The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
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Brigham and Women’s Hospital
- CaO2 :
Oxygen content in arterial blood
- Ca-vO2 :
Difference between oxygen content in arterial and venous blood
- CvO2 :
Oxygen content in mixed venous blood
Diastolic blood pressure
- HCO3 :
Heart failure with preserved ejection fraction
Invasive cardiopulmonary exercise testing
Left ventricular ejection fraction
Mean arterial pressure
Mean pulmonary arterial pressure
- PaCO2 :
Partial pressure of carbon dioxide in arterial blood
Pulmonary arterial hypertension
- PaO2 :
Partial pressure of oxygen in arterial blood
Pulmonary capillary wedge pressure
Pulmonary mechanical limit
- PvCO2 :
Partial pressure of carbon dioxide in venous blood
- PvO2 :
Partial pressure of oxygen in venous blood
Pulmonary vascular resistance
- Q t :
- Q tmax :
Cardiac output at maximum exercise
Right atrial pressure
Respiratory exchange ratio
- SaO2 :
Oxygen saturation in arterial blood
Systolic blood pressure
Systemic oxygen extraction
- SOEH :
Poor SOE group with high PvO2
Poor SOE group with low PvO2
Systemic vascular resistance
- SvO2 :
Oxygen saturation in mixed venous blood
- VCO2 :
Carbon dioxide output
- V E :
- V Emax :
Minute ventilation at peak exercise
- VO2 :
- VO2max :
Maximum oxygen uptake
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Julie Tracy, MS.
Funding was received from Solve ME/CFS Foundation (DS).
Conflict of interest
ABW and DMS funded by NIH 2R01HL060234-12A1 and U01HL125215-01. ARO supported by the Dunlevie Family Fund. The remaining authors have no conflicts of interest.
All the procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
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Communicated by I. Mark Olfert.
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Melamed, K.H., Santos, M., Oliveira, R.K.F. et al. Unexplained exertional intolerance associated with impaired systemic oxygen extraction. Eur J Appl Physiol 119, 2375–2389 (2019). https://doi.org/10.1007/s00421-019-04222-6
- Cardiopulmonary exercise testing
- Exertional intolerance
- Poor systemic oxygen extraction
- Chronic fatigue syndrome