European Journal of Applied Physiology

, Volume 119, Issue 11–12, pp 2529–2544 | Cite as

Steady-state cerebral blood flow regulation at altitude: interaction between oxygen and carbon dioxide

  • Hailey C. Lafave
  • Shaelynn M. Zouboules
  • Marina A. James
  • Graeme M. Purdy
  • Jordan L. Rees
  • Craig D. Steinback
  • Peter Ondrus
  • Tom D. Brutsaert
  • Heidi E. Nysten
  • Cassandra E. Nysten
  • Ryan L. Hoiland
  • Mingma T. Sherpa
  • Trevor A. DayEmail author
Original Article


High-altitude ascent imposes a unique cerebrovascular challenge due to two opposing blood gas chemostimuli. Specifically, hypoxia causes cerebral vasodilation, whereas respiratory-induced hypocapnia causes vasoconstriction. The conflicting nature of these two superimposed chemostimuli presents a challenge in quantifying cerebrovascular reactivity (CVR) in chronic hypoxia. During incremental ascent to 4240 m over 7 days in the Nepal Himalaya, we aimed to (a) characterize the relationship between arterial blood gas stimuli and anterior, posterior and global (g)CBF, (b) develop a novel index to quantify cerebral blood flow (CBF) in relation to conflicting steady-state chemostimuli, and (c) assess these relationships with cerebral oxygenation (rSO2). On rest days during ascent, participants underwent supine resting measures at 1045 m (baseline), 3440 m (day 3) and 4240 m (day 7). These measures included pressure of arterial (Pa)CO2, PaO2, arterial O2 saturation (SaO2; arterial blood draws), unilateral anterior, posterior and gCBF (duplex ultrasound; internal carotid artery [ICA] and vertebral artery [VA], gCBF [{ICA + VA} × 2], respectively) and rSO2 (near-infrared spectroscopy). We developed a novel stimulus index (SI), taking into account both chemostimuli (PaCO2/SaO2). Subsequently, CBF was indexed against the SI to assess steady-state cerebrovascular responsiveness (SS-CVR). When both competing chemostimuli are taken into account, (a) SS-CVR was significantly higher in ICA, VA and gCBF at 4240 m compared to lower altitudes, (b) delta SS-CVR with ascent (1045 m vs. 4240 m) was higher in ICA vs. VA, suggesting regional differences in CBF regulation, and (c) ICA SS-CVR was strongly and positively correlated (r = 0.79) with rSO2 at 4240 m.


Cerebral blood flow Cerebrovascular reactivity High altitude Hypoxia Hypocapnia 



Arterial blood gas


Arterial oxygen content


Cerebrovascular conductance


Cerebral blood flow


Cerebrovascular reactivity


Cerebral blood velocity


Cerebral oxygen delivery


Global cerebral blood flow


Internal carotid artery


Pressure or arterial carbon dioxide


Pressure of arterial oxygen


Regional cerebral oxygen saturation


Arterial oxygen saturation


Stimulus index (PaCO2/SaO2)


Steady-state cerebrovascular reactivity


Steady-state cerebrovascular conductance reactivity


Vertebral artery



We gratefully acknowledge the time and effort of our research participants and our Sherpa guide team. The principal investigator (TAD) dedicates this manuscript to the memory of Dr. Christopher Willie.

Author contributions

HCL: data analysis, intellectual contribution, first draft of manuscript, and manuscript editing; SMZ: data analysis and manuscript editing; MAJ, GMP, JLR, PO, TDB, HEN, and CEN: data collection, manuscript editing; CDS, intellectual contribution, assistance with ethics, and manuscript editing; RLH: intellectual contribution and manuscript editing, MTS: Nepalese collaboration, assistance with ethics in Nepal, and manuscript editing; TAD: study design, expedition organizer, ethical clearance, funding, data analysis, intellectual contribution, and manuscript editing. All listed co-authors approved the final version of the manuscript, agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, all persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.


