Content uploaded by Chris Imray
Author content
All content in this area was uploaded by Chris Imray on Apr 28, 2016
Content may be subject to copyright.
Experimental Physiology
Exp Physiol 000.0 (2016) pp 1–6 1
Symposium Report
Symposium Report
Lessons from altitude: cerebral perfusion insights
and their potential translational clinical significance
Chris Imray
1,2,3
1
Department of Vascular Surgery, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
2
Warwick Medical School, Warwick University, Coventry, UK
3
Coventry University, Coventry, UK
New Findings
r
What is the topic of this review?
The long-held assumption that transcranial Doppler middle cerebral artery velocity is a
surrogate for cerebral blood flow has been questioned in certain circumstances, particularly
where tissue o xygenation changes.
r
What advances does it highlight?
Cerebral venous outflow restriction appears to be implicated in the development of
high-altitude cerebral oedema.
Rapid ascent to high altitude commonly results in acute mountain sickness and, on occasion,
potentially fatal high-altitude cerebral oedema. The exact pathophysiological mechanisms
behind these syndromes remain to be determined. One of the main theories to explain the
development of acute mountain sickness is an increase in intracranial pressure. Vasogenic
(extracellular water accumulation attributable to increased permeability of the blood–brain
barr i er) and cytotoxic (intracellular) oedema have also been postulated as potential mechanisms
that underlie high-altitude cerebral oedema. Recently published finding s derived from a very
challenging field study (obtained at altitudes of up to 7950 m), substantiated by sea-level hypoxic
magnetic resonance angiography studies, have given new insights into the maintenance of
cerebral blood flow at altitude. This report provides new perspectives and p otential mechanisms
to account for the maintenance of cerebral oxygen delivery at high and extreme altitude. In
particular, the long-held assumption that transcranial Doppler middle cerebral artery velocity
is a surrogate for cerebral blood flow has been shown to be incorrect in certain circumstances.
The emerging evidence for a potential third mechanism, namely the restrictive venous outflow
hypothesis, in the development of high-altitude cerebral oedema, over and above the accepted
vasogenic and cytotoxic hypotheses, is also appraised.
(Received 4 January 2016; accepted after revision 30 March 2016; first published online 8 April 2016)
Corresponding author C.H.E Imray: Department of Vascular Surgery, University Hospitals Coventry and Warwickshire
NHS Trust, Coventry CV2 2DX, UK. Email: chrisimray@aol.com
Altitude as a model for critical illness
Adapting knowledge derived from basic science research
that is relevant to clinical medicine is the goal of
translational research (Imray et al. 2015). Studies
of healthy individuals under extreme physiological
stress (such as extreme heat, cold or hypoxia) have
provided insigh ts into some of the basic but novel
pathophysiological mechanisms reported in acute severe
life-threatening illnesses. The response of healthy humans
to extreme altitude might be a useful model for hypoxic
patients in intensive care, and this model has recently
been explored extensively (Swenson et al. 2014).
C
2016 The Authors. Experimental Physiology
C
2016 The Physiological Society DOI: 10.1113/EP085813
2 Exp Physiol 000.0 (2016) pp 1–6
C. Imray
Vascular disease is a common and growing feature
of Western s ociety and accounts for a very significant
disease burden (Yusuf et al. 2001). Carotid artery disease
is common and results in significant morbidity and
mortality (Johnston et al. 2009). One of the pathological
processes observe d in carotid artery disease involves
narrowing of the internal carotid by atheromatous
plaque, and this can result in subsequent plaque rupture,
with downstream embolization. This can lead to focal
neurological events, such as transient ischaemic attacks
or stroke (Imray & Tiivas, 2005). Cerebral microemboli
can be detected using transcranial Doppler (TCD), and
thecerebralembolicloadappearstoberelatedtotherisk
of subsequent stroke (Molloy & Markus, 1999). Emboli
tend to be mainly platelet in origin and so may be
controllable with oral or intravenous antiplatelet agents
(van Dellen et al. 2008). These non-invasive portable
ultrasound techniques have subsequently proved to be
practical in the field.
