Respiratory Physiology & Neurobiology 158 (2007) 251–265

Treatment of chronic mountain sickness:

Critical reappraisal of an old problem
Marı́a Rivera-Ch a,∗ , Fabiola León-Velarde a , Luis Huicho b,c,d
a Departamento de Ciencias Biológicas, Facultad de Ciencias y Filosofı́a, Instituto de Investigaciones de Altura,
Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, Lima LI 31, Peru
b Departamento Académico de Pediatrı́a, Universidad Nacional Mayor de San Marcos, Lima LI 5, Lima, Peru
c Departamento Académico de Pediatrı́a, Universidad Peruana Cayetano Heredia, LI 5, Lima Peru
d Instituto de Salud del Niño, LI 5, Lima, Peru

Accepted 1 May 2007

Abstract
A review is made on the different treatment strategies essayed to date in the management of chronic mountain sickness (CMS). After a brief
presentation of the epidemiology and of the pathophysiological mechanisms proposed for explaining the disease, the advantages and drawbacks of
the different treatment approaches are discussed, along with their pathopysiological rationale. A particular emphasis is dedicated to the scientific
foundations underlying the development of acetazolamide and angiotensin-converting enzyme inhibitors as promising therapeutic agents for CMS,
as well as the clinical evidence existing so far on their usefulness in the treatment of CMS. Various methodological issues that need to be addressed
in future clinical studies on efficacy of therapies for CMS are discussed. There is also a brief discussion on potential treatment options for chronic
high altitude pulmonary hypertension. Closing remarks on the need of taking increasingly into account the development and implementation of
preventive measures are made.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Chronic mountain sickness; High altitude; Treatment

1. Introduction policies. He stubbornly taught us that basic science is funda-

When we were invited to write a paper for this special issue
in honor of Dr. Carlos Monge Cassinelli, we recalled once again
the inspiring atmosphere prevailing at our laboratory. There he
passionately discussed with us on almost every issue relevant to
understanding how living organism function as integral systems,
including the fascinating area of oxygen cascade in biological
systems. Of course, human exposure to chronic hypoxia and
CMS occupied a prominent place, following a tradition initi-
ated decades before by Dr. Carlos Monge Medrano, who had
described the condition for the first time in 1925 (Monge-M,
1925). Albeit our main motivation was intellectual challenge, Dr.
Monge Cassinelli was always aware on the importance of CMS
as a problem of countless underserved highland inhabitants, who
deserved higher priority in the development of national health
∗ Corresponding author. Tel.: +51 1 93488786; fax: +51 1 3190019.
E-mail addresses: mrivera@upch.edu.pe (M. Rivera-Ch),
vrinve@upch.edu.pe (F. León-Velarde), lhuicho@gmail.com (L. Huicho).
mental for building a prosperous nation. But he also believed in
public health as a respectable science with an enormous potential
for improving life quality of people. This is a humble and yet well
deserved tribute to a man who taught us, with his own example,
that it is possible to perform sustained and high quality research
while actively struggling for better scenarios in our own coun-
try, and furthermore that we can pursue horizontal, relevant, and
productive joint ventures with scientific colleagues throughout
the world.
Several publications have been devoted to various aspects of
CMS including epidemiology, pathophysiological basis, clinical
features and treatment strategies (Leon-Velarde, 1993; Leon-
Velarde et al., 1993; Monge-C et al., 1992; Sime et al., 1975;
Winslow and Monge-C, 1987). We will focus in this review
on the quality of evidence supporting the different treatment
approaches and on the rationale behind their use, after a brief
overview on the epidemiology and pathophysiology of CMS,
in order to have a better idea of the burden that this disease
represents, and also for better understanding the rationale of
the therapies investigated so far. Wherever relevant, we will

