Surviving Without Oxygen: How Low Can the Human Brain Go?

Abstract

Bailey, Damian M., Christopher K. Willie, Ryan L. Hoiland, Anthony R. Bain, David B. MacLeod, Maria A. Santoro, Daniel K. DeMasi, Andrea Andrijanic, Tanja Mijacika, Otto F. Barak, Zeljko Dujic, and Philip N. Ainslie. Surviving without oxygen: how low can the human brain go? High Alt Med Biol 18:73–79, 2017.—Hypoxic cerebral vasodilation is a highly conserved physiological response coupling cerebral O₂ delivery (CDO₂) to metabolic demand with increasingly important roles identified for the red blood cell (sensor) and nitric oxide (effector). In the current article, we reexamine previously published cerebral blood flow (CBF) and arterial blood gas data obtained in freedivers and mountaineers, extreme athletes in whom the lowest arterial partial pressures of O₂ (19–23 mmHg) and greatest extremes of carbon dioxide (16–61 mmHg) were recorded during (acute) maximal static dry apnea or (chronic) exposure to terrestrial high altitude. Data highlight compensatory increases in CBF (+96% in freedivers to +209% in mountaineers relative to normoxic baseline controls) that were sufficient to sustain CDO₂ (+24% in freedivers to +183% in mountaineers) even in the face of the most severe reductions in arterial O₂ content (−61% in freedivers to −9% in mountaineers) reported in the literature, consistent with the conservation of mass principle. These unique findings highlight to what extent cerebral vasodilation likely contributes toward these athletes' extraordinary abilities to survive in such harsh environments characterized by physiological extremes of hypoxemia, alkalosis, and acidosis helping define the human brain's remarkable limits of tolerance.

Introduction

Paleoclimate and evolution of the human brain

Environmental pressures caused by climatic fluctuations have long been assumed to play a key role in hominin speciation and adaptation (Maslin et al., 2015). The inexorable rise in the paleoatmospheric O₂ concentration throughout the Proterozoic Eon of the Precambrian period (∼2500–540 million years ago) catalyzed life on Earth (Berner et al., 2007) with chemical reduction by the mitochondrial electron transport chain evolving into the primary source of adenosine triphosphate (ATP) for the respiring eukaryote (Nisbet and Sleep, 2001). The human brain exemplifies our reliance on O₂ since, unlike most other organs, its evolutionary “drive for size” means that it is now committed to a continually active state, demanding a disproportionate 20% of the body's basal O₂ budget, more than 10 times that expected from its mass alone (Bailey et al., 2009a; Bailey, 2016). This obligatory requirement to process large amounts of O₂ over a relatively small tissue mass is required to support the high rate of ATP formation to fuel the maintenance of ionic equilibria and uptake of neurotransmitters for synaptic transmission (Alle et al., 2009).

However, this obligatory high rate of O₂ consumption is associated with high “vulnerability for failure” given the brain's paradoxically limited O₂ reserves. Indeed, assuming an average brain tissue partial pressure of O₂ (PO₂) of ∼25 mmHg and lack of O₂-binding proteins, its O₂ content is a meagre ∼30 nmol/mL such that given an average cerebral metabolic rate of oxygen (CMRO₂) of 30 nmol/mL/s, the O₂ present would sustain metabolism for at best 1 second if blood supply were to be interrupted by anoxia (Leithner and Royl, 2014). Unable to compromise on its excessive energy budget, failure of ATP-dependent ion exchangers results in the breakdown of ionic gradients and membrane depolarization triggering a cytotoxic increase in intracellular Ca²⁺ concentration and uncontrolled release of excitatory neurotransmitters that ultimately converge in neuronal death (Lipton, 1999).

Yet, O₂ is not the only atmospheric gas to have shaped life on Earth with an equally important role identified for carbon dioxide (CO₂), the key substrate for oxygenic photosynthesis (Cummins et al., 2014). The human brain has since evolved heightened sensitivity to PaCO₂/H⁺ (more so than PaO₂) that extends throughout the cerebrovasculature, from the large extracranial and intracranial conduit and middle cerebral arteries through to the smallest pial arterioles and parenchymal vessels, prioritizing the buffering of brain tissue pH for stabilization of chemosensory and autonomic control at the level of the brainstem (Kety and Schmidt, 1948a; Willie et al., 2014). Given that the brain's O₂-CO₂ balance is so delicate, it would therefore seem intuitive for evolution to favor defense mechanisms capable of sensing “crosstalk” between these respiratory gases and orchestrating the coordinated transmission of vasoactive signals to the cerebrovasculature coupling local cerebral O₂ delivery (CDO₂) to tissue metabolic demand.

