Netherlands Journal of Critical Care
Copyright © 2011, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received September 2010; accepted January 2011
Review
Research on Mount Everest: Exploring Adaptation to Hypoxia to Benefit the Critically Ill Patient
JM van der Kaaij1,2, DS Martin1, MG Mythen3, MP Grocott1, 4
1 Centre for Altitude Space and Extreme Environment Medicine University College London (UCL), Institute of Child Health, London,
United Kingdom
2 Department of Anaesthesiology, VU Medical Centre, Amsterdam, The Netherlands
3 Smiths Medical Professor of Anaesthesia and Critical Care, Portex Unit, UCL Institute of Child Health, London, United Kingdom
4 Critical Care Research Unit, Southampton University Hospitals NHS Trust, Southampton, United Kingdom
Abstract - Critically ill patients often suffer from hypoxaemia to which the response of the human body is far from understood. As this
category of patients form a heterogenous group, they are difficult to study. In contrast to animal and cellular models, a new paradigm
was suggested by the University College London (UCL) Centre for Altitude Space and Extreme Environment (CASE) Medicine, involving
exposure of healthy volunteers to environmental hypobaric hypoxia in a controlled manner. This is based on the assumption that ascent
to high altitude will trigger adaptive processes similar to the ones occurring in critically ill patients suffering from hypoxaemia, thereby
obtaining better understanding of adaptive and maladaptive processes caused by hypoxaemia in a clinical context. In the spring of
2007 the medical research expedition Caudwell Xtreme Everest (CXE) took place on the slopes of Mount Everest in Nepal. Twentyfour investigator subjects (from a total of 60 investigators) and 198 volunteer subjects were studied over a period of three months.
Specific hypotheses about oxygen delivery, oxygen consumption and metabolic efficiency were tested. Inter-individual responses to
environmentally induced hypoxaemia were described and beneficial phenotypes and genotypes sought. In this article an explanation
of this approach to hypoxia research along with an overview of the CXE expedition are presented. The results available to date are
described in detail. Ultimately, the aim is to translate the knowledge obtained into further interventional research and practice in the
clinical setting in the hope of improving the care of patients in whom hypoxaemia is a fundamental problem.
Keywords -
hypobaric hypoxia, hypoxia adaptation pathways, microcirculation, cellular metabolism, critically ill, translational research
Introduction
In critically ill patients, regardless of their underlying pathology,
hypoxaemia (reduced arterial oxygenation) is common and may
be caused by a variety of underlying pathologies [1]. Hypoxaemia,
regardless of its cause, can result in tissue hypoxia (reduced cellular
and mitochondrial oxygen availability). Hypoxia may generate
a stimulus for cellular dysfunction, particularly when combined
with systemic inflammation [2]. Our understanding of the human
response to hypoxaemia is far from complete and difficulties that
arise from studying the heterogeneous group of patients that
populate intensive care units contribute to this. Animal and cellular
models have been proposed to help elucidate mechanisms that
may explain adaptation to oxygen deprivation but these approaches
also have significant limitations [3-6].
Healthy individuals ascending to high altitude are exposed to
a decline in the atmospheric partial pressure of oxygen (hypobaric
hypoxia), which results in a reduction of inspired, alveolar and
arterial partial pressures of oxygen. The physiological responses
to this ‘insult’ are likely to be similar to responses evoked in
hypoxaemic patients [7,8]. It is therefore hypothesized that a better
understanding will be obtained of the processes that occur when
Correspondence
JM van der Kaaij
E-mail: [email protected]
240
NETH J CRIT CARE - VOLUME 15 - NO 5 - OCTOBER 2011
patients succumb to sub-acute hypoxaemia as a result of disease,
by studying the effects of hypobaric hypoxia in healthy volunteers
[1]. This conceptual framework inspired a team of scientific and
medical investigators to organise a research expedition in the
spring of 2007 to Mount Everest in Nepal, the summit of which is
the highest point on the surface of the Earth (8848m). The project
was called Caudwell Xtreme Everest (CXE) and was organised by
the University College of London (UCL) Centre for Altitude Space
and Extreme Environment (CASE) Medicine.
During a three month stay at altitude, the team studied a total
of 222 subjects as they walked to the base camp of Mount Everest
(5300m) and went on to perform investigations in a sub-group of
this cohort (‘climbers’) to a maximum altitude of 8400m on the
mountain. The aim was to study individual physiological responses
to sustained hypobaric hypoxia, measuring specific variables and
relating them to genetic variations.
The ultimate and novel goal was that lessons learnt on the
mountain would drive translational research in the clinical setting
and directly benefit patients; in a sense bringing knowledge
‘from mountainside to bedside’ [1,7]. This review discusses the
objectives and conduct of the expedition along with some of the
results of studies published to date and their possible implications
and relevance for practice in intensive care.
Netherlands Journal of Critical Care
Research on Mount Everest: Exploring Adaptation to Hypoxia to Benefit the Critically Ill Patient
Why is the mountain a good laboratory?
In the past a number of studies have been performed in hypoxic
environments both at altitude in the field and in hypobaric chambers
[9-14]. The Operation Everest series of studies had a duration of
about six weeks with four to eight subjects. They were performed
in the controlled environment of a decompression chamber to
exclude ‘mountain’ factors such as cold, inadequacies in intake
of food and fluids, exhaustion, and anxiety [13]. Their aim was
to understand better the adaptation of humans to environmental
hypoxia by examining changes in the oxygen transport system.
Stresses found in a mountainous environment were taken away
by providing ambient temperature control, availability of excellent
and ample food, access to communication devices such as radio
and telephone, and exercise facilities. Despite the constitution
of this ‘hypobaric paradise’ the subjects experienced similar
symptoms to those found in subjects participating in research in
a true mountainous environment: sore throat and cough, sleep
disturbance, decreased mental and physical activities [13].
