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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

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.

Keywords

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

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

Qt

Cardiac output

Qtmax

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

VE

Minute ventilation

VEmax

Minute ventilation at peak exercise

VO2

Oxygen uptake

VO2max

Maximum oxygen uptake

Notes

Acknowledgements

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

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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