Cerebral perfusion on ascent to altitude
The barometric pressure falls with increasing altitude
and with it also the partial pressure of atmospheric and
inspired oxygen. Acclimatization to this environmental
hypobaric hypoxic stress involves a number of adaptive
processes, including hyperventilation and an increase in
haematocrit, which tend to restore arterial oxygen content
toward sea level values (Imray et al. 2011). In addition,
increased cerebral blood flow (CBF) is believed to be one
compensatory mechanism ser ving to maintain normal
ox ygen flux to the br ain in the face of arterial hypoxaemia.
Although other measures of cerebral perfusion, such as
nitrous oxide washout (Severinghaus et al. 1966) and
xenon (Jensen et al. 1985), have been used in the past,
TCD has the attraction of being both non-invasive and
portable, making it a potentially attractive investigative
tool for altitude studies. The technique uses a 2 MHz
probe focused at 5 cm to measure the velocity of the
blood within the middle cerebra l artery (MCA).
Over the years, the term ‘flow’ velocity has been widely
incorporated, and makes the assumption that there is no
change in the MCA diameter (and so velocity would be
an accurate surrogate of flow; Serrador et al. 2000). The
TCD measurement of ‘flow velocity’ in the MCA has been
extensively used to assess CBF dynamics both at rest and
during exercise at altitude, and this was reviewed by Wilson
et al. (2009). However, the assumption that velocity is
a surrogate for flow has been disputed (Giller, 2003).
Furthermore, an opposite or contradictory assumption
is made in many clinical situations; in the management
of subarachnoid hemorrhage, for example, changes in
TCD-derived blood velocity are assumed to represent
changes in vessel diameter (vasospasm). In the past, the
measurement of MCA diameter has only been possible
by direct vision at surgery (Giller et al. 1993), by use
of contrast angiography (Du Boulay & Symon, 1971) or
magnetic resonance angiography (Valdueza et al. 1997);
techniques inappropriate for field studies.
Transcranial colour Doppler power signal has
previously been used to infer MCA cross-sectional area
indirectly in a laboratory setting (Poulin, 1996). The
recent development of portable ultrasound devices that
incorporate both two-dimensional colour flow mapping
and concurrent pulse wave Doppler ultrasonography
permits measurement of both the vessel diameter and
the velocity of the blood within it. The two-dimensional
ultrasound ensures that the same segment of the artery
can be reliably visualized and assessed. This approach has
nove l utility, but there are potential serious theoretical
limitations with the use of colour Doppler when
measuring vessel diameter, including the influence of gain
settings. To that end, a validation study directly comparing
transcranial colour Doppler and magnetic resonance
angiog raphy was performed (Wilson et al. 2011a), and
transcranial Doppler and magnetic resonance imaging
(MRI)-measured vessel diameters correlated closely [r =
0.82 (Pearson’s), r
2
= 0.67].
Using transcr anial colour Doppler in the first published
field study of cerebral perfusion above 5500 m (at 7950 m),
it was found that exposure to extreme hypobaric hypoxia
was associated with an increase in MCA diameter
(Wilson et al. 2011a). The MCA dilatation was rapidly
reversed by inhaled supplemental oxygen. These field
transcranial colour Doppler findings have subsequently
been replicated using mag netic resonance angiography
in acute hypoxia at sea level. The increased diameter,
as opposed to increased blood velocity, was the major
factor increasing CBF and maintaining cerebral oxygen
delivery at extreme altitude (>5300 m). Others have
independently confirmed these observations in bulk flow
within extracranial vessels internal carotid artery (i.e.
internal carotid artery; Willie et al. 2012; Ogoh et al.
2013). Middle cerebral artery vasodilatation may have
implications for the pathogenesis of cerebral high-altitude
illness and the acclimatization process. Future studies
inferri ng CBF from TCD velocity measurements at
altitude and clinical studies where oxygenation may
change should take vessel caliber into account.
It is important to acknowledge that the culmination of
the findings presented challenge current dogma regarding
cerebral vessel function during physiological hypoxia.