Furthermore, comparable values to those measured in field studies
were found for many variables, such as maximum oxygen uptake
and weight loss [13], suggesting that the ‘mountain stress factors’
are not significant confounding factors for studies conducted in
the field. Moreover, chamber studies are very resource intensive
due to the requirement for continuous medical and technical cover.
Additional problems for large chamber studies are the limited
Figure 1. Ascent profiles for trekkers and investigators respectively, from Kathmandu (1300m) to Everest Base Camp (EBC,
5300m). The investigators spent two additional days in Namche
Bazaar (3500m) for reasons of logistical demands and time
required for testing.
availability of hypoxic chamber facilities, the risk of decompression
sickness in investigators [15,16] and the difficulties of recruitment
of volunteers to spend prolonged periods in close confinement.
Of note, the environmental conditions within the tents and
shelters where experiments were conducted during CXE, showed
substantially less variation than ambient conditions, and were
similar to many laboratory environments [17].
Hypotheses of cxe
The CXE expedition set out to address two primary hypotheses
[18,19]. The first hypothesis was that factors other than those
related to global oxygen transport (cardiac output, ventilation, and
Table 1. Arterial blood gas measurements and calculated values
for pulmonary gas exchange from 4 subjects at an altitude of
8400 m, during descent from the Summit of Mount Everest.*
Variable
Subject number
Group
1
2
3
4
pH
7.55
7.45
7.52
7.60
mean
7.53
PaO2 (kPa)*
3.93
2.55
2.80
3.83
3.28
PaCO2 (kPa)*
1.64
2.10
2.0
1.37
1.77
Bicarbonate
(mmol/liter)†
10.50
10.67
11.97
9.87
10.80
Base Excess †
-6.3
-9.16
-6.39
-5.71
-6.9
Lactate (mmol/
liter)
2.0
2.0
2.9
1.8
2.2
SaO2 (%)†
68.1
34.4
43.7
69.7
54,00
PAO2 (kPa)*
4.32
3.58
3.65
4.43
4.00
A-a oxygen
difference (kPa)*
0.39
1.04
0.86
0.60
0.72
Haemoglobin
(mmol/liter)§
12.54
11.61
11.67
12.04
11.87
*PaCO2 denotes partial pressure of arterial carbon dioxide, PAO2
partial pressure of alveolar oxygen, PaO2 partial pressure of arterial oxygen, and SaO2 calculated arterial oxygen saturation.
†To convert the values for PaO2, PaCO2, PAO2, and the alveolararterial oxygen difference to kilopascals, multiply by 0.1333.
‡These values were calculated with the use of the algorithms currently approved by the Clinical Laboratory Standards Insti-
tute [37].
§The values obtained for haemoglobin are the mean values of
measurements obtained at 5300 m (17,388 ft) 9 days be-
fore and 8 days after the arterial blood sampling.
¶The respiratory exchange ratio was measured at an elevation of
7950m while the subject was resting.
║No measured respiratory exchange ratio was available for this
subject; the value was derived from the mean values for the other
three subjects.
**PAO2 was calculated with the use of the full alveolar gas equation.
This table has been reproduced with permission of the authors (Grocott MPW and Martin DS et al.) and Copyright holder Massachusetts
Medical Society, who published the original table in N Engl J Med
2009;360:140-9. Article DOI: 10.1056/NEJMoa0801581.
NETH J CRIT CARE - VOLUME 15 - NO 5 - OCTOBER 2011
241
Netherlands Journal of Critical Care
JM van der Kaaij, DS Martin, MG Mythen, Mike P Grocott
haemoglobin concentration) would in part explain the observed
inter-individual differences in performance at altitude. This was
based on studies that have previously demonstrated that at altitude,
maximum oxygen uptake (VO2max), a measure of maximum
exercise capacity, remains reduced compared to sea level values
despite adequate acclimatization, reflected by normalization of
arterial oxygen content (CaO2) [20-22]. Furthermore, exercise
capacity at high altitude differs markedly between individuals and
these differences cannot be explained by simple measures of
oxygen flux, or by specific differentiating physiological features at
sea level [23]. These other factors that were investigated included
alterations in the microcirculation that might limit oxygen delivery
within the tissues [24] and a down-regulation of cellular metabolism
[25,26].
The second hypothesis was that genotype differences would
explain a substantial proportion of inter-individual variation in
environmentally induced phenotypes. In lowlanders ascending to
altitude, as well as in critically ill patients, insertion variants of the
angiotensin converting enzyme (ACE) gene have been associated
with better performance and improved outcome respectively
[27-31]. Furthermore, the assumption is that large populations
could only have lived for generations in an extreme environment
of hypobaric hypoxia by evolving towards a beneficially adapted
genotype (and phenotype) [32]. We therefore explored whether
the genotypes associated with beneficial phenotypes in healthy
lowland subjects exposed to hypoxia for days and weeks (‘rapid
responders’ to hypobaric hypoxia) could reveal underlying adaptive
mechanisms [33].
Methodology of the studies
Design
We approached the hypotheses with a number of core and
supporting studies, together forming the foundation of this
longitudinal observational cohort study. A total of 222 healthy
subjects were studied prospectively whilst being exposed in a
progressive and controlled manner to environmental hypobaric
hypoxia, during a trek from Lukla (2800m) to Everest Base Camp
(EBC, 5300m) in Nepal, in the spring of 2007.
A small parallel study (up to 3900m), the Smith Medical Young
Everest Study, acquired unique observational data on a group of
nine children between six and thirteen years of age. Results of
these observations and its implications are described in detail
elsewhere [34]. Approval for all studies was gained from the UCL
Committee on the Ethics of Non-NHS Human Research and was
accompanied by a comprehensive risk management plan.
