Abstract
With ascent to high altitude (HA), compensatory increases in cerebral blood flow and oxygen delivery must occur to preserve cerebral metabolism and consciousness. We hypothesized that this compensation in cerebral blood flow and oxygen delivery preserves tolerance to simulated hemorrhage (via lower body negative pressure, LBNP), such that tolerance is similar during sustained exposure to HA vs. low altitude (LA). Healthy humans (4F/4 M) participated in LBNP protocols to presyncope at LA (1130 m) and 5–7 days following ascent to HA (3800 m). Internal carotid artery (ICA) blood flow, cerebral delivery of oxygen (CDO2) through the ICA, and cerebral tissue oxygen saturation (ScO2) were determined. LBNP tolerance was similar between conditions (LA: 1276 ± 304 s vs. HA: 1208 ± 306 s; P = 0.58). Overall, ICA blood flow and CDO2 were elevated at HA vs. LA (P ≤ 0.01) and decreased with LBNP under both conditions (P < 0.0001), but there was no effect of altitude on ScO2 responses (P = 0.59). Thus, sustained exposure to hypobaric hypoxia did not negatively impact tolerance to simulated hemorrhage. These data demonstrate the robustness of compensatory physiological mechanisms that preserve human cerebral blood flow and oxygen delivery during sustained hypoxia, ensuring cerebral tissue metabolism and neuronal function is maintained.
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References
Aguiar M, Stolzer A, Boyd DD (2017) Rates and causes of accidents for general aviation aircraft operating in a mountainous and high elevation terrain environment. Accid Anal Prev 107:195–201. https://doi.org/10.1016/j.aap.2017.03.017
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):661–670. https://doi.org/10.1042/CS20130343
Anderson GK, Rosenberg AJ, Barnes HJ, Bird J, Pentz B, Byman BRM, Jendzjowsky N, Wilson RJA, Day TA, Rickards CA (2021) Peaks and valleys: oscillatory cerebral blood flow at high altitude protects cerebral tissue oxygenation. Physiol Meas 42:064005. https://doi.org/10.1088/1361-6579/ac0593
Barioni NO, Derakhshan F, Tenorio Lopes L, Onimaru H, Roy A, McDonald F, Scheibli E, Baghdadwala MI, Heidari N, Bharadia M, Ikeda K, Yazawa I, Okada Y, Harris MB, Dutschmann M, Wilson RJA (2022) Novel oxygen sensing mechanism in the spinal cord involved in cardiorespiratory responses to hypoxia. Sci Adv 8(12):eabm1444. https://doi.org/10.1126/sciadv.abm1444
Bartsch P, Gibbs JS (2007) Effect of altitude on the heart and the lungs. Circulation 116(19):2191–2202. https://doi.org/10.1161/CIRCULATIONAHA.106.650796
Boyd J, Haegeli P, Abu-Laban RB, Shuster M, Butt JC (2009) Patterns of death among avalanche fatalities: a 21-year review. CMAJ 180(5):507–512. https://doi.org/10.1503/cmaj.081327
Curran-Everett D (2020) Evolution in statistics: P values, statistical significance, kayaks, and walking trees. Adv Physiol Educ 44(2):221–224. https://doi.org/10.1152/advan.00054.2020
Curran-Everett D, Benos DJ (2004) Guidelines for reporting statistics in journals published by the American physiological society. Am J Physiol 287:R247-249. https://doi.org/10.1152/ajpregu.00346.2004
Evans DH (1985) On the measurement of the mean velocity of blood flow over the cardiac cycle using Doppler ultrasound. Ultrasound Med Biol 11(5):735–741. https://doi.org/10.1016/0301-5629(85)90107-3
Heistad DD, Wheeler RC (1970) Effect of acute hypoxia on vascular responsiveness in man. I. Responsiveness to lower body negative pressure and ice on the forehead. II. Responses to norepinephrine and angiotensin. 3. Effect of hypoxia and hypocapnia. J Clin Invest 49(6):1252–1265. https://doi.org/10.1172/JCI106338
Hinojosa-Laborde C, Shade RE, Muniz GW, Bauer C, Goei KA, Pidcoke HF, Chung KK, Cap AP, Convertino VA (2014) Validation of lower body negative pressure as an experimental model of hemorrhage. J Appl Physiol 116(4):406–415. https://doi.org/10.1152/japplphysiol.00640.2013