More research is needed to define the physiological range
over which cerebral vessel dilatation may occur or in what
populations this may be observed (or not). Putting this
into context, it should be noted that interpretation of
data collected using other methods, and in particular
TCD, may be misleading. For instance, the increase in
flow velocity measured during hypoxia using TCD is not
wrong, but may be an underrepresentation. Researchers
C
2016 The Authors. Experimental Physiology
C
2016 The Physiological Society
Exp Physiol 000.0 (2016) pp 1–6 3
Cerebral perfusion insights and their potential clinical significance
and/or clinicians should be aware of the limitations when
interpreting results that do not take into account possible
changes in MCA diameter.
High-altitude cerebral oedema and current concepts
Ross (1985) proposed that variations in cerebral and spinal
compliance (the ability to accommodate hypoxia- induced
cerebral swelling) between individuals could account for
the ‘random nature’ of the headache that occurs at
altitude (Hackett & Roach, 2001). This formed the basis
of the currently accepted pathogenesis of acute mountain
sickness (AMS). An additional physiological component
of exercise-exacerbated hypoxaemia (that is hypothesized
to worsen cerebral swelling) has been incorporated into
the theory, and likewise, hypoxia during sleep may
compound the situation (Bailey et al. 2006). Free radical
formation, nitric oxide and inflammatory m diators (e.g.
vascular endothelial growth factor) have been proposed as
mechanistic links between hypoxia and oedema for mation
(Wilson et al. 2009). Unfortunately, there is little evidence
to suggest that hypoxia causes cerebral oedema sufficiently
(at least in AMS) to account for the severe headache, and
such swelling does not correlate with headache symptoms
(Bailey et al. 2006; Kall enberg et al. 2007). Evidence
for a rise in intracranial pressure (ICP) is also sparse
(Wilson et al. 2009). Cerebral oedema itself is far more
common in conjunction with high-altitude pulmonary
oedema (Hackett et al. 1998; Fagenholz et al. 2007).
Currently, high-altitude cerebral oedema is a clinical
diagnosis defined as symptoms of AMS plus gait ataxia
or mental status changes, or both ataxia and mental status
changes. The term ‘cerebral oedema’ normally implies an
underlying pathological process that may not be the case
in all patients with this clinical diagnosis. This misnomer
may potentially distra ct from other pathological processes
(including hypoxia itself) that could account for altered
neurology in some people at altitude.
The initial cause of high-altitude headache might
theoretically be venous congestion. This occurs before the
limits of cranial compliance are reached (hence, before a
rise in ICP) and before cerebral oedema forms. A rise in
ICP and vasogenic oedema formation, if and when they
do occur, may well be sequelae to early cerebral venous
congestion.
The retinal vasculature, because of its direct connection,
is often considered to reflect changes in cerebral
vasculature (Patton et al. 2005). A number of studies
have demonstrated retinal artery dilatation/increased
tortuosity and vein distension with hypobaric hypoxia. In
24 subjects ascending to 5300 m, retinal venous distension
correlated with the sum of an individual’s headache scores
during the ascent (Wilson et al. 2013). Although arterial
distension was also noted, there was no correlation with
headache. Willmann et al. (2013) also found evidence
of retinal artery and venous dilatation on ascent to
4559 m, but have questioned the restricted venous
outflow hypothesis because they found no association with
headache.
Initial interest in venous changes with hypoxia resulted
from a pilot study using susceptibility weighted MRI after
3 h of 12% hypoxia (Wilson et al. 2013). The dramatic
increase in venous caliber, however, could have been
an artifact and influenced by the altered susceptibility
weighting (MRI signal characteristics) of deoxygenated
blood. The study was therefore repeated with 1 h of
11% hypoxia using gadolinium (which does not alter
susceptibility in hypoxia) enhanced T1 imaging,andagain,
venous prominence increased with hypoxia.
In a recent hypoxic study (Sagoo et al. 2016), there
is further evidence implicating the venous system in the
development of hig h-altitude cerebral oedema. Subjects
were exposed to 22 h of continuous normobaric hypoxia
(fractional inspired O
2
= 0.12, approximately equivalent
to an altitude of 4400 m) inside a 2 m × 2m× 1.6 m
hypoxic tent. Hypoxic generators were used, and build-up
of carbon dioxide within the tent was controlled with
an air pump, which pumped the tent air through soda
lime scrubbers. Baseline physiological measurements,
venous blood samples and MRI scans were obtained
at normoxia (fractional inspired O
2
= 0.21). Inspired
oxygen and carbon dioxide concentrations were checked
every 15 min for the first 2 h, every 30 min from 2 to
10 h, and then every 2 h from 12 to 22 h. Extended
MRI-compatible tubing and a tight-fitting mask that were
connected to one of the three hypoxic generators enabled
the subjects to remain hypoxic during the MRI studies.