Subjects
The study participants were divided in two distinctive groups,
‘trekkers’ and ‘investigators’. Recruitment of trekkers was from
the general public who expressed an interest in participating in
Fig 2-A. Setting up the laboratory in Camp 2, in the Western Cwm of Everest (6400m)
242
NETH J CRIT CARE - VOLUME 15 - NO 5 - OCTOBER 2011
Netherlands Journal of Critical Care
Research on Mount Everest: Exploring Adaptation to Hypoxia to Benefit the Critically Ill Patient
the expedition, following public advertisements. This trekker group
comprised 198 subjects of which 73 were female. The investigator
group was composed of 24 subjects who were selected from the
total of 60 investigators involved in the planning and conduct of
the project in the field. The investigators were further divided into
two cohorts: ‘base camp team’ (n=10, 4 females) who remained at
Everest Base Camp (EBC) (5300m ± 500m), and ‘climbers’ (n=14,
2 females) who ascended to various heights on Mount Everest,
with the maximum at 8848m. Selection criteria as well as baseline
characteristics of the study population are described elsewhere
[17]. The set-up was as such that the prolonged stay at high altitude
of the investigators would also enable follow-up of adaptation to
more chronic hypoxia.
Ascent profile
All subjects were tested in London (sea level, 75m) prior to
departure to Nepal. Ascent profiles differed between trekkers and
investigators but within their respective groups, ascent profiles
were identical throughout (figure 1) [35]. The duration of ascent
for the trekkers was one to three days slower than the number
of days usually scheduled by many commercial operators. It was
deliberately designed as such to minimise the incidence of altitude
related illness in the subjects and to enable as many of them as
Fig 2-B. Measuring oxygen consumption via breath-by-breath
gas analysis in a member of the climbing team in the laboratory
at 7950m (South Col)
possible to complete the trek and provide a full dataset. Once
testing at EBC was completed the trekkers descended back to
Lukla whilst the base camp staff investigators remained at EBC
(± 500m) and climber-investigators ascended and descended the
mountain until the end of the expedition.
Logistics
The size of the expedition together with the remoteness of the
research locations also presented a substantial logistic challenge.
In total 26,000 kg of equipment was shipped to Kathmandu (Nepal)
from where over a half million individual items needed to be
transported to the various field laboratories. This was achieved by
a dedicated logistics team working in partnership with a trekking/
mountaineering company. The roles of over 40 Sherpas were
invaluable. In the years building up to the CXE 2007, extensive
validation of laboratory equipment was done in environmental
chambers. A pilot expedition to the Alps (in 2006) and two
successful expeditions to the summit of Cho Oyu (8201m) (in 2005
and 2006) were undertaken to ensure investigators and equipment
would operate adequately at these high altitudes.
Fig 3. member of the climbing team ‘dressed’ with an arterial
line and nasogastric tube awaiting his lactate threshold cardiopulmonary exercise test and gastric tonometry
NETH J CRIT CARE - VOLUME 15 - NO 5 - OCTOBER 2011
243
Netherlands Journal of Critical Care
JM van der Kaaij, DS Martin, MG Mythen, Mike P Grocott
Studies
A total of ten different studies were designated as ‘core’ and all
subjects participated in these unless exclusion criteria were met
[17]. The studies could be divided into eight topics:
• oxygen transport and metabolic efficiency (breath-by-breath
analysis during cardiopulmonary exercise at set workloads to
obtain insight in oxygen economics with increasing levels of
hypobaric hypoxia);
• maximum exercise capacity combined with assessment of leg
muscle and brain saturations during cardiopulmonary exercise;
• measurement of systemic saturations;
• measurement of inflammatory biomarkers and markers of tissue
injury and oxidative stress, and nitric oxide metabolites, where
the aim was to identify biomarkers associated with beneficial
and maladaptive responses to the exposure to hypobaric
hypoxia, and to explore the interaction between hypoxaemia
and inflammation;
• neurocognitive functioning (neuropsychometric tests assessing
changes in skills as cognition, memory, attention and fine motor
skills, following exposure to longer-term environmental hypoxia.
In addition Trans-Cranial Doppler (TCD) measurements,
pupillometry, saccadometry and retinal photography, as well
cerebral tissue oxygenation (NIRS) were collected in order to
correlate with the functional measures of cognition);
• lung function;
• genetophysiology. Blood samples from all subjects taken in
London provided the genetic material for analysis of specific
candidate genes, genes known or believed to be involved in
the response to hypoxia [33]. These will be correlated with
the observed phenotypes in their response to exposure to
hypobaric hypoxia;
• symptom diary. This included a daily assessment of symptoms
and simple physiological variables as well as a short exercise
challenge.
Studies were conducted at sea level (75m) and thereafter during
the trek sequentially in Kathmandu (1300m), Namche Bazaar
(3500m), Pheriche (4250m), and Everest Base Camp (5300m). The
climbing team was also studied at Camp 2, in the Western Cwm of
Everest (6400m) (figure 2-A) and at the South Col (7950m) (Figure
2-B) and at the Balcony (8400m). Laboratory characteristics are
described elsewhere [17]. Subgroups of both groups of subjects
participated in additional studies that, by the nature of the research
question, were not performed in every single laboratory. These
studies included description of the sublingual microcirculation,
gastric tonometry (figure 3), brain magnetic resonance imaging (at
sea level before and after the trek) as well as vascular changes
(Doppler ultrasound), cardiac function (electrocardiography and
echo), smell, oxygen transport at extreme altitude (arterial blood
gases), and mitochondrial functioning (muscle biopsies).
Summarized results so far
To our knowledge, this is the largest group of subjects that has been
studied in such detail at altitude. Although trekkers and investigators
followed the same route and were submitted to the same set of
core studies, data from these groups can be compared but not
244
NETH J CRIT CARE - VOLUME 15 - NO 5 - OCTOBER 2011
combined – due to the highly-selected nature of the investigator
group. Published data so far are mainly from the investigators
group and from the preparatory Cho Oyu expeditions, due to the
vast amount of data obtained from the trekkers. Developments in
technology allowed the use of novel devices for measurements
and imaging of physiological and pathophysiological changes at
altitude and provided a first validation of the use of some of these
devices at altitude. Testing, trekking, and climbing goals were
achieved in a safe and controlled manner.