In the current article, we reexamine previously published cerebral blood flow (CBF) and arterial blood gas data obtained in freedivers and mountaineers, extreme athletes in whom the lowest PaO₂'s and greatest extremes of PaCO₂ (from respiratory alkalosis in the mountaineer to acidosis in the freediver) to date have been documented in the literature. These unique datasets reveal that even at physiological, if not indeed pathological extremes of systemic hypoxemia and hypo/hypercapnia, adaptive increases in CBF and corresponding CDO₂ are sufficient to compensate for any potential reductions in arterial O₂ content (CaO₂), such that cerebral homeostasis is preserved consistent with the conservation of mass principle.

Materials and Methods

Landmark performances

History reveals to what extent human tolerance to physiological extremes of hypoxia, alkalosis, and acidosis has traditionally been underestimated by the scientific community. The mountaineer Edward Norton got to within 300 m of the summit of Mt. Everest in 1924 without supplementary O₂ and numerous failed attempts in the years that followed, including laboratory simulations led the physiological community to predict that an “oxygenless” ascent would prove physiologically impossible (West, 2009). However, the remaining 3% was successfully negotiated by Reinhold Messner and Peter Habeler, and the world's highest mountain finally conquered, albeit some 54 years later. Medical opinion was equally divided when the freedivers, Jacques Mayol and Enzo Maiorca, attempted to dive below 50 m without any breathing apparatus in the late 1960s. While both survived the challenge and later went on to exceed 100 m, precisely how modern-day world record holders, such as Herbert Nitsch (who descended to 214 m attached to a metal sled and fixed line during the “No Limits” discipline) and Stéphane Mifsud (who achieved an 11 minutes 35 seconds breath-hold with the respiratory tract immersed in water during the “Static Apnea” discipline), achieve such remarkable performances remains, at best enigmatic.

Landmark studies

We reexamined published data from three unique studies detailed below:

Mountaineers

Arterial samples were obtained from the femoral artery of four acclimatized mountaineers at an altitude of 8400 m on Mt. Everest following descent from the summit having spent 30 minutes breathing ambient air preceded by supplementary O₂ (2–3 L/min while climbing, 0.5 L/min while sleeping above 7100 m) (Grocott et al., 2009). Individual data were available for all mountaineers in the published article. However, given that it was not possible to measure CBF at this elevation due to adverse weather, we interrogated a separate publication by the same group in a subset of five mountaineers (group not individual data available) incorporating transcranial doppler ultrasound of the right cerebral middle artery performed at the lower elevation of 7950 m, 30 minutes following removal of supplementary O₂ (Wilson et al., 2011). These are the highest elevations where such measurements have been performed.

Freedivers

Fifteen elite freedivers (seven having placed top 10 in the world) were examined during a static dry (laboratory-based) apnea. Individual data were made available for all freedivers (Dr. C.K. Willie, personal communication). Volumetric flow was measured continuously using near-concurrent duplex vascular ultrasound measures of blood flow through the right internal carotid and left vertebral arteries complemented by serial samples obtained from the radial artery for blood gas analysis (Willie et al., 2015a).

Results and Discussion

Respiratory gas extremes and cerebral vasodilation: significance and mechanisms

A comparison of arterial blood gas results is outlined in Table 1, including an as of yet unpublished presentation of the most hypoxemic individuals in whom the lowest PaO₂'s (19–23 mmHg) and greatest extremes of PaCO₂ (16–61 mmHg) were recorded. Despite exhibiting the lowest PaO₂ and SaO₂, polycythemia attenuated the reduction in CaO₂ observed in the mountaineer such that the freediver was ultimately the most hypoxemic. Given that supplemental O₂ is prescribed to patients when P_aO₂ falls <60 mmHg (consistent with the clinical diagnosis of respiratory failure) and risk of death increases exponentially <25 mmHg, combined with the increased mortality observed in hospitalized patients with PaCO₂'s of <35 or >45 mmHg (Laserna et al., 2012), puts their extraordinary tolerance to hitherto unchartered extremes of hypoxemia, alkalosis, and acidosis into clearer physiological perspective.

Table 1.