The subjects were scanned at rest and did not undertake
exercise during the study period. Subjects ate and drank
ad libitum,werekeptwellhydratedandsleptatvarious
points between the 12 and 22 h time points.
Thenovelfeatureofthisstudywasthatarterial
inflow, large and small vessel venous outflow, cerebral
oedema [apparent diffusion coefficient (ADC)], brain
parenchymal volumes and intracranial cerebrospinal fluid
volumes were measured repeatedly and simultaneously
over a 22 h period of sustained hypoxia. As a consequence,
the study g ives insights into the time course of both
the adaptive and the potentially maladaptive processes
on acute exposure to a fractional inspired O
2
of 0.12.
The combination of time (including overnight) and a
simulated altitude of 4400 m represents the sort of stimulus
that would be expected to cause a significant level of
acute high-altitude illness. Cerebral oxygen delivery was
maintained by increases in MCA velocity and diameter.
In addition, this study has shown, for the first time,
a possible mechanistic link between hypoxia, increased
arterial inflow, a hypothesized rise in Starling pressures
and the subsequent development of parenchymal brain
oedema and the clinical development of AMS.
C
2016 The Authors. Experimental Physiology
C
2016 The Physiological Society
4 Exp Physiol 000.0 (2016) pp 1–6
C. Imray
This study appears to unify the arterial inflow and
restricted venous outflow hypotheses. With the demon-
strated increase in arterial inflow, there will be an
associated increase in venous outflow. This has previously
been hypothesized and then shown to be associated with
high-altitude headache (Wilson & Imray, 2016; Sagoo et al.
2016).
Small vessel venocompression appeared towards the
endofthisstudyandisprobablyaresultofthe
simultaneous cerebral oedema that was developing.
Exploring this further, and based upon Poiseuille’s Law,
in order to sustain the increased arterial inflow there
must be either an increase in driving pressure or an
increase in venous diameter. Based upon this study, the
change observed in the large intracerebral veins is, at best,
modest, and in fact, there appeared to be an element of
small vessel venous restriction, implying that the increased
CBF seen in hypoxia is maintained by increased driving
pressures. The changes in driving pressures would result
in changes in the Starling pressures, with increases in
the venous capillary hydrostatic pressure. It should be
noted that in this study the ‘venous outflow restric tion’
appears to be associated with smaller venous vessels
rather than the large vessels/anatomical variants described
by Wilson et al. (2013). These postulated changes in
Starling pressures could, in turn, account for early oedema
formation. The observed rise in oedema between 11
and 22 h might be a time-based effect, or alternatively,
the formation of oedema might be exacerbated by 8 h
of recumbency, which would further increase capillary
backpressure.
Late rises in ADC values within the genu and splenium
of the corpus callosum confirm the build-up of regional
water content and are an indirect measure of cerebral
oedema. This supports the findings of Hackett et al.
(1998). We found that the observed increase in brain
parenchymal volumes at 22 h was associated with
decreased brain cerebrospinal fluid volumes (confirming
‘internal validation’ of our methodology of independently
measuring the segmented cerebrospinal fluid and brain
parenchymal volumes) and also a reduction in s mall
venous vessel volumes [susceptibility weighted imaging
(SWI) sequence] at 22 h, further increasing the Starling
pressure driving oedema formation. A decreased ability
to buffer these parenchymal brain volume changes will be
reflected by increases in ICP and, eventually, high-altitude
cerebral oedema (Imray et al. 2011). A possible novel
mechanism that involves local oedema causing a reduction
in postcapillary venous diameters has b een observed,
and the same mechanism may be implicated in raised
ICP from other causes. Interestingly, a correlation was
found between the cumulative Lake Louise score and
an increase in brain white matter volume at 22 h. This
study supports certain aspects of the publication by
Lawley et al. (2014), where they found that an increase
in brain volume (predominantly in the grey matter) at
10 h was associated with a reduction in the cerebral
component of cerebrospinal fluid. They also found a
statistically significant relationship between the change
in ICP (measured non-invasively by MRI) and severity of
AMS after 10 h. We studied our subjects for a further 12 h
and found, as would be predicted, higher levels of AMS
symptoms. In addition, we found a later increase in total
brain parenchymal volume (grey and white matter) at 22
h compared with baseline.