Arterial blood gases and oxygen content
Direct field measurements of the arterial partial pressure of oxygen
(PaO2) were made and CaO2 calculated in 10 climbers breathing
ambient air at different altitudes up to a maximum of 8400m, in
order to define the limits of tolerance to hypoxia [36]. Arterial blood
samples were obtained at 75m (London), 5300m (EBC), 6400m
(Camp 2), 7100m (Camp 3), and because of adverse weather
conditions at 8400m (the Balcony) instead of the summit (8848m).
All subjects were taken off supplemental oxygen (breathing
ambient air) for at least 20 minutes prior to blood sampling. In
the four subjects tested at 8400m, the mean arterial blood gas
measurements and calculated values for pulmonary gas exchange
were as shown in Table 1. Up to an altitude of 7100m, the mean
arterial oxygen was comparable to what was measured at sea levels
(197.1 ml/L). At 8400m the mean CaO2 was decreased to 145.8
ml/L and showed marked inter-individual variability (range 89.7190.7 ml/L). The variability could be explained by inter-individual
variation in the briskness of their hypoxic ventilatory response and
depression, which physiologically occur following acute exposure
and re-exposure to hypobaric hypoxia. Upon heavy exercise the
alveolar-arterial oxygen difference (Aa-DO2) increases at sea level
[38]. Wagner et al. not only confirmed this observation but also
showed that resting Aa-DO2 levels decrease with falling PaO2 [39].
Furthermore, he showed that the measured and predicted Aa-DO2
levels differed with increasing levels of exercise and with increase
in altitude [39]. Based on both theory and empirical data [40],
we expected the Aa-DO2 in the climbers to be around 0.27kPa.
However, the mean calculated Aa-DO2 was 0.72 kPa (range
0.39-1.04 kPa). This higher gradient may have been the result
of subclinical pulmonary oedema or inhomogenous pulmonary
vasoconstriction affecting ventilation perfusion matching [41,42],
thereby contributing to the low measured PaO2. The finding that
none of the subjects were severely hyperlactatemic despite the
chronic hypoxaemia is consistent with findings in resting subjects
at a simulated altitude of 8848m [20]. This supports the idea that
cellular adaptation to chronic hypoxaemia may tend towards a more
efficient use of oxygen preventing anaerobic cellular metabolism,
rather than relying on anaerobic metabolism.
Microcirculatory blood flow at high altitude
The first direct visualisation of the sublingual microcirculation was
made in 12 healthy volunteers ascending the 8201m high mountain
Cho Oyu in 2006 [43]. Recordings were acquired using sidestream
dark-field (SDF) imaging by a hand-held microscope emitting
green light from its tip at a wavelength of 548nm to illuminate
the sublingual mucosa [24, 44]. This pilot study established
Netherlands Journal of Critical Care
Research on Mount Everest: Exploring Adaptation to Hypoxia to Benefit the Critically Ill Patient
the use of the SDF camera in this environment in visualising the
microcirculation and obtaining quantitative data. On Everest,
further images were obtained in the investigators group up to an
altitude of 7950m [45]. Based on the findings in the pilot study
[44] it was hypothesized that hypobaric hypoxia would reduce the
blood flow within the sublingual microcirculation and increase the
capillary vessel density. From the base camp staff (EBC) subjects
(n=10) images were obtained at 75m, 3500m, on arrival at 5300m
(5300m-a) and 54 days later at 5300m (5300m-b). The climbers
(n=14) were studied at these same altitudes and furthermore
at 6400m and 7950m. At this latter altitude, supplemental
oxygen was administered to the subjects prior to and during
imaging. From the images of all subjects at every study point, a
microcirculatory flow index (MFI) (no flow / intermittent flow / slow
flow / continuous or normal flow) could be calculated. Compared
with sea level, the median MFI was significantly reduced at all
altitudes, both in small (< 25 μm diameter) and medium-sized (2650 μm diameter) vessels. MFI in these vessels after prolonged
stay at altitude was significantly lower than on arrival at 5300m.
Mean vessel density increased significantly at all altitudes with no
further change during prolonged stay. The climbers compared to
the EBC-subjects showed a significantly lower MFI in small and
medium-sized vessels. Supplemental oxygen at 7950m tended to
further reduce median MFI, and increase vessel density, but interindividual variability was seen. Peripheral oxygen saturation (SpO2),
taken at every altitude during image-acquisition, did not correlate
with any microcirculatory measurement, nor did the haematocrit.
Although the used technique has its limitations [45], the described
findings support previous work on this imaging modality [44].
Figure 4. Graph representing a Near-Infrared Spectroscopy
(NIRS) plot, taken at sea level (75m). [A], start of unloaded
cycling; [B], start of loaded cycling; [C], maximum oxygen consumption.
The interpretation of the results, however, is not straightforward.
A possible explanation for the increase in vessel density could
be recruitment of ‘resting’ vessels in the microvascular network
initiated by hypoxaemia, leading to a reduction of the intercapillary
distance, slowing of blood flow, and shortening of tissue transit time
[45]. Increase in vessel density could also follow neovascularisation,
promoted by increased levels of vascular endothelial growth factors
[45,46]. Exploring these and alternative underlying mechanisms is
required to understand the microcirculatory response to chronic
hypoxaemia at altitude and in critically ill patients, and warrants
further investigations.
Tissue oxygenation
Near infra red spectroscopy (NIRS) is a non-invasive technique
for continuous monitoring of tissue and cerebral microcirculatory
oxygenation by reflecting the venous haemoglobin oxygen status
[47]. We used this technique to observe changes in tissue oxygen
saturation (StO2) in the vastus lateralis muscle during incremental
cardiopulmonary exercise testing, as the capacity to exercise is
governed by the equilibrium of oxygen supply and utilisation [48].