Comparison of Arterial Blood Gases in Mountaineers and Freedivers

Classification Discipline	Most hypoxemic individuals		Group data
Achievement	Mountaineer (n = 1) Exposure to 8400 m	Freediver (n = 1)^a Apnea of 435 seconds	Mountaineers (n = 4) Exposure to 8400 m	Freedivers (n = 15) Apnea of 316 ± 60 seconds	Normative data (reference values) ^b
PaO₂ (mmHg)	19	23	25 ± 5	30 ± 7^c	80–100
PaCO₂ (mmHg)	16	61	13 ± 3	51 ± 7^c	32–48
SaO₂ (%)	34	38	54 ± 18	57 ± 11^c	95–99
Hb (g/dL)	18.7	14.5	19.3 ± 0.7^c	14.3 ± 0.4^c	12.0–17.5
TCO₂ (mmol/L)^d	11	30	11 ± 1^c	27 ± 2^c	23–30
CaO₂ (mL/dL)^d	9.0	7.6	14.6 ± 5.3	17.0 ± 3.9	15.8–22.3
pH (U)	7.45	7.28	7.53 ± 0.06^c	7.35 ± 0.03^c	7.35–7.45
Lactate (mmol/L)	2.0	1.0	2.2 ± 0.5^c	0.8 ± 0.4^c	0.5–1.6
Base excess (U)	−9.2	0.3	−6.9 ± 1.6^c	−0.8 ± 0.9^c	−3.0–3.0
Bicarbonate (mmol/L)	10.7	28.7	10.8 ± 0.9^c	25.5 ± 2.0^c	22–27

Freediver and mountaineer data based on publications of Willie et al. (2015a) and Grocott et al. (2009), respectively. Group data expressed as mean ± SD; PaO₂/PaCO₂, arterial partial pressure of oxygen/carbon dioxide; SaO₂, arterial oxyhemoglobin saturation; Hb, hemoglobin.

Dr. C.K. Willie (personal communication).

Includes male and female values.

Different (p < 0.05) between disciplines assessed by independent samples t-tests following confirmation of distribution normality (Shapiro–Wilk W tests).

Calculated from raw data: TCO₂, total carbon dioxide = [HCO₃⁻] + αPCO₂, where α = 0.226 mmol/L/kPa (kPa = mmHg × \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} $$ { \frac { 101.3 } { 760 } } $$ \end{document} ) and CaO₂, arterial oxygen content = SaO₂ × Hb × 1.39 + (PaO₂ × 0.003).

These unique datasets provide unique insight into the underlying mechanisms, notably the extent to which cerebral vasodilation likely promotes survival in such harsh environmental extremes. As illustrated in Figure 1A, this highly conserved physiological response compensates for any reduction in CaO₂ even at the physiological extremes of arterial hypoxemia highlighting the brain's ability to defend against any potential threat to oxygenation. We observe a doubling of CBF in the freediver such that CDO₂ (Fig. 1B) always remains preserved especially considering the reduction in CMRO₂ recently documented in freedivers near apnea breakpoint, a consequence of the remarkable hypercapnia endured by these athletes (Bain et al., 2016). Thus, the combined benefits of cerebral hypometabolism and elevated capillary to mitochondrial O₂ diffusive conductance, the primary resistance to vascular O₂ transport (Wagner, 1996), likely optimize O₂ demand–supply coupling to protect the brain from severe hypoxemia, part of a coordinated defense strategy commonly observed in (more) hypoxia-tolerant ectothermic species and diving mammals (Lutz et al., 2003; Bailey et al., 2009a).

FIG. 1.

Relative increases in CBF (A) and oxygen delivery (CDO₂: B) observed across the spectrum of reductions in arterial oxygen content (CaO₂) during passive exposure to acute hypoxia lasting <24 hours (n = 84). Filled/open symbols reflect poikilocapnic/isocapnic exposure to hypoxia (10%–18% F_IO₂). Δcalculated as \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} $$ { \frac { { \rm { hypoxia \ } } - { \rm { normoxia \ } } } { { \rm { normoxia } } } } { \rm { \ } } \times { \rm { \ } } 100 { \rm { \ } } \left( { \rm { \% } } \right)$$ \end{document} . Note (1) the reductions in CaO₂ observed in the (individual) freediver and mountaineer described in Table 1 are the most marked recorded in the human literature to date and (2) marked hyperemia and corresponding increase in CDO₂ observed in the freediver (CBF not measured in the mountaineer at the prevailing CaO₂) consistent with that predicted from group mean data (identical slopes) (Kety and Schmidt, 1948b; Cohen et al., 1967; Shapiro et al., 1970; Bailey et al., 2009b; Wilson et al., 2011; Willie et al., 2012, 2015b; Ainslie et al., 2014; Hoiland et al., 2015; Sagoo et al., 2016). CBF, cerebral blood flow.