Hoiland RL, Bain AR, Rieger MG, Bailey DM, Ainslie PN (2016) Hypoxemia, oxygen content, and the regulation of cerebral blood flow. Am J Physiol Regul Integr Comp Physiol 310(5):R398-413. https://doi.org/10.1152/ajpregu.00270.2015
Hoiland RL, Howe CA, Coombs GB, Ainslie PN (2018) Ventilatory and cerebrovascular regulation and integration at high-altitude. Clin Auton Res 28(4):423–435. https://doi.org/10.1007/s10286-018-0522-2
Huang SY, Moore LG, McCullough RE, McCullough RG, Micco AJ, Fulco C, Cymerman A, Manco-Johnson M, Weil JV, Reeves JT (1987) Internal carotid and vertebral arterial flow velocity in men at high altitude. J Appl Physiol 63(1):395–400. https://doi.org/10.1152/jappl.1987.63.1.395
Jensen JB, Wright AD, Lassen NA, Harvey TC, Winterborn MH, Raichle ME, Bradwell AR (1990) Cerebral blood flow in acute mountain sickness. J Appl Physiol 69(2):430–433. https://doi.org/10.1152/jappl.1990.69.2.430
Johnson BD, van Helmond N, Curry TB, van Buskirk CM, Convertino VA, Joyner MJ (2014) Reductions in central venous pressure by lower body negative pressure or blood loss elicit similar hemodynamic responses. J Appl Physiol 117(2):131–141. https://doi.org/10.1152/japplphysiol.00070.2014
Kay VL, Rickards CA (2016) The role of cerebral oxygenation and regional cerebral blood flow on tolerance to central hypovolemia. Am J Physiol Regul Integr Comp Physiol 310(4):R375-383. https://doi.org/10.1152/ajpregu.00367.2015
Kay VL, Sprick JD, Rickards CA (2017) Cerebral oxygenation and regional cerebral perfusion responses with resistance breathing during central hypovolemia. Am J Physiol Regul Integr Comp Physiol 313(2):R132–R139. https://doi.org/10.1152/ajpregu.00385.2016
Kety SS, Schmidt CF (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(4):484–492. https://doi.org/10.1172/JCI101995
Lafave HC, Zouboules SM, James MA, Purdy GM, Rees JL, Steinback CD, Ondrus P, Brutsaert TD, Nysten HE, Nysten CE, Hoiland RL, Sherpa MT, Day TA (2019) Steady-state cerebral blood flow regulation at altitude: interaction between oxygen and carbon dioxide. Eur J Appl Physiol 119(11–12):2529–2544. https://doi.org/10.1007/s00421-019-04206-6
Lucas SJ, Burgess KR, Thomas KN, Donnelly J, Peebles KC, Lucas RA, Fan JL, Cotter JD, Basnyat R, Ainslie PN (2011) Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m. J Physiol 589(Pt 3):741–753. https://doi.org/10.1113/jphysiol.2010.192534
Millet GP, Debevec T (2020) CrossTalk proposal: barometric pressure, independent of P O 2, is the forgotten parameter in altitude physiology and mountain medicine. J Physiol 598(5):893–896. https://doi.org/10.1113/JP278673
Millet GP, Faiss R, Pialoux V (2012) Point: hypobaric hypoxia induces different physiological responses from normobaric hypoxia. J Appl Physiol 112(10):1783–1784. https://doi.org/10.1152/japplphysiol.00067.2012
Naeije R (2010) Physiological adaptation of the cardiovascular system to high altitude. Prog Cardiovasc Dis 52(6):456–466. https://doi.org/10.1016/j.pcad.2010.03.004
Naeije R, Melot C, Mols P, Hallemans R (1982) Effects of vasodilators on hypoxic pulmonary vasoconstriction in normal man. Chest 82(4):404–410. https://doi.org/10.1378/chest.82.4.404
Pollard V, Prough DS, DeMelo AE, Deyo DJ, Uchida T, Stoddart HF (1996) Validation in volunteers of a near-infrared spectroscope for monitoring brain oxygenation in vivo. Anesth Analg 82(2):269–277. https://doi.org/10.1097/00000539-199602000-00010
Rasmussen P, Siebenmann C, Diaz V, Lundby C (2013) Red cell volume expansion at altitude: a meta-analysis and Monte Carlo simulation. Med Sci Sports Exerc 45(9):1767–1772. https://doi.org/10.1249/MSS.0b013e31829047e5
