Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations

Abstract

Background: Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking.

Methods: Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case-control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed.

Results: Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, $\dot{\text{V}}$ e, $\dot{\text{V}}$ O₂, $\dot{\text{V}}$ CO₂, $\dot{\text{V}}$ _T, HR, O₂pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for $\dot{\text{V}}$ e/ $\dot{\text{V}}$ CO₂, PetCO_2, O₂pulse, work, $\dot{\text{V}}$ O₂ and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1.

Conclusions: Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered.

Trial registration number: ClinicalTrials.gov, retrospectively registered, ID# NCT04026425, date of registration: 2019-07-17.

Keywords: Autonomic dysfunction; Cardiopulmonary exercise test; Chronic fatigue syndrome; Fatigue; Functional impairment; ME/CFS; Post exertional malaise; Two-day CPET.

Fig. 1

Work-related variables for CPET-1 and CPET-2 for ME/CFS and controls. Changes in measures related to cardiopulmonary exercise tests (CPET) across ventilatory/anaerobic threshold (VAT) and peak exercise in ME/CFS (n = 84) and controls (CTL; n = 71) and VO₂peak-matched pairs (n = 55). Measures were collected during cardiopulmonary exercise tests (CPET) across day 1 (CPET-1) and day 2 (CPET-2) and include work (A, B), time to level (C, D), and rating of perceived exertion (RPE; E, F). Data were analyzed using 2-way repeated measures ANOVA and are presented as mean ± SD. *denotes p ≤ 0.05 between CPETs, **p ≤ 0.01 between CPETs, ^ap ≤ 0.05 between groups for CPET-1, ^aap ≤ 0.01 between groups for CPET-1, ^bp ≤ 0.05 between groups for CPET-2, ^bbp ≤ 0.01 between groups for CPET-2

Fig. 2

Ventilatory variables for CPET-1 and CPET-2 for ME/CFS and controls. Changes in measures related to ventilatory function across rest, ventilatory/anaerobic threshold (VAT), and peak exercise in ME/CFS (n = 84) and controls (CTL; n = 71) and VO₂peak-matched pairs (n = 55). Measures were collected during cardiopulmonary exercise tests (CPET) across day 1 (CPET-1) and day 2 (CPET-2) and include tidal volume (TV; A, B), respiratory rate (RR; C, D), minute ventilation (VE; E, F), relative (G, H) and absolute (I, J) O₂ consumption, CO₂ production (K, L), ventilatory equivalents of O₂ (VE/VO₂; M, N) and CO₂ (VE/VCO₂; O, P), and respiratory exchange ratio (RER; Q, R). Data were analyzed using 2-way repeated measures ANOVA and are presented as mean ± SD. *denotes p ≤ 0.05 between CPETs, **p ≤ 0.01 between CPETs, ^ap ≤ 0.05 between groups for CPET-1, ^aap ≤ 0.01 between groups for CPET-1, ^bp ≤ 0.05 between groups for CPET-2, ^bbp ≤ 0.01 between groups for CPET-2

Fig. 3

Hemodynamic variables for CPET-1 and CPET-2 for ME/CFS and controls. Changes in measures related to hemodynamic function across rest, ventilatory/anaerobic threshold (VAT), and peak exercise in ME/CFS (n = 84) and controls (CTL; n = 71) and VO₂peak-matched pairs (n = 55). Measures were collected during cardiopulmonary exercise tests (CPET) across day 1 (CPET-1) and day 2 (CPET-2) and include heart rate (HR; A, B), systolic blood pressure (SBP; C, D), diastolic blood pressure (DBP; E, F), pulse pressure (PP; G, H), rate pressure product (RPP; I, J), and O₂pulse (K, L). Data were analyzed using 2-way repeated measures ANOVA and are presented as mean ± SD. *denotes p ≤ 0.05 between CPETs, **p ≤ 0.01 between CPETs, ^ap ≤ 0.05 between groups for CPET-1, ^aap ≤ 0.01 between groups for CPET-1, ^bp ≤ 0.05 between groups for CPET-2, ^bbp ≤ 0.01 between groups for CPET-2

Fig. 4

End tidal gas measures throughout CPET-1 and CPET-2 for ME/CFS and controls. Changes in measures related to end tidal gases across rest, ventilatory/anaerobic threshold (VAT), and peak exercise in ME/CFS (n = 84) and controls (CTL; n = 71) and VO₂peak-matched pairs (n = 55). Measures were colleged during cardiopulmonary exercise tests (CPET) across day 1 (CPET-1) and day 2 (CPET-2) and include end tidal O₂ (A, B) and end tidal CO₂ (C, D). Data were analyzed using 2-way repeated measures ANOVA and are presented as mean ± SD. *denotes p ≤ 0.05 between CPETs, **p ≤ 0.01 between CPETs, ^ap ≤ 0.05 between groups for CPET-1, ^aap ≤ 0.01 between groups for CPET-1, ^bp ≤ 0.05 between groups for CPET-2, ^bbp ≤ 0.01 between groups for CPET-2

Fig. 5

Clinical impairment of ME/CFS and controls during CPET-1 and CPET-2. Impairment status of ME/CFS (n = 84) and controls (CTL; n = 71), and VO₂peak-matched pairs (n = 55) was assigned using established impairment ratings of Weber & Janicki (1985) and Arena & Sietsema (2011) for VO₂ at ventilatory/anaerobic threshold (VAT; A, B), VO₂peak (C, D) and VE/VCO₂ at VAT (E, F). Data are expressed as percentage of cases within each of the impairment classifications for CPET-1 and CPET-2