Emerging evidence supports a key regulatory role for nitric oxide (NO) as a downstream signaling molecule with the capacity to control and coordinate hypoxic vasodilation, catalyzed by the allosteric transition of Hb from the relaxed (oxy) to tense (deoxy) state with separate roles for the stable metabolites, nitrite, and S-nitrosoHb widely contested given their ability to conserve and transfer bioactivity within the microcirculation (Stamler et al., 1997; Cosby et al., 2003). The emerging picture, at least in hypoxia-tolerant vertebrates, including humans indigenous to terrestrial high altitude (native highlanders), suggests that an adaptive increase in vascular and tissue NO bioavailability serves to reduce CMRO₂, enhance cytoprotection against oxidative damage, and improve coupling of flow and metabolism (Umbrello et al., 2013; Fago and Jensen, 2015). In further support, dietary nitrate supplementation has been shown to exert an O₂-conserving effect, elevate SaO₂, and improve maximal apnea performance (Patrician and Schagatay, 2016). This contrasts with the opposing, generally maladaptive responses typically observed in (less hypoxia tolerant) native lowlanders during prolonged exposure to high altitude that include elevations in basal metabolic rate (BMR), free radical-mediated scavenging of NO, and vascular endothelial impairment (Bailey et al., 2010).

Atmosphere versus biosphere: battle of the gases

While both athletes share the common feature of severe arterial hypoxemia, the environmental challenges to which they are exposed and corresponding physiological demands are markedly different (Fig. 1A) suggesting that the mechanisms by which CDO₂ is sustained may differ between groups. Cerebral vasodilation depends on the magnitude and duration of the hypoxic stimulus, extent of acid–base adjustment, intrinsic cerebral reactivity to changes in O₂, CO₂, pH, and systemic/local release of vasoactive metabolites (Ainslie et al., 2016). High-altitude mountaineering is characterized by long-term exposure to hypobaric hypoxia, increased BMR, hyperventilation-induced hypocapnia, respiratory alkalosis, normotension, and polycythemia, whereas freediving is characterized by short-term exposure to normobaric hypoxia during apnea, decreased BMR, hypercapnia, respiratory acidosis, and hypertension subsequent to chemoreflex activation of the sympathetic nervous system, with normal Hb concentrations. Freedivers also have to contend with the additional challenge of elevated hydrostatic pressure when competing “at depth” in select disciplines (e.g., 22.3 ATA during Herbert Nitsch's No Limits world record) and complications associated with pulmonary barotrauma, nitrogen narcosis, decompression sickness, and high pressure neurological syndrome (Lindholm and Lundgren, 2009). Indeed, it is intriguing to note that the lowest PO₂'s recorded in humans can arise from opposing ends of the atmospheric–biospheric pressure spectrum.

The overall CBF response to high altitude reflects the net balance of two opposing physiological stimuli, hypoxic vasodilation versus hyperventilation-induced hypocapnic vasoconstriction. Despite the brain's increased sensitivity to PaCO₂ (Kety and Schmidt, 1948a; Willie et al., 2012), the balance is tipped in favor of hypoxic vasodilation during prolonged exposure to extreme altitude reflecting the overarching drive to preserve CDO₂ as illustrated in Figure 1A, B. Indeed, it is remarkable that extreme hypoxemia in the mountaineers evoked an order of magnitude more vasodilation (technical differences acknowledged) compared to the synergism expected between extreme hypoxemia, hypercapnia, and hypertension in the freediver. Indeed, it is of interest to note that despite marked differences in the environmental challenges encountered and varying PaCO₂'s, the slope of the ΔCBF-CaO₂ relationship for the single (most hypoxemic) freediver is identical to the average slope observed for the mountaineers during acute hypoxia.

The observed differences in acid–base balance are likely to exert opposing effects on the athletes' respective O₂-Hb dissociation curves given the inverse relationship between O₂-Hb binding affinity, pH, and pCO₂ (Bohr effect) (Bohr et al., 1904). Respiratory alkalosis (mountaineer) will cause a leftward (increased O₂-Hb affinity) facilitating greater O₂ uptake in the lung for any given alveolar PO₂, although this is likely to be countered at least to some extent by 2,3 diphosphoglycerate formation (Mairbaurl et al., 1993). In contrast, respiratory acidosis (freediver) will cause a rightward shift (decreased O₂-Hb affinity) favoring O₂ off-loading to the tissues. Evidence generally favors a leftward shift as being the most beneficial during severe hypoxia (Petschow et al., 1977) given that the slope of the O₂-Hb dissociation curve at the prevailing alveolar PO₂'s is steeper than the slope at the tissue PO₂'s (Turek et al., 1984) rendering Nitsch's freediving record even more impressive. Furthermore, respiratory alkalosis blunts sympathetic tone, pulmonary vasoconstriction, and cerebral vasodilation, whereas the opposite occurs in response to hypercapnic acidosis further highlighting the complex relationship between acid–base balance and physiological responses to hypoxia (Swenson, 2016).

