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Cited by 5High Altitude and HypoxiaCardiovascular and exercise physiologyExercise and Physiological Responses

The DOI matches its Crossref record; 72 of the 72 references it cites were found in a registry or an index; none of the 61 sources its claims cite is checked for support yet.

Effect of live‐high, train‐low strategy induced by chronic low‐dose carbon monoxide exposure on haematological parameters and performance in trained individuals

Open access
Villanova, Simone, Porcelli, Simone, Ekström, Lena, Cardinale, Daniele A.·2026·Experimental Physiology
DOI 10.1113/ep093005PMC PMC13140526
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Abstract

Altitude training enhances haematological adaptations and endurance at sea level, typically requiring exposure to ∼2500 m altitude for 3–4 weeks. Emerging evidence suggests that low‐dose carbon monoxide (CO) inhalation might mimic hypoxia and might be used by elite athletes. In this study, we examine whether periodic low‐dose CO exposure can replicate the live‐high, train‐low model in well‐trained individuals, focusing primarily on haematological and performance effects of CO exposure, with haematological markers commonly used to interpret haemoglobin mass changes discussed as exploratory. Eight well‐trained individuals (four males and four females) participated in a randomized crossover study. They completed two training blocks of 4 weeks at sea level: one with CO inhalation (INCO) to simulate live‐high, train‐low and one with ambient air as a control (AIR), separated by a 6 month washout. Haematological variables, in vivo muscle oxidative capacity and performance metrics were assessed before and after each intervention. After INCO, haemoglobin mass ( p = 0.018; +53.6 ± 10.8 g. vs. +0.8 ± 11.8 g), red blood cell volume ( p = 0.032; +156.6 ± 66.7 mL vs. −65.1 ± 50.7 mL) and blood volume ( p = 0.036; +240.4 ± 120.5 mL vs. −208.3 ± 167.5 mL) increased significantly compared with AIR. INCO significantly reduced immature reticulocytes ( p = 0.04), but muscle oxidative capacity and performance metrics remained unchanged. These findings suggest that daily low‐dose CO exposure at sea level over 4 weeks enhanced haematological adaptations more than standard training but did not affect muscle oxidative capacity or performance.

Overview

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TL;DR

In a randomized crossover study of eight well-trained swimmers, 4 weeks of low-dose carbon monoxide inhalation at sea level increased haemoglobin mass, red blood cell volume, and blood volume compared with ambient-air control. However, muscle oxidative capacity and swimming performance metrics did not improve.

Key findings

  • Haemoglobin mass increased after INCO vs AIR: +53.6 ± 10.8 g vs +0.8 ± 11.8 g (treatment effect p = 0.018; time effect p = 0.013), corresponding to a 5.7% increase vs 0.1%.
  • Red blood cell volume increased after INCO vs AIR: +156.6 ± 66.7 mL vs −65.1 ± 50.7 mL (p = 0.032), and blood volume increased: +240.4 ± 120.5 mL vs −208.3 ± 167.5 mL (p = 0.036).
  • Immature reticulocyte fraction decreased significantly post-INCO (time effect p = 0.031; treatment effect p = 0.042), while [Hb], HCT, and other standard haematological markers showed no significant time or treatment effects.
  • Muscle oxidative capacity and submaximal/maximal swimming performance metrics remained unchanged; the estimated hypoxic dose for INCO was 847.9 km h.

Methods

  • Eight well-trained individuals (four males, four females) completed a single-blind, randomized crossover study with two 4-week sea-level training blocks: INCO (CO inhalation to simulate live-high, train-low) and AIR (ambient air placebo), separated by a ~6-month washout.
  • CO was inhaled three times daily at rest, 6 days/week, with boluses tailored to raise [COHb]; mean [COHb] was 9.0% [1.9, 16.0] for INCO and 1.1% [1.0, 1.2] for AIR.
  • Outcomes included Hbmass and intravascular blood volumes by CO-rebreathing, haematological and urinary steroid markers, muscle oxidative capacity by NIRS, and swimming performance/lactate profile; analysis used ANCOVA with baseline as covariate, paired t-tests, and univariate ANOVA.

Limitations

  • The paper states the small sample size of eight participants may limit generalizability, the mechanism of the erythropoietic response could not be explained, no skeletal muscle biopsy was obtained, performance testing lacked a tapering phase, and only one baseline sample limited Athlete Biological Passport adaptive-model assessment.
  • The text also makes evident that V̇O2max and erythropoietin were not measured, so the link between increased Hbmass and maximal aerobic capacity or the proposed erythropoietin drive could not be directly assessed.
  • The study was single-blind, and the authors note the performance tests and post-intervention timing may have been insufficient to capture benefits of increased blood oxygen-carrying capacity.

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Integrity signals

Registry

Crossref · 10.1113/ep093005

Cites

72 of 72 references verified0 citation errors · 0 not checkable

Statistics

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Figures

FIGURE 1 Column bar charts showing the mean + SD and individual data points (circle, male; and triangle, female) following the ‘live‐high, train‐low’ approach with carbon monoxide inhalation (INCO; n = 8) and the ‘sea‐level control’ approach (AIR; n = 7) for haemoglobin mass (Hbmass; a), red blood cell volume (RBCV; b), plasma volume (PV; c) and total blood volume (BV; d). *Differences between the two training periods (INCO vs. AIR).
FIGURE 1 Column bar charts showing the mean + SD and individual data points (circle, male; and triangle, female) following the ‘live‐high, train‐low’ approach with carbon monoxide inhalation (INCO; n = 8) and the ‘sea‐level control’ approach (AIR; n = 7) for haemoglobin mass (Hbmass; a), red blood cell volume (RBCV; b), plasma volume (PV; c) and total blood volume (BV; d). *Differences between the two training periods (INCO vs. AIR).CC BY · PubMed Central

Verification

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Citations

Cites

1 retracted

Research works printed but not linked: 3

  1. Haldane J. B. S., 1912, The dissociation of oxyhemoglobin in human blood during partial CO poisoning, The Journal of Physiology, 45, 1912
  2. Olbrecht J., 1992, Biomechanics and medicine in swimming. swimming science VI, 243
  3. WHO guidelines for indoor air quality: selected pollutants

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Metadata

Authors
Villanova, S., Porcelli, S., Ekström, L., & Cardinale, D. A.
Affiliations
  • Foro Italico University of Rome (IT)
  • University of Pavia (IT)
  • Karolinska Institutet (SE)
Corresponding author
Cardinale, Daniele A.
ORCID
Venue
Experimental Physiology
Publisher
Wiley
Published
2026-01-12
Volume
111
Issue
4
Pages
1891-1903
ISSN
  • 0958-0670 (ISSN-L)
  • 1469-445X
DOI
10.1113/ep093005
PMC
PMC13140526
OpenAlex
W7123355368
Cited by
5
References
72
Citations by year
2026: 5
FWCI
15.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental Physiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Diva portal (Dalarna University Library) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Karolinska Institutet
Topics
  • Health Sciences › Medicine › Physiology (medical) › High Altitude and Hypoxia
  • Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
  • Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
Keywords
carbon monoxide inhalation, live high-train low, altitude training, hemoglobin mass, erythrocyte volume, blood volume, reticulocytes, muscle oxidative capacity, endurance performance, trained athletes
MeSH terms
Adaptation, Physiological, Adult, Altitude, Hypoxia, Carbon Monoxide, Female, Hemoglobins, Humans, Male, Oxygen Consumption, Physical Endurance, Exercise, Muscle, Skeletal, Cross-Over Studies, Young Adult, Athletes

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Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.