obesity. Our study outcomes in this specific population are in line with preceding studies showing higher PETCO₂ at peak exercise, while these alterations were positively affected when patients were treated with CPAP [8, 29, 30].

ΔPETCO₂ max-peak is an objective and reproducible index that is unaffected by influences related to threshold determination and it can be easily measured in any CPET. ROC analysis showed that ΔPETCO₂ max-peak was a good predictor of OSA and a cut-off value of 1.71 mmHg can be proposed with a good sensitivity and a fair specificity. However, a reduction of PETCO₂ of less than 2 mmHg at peak exercise might be of interest for clinical decision making (sensitivity 74%, specificity 67%). Considering that OSA is more frequent in patients with moderate-severe obesity, this cut-off may help physicians to better interpret CPET values according to patients’ history and symptoms, and to further investigate the potential presence of apnea/hypopnea during sleep, when appropriate.

In this study, patients’ physical activity level was not recorded. Thus, it could not be excluded that differences in VO₂ peak between Ob-OSA and other groups may be due, at least in part, to training levels. Indeed, a proposal for future studies could be the implementation of an objective physical activity monitoring system via accelerometers or at least via a physical activity screening questionnaire.

PETCO₂ has been used to indirectly estimate arterial CO₂ pressure but these values may not match because of ventilation-perfusion mismatch. However, the exclusion criteria used in this study and the substantial normality of VE/VCO₂ slope values should have minimized the risk of such pathological conditions. Future research projects may provide arterial or transcutaneous blood gases measurements to further address these issues.