Pushing the limits of hypoxemia and hyperemia

Since the mid to late 1940s, the No-Limits freediving world record has improved by a remarkable 720% (from 30 to 216 m) compared with other sports, for example, a 6% improvement in the 100 m sprint world record observed over a similar time frame (from 10.20 to 9.58 seconds). The question thus arises as to what is the maximum depth or lowest PaO₂ that the healthy human can ultimately tolerate before loss of consciousness (LOC) ensues, herein referred to as the critical PaO₂ (PaO_2CRIT)? Pioneering studies reported PaO_2CRIT values in the range of 16–20 mmHg during instantaneous hypoxia induced by rapid decompression (1 second) or nitrogen hyperventilation (17 seconds) (Ernsting, 1963). While such challenges are clearly supraphysiological, LOC generally supervenes when the jugular venous (jv) PO₂ falls to ∼20 mmHg (range 17–20 mmHg), which corresponds to an approximate SvO₂ (upper limit) of 32% (Severinghaus, 1966) and calculated CvO₂ of 6.8/100 mL (assuming a Hb concentration of 15 g/dL). From these figures, it is possible to approximate the PaO_2CRIT assuming a global (average) CBF of 46 mL/100 g/min (36–56 mL/100 g/min) equivalent to 644 mL/min (504–784 mL/min) assuming an average brain mass of 1400 g (1300–1500 g) and average CMRO₂ of 3.0 mL/100 g/min (2.6–3.4 mL/100 g/min) or 42 mL/min (36–48 mL/100 g/min) (Madsen et al., 1993). Using the average values cited, the CaO₂-CvO₂ can thus be derived using the Fick Principle: \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document} \begin{align*} { \rm { Ca } } { { \rm { O } } _ { \rm { 2 } } } { \rm { \hbox { - } Cv } } { { \rm { O } } _ { \rm { 2 } } } { \rm { = } } { \frac { { { \rm { CMRO } } _ { \rm { 2 } } } } { { \rm { CBF } } } } = { \frac { 42 } { 644 } } { \rm { ( \times 100 ) = 6 } } { \rm { .5 } } \ { \rm { mL / 100 } } \ { \rm { mL } } { \rm { . } } \end{align*} \end{document}

This equates to an (uncompensated) CaO₂ of 13.3/100 mL (6.8 + 6.5/100 mL) as the average minimum to avoid LOC or SaO_2CRIT of ∼65% and PaO_2CRIT of ∼35 mmHg, values that are far in excess of those recorded in the two most hypoxemic athletes documented in Table 1, suggesting that other compensatory factors, notably cerebral vasodilation (and acid–base adjustments) are contributing. In support, recalculation of the Fick Principle demonstrates that the doubling of CBF observed in the freediver has the effect of further lowering SaO_2CRIT to ∼40% and PaO_2CRIT to ∼23 mmHg (latter corrected for prevailing pH and base excess), almost identical to the values observed (Table 1). These values are likely to be even lower for the mountaineers given such pronounced hyperemia, although unlikely to fall below 20 mmHg, which appears to be the lower limit observed in patients with severe respiratory disease who also exhibit polycythemia and maximal cerebral vasodilation (Refsum, 1963).

Whether prolonged exposure to extreme hypoxia in the Wilson et al. (2011) study represents maximal dilation of the cerebral vessels is unknown. It would be interesting to examine if experimental manipulation of PaCO₂ would incur further increases given the ∼5.5% increase in CBF per mmHg increase in PaCO₂ reported during iso-oxic end-tidal forcing (Willie et al., 2012). However, the CBF response at physiological extremes of hypoxia–hypercapnea is not a simple summative dose–response. Emerging evidence suggests that severe hypoxia blunts the normal cerebrovascular reactivity to CO₂ possibly due to exhaustion of the cerebral vasodilatory reserve (Fan and Kayser, 2013) or alternatively, to protect against severe blood–brain barrier disruption and complications associated with extracellular vasogenic cerebral edema (Bailey et al., 2009c).

Notwithstanding the uncertainties associated with acid–base adjustments and corresponding shifts in the O₂-Hb dissociation curve as outlined, these calculations are at the very least hypothesis testing and demonstrate that these athletes are operating very close to, if not indeed at, the very limit of human consciousness, findings corroborated by the high incidence of LOC and loss of motor control (confusion, loss of postural control, faltering vision, speech problems) recorded among competitive freedivers, clinical signs that are the frustrating cause for disqualification. Furthermore, emerging MRI and immunochemical evidence suggests that extremes of freediving and high-altitude mountaineering may be associated with structural brain damage (Bailey et al., 2009a; Gren et al., 2016) with potential long-term neuropsychological consequences. This contrasts with the extraordinary hypoxia tolerance exhibited by diving mammals, including the seal that is capable of enduring PaO₂'s as low as 7–10 mmHg without cerebral integrity being compromised (Elsner et al., 1970).

