Decreased oxygen extraction during cardiopulmonary exercise test in patients with CFS: Implications for exercise intolerance

Journal Article: Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome

Vermeulen, R. C. W.* and v. E. I. W. G. Vermeulen. “Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome.” J Transl Med, 2014, 12: 20.

* Correspondence:
CFS/ME Medical Centre Amsterdam, Waalstraat 25-31, Amsterdam 1078BR, Netherlands

This article has previously been mentioned in a post: here.



The insufficient metabolic adaptation to exercise in Chronic Fatigue Syndrome (CFS) is still being debated and poorly understood.


We analysed the cardiopulmonary exercise tests of CFS patients, idiopathic chronic fatigue (CFI) patients and healthy visitors. Continuous non-invasive measurement of the cardiac output by Nexfin® (BMEYE B.V. Amsterdam, the Netherlands) was added to the cardiopulmonary exercise tests. The peak oxygen extraction by muscle cells and the increase of cardiac output relative to the increase of oxygen uptake (ΔQ’/ΔV’O2) were measured, calculated from the cardiac output and the oxygen uptake during incremental exercise.


The peak oxygen extraction by muscle cells was 10.83 ± 2.80 ml/100ml in 178 CFS women, 11.62 ± 2.90 ml/100 ml in 172 CFI, and 13.45 ± 2.72 ml/100 ml in 11 healthy women (ANOVA: P=0.001), 13.66 ± 3.31 ml/100 ml in 25 CFS men, 14.63 ± 4.38 ml/100 ml in 51 CFI, and 19.52 ± 6.53 ml/100 ml in 7 healthy men (ANOVA: P=0.008). The ΔQ’/ΔV’O2 was > 6 L/L (normal ΔQ’/ΔV’O2 ≈ 5 L/L) in 70% of the patients and in 22% of the healthy group.


Low oxygen uptake by muscle cells causes exercise intolerance in a majority of CFS patients, indicating insufficient metabolic adaptation to incremental exercise. The high increase of the cardiac output relative to the increase of oxygen uptake argues against deconditioning as a cause for physical impairment in these patients.

Background & Discussion

Exercise intolerance is, almost universally, experienced by people with ME/CFS (and Idiopathic Chronic Fatigue – CFI). Like the illness itself, it varies in intensity. Objective tests for physical impairment measure the maximal oxygen uptake (V’O2) during a cardiopulmonary exercise test (CPET).

The authors state that most studies agree that peak V’O2 is lower in ME/CFS, but we need to understand the cause of the lower peak V’O2 to explain the pathogenesis (the biochemical mechanism that led to this).

The V’O2 depends on the uptake, transport and metabolism of oxygen in the muscle cells during physical exercise. In most CPET studies in ME/CFS patients, the limitation of peak V’O2 is not attributed to a lower uptake and transport of oxygen to the muscle. A lower metabolic capacity of the muscle cell would change the demand for oxygen and thus lower the oxygen extraction (C(a-v)O2) and increase the cardiac output relative to V’O2 (ΔQ’/ΔV’O2).

In previous studies the authors and others did not find that impaired mitochondrial activity to be a cause for a lower peak V’O2 in ME/CFS patients but abnormal mitochondrial activity was reported by some in ME/CFS and CFI patients [1][2].

The authors set out to retrospectively analyse data from patients who attended the CFS Medical Centre Amsterdam and determine to what extent the physical impairment in CFS and CFI was attributable to changes in uptake, transport and metabolism of oxygen in the muscle cells. These consisted of a total of 444 subjects who attended between June 2008 and June 2013: 203 CFS patients (178 women), 223 CFI patients (172 women) and 18 healthy visitors (11 women).

They wished to determine to what extent the intolerance to exercise in ME/CFS (and CFI – Idiopathic Chronic Fatigue) was attributable to changes in uptake, transport and metabolism of oxygen in the muscle cells. They also collected data from sedentary men and women (those who exercised less than 1 hour per week) as controls.

They subjected the patients to cardiopulmonary exercise tests (CPETs) which comprised a symptom limited CPET on a cycle ergometer. The protocol was described in a previous paper of the authors’ in 2010. It involved “3 min without activity, 3 min of unloaded pedalling, followed by cycling against increasing resistance until exhaustion (ramp protocol) and concluded by 3 min cycling without resistance… Verbal encouragement was used to maximise performance during the last phase of incremental exercise. Exhaustion of the leg muscles was the limiting symptom in all participants.”

Various measurements were made including: V’O2, oxygen saturation (both continuously measured) and blood pressure (measured every 2 min). Oxygen extraction (and ΔQ’/ΔV’O2) were calculated from the oxygen uptake and the cardiac output.

The researchers found the most probable cause for the low peak V’O2, the low oxygen extraction and the high ΔQ’/ΔV’O2 in CFS and CFI patients was an attenuated cell metabolism, that is lower than normal energy production in one’s cells. Low oxygen extraction was also reported for a number of other disorders including mitochondrial pathology, systemic lupus erythematosus (SLE), HIV and myophosphorylase deficiency.

The mean O2 extraction at maximal workload in fatigue patients was comparable to asymptomatic HIV infected individuals.

Surprisingly, the peak V’O2 of 73 CFS patients and 59 CFI patients was the same as or higher than the mean peak V’O2 of healthy sedentary people. All CFS and CFI patients, however, experienced a physical impairment that was severe enough for their diagnosis. The authors made the conclusion that this must be because the subjective experience of physical impairment and the objective peak V’O2 in the CPET are not identical.

The authors ask if the mitochondria are intact in ME/CFS patients then the low oxygen extraction in a subgroup of ME/CFS patients might be due to a “downregulation of the activity in vivo” – meaning the activity of the mitochondria in the body has been decreased by some regulatory process.

Conclusion & Limitations of the Study

This retrospective study showed that a low oxygen extraction (and a high ΔQ’/ΔV’O2) were consistent with a metabolic cause for exercise intolerance in 70% of ME/CFS patients in the study. This argues against deconditioning as the cause of physical impairment in people with ME/CFS, rather insufficient cell metabolism being responsible.

The main limitation of the study was that no laboratory data were collected on the healthy subjects. So undiagnosed diseases could not be ruled out for this group.

Additional References

Vermeulen, R. C. W., et al. “Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity.” J Transl Med, 2010, 8: 93.

Myhill, S., et al. “Chronic fatigue syndrome and mitochondrial dysfunction.” Int. J. Clin. Exp. Med., 2009, 2(1): 1-16.

Vernon, S. D., et al. “Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus.” BMC Infect. Dis., 2006, 6: 7.

Taivassalo, T., et al. “The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients.” Brain, 2003, 126(Pt 2): 413-423.

Cade, W. T., et al. “Decreased peak arteriovenous oxygen difference during treadmill exercise testing in individuals infected with the human immunodeficiency virus.” Arch Phys Med Rehabil, 2003, 84(11): 1595-1603.

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