Richardson DW, Kontos HA, Raper AJ, Patterson JL Jr (1967) Modification by beta-adrenergic blockade of the circulatory respones to acute hypoxia in man. J Clin Invest 46(1):77–85. https://doi.org/10.1172/JCI105513
Rickards CA (2015) Cerebral blood-flow regulation during hemorrhage. Compr Physiol 5(4):1585–1621. https://doi.org/10.1002/cphy.c140058
Rickards CA, Johnson BD, Harvey RE, Convertino VA, Joyner MJ (2015) Barnes JN (2015) Cerebral blood velocity regulation during progressive blood loss compared with lower body negative pressure in humans. J Appl Physiol (1985) 119(6):677–685. https://doi.org/10.1152/japplphysiol.00127.2015
Rowell LB, Blackmon JR (1986) Lack of sympathetic vasoconstriction in hypoxemic humans at rest. Am J Physiol 251(3 Pt 2):H562-570. https://doi.org/10.1152/ajpheart.1986.251.3.H562
Rowell LB, Seals DR (1990) Sympathetic activity during graded central hypovolemia in hypoxemic humans. Am J Physiol 259(4 Pt 2):H1197-1206. https://doi.org/10.1152/ajpheart.1990.259.4.H1197
Rupp T, Esteve F, Bouzat P, Lundby C, Perrey S, Levy P, Robach P, Verges S (2014) Cerebral hemodynamic and ventilatory responses to hypoxia, hypercapnia, and hypocapnia during 5 days at 4350 m. J Cereb Blood Flow Metab 34(1):52–60. https://doi.org/10.1038/jcbfm.2013.167
Schlittler M, Gatterer H, Turner R, Regli IB, Woyke S, Strapazzon G, Rasmussen P, Kob M, Mueller T, Goetze JP, Maillard M, van Hall G, Feraille E, Siebenmann C (2021) Regulation of plasma volume in male lowlanders during 4 days of exposure to hypobaric hypoxia equivalent to 3500 m altitude. J Physiol 599(4):1083–1096. https://doi.org/10.1113/JP280601
Severinghaus JW, Chiodi H, Eger EI 2nd, Brandstater B, Hornbein TF (1966) Cerebral blood flow in man at high altitude. Role of cerebrospinal fluid pH in normalization of flow in chronic hypocapnia. Circ Res 19(2):274–282. https://doi.org/10.1161/01.res.19.2.274
Sheets A, Wang D, Logan S, Atkins D (2018) Causes of death among avalanche fatalities in colorado: a 21-year review. Wilderness Environ Med 29(3):325–329. https://doi.org/10.1016/j.wem.2018.04.002
Siebenmann C, Cathomen A, Hug M, Keiser S, Lundby AK, Hilty MP, Goetze JP, Rasmussen P, Lundby C (2015) Hemoglobin mass and intravascular volume kinetics during and after exposure to 3,454-m altitude. J Appl Physiol (1985) 119(10):1194–1201. https://doi.org/10.1152/japplphysiol.01121.2014
Siebenmann C, Robach P, Lundby C (2017) Regulation of blood volume in lowlanders exposed to high altitude. J Appl Physiol 123(4):957–966. https://doi.org/10.1152/japplphysiol.00118.2017
Subudhi AW, Olin JT, Dimmen AC, Polaner DM, Kayser B, Roach RC (2011) Does cerebral oxygen delivery limit incremental exercise performance? J Appl Physiol 111(6):1727–1734. https://doi.org/10.1152/japplphysiol.00569.2011
Thomas KN, Lewis NC, Hill BG, Ainslie PN (2015) Technical recommendations for the use of carotid duplex ultrasound for the assessment of extracranial blood flow. Am J Physiol Regul Integr Comp Physiol:ajpregu 00211:02015. https://doi.org/10.1152/ajpregu.00211.2015
van Helmond N, Johnson BD, Holbein WW, Petersen-Jones HG, Harvey RE, Ranadive SM, Barnes JN, Curry TB, Convertino VA, Joyner MJ (2018) Effect of acute hypoxemia on cerebral blood flow velocity control during lower body negative pressure. Physiol Rep. https://doi.org/10.14814/phy2.13594
Weisbrod CJ, Minson CT, Joyner MJ, Halliwill JR (2001) Effects of regional phentolamine on hypoxic vasodilatation in healthy humans. J Physiol 537(Pt 2):613–621. https://doi.org/10.1111/j.1469-7793.2001.00613.x
Wilkins BW, Schrage WG, Liu Z, Hancock KC, Joyner MJ (2006) Systemic hypoxia and vasoconstrictor responsiveness in exercising human muscle. J Appl Physiol 101(5):1343–1350. https://doi.org/10.1152/japplphysiol.00487.2006
