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Unexplained exertional intolerance associated with impaired systemic oxygen extraction



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


Cardiac index

CvO2 :

Oxygen content in mixed venous blood


Diastolic blood pressure


Hemoglobin concentration

HCO3 :



Heart failure


Heart failure with preserved ejection fraction


Heart rate




Invasive cardiopulmonary exercise testing


Left ventricular ejection fraction


Mean arterial pressure


Mitochondrial myopathies


Mean pulmonary arterial pressure


Normal subjects

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 hypertension


Arterial pH


Venous pH


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 :

Cardiac output

Q tmax :

Cardiac output at maximum exercise


Right atrial pressure


Respiratory exchange ratio


Respiratory rate

SaO2 :

Oxygen saturation in arterial blood


Systolic blood pressure


Systemic oxygen extraction


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 :

Minute ventilation

V Emax :

Minute ventilation at peak exercise

VO2 :

Oxygen uptake

VO2max :

Maximum oxygen uptake


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Julie Tracy, MS.


Funding was received from Solve ME/CFS Foundation (DS).

Author information




KM, MS, RO, MU, AO, AW, and DS performed data collection and analysis. DF and DM performed study design. KM and DS wrote the manuscript. All the authors reviewed, edited, and approved the manuscript.

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Correspondence to Kathryn H. Melamed.

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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.

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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).

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  • Cardiopulmonary exercise testing
  • Exertional intolerance
  • Poor systemic oxygen extraction
  • Hyperventilation
  • Chronic fatigue syndrome