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Eur J Appl Physiol. 2019 Sep 6. doi: 10.1007/s00421-019-04222-6. [Epub ahead of print]

Unexplained exertional intolerance associated with impaired systemic oxygen extraction.

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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.
Division of Pulmonary and Critical Care Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
Heart and Vascular Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Respiratory Diseases, Dept of Medicine, Federal University of São Paulo (Unifesp), São Paulo, Brazil.
Infectious Disease Unit, Medical Services, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Boston Adult Congenital Heart Service, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.



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; Chronic fatigue syndrome; Exertional intolerance; Hyperventilation; Poor systemic oxygen extraction


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