As a consequence, increases in cerebral vessel
diameter, which would potentially augment cerebral
blood flow, might have an important effect on ICP. It
follows that the use of TCD may underestimate the
interpretation/prediction of changes in ICP and have
implications on associated conditions.
Wider clinical relevance
The results of this study may have important
translational implications. Intracranial pressure is the
primary neurological parameter that guides therapy on
neuro-intensive care. Understanding the cerebrovascular
interactions that affect ICP is vital in the management
of both t rauma and stroke patients. The optimization of
cerebral perfusion pressure is determined by ICP (cerebral
perfusion pressure = mean arterial pressure minus ICP).
Intracranial venous outflow pressure closely correlates
with ICP (Johnston & Rowan, 1974).
The effects of carbon dioxide and hyperventilation
on CBF are well known. The effects of hypoxia, and
in particular, the changes that occur over a period of
time, may aid the understanding of the interplay between
chest and intracranial physiology. Hypoxia, for example
secondary to chest sepsis or adult respiratory distress
syndrome, is common in the neurocritical patient (Lee
& Rincon, 2012).
As such, the management of cerebral oxygenation and
carbon dioxide is integr al to good neurocritical care and
is likely to be crucial to optimizing the correct therap eutic
regimen. Hypoxia resulted in parenchymal brain swelling
(Sagoo et al. 2016). Subsequent development of cerebral
oedema was found, which could eventually result in an
increase in ICP. This was attri buted to compression of
the cerebral venous system, restricting venous outflow,
and possibly, a Starling resistor mechanism (Simard et al.
2007). In an animal model, venous hypertension has been
associated with increases in brain volume, and this was
caused by vessel dilatation. Cerebral oedema only occurred
if there was also associated cerebral tissue injury (Cuypers
et al. 1976). Acute hypoxia can cause tissue injury through
a number of different mechanisms, such as direct damage
to basal membrane structures (Miserocchi et al. 2001),
vascular endothelial growth factor (Dorward et al. 2007)
or free radicals (Bailey et al. 2004).
C
2016 The Authors. Experimental Physiology
C
2016 The Physiological Society
Exp Physiol 000.0 (2016) pp 1–6 5
Cerebral perfusion insights and their potential clinical significance
References
Bailey DM, Kleger GR, Holzgraefe M, Ballmer PE & B
¨
artsch P
(2004). Pathophysiological significance of peroxidative
stress, neuronal damage, and membrane permeability in
acute mountain sickness. JApplPhysiol96, 1459–1463.
Bailey DM, Roukens R, Knauth M, Kallenberg K, Christ S,
Mohr A, Genius J, Storch-Hagenlocher B, Meisel F,
McEnenyJ,YoungIS,SteinerT,HessK&B
¨
artsch P (2006).
Free radical-mediated damage to barrier function is not
associated with altered brain morphology in high-altitude
headache. J Cereb Blood Flow Metab 26, 99–111.
Cuypers J, Matakas F & Potolicchio SJ (1976). Effect of central
venous pressure on brain tissue pressure and brain volume.
JNeurosurg45, 89–94.
Dorward DA, Thompson AA, Baillie JK, MacDougall M &
Hirani N (2007). Change in plasma vascular endothelial
growth factor during onset and recovery from acute
mountain sickness. Respir Med 101, 587–594.
Du Boulay GH & Symon L (1971). The anaesthetist’s effect
upon the cerebral arteries. Proc R Soc Med 64, 77–80.
Fagenholz PJ, Murray AF, Gutman JA, Findley JK & Harris NS
(2007). New- onset anxiety disorders at high altitude.
Wilderness Environ Med 18, 312–316.