While global CDO₂ in humans may appear well preserved both at rest and even during maximal exercise in hypoxia, the overall reduction in jv (Ainslie et al., 2014) and (derived) cerebral mitochondrial PO₂ (Bailey et al., 2011) reported in the literature suggests that it is heterogeneous and regional PO₂ deficits likely coexist, which has important implications for regional susceptibility to damage or indeed adaptation. Regional differences in the CBF, and hence CDO₂ response to hypoxia, have since been observed, complicated in part by differing analytical techniques, experimental designs, and fact that the entire cerebral arterial tree including large arteries of the neck exhibit differential reactivities to PaO₂ and PaCO₂ (Willie et al., 2014). Increased CBF reactivity has been reported in the putamen, brain stem, thalamus, caudate nucleus, nucleus accumbens, and pallidum using H₂¹⁵O positron emission tomography (Binks et al., 2008), whereas single photon emission computed tomography has identified predilection for the anterior cingulate cortex, right temporal lobe, sensory motor cortices, prefrontal cortex, and basal ganglia (Pagani et al., 2011). Collectively, these findings have been taken to reflect the selective preservation of CDO₂ to phylogenetically older regions of the brain responsible for more vital aspects of homeostatic function, a feature that may have provided a selective advantage.

Conclusion

A reexamination of published data from freedivers and mountaineers, extreme athletes in whom the lowest PaO₂'s and greatest extremes of PaCO₂ to date have been recorded, highlights to what extent compensatory increases in CBF are sufficient to preserve CDO₂ consistent with the conservation of mass principle. While the molecular mechanisms underlying O₂-CO₂ sensing remain elusive, cerebral vasodilation likely contributes toward these athletes' extraordinary abilities to survive in such harsh environments characterized by physiological extremes of hypoxemia, alkalosis, and acidosis helping define the human brain's remarkable limits of tolerance.

Footnotes

Acknowledgments

Aspects of this work were supported by the Higher Education Funding Council for Wales (D.M.B.), Canada NSERC Discovery Grant (P.N.A.), and FP7-PEOPLE-2010-ITN-264816 PHYPODE Grant (Z.D.). D.M.B. is the Reichwald Family UBC Southern Medical Program Chair in Preventive Medicine, C.K.W. is a Vanier Canada graduate scholar, and P.N.A. is a Canada Research Chair in Cerebrovascular Physiology.

Authors' Contributions

D.M.B. drafted the article and revisions thereof; co-authors approved the final article for submission.

Author Disclosure Statement

No competing financial interests exist.

References

Ainslie

, Hoiland

, and Bailey

. (2016). Lessons from the laboratory; integrated regulation of cerebral blood flow during hypoxia. Exp Physiol. DOI: 10.1113/EP085671.

Ainslie

, Shaw

, Smith

, Willie

, Ikeda

, Graham

, and Macleod

. (2014). Stability of cerebral metabolism and substrate availability in humans during hypoxia and hyperoxia. Clin Sci, 126:661–670.

Alle

, Roth

, and Geiger

. (2009). Energy-efficient action potentials in hippocampal mossy fibers. Science, 325:1405–1408.

Bailey

. (2016). The brain in hypoxia; curiosity, cause and consequence. Exp Physiol, 101.9:1157–1159.

Bailey

, Bartsch

, Knauth

, and Baumgartner

. (2009a). Emerging concepts in acute mountain sickness and high-altitude cerebral edema: From the molecular to the morphological. Cell Mol Life Sci, 66:3583–3594.

Bailey

, Dehnert

, Luks

, Menold

, Castell

, Schendler

, Faoro

, Gutowski

, Evans

, Taudorf

, et al. (2010). High-altitude pulmonary hypertension is associated with a free radical-mediated reduction in pulmonary nitric oxide bioavailability. J Physiol, 588:4837–4847.

Bailey

, Taudorf

, Berg

, Lundby

, Pedersen

, Rasmussen

, and Moller

. (2011). Cerebral formation of free radicals during hypoxia does not cause structural damage and is associated with a reduction in mitochondrial PO₂; evidence of O₂-sensing in humans?. J Cereb Blood Flow Metab, 31:1020–1026.

Bailey

, Taudorf

, Berg

RMG

, Jensen

, Lundby

, Evans

, James

, Pedersen

, and Moller

. (2009b). Transcerebral exchange kinetics of nitrite and calcitonin gene-related peptide in acute mountain sickness: Evidence against trigeminovascular activation?. Stroke, 40:2205–2208.