Financial support for this work was provided by (a) Natural Sciences and Engineering Research Council of Canada (NSERC) Undergraduate Student Research Assistantship (SZ, HL); (b) Alberta Innovates Health Solution Summer studentship (CN); (c) Government of Alberta Student Temporary Employment Program (SZ), and NSERC Discovery grants (TAD; RGPIN-2016-04915; CDS RGPIN-2015-06637).

Compliance with ethical standards

Conflict of interest

The author declares that they have no conflict of interest.


  1. Ainslie PN, Ogoh S (2010) Regulation of cerebral blood flow in mammals during chronic hypoxia: a matter of balance. Exp Physiol 95:251–262PubMedGoogle Scholar
  2. Ainslie PN, Poulin MJ (2004) Ventilatory, cerebrovascular, and cardiovascular interactions in acute hypoxia: regulation by carbon dioxide. J Appl Physiol 97:149–159PubMedGoogle Scholar
  3. Ainslie PN, Subudhi A (2014) cerebral blood flow at high altitude. High Alt Med Biol 15:133–140PubMedGoogle Scholar
  4. Ainslie PN, Shaw AD, Smith KJ, Willie CK, Ikeda K, Graham J, Macleod DB (2014) Stability of cerebral metabolism and substrate availability in humans during hypoxia and hyperoxia. Clin Sci (Lond) 126(9):661–670Google Scholar
  5. Bakker A, Smith B, Ainslie PN, Smith K (2012). Near-infrared spectroscopy, applied aspects of ultrasonography in humans. In: Philip A (ed) Near-infrared spectroscopy. ISBN: 978-953-51-0522-0, InTech. Accessed 1 Mar 2019Google Scholar
  6. Bernardi L, Schneider A, Pomidori L, Paolucci E, Cogo A (2006) Hypoxic ventilatory response in successful extreme altitude climbers. Eur Respir J 27:165–171PubMedGoogle Scholar
  7. Binks A, Cunningham V, Adams L, Banzett R (2008) Gray matter blood flow change is unevenly distributed during moderate isocapnic hypoxia in humans. J Appl Physiol 104:212–217PubMedGoogle Scholar
  8. Brown M, Wade J, Marshall J (1985) Fundamental importance of arterial oxygen content in the regulation of cerebral blood flow in man. Brain 108:81–93PubMedGoogle Scholar
  9. Bruce CD, Steinback CD, Chauhan U, Pfoh J, Abrosimova M, Vanden Berg ER, Skow R, Davenport M, Day TA (2016) Quantifying cerebrovascular reactivity in anterior and posterior cerebral circulations during voluntary breath holding. Exp Physiol 101:1517–1527PubMedGoogle Scholar
  10. Bruce CD, Saran G, Pfoh JR, Leacy JK, Zouboules SM, Mann CR, Peltonen JDB, Linares AM, Chiew AE, O’Halloran KD, Sherpa MT, Day TA (2018) What is the point of the peak? assessing steady-state respiratory chemoreflex drive in high altitude field studies. In: Gauda E, Monteiro M, Prabhakar N, Wyatt C, Schultz H (eds) Arterial chemoreceptors. Advances in experimental medicine and biology, vol 1071, chapter 2. Springer, Cham, pp 13–23Google Scholar
  11. Brugniaux J, Hodges A, Hanly P, Poulin M (2007) Cerebrovascular responses to altitude. Respir Physiol Neurobiol 158:212–223PubMedGoogle Scholar
  12. Chernecky CC, Berger BJ (2004) Laboratory tests & diagnostic procedures. Elsevier Inc., PhiladelphiaGoogle Scholar
  13. Dempsey JA, Forster HV (1982) Mediation of ventilatory adaptations. Physiol Rev 62:262–346PubMedGoogle Scholar