Giller CA (2003). The Emperor has no clothes: velocity, flow,
and the use of TCD. J Neuroimaging 13, 97–98.
Giller CA, Bowman G, Dyer H, Mootz L & Krippner W (1993).
Cerebral arterial diameters during changes in blood pressure
and carbon dioxide duri ng craniotomy. Neurosurgery 32,
737–741.
Hackett PH & Roach RC (2001). High-altitude illness. NEngl
JMed345, 107–114.
Hackett PH, Yarnell PR, Hill R, Reynard K, Helt J &
McCormick J (1998). High-altitude cerebral edema
evaluated with magnetic resonance imaging: clinical
correlation and pathophysiology. JAMA 280, 1920–1925.
Imray C, Booth A, Wright A & Br a dwell A (2011). Acute
altitude illnesses. BMJ 343, d4943.
Imray CHE, Grocott MPW, Wilson MH, Hughes A & Auerbach
PS (2015). Extreme, expedition and wilder ness medicine.
Lancet 386, 2520–2525.
Imray CHE & Tiivas CAS (2005). Are some strokes pre ventable?
The potential role of transcranial doppler in transient
ischaemic attacks of carotid origin. Lancet Neurol 4, 580–586.
Jensen JB, Wright AD, Lassen NA, Harvey TC, Winterborn
MH, Raichle ME & Bradwell AR (1985). Cerebral blood flow
in acute mountain sickness. JApplPhysiol69, 430–433.
Johnston IH & Rowan JO (1974). Raised intracranial pressure
and cerebral blood flow. 3. Venous outflow tract pressures
and vascular resistances in experimental intracr a nial
hypertension. J Neurol Neurosurg Psychiatry 37, 392–402.
Johnston SC, Mendis S & Mathers CD (2009). Global variation
in stroke burden and mortalit y: estimates from monitoring,
surveillance, and modelling. Lancet Neurol 8, 345–354.
Kallenberg K, Bailey DM, Christ S, Mohr A, Roukens R,
Menold E, Steiner T, B
¨
artsch P & Knauth M (2007).
Magnetic resonance imaging evidence of cytotoxic cerebral
edema in acute mountain sickness. J Cereb Blood Flow Metab
27, 1064–1071.
Lawley JS, Alperin N, Bagci AM, Lee SH, Mullins PG, Oliver SJ
& Macdonald JH (2014). Normobaric hypoxia and
symptoms of acute mountain sickness: elevated brain
volume and intracranial hypertension. Ann Neurol 75,
890–898.
Lee K & Rincon F (2012). Pulmonary complications in
patients with severe brain injury. Crit Care Res Pract 2012,
207247.
Miserocchi G, Passi A, Negrini D, Del Fabbro M & De Luca G
(2001). Pulmonary interstitial pressure and tissue matrix
structure in acute hypoxia. Am J Physiol Lung Cell Mol
Physiol 280, L881–L887.
Molloy J & Markus HS (1999). Asymptomatic embolization
predicts stroke and TIA risk in patients with carotid artery
stenosis. Stroke 30, 1440–1443.
Ogoh S, Sato K, Nakahara H, Okazaki K, Subudhi AW &
Miyamoto T (2013). Effect of acute hypoxia on blood flow in
vertebral and internal carotid arteries. Exp Physiol 98,
692–698.
Patton N, Aslam T, MacGillivray T, Pattie A, Deary IJ &
Dhillon B (2005). Retinal vascular image analysis as a
potential screening tool for cerebrovascular disease: a
rationale based on homology between cerebral and retinal
microvasculatures. JAnat206, 319–348.
Poulin MJ & Robbins PA (1996). Indexes of flow and
cross-sectional area of the middle cerebral artery using
Doppler ultrasound during hypoxia and hypercapnia in
humans. Stroke 27, 2244–2250.
Ross RT (1985). The random nature of cerebral mountain
sickness. Lancet 1, 990–991.
Sagoo RS, Hutchinson CE, Wright A, Handford C, Parsons H,
Sherwood V, Wayte S, Nagaraja S, Ng’Andwe E, Wilson MH
& Imray CH; Birmingham Medical Research and Expedition
Society (2016). Magnetic resonance investigation into the
mechanisms involved in the development of high-altitude
cerebral edema. J Cereb Blood Flow Metab doi:
0271678X15625350. [Epub ahead of print].
