preventative measure against altitude sickness. The
study demonstrated increased prophylactic effect of
dexamethasone compared to acetazolamide, but that
dexamethasone caused greater side effects limiting
its effectiveness. In eight trials assessing the efficacy
of dexamethasone in altitude sickness prevention
above 4000m, daily doses of dexamethasone at
8mg, 12mg, and 16mg were found to be more
effective than the placebos. In nine trials testing
acetazolamide efficacy at over 4000m, 750mg per
day was found to be more effective than the placebo.
A direct correlation was found between ascent rate
and relative risk of developing altitude sickness for
both acetazolamide and dexamethasone. Lower
doses of acetazolamide (500mg) and dexamethasone
(0.5mg and 2mg) demonstrated no significant
difference in the prevention of altitude sickness
when compared to the placebo. Increased severity of
adverse effects including depression were observed
in trials studying dexamethasone when compared
to acetazolamide which may correlate to a higher
compliance rate in those taking acetazolamide
compared to dexamethasone (Dumont et al., 2000).
Methazolamide is another carbonic anhydrase
inhibitor, but with a lower plasma protein affinity
than acetazolamide. As a result of lower affinity for
plasma proteins, methazolamide is capable of more
rapid diffusion into the tissues and is associated with
fewer side effects. In a study comparing the efficacy
of methazolamide and acetazolamide, methazolamide
– given as a dose of 150mg per day – was found to
be as effective as acetazolamide – given as a dose of
500mg per day. Calcium ion receptor blockers such
as nifedipine, as well as phosphodiesterase inhibitors,
have also been indicated for effective prevention
of HAPE. The efficacy of a daily dose of nifedipine
(60mg) was analysed in two studies and was found to
be more effective than the placebo for prevention of
HAPE and HACE however, no significant difference
between nifedipine and the placebo was found for
preventing AMS (Wright et al., 1983; Ellsworth et al.,
1987; Imray et al., 2010).
38
Conclusion
To conclude, whilst the basic underlying principles
of altitude sickness are understood in terms of
decreasing barometric pressure resulting in decreased
oxygen delivery to the tissues, a full understanding of
the way in which this reduced oxygen delivery results
in what we understand as the altitude sicknesses such
as AMS, HACE and HAPE requires further research.
The key pathophysiology of AMS and HACE can be
summarised as the increased cerebral blood flow and
vascular permeability that result in fluid accumulation
within the brain. Whilst vasogenic oedema in HACE
has been confirmed using imaging techniques, further
research is required into the precise mechanisms
behind haemorrhagic conversion and the progression
of AMS too HACE. There is a clearer understanding
of the causes of HAPE including evidence for the
inhibition of ENaC resulting in fluid accumulation
in the lungs. However, research into HPV as a
cause of diffuse vasoconstriction throughout the
lungs due to environmental hypoxia at altitude may
provide evidence to back up current theory. In terms
of prophylactics, the most effective preventative
measure would be to avoid high altitudes of above
2500m. Where avoidance is not possible, allowing
sufficient time for acclimatisation alongside the
use of supplementary oxygen would be advisable.
Chemoprophylactics may also be used in addition
to acclimatisation, but the evidence suggests that
their use would be inadvisable as a replacement. This
paper only discusses the more common prophylactics,
and there are other newer drugs that may be of
benefit, however the evidence is not yet sufficient for
comparison to the gold-standards of acetazolamide
and dexamethasone, although methazolamide is
likely to replace the use of acetazolamide within the
next decade in lieu of long-term studies due to the
apparent improved efficacy and decreased associated
side-effects of methazolamide in comparison to
acetazolamide.