Good quality data were obtained at sea level, on arrival and before
departure from EBC 5300m from 16 of the 24 investigators (figure
4 and 5). The ‘base camp team’ subjects, who were exposed to a
constant level of hypobaric hypoxia during prolonged stay at EBC,
showed a more rapid decrease in muscle oxygenation towards the
end of the two months. In comparison, a slower rate and smaller
magnitude of desaturation was seen in the ‘climbers’ subjects. This
may be explained by a higher haemoglobin level in the ‘climbers’
Figure 5. Graph representing a Near-Infrared Spectroscopy
(NIRS) plot (of the same subject as represented in Figure 4) at
altitude, obtained after 54 days at Everest Base Camp (5300m).
[A], start of unloaded cycling; [B], start of loaded cycling; [C],
maximum oxygen consumption.
Figure 4 and 5 show a typical Near-Infrared Spectroscopy (NIRS) plot. The figures were taken from the original with permission of the authors (Martin DS et al.). The original figures have been published 30 November 2009, by copyright holder Biomed Central Ltd, in Critical Care 2009, 13(Suppl
5):S7 (doi:10.1186/cc8005), online available at http://ccforum.com/content/13/S5/S7
NETH J CRIT CARE - VOLUME 15 - NO 5 - OCTOBER 2011
245
Netherlands Journal of Critical Care
JM van der Kaaij, DS Martin, MG Mythen, Mike P Grocott
due to exposure to a more severe level of hypobaric hypoxia (higher
altitude) with corresponding increase in CaO2. Alternatively they
may be protected by mechanisms following the process of hypoxic
preconditioning, secondary to periods of exposure to more severe
hypobaric hypoxia. These mechanisms could involve changes in
the microcirculatory blood flow to the skeletal muscle, influences
on the affinity of oxygen to haemoglobin or its ability to diffuse
within the muscle; all processes taking place at the distal end of
the oxygen cascade, the peripheral circulation [48].
Skeletal muscle energetics
31
P magnetic resonance spectroscopy (31P-MRS) and magnetic
resonance imaging (MRI) were used to assess the metabolic
response in skeletal muscle to hypobaric hypoxia [49]. A total
of seven trekkers and seven climbers (of whom four summitted
the 8848m high Mount Everest) were studied prior to departure
to Nepal. A protocol of a series of plantar flexion exercises and
recovery was followed whilst the subject was in the bore of the
magnetic resonance system. Muscle morphology and energetics
measurements were taken following each exercise or recovery
bout. All trekkers were retested within 48 hours after returning from
Everest Base Camp (5300m) to sea level. All climbers ascended
to at least 7950 m (South Col). Five of them were retested within
seven days following their return to sea level. Pre-trek, a significant
difference was seen in muscle cytosolic inorganic phosphate
(Pi), the climbers having a higher concentration. Furthermore,
the climbers had better pre-trek mitochondrial function than the
trekkers, supported by significantly shorter phosphocreatinine
recovery halftimes (PCrt1/2) in the climbers. Whether this is a result
of self-selected beneficial phenotype (experienced climbers
knowing to respond well to exposure to high altitude versus
altitude-naive trekkers), stable modifications in phenotype following
altitude exposure, unusually persistent conventional physiological
adaptations caused by repeated hypoxia exposure, a combination
of these suggestions or other underlying mechanisms is unknown
and warrants further investigation [49]. The effect of altitude
exposure to muscle morphology and energetics was similar in both
groups: post-trek, resting cytosolic [Pi] was raised significantly to
pre-trek and a loss of 4% calf muscle cross sectional area was
found significant. With unchanged PCrt1/2, this finding showed a
reduction of the muscle aerobic capacity. Nevertheless, that did
not affect the muscle function as exercises could be completed in
a similar way post-trek to pre-trek. Furthermore, exercising skeletal
muscle high energy phosphate metabolites remained unchanged.
The underlying mechanisms for the total of findings require further
specifically targeted experiments.
Cardiac function and energy metabolism
It is thought that hypoxia from impaired oxygen delivery to the heart
as a result of coronary atherosclerosis, activates hypoxic signalling
pathways, thereby mediating diastolic dysfunction [50]. We
therefore hypothesized that hypobaric hypoxia may cause changes
in cardiac high energy metabolism resulting in cardiac dysfunction
[51]. In 14 trekkers cardiac energy metabolism (expressed by the
phosphocreatinine (PCr)/ATP ratio) and measurements of cardiac
mass, volumes, and function were assessed using 31P magnetic
246
NETH J CRIT CARE - VOLUME 15 - NO 5 - OCTOBER 2011
resonance spectroscopy (31P-MRS) and echocardiography and
magnetic resonance (MR) imaging respectively. Measurements
were taken at sea level within three weeks prior to departure for
Nepal, then within 48 hours after return from the trek to Everest
Base Camp (5300m) and again six months later. Post-trek
compared to pre-trek, a significant reduction was seen in left
ventricular mass, both left and right ventricular stroke volumes,
and peak left ventricular filling rates (assessed during diastole and
mitral inflow, expressed as the ratio between the passive filling of
the ventricle (Early wave) and the active filling with atrial systole
(Atrial wave), the E/A ratio. Furthermore, PCr/ATP ratio was found
to be decreased by 18%. All observed abnormalities reversed to
pre-trek measurements at the six months interval. The findings
of reduced myocardial energetics are similar to observations in
patients with limited oxygen delivery from coronary disease [52],
native high altitude-acclimatized Sherpas [53], and animals [54].
They suggest that a reduction in cardiac high energy levels may
be a universal response to periods of prolonged reduced oxygen
availability [51]. The underlying cellular mechanisms are unknown
and require further investigation to understand its implications
for cardiac metabolism and function in order to advance our
understanding of hypoxia-related disease.