Bailey

, Taudorf

, Berg

RMG

, Lundby

, McEneny

, Young

, Evans

, James

, Shore

, Hullin

, et al. (2009c). Increased cerebral output of free radicals during hypoxia: Implications for acute mountain sickness?. Am J Physiol Regul Integr Comp Physiol, 297:R1283–R1292.

10.

Bain

, Ainslie

, Hoiland

, Barak

, Cavar

, Drvis

, Stembridge

, MacLeod

, Bailey

, Dujic

, et al. (2016). Cerebral oxidative metabolism is decreased with extreme apnea in humans; impact of hypercapnia. J Physiol, 594:5317–5328.

11.

Berner

, Vandenbrooks

, and Ward

. (2007). Evolution. Oxygen and evolution. Science, 316:557–558.

12.

Binks

, Cunningham

, Adams

, and Banzett

. (2008). Gray matter blood flow change is unevenly distributed during moderate isocapnic hypoxia in humans. J Appl Physiol, 104:212–217.

13.

Bohr

, Hasselbalch

, and Krogh

. (1904). Über einen in biologischer beziehung wichtigen einfluss, den die kohlensäurespannung des blutes auf dessen sauerstoffbindung übt. Scand Arch Physiol, 16:401–412.

14.

Cohen

, Alexander

, Smith

, Reivich

, and Wollman

. (1967). Effects of hypoxia and normocarbia on cerebral blood flow and metabolism in conscious man. J Appl Physiol, 23:183–189.

15.

Cosby

, Partovi

, Crawford

, Patel

, Reiter

, Martyr

, Yang

, Waclawiw

, Zalos

, Xu

, et al. (2003). Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med, 9:1498–1505.

16.

Cummins

, Selfridge

, Sporn

, Sznajder

, and Taylor

. (2014). Carbon dioxide-sensing in organisms and its implications for human disease. Cell Mol Life Sci, 71:831–845.

17.

Elsner

, Shurley

, Hammond

, and Brooks

. (1970). Cerebral tolerance to hypoxemia in asphyxiated Weddell seals. Respir Physiol, 9:287–297.

18.

Ernsting

. (1963). The effect of brief profound hypoxia upon the arterial and venous oxygen tensions in man. J Physiol, 169:292–311.

19.

Fago

, and Jensen

. (2015). Hypoxia tolerance, nitric oxide, and nitrite: Lessons from extreme animals. Physiology, 30:116–126.

20.

Fan

, and Kayser

. (2013). The effect of adding CO₂ to hypoxic inspired gas on cerebral blood flow velocity and breathing during incremental exercise. PLoS One, 8:e81130.

21.

Gren

, Shahim

, Lautner

, Wilson

, Andreasson

, Norgren

, Blennow

, and Zetterberg

. (2016). Blood biomarkers indicate mild neuroaxonal injury and increased amyloid beta production after transient hypoxia during breath-hold diving. Brain Inj, 30:1226–1230.

22.

Grocott

, Martin

, Levett

, McMorrow

, Windsor

, Montgomery

, and Caudwell Xtreme Everest Research G. (2009). Arterial blood gases and oxygen content in climbers on Mount Everest. N Engl J Med, 360:140–149.

23.

Hoiland

, Ainslie

, Wildfong

, Smith

, Bain

, Willie

, Foster

, Monteleone

, and Day

. (2015). Indomethacin-induced impairment of regional cerebrovascular reactivity: Implications for respiratory control. J Physiol, 593:1291–1306.

24.

Kety

, and Schmidt

. (1948a). 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, 27:484–492.

25.

Kety

, and Schmidt

. (1948b). The nitrous oxide method for the quantitative determination of cerebral blood flow in man: Theory, procedure and normal values. J Clin Invest, 27:476–484.

26.

Laserna

, Sibila

, Aguilar

, Mortensen

, Anzueto

, Blanquer

, Sanz

, Rello

, Marcos

, Velez

, et al. (2012). Hypocapnia and hypercapnia are predictors for ICU admission and mortality in hospitalized patients with community-acquired pneumonia. Chest, 142:1193–1199.

27.

Leithner

, and Royl

. (2014). The oxygen paradox of neurovascular coupling. J Cereb Blood Flow Metab, 34:19–29.

28.

Lindholm

, and Lundgren

. (2009). The physiology and pathophysiology of human breath-hold diving. J Appl Physiol, 106:284–292.

29.

Lipton

. (1999). Ischemic cell death in brain neurons. Physiol Rev, 79:1431–1568.

30.

Lutz

, Nilsson

, and Prentice

. (2003). The Brain Without Oxygen; Causes of Failure-Physiological and Molecular Mechanisms for Survival. Kluwer Academic Publishers, Dordrecht.

31.