  14. Dempsey JA, Powell FL, Bisgard GE, Blain GM, Poulin MJ, Smith CA (2014) Role of chemoreception in cardiorespiratory acclimatization to, and deacclimatization from, hypoxia. J Appl Physiol 116:858–866PubMedGoogle Scholar
  15. Faraci F, Heistad D, Mayhan W (1987) Role of large arteries in regulation of blood flow to brain stem in cats. J Physiol 387:115–123PubMedPubMedCentralGoogle Scholar
  16. Feddersen B, Neupane P, Thanbichler F, Hadolt I, Sattelmeyer V, Pfefferkorn T, Waanders R, Noachtar S, Ausserer H (2015) Regional differences in the cerebral blood flow velocity response to hypobaric hypoxia at high altitudes. J Cereb Blood Flow Metab 35:1846–1851PubMedPubMedCentralGoogle Scholar
  17. Flück D, Siebenmann C, Keiser S, Cathomen A, Lundby C (2015) Cerebrovascular reactivity is increased with acclimatization to 3,454 M altitude. J Cereb Blood Flow Metab 35:1323–1330PubMedPubMedCentralGoogle Scholar
  18. Ge R, Babb TG, Sivieri M, Resaland GK, Karlsen T, Stray-Gundersen J, Levine BD (2006) Urine acid–base compensation at simulated moderate altitude. High Alt Med Biol 7:64–71PubMedGoogle Scholar
  19. Gonzalez-Alonso J, Richardson R, Saltin B (2001) Exercising skeletal muscle blood flow in humans responds to reduction in arterial oxyhaemoglobin, but not to altered free oxygen. J Physiol 530:331–341PubMedPubMedCentralGoogle Scholar
  20. Grocott M, Martin D, Levett D, McMorrow R, Windsor J, Montgomery H (2009) Arterial blood gases and oxygen content in climbers on mount everest. N Engl J Med 360:140–149PubMedGoogle Scholar
  21. Hadolt I, Litscher G (2003) Noninvasive assessment of cerebral oxygenation during high altitude trekking in the Nepal Himalayas (2850–5600 m). Neurol Res 25:183–188PubMedGoogle Scholar
  22. Hoiland R, Ainslie P, Wildfong K, Smith K, Bain A, Willie C, Foster G, Monteleone B, Day T (2015) Indomethacin-induced impairment of regional cerebrovascular reactivity: implications for respiratory control. J Physiol 593:1291–1306PubMedPubMedCentralGoogle Scholar
  23. Hoiland R, Bain R, Rieger M, Bailey D, Ainslie P (2016) Hypoxemia, oxygen content, and the regulation of cerebral blood flow. Am J Physiol Regul Integr Comp Physiol 310:R398–413PubMedGoogle Scholar
  24. Hoiland R, Smith K, Carter H, Lewis N, Tymko M, Wildfong K, Bain A, Green D, Ainslie P (2017) Shear-mediated dilation of the internal carotid artery occurs independent of hypercapnia. Am J Physiol Circ Physiol 313:H24–H31Google Scholar
  25. Hoiland RL, Howe CA, Coombs GB, Ainslie PN (2018) Ventilatory and cerebrovascular regulation and integration at high-altitude. Clin Auton Res 28(4):423–435PubMedGoogle Scholar
  26. Jensen J, Sperling B, Severinghaus J, Lassen N (1996) Augmented hypoxic cerebral vasodilation in men during 5 days at 3,810 m altitude. J Appl Physiol 80:1214–1218PubMedGoogle Scholar
  27. Kety S, Schmidt C (1948) The effects of altered arterial tensions of carbon dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of normal young men. J Clin Invest 27:484–492PubMedPubMedCentralGoogle Scholar
  28. Kim J, Baek S (2011) Circumferential variations of mechanical behavior of the porcine thoracic aorta during the inflation test. J Biomech 44:1941–1947PubMedGoogle Scholar