Wilkins BW, Pike TL, Martin EA, Curry TB, Ceridon ML, Joyner MJ (2008) Exercise intensity-dependent contribution of beta-adrenergic receptor-mediated vasodilatation in hypoxic humans. J Physiol 586(4):1195–1205. https://doi.org/10.1113/jphysiol.2007.144113
Willie CK, Macleod DB, Shaw AD, Smith KJ, Tzeng YC, Eves ND, Ikeda K, Graham J, Lewis NC, Day TA, Ainslie PN (2012) Regional brain blood flow in man during acute changes in arterial blood gases. J Physiol 590(Pt 14):3261–3275. https://doi.org/10.1113/jphysiol.2012.228551
Willie CK, Smith KJ, Day TA, Ray LA, Lewis NC, Bakker A, Macleod DB, Ainslie PN (2014) Regional cerebral blood flow in humans at high altitude: gradual ascent and 2 wk at 5,050 m. J Appl Physiol 116(7):905–910. https://doi.org/10.1152/japplphysiol.00594.2013
Woodman RJ, Playford DA, Watts GF, Cheetham C, Reed C, Taylor RR, Puddey IB, Beilin LJ, Burke V, Mori TA, Green D (2001) Improved analysis of brachial artery ultrasound using a novel edge-detection software system. J Appl Physiol 91(2):929–937. https://doi.org/10.1152/jappl.2001.91.2.929
Zhao J, You G, Yin Y, Zhang Y, Wang Y, Chen G, Zhao L, Zhou H (2018) Acute high-altitude exposure shortens survival after uncontrolled hemorrhagic shock in rats. J Surg Res 226:150–156. https://doi.org/10.1016/j.jss.2018.01.028
Acknowledgements
The authors thank our participants for their time and cheerful participation in this study. We also thank all other members of the White Mountain 2019 expedition team, and the staff at the Barcroft Research Laboratory for their generous support and service throughout the expedition.
Funding
Funding for this study was provided, in part, by an American Heart Association Grant-in-Aid (CAR; 17GRNT33671110), a Natural Sciences and Engineering Research Council of Canada Discovery Grant (TAD; RGPIN-2016-04915), a University of Calgary Research Grant Committee (RJAW), a NSERC Discovery grant (RJAW), and training fellowships awarded to GKA through a National Institutes of Health-supported Neurobiology of Aging Training Grant (T32 AG020494, Principal Investigator: N. Sumien) and an American Heart Association Predoctoral Fellowship (20PRE35210249), and to AJR through a Ruth L. Kirchstein NRSA F32 Postdoctoral Fellowship (1F32 HL144082-01A1). NGJ was a Parker B Francis Fellowship Recipient.
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AJR was responsible for conducting experiments, data analysis, drafting the work and revising it critically for important intellectual content, and final approval of the version to be published. GKA was responsible for conducting experiments, data analysis, revising the work for important intellectual content, and final approval of the version to be published. HJB was responsible for data analysis, revising the work for important intellectual content, and final approval of the version to be published. JB, BP, and BRMB were responsible for conducting experiments, revising the work for important intellectual content, and final approval of the version to be published. NJ, RJW, and TAD were responsible for coordinating and supervising the expedition, revising the work for important intellectual content, and final approval of the version to be published. CAR was responsible for conception of the work, obtaining funding for the study, conducting experiments, supervising data analysis, drafting the work and revising it critically for important intellectual content, and final approval of the version to be published.
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Rosenberg, A.J., Anderson, G.K., McKeefer, H.J. et al. Hemorrhage at high altitude: impact of sustained hypobaric hypoxia on cerebral blood flow, tissue oxygenation, and tolerance to simulated hemorrhage in humans. Eur J Appl Physiol (2024). https://doi.org/10.1007/s00421-024-05450-1
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DOI: https://doi.org/10.1007/s00421-024-05450-1