Discussion: the journey from mountainside to bedside
The CXE Research Group had a mission: “to conduct research
into hypoxia and human performance at extreme altitude aimed
at improving the care of the critically ill and other patients where
hypoxia is a fundamental problem” (www.xtreme-everest.co.uk).
Studying healthy volunteers has the advantage of observations
not being influenced by specific disease or medical intervention
components as would be the case in a study population of patients,
especially the heterogeneous group that critically ill patients form.
The identical ascent profiles followed in each cohort meant that any
physiological differences detected between individuals were likely
to be a result of variability in adaptation to hypoxia, rather than
differential hypoxic exposure. The large quantity of data obtained
during the CXE expedition from 222 subjects being gradually
exposed to hypobaric hypoxia, gives significant statistical power
to explore inter-individual variation in adaptation to hypoxia. The
obtained physiological variables from all subjects at different
altitudes, in combination with analysis of biomarkers, and
transcriptomic and proteomic analysis of cellular material derived
from muscle biopsies, should provide insight into functional changes
in cellular and mitochondrial oxygen use in response to hypobaric
hypoxia. Moreover, it may disclose novel mechanisms controlling
cellular function in hypobaric hypoxia and in disease. Eventually we
hope to be able to distinguish ‘rapid responsive’ phenotypes from
‘slow responders’. A decrease in the partial pressures of oxygen
within the human body, evokes a response in transcription of genes
involved. A series of mechanisms evolve in an increase in levels of
Hypoxia-Induced Transcription (HIF) factor [33,55]. Heterodimers
HIF-1 and HIF-2 αβ are very likely to play a role in the acclimitization
changes following exposure to hypoxia, as they activate the
transcription of target genes involved in responses to changes in
oxygen levels [55]. Furthermore, in mice it has been demonstrated
that partial deficiency of HIF-1 α impairs the physiological response
Netherlands Journal of Critical Care
Research on Mount Everest: Exploring Adaptation to Hypoxia to Benefit the Critically Ill Patient
to both continuous and intermittent hypoxia [55]. Differently said,
target sequences on genes will vary between genes, thereby not
eliciting the same amount of expression between each individual
upon exposure to hypoxia [33]. Analysis of genetic material and
comparison between the two phenotypes is likely to reveal variations
in allelic frequencies, resulting in changes in gene products as
well as original candidate genes [33] to which treatment could
ultimately be targeted. Separately, the pathophysiological insights
deriving from this model of field study will require validation by
applying them to the clinical setting. Use of the numerous technical
devices could be of value in this. In the future, critically ill patients
might be assigned to ‘good adaptor’ or ‘bad adaptor’ genotypes
and alternative treatments administered. Target blood gas values
might be redefined and permissive hypoxaemia evaluated in these
‘good adaptor’ patients. Furthermore, the fraction of administrated
oxygen to patients suffering from chronic hypoxaemia might
become ‘genotype-directed’ as too high a concentration of oxygen
might worsen already maladaptive response processes [45].
The preliminary results of the CXE expedition will drive
new research in healthy volunteers, in the hypobaric hypoxic
environment and in patients in the clinical environment. The results
so far have generated new hypotheses and the possibility of future
interventions. Last summer, UCL CASE Medicine embarked upon a
new three-week project, Xtreme Alps 2010 to the Capanna Regina
Margherita (4554m), where the focus was on an interventional
study along with novel observational studies. Ultimately, the hope
is that this approach will contribute to a better understanding of the
pathophysiological processes involved in adaptation to hypoxaemia
and thereby improve care and outcome for the critically ill patients
where this is a problem.
Conclusion
CXE demonstrated that it was possible to safely conduct a
longitudinal observational cohort study of a large group of subjects
in a natural hypobaric environment. By using this model, the CASE
Medicine team hope to obtain better insights into the different
components of hypoxia adaptation pathways and to define genes
associated with a good response to a hypoxic insult. Ultimately the
goal is to translate this knowledge to the clinical setting, bringing it
from mountainside to bedside, so that critically ill and other patients
suffering from hypoxia will benefit from specific targeted therapies.
Acknowledgement
The current research was funded from a variety of sources, none
of which are public. Mr John Caudwell, BOC Medical (now part
of Linde Gas therapeutics), Eli Lilly Critical Care, The London
Clinic, Smiths Medical, Deltex Medical and The Rolex Foundation
(unrestricted grants). Peer reviewed research grants were awarded
by the Association of Anaesthetists of Great Britain and Ireland
(AAGBI), the UK Intensive Care Foundation and the Sir Halley
Stewart Trust. The CXE volunteers who trekked to Everest base
camp also kindly donated to support the research. Some of this
work was undertaken at University College Hospitals including
University College London Comprehensive Biomedical Research
Centre, which received a portion of funding from the UK Department
of Health Research Biomedical Research Centres funding scheme.
All funding was unrestricted. None of the funding bodies or funders
for any of the authors listed below had any role in the study design,
data collection, data analysis, data interpretation, manuscript
preparation or decision to publish.
References
1
Grocott M, Montgomery H, Vercueil A. High altitude physiology and pathophysiology:
11 Pugh LG, Gill MB, Lahiri S, Milledge JS, Ward MP, West JB. Muscular exercise at great
implications and relevance for intensive care medicine. Crit Care. 2007; 11(1):203. Review.
altitudes. J Appl Physiol. 1964 May;19:431-40.
2
12 West JB. Climbing Mt. Everest without oxygen: an analysis of maximal exercise during
Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine-
mediated, metabolic response to overwhelming systemic inflammation. Lancet. 2004 Aug
extreme hypoxia. Respir Physiol. 1983 Jun;52(3):265-79.
7-13;364(9433):545-8.
13 Houston CS, Sutton JR, Cymerman A, Reeves JT. Operation Everest II: man at extreme
3
altitude. J Appl Physiol. 1987 Aug;63(2):877-82.
Esmon CT. Why do animal models (sometimes) fail to mimic human sepsis? Crit Care
Med. 2004 May;32(5 Suppl):S219-22. Review.