Madsen

, Holm

, Herning

, and Lassen

. (1993). Average blood flow and oxygen uptake in the human brain during resting wakefulness: A critical appraisal of the Kety-Schmidt technique. J Cereb Blood Flow Metab, 13:646–655.

32.

Mairbaurl

, Oelz

, and Bartsch

. (1993). Interactions between Hb, Mg, DPG, ATP, and Cl determine the change in Hb-O₂ affinity at high altitude. J Appl Physiol, 74:40–48.

33.

Maslin

, Shultz

, and Trauth

. (2015). A synthesis of the theories and concepts of early human evolution. Philos Trans R Soc London B Biol Sci, 370:20140064.

34.

Nisbet

, and Sleep

. (2001). The habitat and nature of early life. Nature, 409:1083–1091.

35.

Pagani

, Salmaso

, Sidiras

, Jonsson

, Jacobsson

, Larsson

, and Lind

. (2011). Impact of acute hypobaric hypoxia on blood flow distribution in brain. Acta Physiol, 202:203–209.

36.

Patrician

, and Schagatay

. (2016). Dietary nitrate enhances arterial oxygen saturation after dynamic apnea. Scand J Med Sci Sports. DOI: 10.1111/sms.12684.

37.

Petschow

, Wurdinger

, Baumann

, Duhm

, Braunitzer

, and Bauer

. (1977). Causes of high blood O₂ affinity of animals living at high altitude. J Appl Physiol Respir Environ Exerc Physiol, 42:139–143.

38.

Refsum

. (1963). Relationship between state of consciousness and arterial hypoxaemia and hypercapnia in patients with pulmonary insufficiency, breathing air. Clin Sci, 25:361–367.

39.

Sagoo

, Hutchinson

, Wright

, Handford

, Parsons

, Sherwood

, Wayte

, Nagaraja

, Ng'Andwe

, Wilson

, et al. (2016). Magnetic resonance investigation into the mechanisms involved in the development of high-altitude cerebral edema. J Cereb Blood Flow Metab pii:0271678X15625350.

40.

Severinghaus

. (1966). Blood gas calculator. J Appl Physiol, 21:1108–1116.

41.

Shapiro

, Wasserman

, Baker

, and Patterson

Jr. (1970). Cerebrovascular response to acute hypocapnic and eucapnic hypoxia in normal man. J Clin Invest, 49:2362–2368.

42.

Stamler

, Jia

, Eu

, McMahon

, Demchenko

, Bonaventura

, Gernet

, and Piantadosi

. (1997). Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science, 276:2034–2037.

43.

Swenson

. (2016). Hypoxia and its acid-base consequences: From mountains to malignancy. Adv Exp Med Biol, 903:301–323.

44.

Turek

, Kreuzer

, Scotto

, and Rakusan

. (1984). The effect of blood O₂ affinity on the efficiency of O₂ transport in blood at hypoxic hypoxia. Adv Exp Med Biol, 180:357–368.

45.

Umbrello

, Dyson

, Feelisch

, and Singer

. (2013). The key role of nitric oxide in hypoxia: Hypoxic vasodilation and energy supply-demand matching. Antioxid Redox Signal, 19:1690–1710.

46.

Wagner

. (1996). Determinants of maximal oxygen transport and utilization. Annu Rev Physiol, 58:21–50.

47.

West

. (2009). Arterial blood measurements in climbers on Mount Everest. Lancet, 373:1589–1590.

48.

Willie

, Ainslie

, Drvis

, MacLeod

, Bain

, Madden

, Maslov

, and Dujic

. (2015a). Regulation of brain blood flow and oxygen delivery in elite breath-hold divers. J Cereb Blood Flow Metab, 35:66–73.

49.

Willie

, Macleod

, Shaw

, Smith

, Tzeng

, Eves

, Ikeda

, Graham

, Lewis

, Day

, et al. (2012). Regional brain blood flow in man during acute changes in arterial blood gases. J Physiol, 590:3261–3275.

50.

Willie

, MacLeod

, Smith

, Lewis

, Foster

, Ikeda

, Hoiland

, and Ainslie

. (2015b). The contribution of arterial blood gases in cerebral blood flow regulation and fuel utilization in man at high altitude. J Cereb Blood Flow Metab, 35:873–881.

51.

Willie

, Tzeng

, Fisher

, and Ainslie

. (2014). Integrative regulation of human brain blood flow. J Physiol, 592:841–859.

52.

Wilson

, Edsell

, Davagnanam

, Hirani

, Martin

, Levett

, Thornton

, Golay

, Strycharczuk

, Newman

, et al. (2011). Cerebral artery dilatation maintains cerebral oxygenation at extreme altitude and in acute hypoxia-an ultrasound and MRI study. J Cereb Blood Flow Metab, 31:2019–2029.