edema (HAPE) and high-altitude cerebral edema
(HACE) – are uncommon but may be fatal without
prompt recognition and treatment. Rapid ascent to
altitude is one of the most common causes of altitude
sickness – rate of ascent is strongly correlated with
incidence of AMS. However, the incidence of altitude
sickness is also dependent on the degree of individual
susceptibility (a result of the individual’s physiology),
the sleeping altitude, and the final altitude. Incidence
of altitude sickness is increased in those with previous
episodes of altitude sickness, and those returning to
similar heights should exercise extreme caution. Prior
experience of AMS-free ascent to high altitude is
not considered to be predictive of future AMS-free
ascent and altitude sickness may still be experienced
by those with previous AMS-free high altitude
experience (Hackett et al., 1976; Hackett and Roach,
2001; Bärtsch et al., 2005).
Pathophysiology of Altitude
Sickness
The delivery of oxygen to tissues around the body
is reliant on several critical factors including oxygen
concentration, oxygen saturation (SO2), and oxygen
partial pressure (PO2). As elevation above sea level
increases, barometric pressure decreases resulting
in decreased PO2 in the atmosphere and therefore
a decrease in inspired PO2. Ascent to altitudes of
greater than 5500m results in a drop to less than half
the barometric pressure at sea level (148.0 mmHg),
decreasing to only 43.1 mmHg at the summit of
Mt Everest (8848m) (Murray and Horscroft., 2016;
Vandermark et al., 2018).
Acute Mountain Sickness and High Altitude
Cerebral Edema
Acute mountain sickness (AMS) is typically defined as
the presence of a severe headache alongside at least
one other symptom such as nausea, loss of appetite,
or insomnia. Worsening of symptoms may indicate
progression to HACE, which is typically fatal without
treatment. Current understanding suggests that
severe hypoxaemia at altitude may cause increased
cerebral blood flow (CBF) and vascular permeability
resulting in vasogenic edema – a disruption of
the blood-brain barrier that leads to unrestricted
diffusion and accumulation of fluid in the brain (Li et
al., 2018). Vasogenic edema in HACE was confirmed
by Hackett et al (2019) using FLAIR and T2 MRI –
an imaging technique that shows abnormalities as
very bright spots whilst normal cerebrospinal fluid
(CSF) remains dark allowing for easier differentiation.
The most common pathway for reversible restricted
diffusion is abnormal ion transport due to intracellular
swelling and restriction of water diffusion across the
cell membrane potentially resulting from increased
extracellular glutamate (an excitatory neurotransmitter
released by nerve cells in the brain) as a result of
cytokine release – release of signalling molecules
secreted by cells of the immune system. It has been
observed that mild vasogenic edema is present in the
majority of individuals ascending to at least 3000m
– regardless of altitude sickness presentation – due
to increased cerebral perfusion. Hydrostatic forces
are the primary driving force resulting in white matter
vasogenic edema; a “haemorrhagic conversion” of the
vasogenic edema has been implicated at the process
by which vasogenic edema develops into HACE. The
precise mechanisms behind the restricted diffusion
and “haemorrhagic conversion” remain unclear
however, impaired autoregulation, significant capillary
hypertension, and permeability factors such as VEGF
and ROS may be involved (Li et al., 2018; Hackett et
al., 2019)
High Altitude Pulmonary Edema
High altitude pulmonary edema (HAPE) is a severe
and potentially fatal form of altitude sickness
developing in non-acclimatised individuals ascending
to altitudes above 3000m. An excessive rise in
pulmonary artery pressure (PAP) results in reversible
pulmonary capillary leakage due to increased
hydrostatic pressure in the microvasculature and is
believed to be crucial to development of HAPE. This
is supported by evidence demonstrating the increased
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