Unexplained exertional intolerance associated with impaired systemic oxygen extraction

  • Kathryn H. MelamedEmail author
  • Mário Santos
  • Rudolf K. F. Oliveira
  • Mariana Faria Urbina
  • Donna Felsenstein
  • Alexander R. Opotowsky
  • Aaron B. Waxman
  • David M. Systrom
Original Article



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.


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



Brigham and Women’s Hospital


Oxygen content in arterial blood


Difference between oxygen content in arterial and venous blood


Cardiac index


Oxygen content in mixed venous blood


Diastolic blood pressure


Hemoglobin concentration




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


Partial pressure of carbon dioxide in arterial blood


Pulmonary arterial hypertension


Partial pressure of oxygen in arterial blood


Pulmonary capillary wedge pressure


Pulmonary hypertension


Arterial pH


Venous pH


Pulmonary mechanical limit


Partial pressure of carbon dioxide in venous blood


Partial pressure of oxygen in venous blood


Pulmonary vascular resistance


Cardiac output


Cardiac output at maximum exercise


Right atrial pressure


Respiratory exchange ratio


Respiratory rate


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


Oxygen saturation in mixed venous blood


Carbon dioxide output


Minute ventilation


Minute ventilation at peak exercise


Oxygen uptake


Maximum oxygen uptake



Julie Tracy, MS.

Author contributions

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.


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

Compliance with ethical standards

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.

Ethical approval

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.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

421_2019_4222_MOESM1_ESM.docx (94 kb)
Supplementary file1 (DOCX 94 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Kathryn H. Melamed
    • 1
    Email author
  • Mário Santos
    • 2
    • 6
  • Rudolf K. F. Oliveira
    • 3
  • Mariana Faria Urbina
    • 2
    • 6
  • Donna Felsenstein
    • 4
  • Alexander R. Opotowsky
    • 5
    • 6
  • Aaron B. Waxman
    • 2
  • David M. Systrom
    • 2
    • 6
  1. 1.Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLAUniversity of California at Los AngelesLos AngelesUSA
  2. 2.Division of Pulmonary and Critical Care Medicine, Harvard Medical SchoolBrigham and Women’s HospitalBostonUSA
  3. 3.Division of Respiratory Diseases, Dept of MedicineFederal University of São Paulo (Unifesp)São PauloBrazil
  4. 4.Infectious Disease Unit, Medical Services, Harvard Medical SchoolMassachusetts General HospitalBostonUSA
  5. 5.Boston Adult Congenital Heart Service, Harvard Medical SchoolBoston Children’s HospitalBostonUSA
  6. 6.Heart and Vascular Center, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA

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