  29. Krapf R, Beeler I, Hertner D, Hulter HN (1991) Chronic respiratory alkalosis. The effect of sustained hyperventilation on renal regulation of acid-base equilibrium. N Engl J Med 324(20):1394–1401PubMedGoogle Scholar
  30. Lawley J, Macdonald J, Oliver S, Mullins P (2017) Unexpected reductions in regional cerebral perfusion during prolonged hypoxia. J Physiol 595:935–947PubMedGoogle Scholar
  31. Lewis N, Messinger L, Monteleone B, Ainslie P (2014) Effect of acute hypoxia on regional cerebral blood flow: effect of sympathetic nerve activity. J Appl Physiol 116:1189–1196PubMedPubMedCentralGoogle Scholar
  32. Lu D, Kassab G (2011) Role of shear stress and stretch in vascular mechanobiology. J R Soc Interface 8:1379–1385PubMedPubMedCentralGoogle Scholar
  33. Naeije R (2010) Physiological adaptation of the cardiovascular system to high altitude. Prog Cardiovasc Dis 52:456–466PubMedGoogle Scholar
  34. Norcliffe L, Rivera-Ch M, Claydon V, Moore J, Leon-Velarde F, Appenzeller O, Hainsworth R (2005) Cerebrovascular responses to hypoxia and hypocapnia in high-altitude dwellers. J Physiol 566:287–294PubMedPubMedCentralGoogle Scholar
  35. Ogoh S, Sato K, Nakahara H, Okazaki K, Subudhi A, Miyamoto T (2013) Effect of acute hypoxia on blood flow in vertebral and internal carotid arteries. Exp Physiol 98:692–698PubMedGoogle Scholar
  36. Pfoh JR, Steinback CD, Vanden Berg ER, Bruce CD, Day TA (2017) Assessing chemoreflexes and oxygenation in the context of acute hypoxia: implications for field studies. Respir Physiol Neurobiol 246:67–75PubMedGoogle Scholar
  37. Poulin M, Fatemian M, Tansley J, O’Connor D, Robbins P (2002) Changes in cerebral blood flow during and after 48 h of both isocapnic and poikilocapnic hypoxia in humans. Exp Physiol 87:633–642PubMedGoogle Scholar
  38. Prabhakar N (2000) Oxygen sensing by the carotid body chemoreceptors. J Appl Physiol 88:2287–2295PubMedGoogle Scholar
  39. Pugh L (1964) Blood volume and haemoglobin concentration at altitudes above 18,000 ft. (5500m). J Physiol 170:344–354PubMedPubMedCentralGoogle Scholar
  40. Roach R, Koskolou M, Calbet J, Saltin B (1999) Arterial O2 content and tension in regulation of cardiac output and leg blood flow during exercise in humans. Am J Physiol 276:H438–H445PubMedGoogle Scholar
  41. Rubanyi G, Romero J, Vanhoutte P (1986) Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 250:H1145–H1149PubMedGoogle Scholar
  42. Sagarmatha National Park Office (2017) Sagarmatha National Park fact sheet. Sagarmatha National Park Office, Namche BazaarGoogle Scholar
  43. Skow R, MacKay C, Tymko M, Willie C, Smith K, Ainslie P, Day T (2013) Differential cerebrovascular CO2 reactivity in anterior and posterior cerebral circulations. Respir Physiol Neurobiol 189:76–86PubMedGoogle Scholar
  44. Sriram K, Laughlin J, Rangamani P, Tartakovsky D (2016) Shear-induced nitric oxide production by endothelial cells. Biophys J 111:208–221PubMedPubMedCentralGoogle Scholar
  45. Subudhi A, Fan L, Evero O, Bourdillon N, Kayser B, Julian C, Lovering A, Roach R (2014) AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery. Exp Physiol 99:772–781PubMedGoogle Scholar
