Effect of Normobaric Hypoxia on Exercise Performance in Pulmonary Hypertension: Randomized Trial

Abstract

Background: Many patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension (PH) wish to travel to altitude or by airplane, but their risk of hypoxia-related adverse health effects is insufficiently explored.

Research question: How does hypoxia, compared with normoxia, affect constant work-rate exercise test (CWRET) time in patients with PH, and which physiologic mechanisms are involved?

Study design and methods: Stable patients with PH with resting Pao₂ ≥ 7.3 kPa underwent symptom-limited cycling CWRET (60% of maximal workload) while breathing normobaric hypoxic air (hypoxia; Fio₂, 15%) and ambient air (normoxia; Fio₂, 21%) in a randomized cross-over design. Borg dyspnea score, arterial blood gases, tricuspid regurgitation pressure gradient, and mean pulmonary artery pressure/cardiac output ratio (mean PAP/CO) by echocardiography were assessed before and during end-CWRET.

Results: Twenty-eight patients (13 women) were included: median (quartiles) age, 66 (54; 74) years; mean pulmonary artery pressure, 41 (29; 49) mm Hg; and pulmonary vascular resistance, 5.4 (4; 8) Wood units. Under normoxia and hypoxia, CWRET times were 16.9 (8.0; 30.0) and 6.7 (5.5; 27.3) min, respectively, with a median difference (95% CI) of -0.7 (-3.1 to 0.0) min corresponding to -7 (-32 to 0.0)% (P = .006). At end-exercise in normoxia and hypoxia, respectively, median values and differences in corresponding variables were as follows: Pao₂: 8.0 vs 6.4, -1.7 (-2.7 to -1.1) kPa; arterial oxygen content: 19.2 vs 17.2, -1.7 (-3 to -0.1) mL/dL; Paco₂: 4.7 vs 4.3, -0.3 (-0.5 to -0.1) kPa; lactate: 3.7 vs 3.7, 0.9 (0.1 to 1.6) mM (P < .05 all differences). Values for Borg scale score: 7 vs 6, 0.5 (0 to 1); tricuspid pressure gradient: 89 vs 77, -3 (-9 to 16) mm Hg; and mean PAP/CO: 4.5 vs 3.3, 0.3 (-0.8 to 1.4) Wood units remained unchanged. In multivariable regression, baseline pulmonary vascular resistance was the sole predictor of hypoxia-induced change in CWRET time.

Interpretation: In patients with PH, short-time exposure to hypoxia was well tolerated but reduced CWRET time compared with normoxia in association with hypoxemia, lactacidemia, and hypocapnia. Because pulmonary hemodynamics and dyspnea at end-exercise remained unaltered, the hypoxia-induced exercise limitation may be due to a reduced oxygen delivery causing peripheral tissue hypoxia, augmented lactic acid loading and hyperventilation.

Trial registry: ClinicalTrials.gov; No.: NCT03592927; URL: www.clinicaltrials.gov.

Keywords: altitude; chronic thromboembolic pulmonary hypertension; echocardiography; exercise testing; pulmonary arterial hypertension.