14 Richalet JP, Robach P, Jarrot S, Schneider JC, Mason NP, Cauchy E, et al. Operation
4
Everest III (COMEX ‘97). Effects of prolonged and progressive hypoxia on humans during a
Poli-de-Figueiredo LF, Garrido AG, Nakagawa N, Sannomiya P. Experimental models of
sepsis and their clinical relevance. Shock. 2008 Oct; 30 Suppl 1:53-9. Review.
simulated ascent to 8,848 M in a hypobaric chamber. Adv Exp Med Biol. 1999;474:297-317.
5
15 Molenat F, Boussuges A. Operation Everest III (Comex ‘97): altitude-induced decom-
Fink MP. Animal models of sepsis and its complications. Kidney Int. 2008 Oct;74(8):991-
3. Review.
pression sickness during a hypobaric chamber experiment: necessity for circulating venous
6
gas emboli monitoring for the investigators. Chest. 2002 Jan;121(1):173-7.
Giulivi C, Kato K, Cooper CE. Nitric oxide regulation of mitochondrial oxygen consump-
tion I: cellular physiology. Am J Physiol Cell Physiol 291:1225-1231, 2006.
16 Malconian MK, Rock P, Devine J, Cymerman A, Sutton JR, Houston CS. Operation
7
Everest II: Altitude decompression sickness during repeated altitude exposure. Aviat Space
Martin D, Windsor J. From mountainside to bedside: understanding the clinical relevance
of human acclimatisation to high altitude hypoxia. Postgrad Med J. 2008 Dec;84(998):662-
Environ Med. 1987 Jul;58(7):679-82.
7;quiz626. Review.
17 Levett DZH, Martin DS, Wilson MH, Dhillon S, Rigat F, Montgomery HE, et al. Design
8
and conduct of Caudwell Xtreme Everest: an observational cohort study of variation in hu-
Leach RM, Treacher DF. The pulmonary physician in critical care * 2: oxygen delivery and
consumption in the critically ill. Thoracx. 2002 Feb;57(2):170-7. Review.
man adaptation to progressive environmental hypoxia. BMC Med Res Methodol. 2010 Oct
9
21;10(1):98 (Epub ahead of print).
Houston CS, Riley RL. Respiratory and circulatory changes during acclimatization to
high altitude. Am J Physiol. 1947 Jun;149(3):565-88.
18 Grocott M, Richardson A, Montgomery H, Mythen M. Caudwell Xtreme Everest: a field
10 West JB, Lahirir S, Gill MB, Milledge JS, Pugh LG, Ward MP. Arterial oxygen saturation
study of human adaptation to hypoxia. Crit Care. 2007;11(4):151.
during exercise at high altitude. J Appl Physiol. 1962 Jul;17:617-21.
NETH J CRIT CARE - VOLUME 15 - NO 5 - OCTOBER 2011
247
Netherlands Journal of Critical Care
JM van der Kaaij, DS Martin, MG Mythen, Mike P Grocott
19 Grocott M. Can altitude research benefit critically ill patients? JICS, volume 9, Number 1,
38 Dempsey JA, Hanson PG, Henderson KS. Exercise induced arterial hypoxemia in
April 2008:23-5.
healthy human subjects at sea level. J Physiol 355: 161-75, 1984.
20 Sutton JR, Reeves JT, Wagner PD, Groves BM, Cymerman A, Malconian ML, et al.
39 Wagner PD, Sutton JR, Reeves JT, Cymerman A, Groves BM, Malconian MK. Operation
Operation Everest II: oxygen transport during exercise at extreme simulated altitude. J Appl
Everest II: pulmonary gas exchange during a simulated ascent of Mt. Everest. J Appl Physiol.
Physiol. 1988 Apr;64(4):1309-21.
1987 Dec; 63(6):2348-59.
21 Cerretelli P. Limiting factors to oxygen transport on Mount Everest. J Appl Physiol. 1976
40 Hammond MD, Gale GE, Kapitan KS, Ries A, Wagner PD. Pulmonary gas exchange in
May;40(5):658-67.
humans during normobaric hypoxic exercise. J Appl Physiol 61:1749-1757, 1986.
22 Pugh LG, Gill MB, Lahiri S, Milledge JS, Ward MP, West JB. Muscular exercise at great
41 Torre-Bueno JR, Wagner PD, Saltzman HA, Gale GE, Moon RE. Diffusion limitation in
altitudes. J Appl Physiol. 1964 May;19:431-40.
normal humans during exercise at sea level and simulated altitude. J Appl Physiol. 1985
23 Oelz O, Howald H, Di Prampero PE, Hoppeler H, Claassen H, Jenni R, et al. Physiologi-
Mar;58(3):989-95.
cal profile of world-class high-altitude climbers. J Appl Physiol. 1986 May;60(5):1734-42.
42 Wagner PD, Gale GE, Moon RE, Torre-Bueno JR, Stolp BW, Saltzman HA. Pulmonary
24 Ince C. The microcirculation in the motor of sepsis. Crit Care. 2005; 9 Suppl 4:S13-9.
gas exchange in humans exercising at sea level and simulated altitude. J Appl Physiol. 1986
Review.
Jul;61(1):260-70.
25 Hochachka PW, Land SC, Buck LT. Oxygen sensing and signal transduction in meta-
43 Martin DS, Ince C, Goedhart P, Levett DZ, Grocott MP; Caudwell Xtreme Everest Re-
bolic defense against hypoxia: lessons from vertebrate facultative anaerobes. Comp Biochem
search Group. Abnormal blood flow in the sublingual microcirculation at high altitude. Eur J
Physiol A Physiol. 1997 Sep;118(1):23-9.
Appl Physiol. 2009 Jun;106(3):473-8. Epub 2009 Mar 31.