Serrador JM, Picot PA, Rutt BK, Shoemaker JK & Bondar RL
(2000). MRI measures of middle cerebral artery diameter in
conscious humans during simulated orthostasis. Stroke 31,
1672–1678.
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, 274–282.
Simard JM, Kent TA, Chen M, Tarasov KV & Gerzanich V
(2007). Brain oedema in focal ischaemia: molecular
pathophysiology and theoretical implications. Lancet Neurol
6, 258–268.
Swenson ER & Bartsch P (eds.) (2014). High Altitude: Human
Adaptation to Hypoxia.SpringerScience+Business Media,
New York. doi: 10.1007/978-1-4614-8772-2_7.
Valdueza JM, B alzer JO, Villringer A, Vogl TJ, Kutter R &
Einh
¨
aupl KM (1997). Changes in blood flow velocity and
diameter of the middle cerebral artery during
hyperventilation: assessment with MR and transcranial
Doppler sonography. AJNR Am J Neuroradiol 18,
1929–1934.
C
2016 The Authors. Experimental Physiology
C
2016 The Physiological Society
6 Exp Physiol 000.0 (2016) pp 1–6
C. Imray
van Dellen D, Tiivas CA, Jarvi K, Marshall C, Higman DJ &
Imray CH (2008). Transcranial Doppler ultrasonography-
directed intravenous glycoprotein IIb/IIIa receptor antago-
nist therapy to control transient cerebral microemboli before
and after carotid endarterectomy. Br J Surg 95, 709–713.
Willie CK, Macleod DB, Shaw AD, Smith KJ, Tzeng YC, Eves
ND, I keda K, Graham J, Lewis NC, Day TA & Ainslie PN
(2012). Regional brain blood flow in man during acute
changes in arterial blood gases. JPhysiol590, 3261–3275.
Willmann G, Fischer MD, Schommer K, B
¨
artsch P, Gekeler F &
Schatz A (2013). Missing correlation of retinal vessel
diameter with high-altitude headache. Ann Clin Transl
Neurol 1, 59–63.
Wilson MH, Davagnanam I, Holland G, Dattani RS, Tamm A,
Hirani SP, Kolfschoten N, Strycharczuk L, Green C,
Thornton JS, Wright A, Edsell M, Kitchen ND, Sharp DJ,
Ham TE, M urray A, Holloway CJ, Clarke K, Grocott MPW,
Montgomer y H & Imray C; Birmingham Medical Research
Expeditionary Society & Caudwell Xtreme Everest Research
Group (2013). Cerebral venous system and anatomical
predisposition to high-altitude headache. Ann Neurol 73,
381–389.
Wilson MH, Edsell MEG, Davagnanam I, Hirani SP, Martin
DS, Levett DZH, Thornton JS, Golay X, Strycharczuk L,
Newman SP, Montgomery HE, Grocott MPW & Imray
CHE; Caudwell Xtreme Everest Research Group (2011a).
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.
Wilson MH, Imray CHE & Hargens AR (2011b). The headache
of high altitude and microgravity—similarities with clinical
syndromes of cerebral venous hypertension. High Alt Med
Biol 12, 379–386.
Wilson MH, Newman S & Imray CH (2009). The cerebral
effects of ascent to high altitudes. Lancet Neurol 8,
175–191.
Wilson MH & Imray CHE (2016). The cerebral venous system
and hypoxia. JApplPhysiol120, 244–250.
Yusuf S, Reddy S,
ˆ
Ounpuu S & Anand S (2001). Global
burden of cardiovascular diseases: part I: general
considerations, the epidemiologic transition, risk factors,
and impact of urbanization. Circulation 104,
2746–2753.
Additional information
Competing interests
None declared.
Acknowledgements
I would like to acknowledge Mark Wilson, Alex Wright, the
Birmingham Research Expeditionary Society and the Centre for
Altitude, Space and Extreme Environment Medicine for their
support and input.
C
2016 The Authors. Experimental Physiology
C
2016 The Physiological Society
