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Unexplained exertional intolerance associated with impaired systemic oxygen extraction

European Journal of Applied Physiology volume 119, pages 2375–2389 (2019)Cite this article

Abstract

Purpose

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).

Methods

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].

Results

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).

Conclusions

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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Abbreviations

BWH:

Brigham and Women’s Hospital

CaO2 :

Oxygen content in arterial blood

Ca-vO2 :

Difference between oxygen content in arterial and venous blood

CI:

Cardiac index

CvO2 :

Oxygen content in mixed venous blood

DBP:

Diastolic blood pressure

[Hb]:

Hemoglobin concentration

HCO3 :

Bicarbonate

HF:

Heart failure

HFpEF:

Heart failure with preserved ejection fraction

HR:

Heart rate

HV:

Hyperventilators

iCPET:

Invasive cardiopulmonary exercise testing

LVEF:

Left ventricular ejection fraction

MAP:

Mean arterial pressure

MM:

Mitochondrial myopathies

mPAP:

Mean pulmonary arterial pressure

NL:

Normal subjects

PaCO2 :

Partial pressure of carbon dioxide in arterial blood

PAH:

Pulmonary arterial hypertension

PaO2 :

Partial pressure of oxygen in arterial blood

PCWP:

Pulmonary capillary wedge pressure

PH:

Pulmonary hypertension

pHa:

Arterial pH

pHv:

Venous pH

PML:

Pulmonary mechanical limit

PvCO2 :

Partial pressure of carbon dioxide in venous blood

PvO2 :

Partial pressure of oxygen in venous blood

PVR:

Pulmonary vascular resistance

Q t :

Cardiac output

Q tmax :

Cardiac output at maximum exercise

RAP:

Right atrial pressure

RER:

Respiratory exchange ratio

RR:

Respiratory rate

SaO2 :

Oxygen saturation in arterial blood

SBP:

Systolic blood pressure

SOE:

Systemic oxygen extraction

SOEH :

Poor SOE group with high PvO2

SOEL:

Poor SOE group with low PvO2

SVR:

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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Acknowledgements

Julie Tracy, MS.

Funding

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

Author information

Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at UCLA, University of California at Los Angeles, 10833 Le Conte Avenue, 43-229 CHS, Los Angeles, CA, 90095, USA

    Kathryn H. Melamed

  2. Division of Pulmonary and Critical Care Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA

    Mário Santos, Mariana Faria Urbina, Aaron B. Waxman & David M. Systrom

  3. Division of Respiratory Diseases, Dept of Medicine, Federal University of São Paulo (Unifesp), São Paulo, Brazil

    Rudolf K. F. Oliveira

  4. Infectious Disease Unit, Medical Services, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA

    Donna Felsenstein

  5. Boston Adult Congenital Heart Service, Harvard Medical School, Boston Children’s Hospital, Boston, MA, USA

    Alexander R. Opotowsky

  6. Heart and Vascular Center, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Mário Santos, Mariana Faria Urbina, Alexander R. Opotowsky & David M. Systrom

Authors
  1. Kathryn H. Melamed
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  2. Mário Santos
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  3. Rudolf K. F. Oliveira
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  4. Mariana Faria Urbina
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  5. Donna Felsenstein
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  7. Aaron B. Waxman
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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.

Corresponding author

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.

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.

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

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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

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Keywords

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