  46. Swenson ER (2016) Hypoxia and its acid–base consequences: from mountains to malignancy. Adv Exp Med Biol 903:301–323PubMedGoogle Scholar
  47. Teppema L, Dahan A (2010) The ventilatory response to hypoxia in mammals: mechanisms, measurement, and analysis. Physiol Rev 90:675–754PubMedGoogle Scholar
  48. Tymko M, Ainslie P, Smith K (2018) Evaluating the methods used for measuring cerebral blood flow at rest and during exercise in humans. Eur J Appl Physiol 118:1527–1538PubMedGoogle Scholar
  49. Willie C, Macleod D, Shaw A, Smith K, Tzeng Y, Eves D, Ikeda K, Graham J, Lewis C, Day T, Ainslie P (2012) Regional brain blood flow in man during acute changes in arterial blood gases. J Physiol 590:3261–3275PubMedPubMedCentralGoogle Scholar
  50. Willie C, Smith K, Day T, Ray L, Lewis N, Bakker A, Macleod D, Ainslie P (2014a) Regional cerebral blood flow in humans at high altitude: gradual ascent and 2 wk at 5,050 m. J Appl Physiol 116:905–910PubMedGoogle Scholar
  51. Willie C, Tzeng Y, Fisher J, Ainslie P (2014b) Integrative regulation of human brain blood flow. J Physiol 592:841–859PubMedPubMedCentralGoogle Scholar
  52. Willie C, MacLeod D, Smith K, Lewis N, Foster G, Ikeda K, Hoiland R, Ainslie P (2015) The contribution of arterial blood gases in cerebral blood flow regulation and fuel utilization in man at high altitude. J Cereb Blood Flow Metab 35:873–881PubMedPubMedCentralGoogle Scholar
  53. Windsor J, Rodway G (2007) Heights and haematology: the story of haemoglobin at altitude. Postgrad Med J 83:148–151PubMedPubMedCentralGoogle Scholar
  54. Xu F, Liu P, Pascual J, Xiao G, Lu H (2012) Effect of hypoxia and hyperoxia on cerebral blood flow, blood oxygenation, and oxidative metabolism. J Cereb Blood Flow Metab 32:1909–1918PubMedPubMedCentralGoogle Scholar
  55. Zarrinkoob L, Ambarki K, Wåhlin A, Birgander R, Eklund A, Malm J (2015) Blood flow distribution in cerebral arteries. J Cereb Blood Flow Metab 35:648–654PubMedPubMedCentralGoogle Scholar
  56. Zouboules SM, Lafave HC, O’Halloran KD, Brutseart TD, Nysten HE, Nysten CE, Steinback CD, Sherpa MT, Day TA (2018) Renal reactivity: acid-base compensation during incremental ascent to high altitude. J Physiol 596(24):6191–6203PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Hailey C. Lafave
    • 1
  • Shaelynn M. Zouboules
    • 1
  • Marina A. James
    • 2
  • Graeme M. Purdy
    • 2
  • Jordan L. Rees
    • 2
  • Craig D. Steinback
    • 2
  • Peter Ondrus
    • 3
  • Tom D. Brutsaert
    • 4
  • Heidi E. Nysten
    • 5
  • Cassandra E. Nysten
    • 1
  • Ryan L. Hoiland
    • 6
  • Mingma T. Sherpa
    • 7
  • Trevor A. Day
    • 1
    Email author
  1. 1.Department of Biology, Faculty of Science and TechnologyMount Royal UniversityCalgaryCanada
  2. 2.Faculty of Kinesiology, Sport, and RecreationUniversity of AlbertaEdmontonCanada
  3. 3.Department of Family Medicine, Faculty of Medicine and DentistryUniversity of AlbertaEdmontonCanada
  4. 4.University of SyracuseSyracuseUSA
  5. 5.Red Deer Regional HospitalRed DeerCanada
  6. 6.Centre for Heart, Lung, and Vascular HealthUniversity of British ColumbiaKelownaCanada
  7. 7.Kunde Hospital, KhundeSolukhumbuNepal

Personalised recommendations