26 Protti A, Singer M. Bench-to-bedside review: potential strategies to protect or reverse
44 Goedhart PT, Khalilzada M, Bezemer R, Merza J, Ince C. Sidestream Dark Field (SDF)
mitochondrial dysfunction in sepsis-induces organ failure. Crit Care. 2006;10(5):228. Review.
imaging: a novel stroboscopic LED ring-based imaging modality for clinical assessment of
27 Montgomery HE, Marshall R, Hemingway H, Myerson S, Clarkson P, Dollery C, et al.
the microcirculation. Opt Express. 2007 Nov 12;15(23):15101-14.
Human gene for physical performance. Nature. 1998, May 21;393(6682):221-2.
45 Martin DS et al. Changes in sublingual microcirculatory flow index and vessel density on
28 Tsianos G, Woolrich-Burt L, Aitchison T, Peacock A, Watt M, Montgomery H, et al. Fac-
ascent to altitude. Exp Physiol. 2010 Aug;95(8):880-91. Epub 2010 Apr 23.
tors affecting a climber’s ability to ascend Mont blanc. Eur J Appl Physiol 2006 Jan;96(1):32-
46 Walter R, Maggiorini M, Scherrer U, Contesse J, Reinhart WH. Effects of high-altitude
36.
exposure on vascular endothelial growth factor levels in man. Eur J Appl Physiol 85, 113-7.
29 Marshall RP, Webb S, Bellingan GJ, Montgomery HE, Chaudhari B, McAnulty RJ, et al.
47 Mancini DM, Bolinger L, Li H, Kendrick K, Chance B, Wilson JR. Validation of near-
Angiotensin converting enzyme insertion/deletion polymorphism is associated with suscepti-
infrared spectroscopy in humans. J Appl Physiol. 1994 Dec;77(6):2740-7.
bility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002
48 Martin DS, Levett DZ, Mythen M, Grocott MP; Caudwell Xtreme Everest Research
Sep 1; 166(5):646-650.
Group. Changes in skeletal muscle oxygenation during exercise measured by near-infrared
30 Jerng JS, Yu CJ, Wang HC, Chen KY, Cheng SL, Yang PC. Polymorphism of the angio-
spectroscopy on ascent to altitude. Crit Care. 2009;13 Suppl 5:S7. Epub 2009 Nov 30.
tensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome.
49 Edwards LM, Murray AJ, Tyler DJ, Kemp GJ, Holloway CJ, Robbins PA, et al. The effect
Crit Care Med. 2006 Apr;34(4):1001-6.
of high-altitude on human skeletal muscle energetics: 31P-MRS results from the Caudwell
31 Harding D, Baines PB, Brull D, Vassiliou V, Ellis I, Hart A, et al. Severity of meningococcal
Xtreme Everest Expedition. PloS ONE 2010;5(5):e10681
disease in children and the angiotensin-converting enzyme insertion/deletion polymorphism.
50 Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest. 2005
Am J Respir Crit Care Med. 2002 Apr 15;165(8):1103-6.
Mar; 115 (3), 500-8. Review.
32 Grocott MP. Human physiology in extreme environments: lessons from life at the limits?
51 Holloway CJ, Montgomery HE, Murray AJ, Cochlin LE, Codreanu I, Hopwood N, et al.
Postgraduate Medical Journal. 84(987):2-3, 2008 Jan.
Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and
33 Grocott M, Montgomery H. Genetophysiology: using genetic strategies to explore
energy metabolism after a trek to Mt. Everest Base Camp. FASEB J. 201 Oct 26. (Epub
hypoxic adaptation. High Alt Med Biol. 2008 Summer; 9(2):123-9. Review.
ahead of print).
34 Scrase E, Laverty A, Gavlak JC, Sonnapa S, Levett DZ, Martin D, et al. The Young
52 Weiss RG, Bottomley PA, Hardy CJ, Gerstenblith G. Regional myocardial metabolism of
Everest Study: effects of hypoxia at high altitude on cardiorespiratory function and general
high-energy phosphates during isometric exercise in patients with coronary artery disease. N
well-being in healthy children. Arch Dis Child. 2009 Aug;94(8):621-6.
Engl J Med. 1990. Dec 6; 323, 1593-600.
35 Grocott MP, Martin DS, Wilson MH, Mitchel K, Dhillon S, Mythen MG et al. Caudwell
53 Hochachka PW, Clark CM, Holden JE, Stanley C, Ugurbil K, Menon RS. 31P magnetic
xtreme everest expedition. High Alt Med Biol. 2010 Summer; 11(2):133-7
resonance spectroscopy of the Sherpa heart: a phosphocreatinine/adenosine triphosphate
36 Grocott MP, Martin DS, Levett DZ, McMorrow R, Windsor J, Montgomery HE; Caudwell
signature of metabolic defense against hypobaric hypoxia. Proc Natl Acad Sci U.S.A. 1996.
Xtreme Everest Research Group. Arterial blood gases and oxygen content in climbers on
Feb 6; 93, 1215-20.
Mount Everest. N Engl J Med. 2009 Jan 8; 360(2):140-9.
54 Portman M, Standaert T, Ning X-H. Developmental changes in ATP utilization during
37 Ehrmeyer S, Burnett RW, Chatburn RL. Fractional oxyhemoglobin, oxygen content and
graded hypoxia and reoxygenation in the heart in vivo. Am J Physiol 1996. Jan; 270 (1 Pt2).
saturation, and related quantities in blood: terminology, measurement, and reporting. Vol. 12.
H216-H223.
No. 11. Wayne, PA: National Committee for Clinical Laboratory Standards, 1997. (NCCLS
55 Semenza GL. Regulation of physiological responses to continuous and intermittent hy-
document C25-A).
poxia by hypoxia-inducible factor 1. Exp Physiol. 2006 Sep; 91(5): 803-6. Epub 2006 Jun1.
248
NETH J CRIT CARE - VOLUME 15 - NO 5 - OCTOBER 2011