1569-9048/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.resp.2007.05.003
252 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265
also address future potential research avenues on treatment and
prevention.
1.1. Definition, symptoms, and clinical diagnosis
CMS has been defined by a recent international consen-
sus as a clinical syndrome occurring to natives or long-life
residents above 2500 m, characterized by excessive erythro-
cytosis, defined by excessive hemoglobin (Hb) concentration
(females Hb ≥ 19 g/dL; males Hb ≥ 21 g/dL), severe hypoxemia
(low SaO2 ), and in some cases moderate or severe pulmonary
hypertension, which may evolve to cor pulmonale, leading
to congestive heart failure (Leon-Velarde et al., 2005). This
consensus definition emphasizes that clinical manifestations
gradually disappear after descent to lower altitudes and reap-
pear after return to high altitude. It also proposes a CMS score
based on clinical symptoms and Hb concentration for grad-
ing the severity of the disease, which use should allow better
comparability of future studies. Subjects with chronic respira-
tory diseases or those with any underlying chronic condition
that worsens hypoxemia are excluded from this CMS defini-
tion. Clinical features of CMS include dyspnea, palpitations,
insomnia, headache, confusion, loss of appetite, lack of mental
concentration and memory impairment. Patients may also suffer
from decreased exercise tolerance, bone pain, acral paresthesia
and occasionally hemoptysis. Clinical examination may reveal
cyanosis, congestive conjunctivae, and dilatation of retinal ves-
sels. An accentuated second heart sound and cardiomegaly
are frequently evidenced, due to right ventricle hypertrophy.
With the progression of the disease, overt heart failure occurs
eventually.
1.2. Incidence, risk factors, and pathophysiology
Longitudinal studies on the incidence and the role of risk
factors in the development of CMS are lacking. The esti-
mated prevalence of this condition is 15.6% (Leon-Velarde and
Arregui, 1994; Leon-Velarde et al., 1994) on the basis of a cross-
sectional study performed in men resident in Cerro de Pasco, a
Peruvian mining city placed at 4300 m. Risk factors proposed
by the authors included age, obesity, low arterial oxygen sat-
uration (SaO2 ), and low peak expiratory flow. This study also
revealed that chronic respiratory diseases may increase high alti-
tude hypoxemia, contributing to increased symptoms of CMS
(Leon-Velarde et al., 1994). By contrast, prevalence of CMS in
Tibetans has been estimated in 0.91% (Wu et al., 1998) in studies
using the same definition criteria of those in the Peruvian study.
CMS affects quality of life, mental and physical performance
and very likely leads to premature death and accounts for a sub-
stantial morbidity burden in high altitude settings. It has been
proposed therefore that, at least in the Andean region (Bolivia,
Colombia, Ecuador, Peru, Venezuela, and Chile), CMS should
be considered a public health problem and that it should be
included in the health policy priorities of those countries (Leon-
Velarde, 2003). Kyrgyzstan health authorities have also called
for an increased support to research related to CMS and under-
scored the importance of paying more attention to pulmonary
hypertension and cor pulmonale in Kyrgyzstan and China (Leon-
Velarde, 2003).
Aging, worsened hypoventilation during sleep and periodic
breathing are all been proposed as aggravating factors (Leon-
Velarde et al., 1993; Kryger et al., 1978; Normand et al., 1992;
Bernardi et al., 2003; Spicuzza et al., 2004; Sun et al., 1996). It
seems that lifestyle and environmental pollution can also accel-
erate the development of CMS (Frisancho, 1988; Monge-C et
al., 1992). In this regard, it is interesting that mean Hb concen-
tration found in a mining city (Chuquicamata, Chile, 2800 m),
is higher than that found in a non-mining city placed at 4100 m
(Santolaya et al., 1981, 1984/1985).
Issues needing further assessment in future studies include
the appropriate control of contextual and modifying factors.
Environmental pollution can increase frequency and severity of
chronic pulmonary conditions in high altitude settings, obesity
related to western lifestyles adopted by high altitude popula-
tions is increasingly frequent, and genetic factors are proving to
be critical in determining the degree of adaptation to life at high
altitude (Beall et al., 2002).
1.3. Hypoxic ventilatory response (HVR) and CMS
Like many other clinical conditions, CMS is multifactorial
in its origin. Understandably, there is no unanimous agree-
ment on its pathophysiology (Monge-C et al., 1992; Winslow
and Monge-C, 1987; Leon-Velarde, 1993; Leon-Velarde et
al., 1993). Hypoventilation has been proposed as one of the
underlying mechanisms leading to an abnormally enhanced
erythropoiesis, increased red cell mass and blood viscosity, sys-
temic and pulmonary hypertension and heart failure (Reeves and
Weil, 2001; Severinghaus et al., 1966). A blunted HVR has been
shown in subjects with CMS (Sime et al., 1975). The authors
suggested this as the basic underlying cause. However, blunted
HVR has also been demonstrated in some subjects without CMS
(Bainton et al., 1964; Severinghaus et al., 1966). In addition, the
function of the peripheral chemoreceptors has been shown to be
abnormal (León-Velarde et al., 2003a).
Studies were carried out to examine the plasticity of chemore-
flexes to both short- and long-term changes in blood gas tensions
of chronically hypoxic high altitude natives with blunted respira-
tory responses to hypoxia. Natives who had moved to live at sea
level had ventilatory responses to acute hypoxia (few minutes)
similar to that of sea-level controls (Gamboa et al., 2003a,b).
However, responses to sustained hypoxia (20 min) remained
markedly blunted. These results may explain the apparent dis-
crepancy in previous studies with regard to HVR. The basic
notion remaining is that chronic alveolar hypoventilation in sus-
ceptible high altitude natives plays a central role in the genesis
of CMS, enhancing erythropoiesis that results in an abnormally
increased red cell mass and blood viscosity.
1.4. Erythropoiesis and CMS
Many of the clinical features of CMS may be attributed to
the excessive polycythemia, which leads to hyperviscosity of
the blood and consequently impaired blood flow and impaired
 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265
oxygen delivery to several organs including the brain. Paradox-
ically, the increases in red blood cells aimed at increasing the
oxygen carrying capacity lead directly to hyperviscosity, which
eventually worsens hypoxemia. From this pathophysiological
perspective it follows that one therapeutic strategy for CMS is
the development of agents that decrease polycythemia acting
directly or indirectly on EPO-mediated erythropoiesis. There
are various pharmacological and non-pharmacological interven-
tions that have been studied, and others that are being actively
assessed or need to be studied in the future. We offer later the
review of the existing literature on this therapeutic approach.
1.5. The autonomic nervous system and CMS
There is a recent update of the pathopysiological basis of
CMS with emphasis on changes occurring at the autonomic
control level, including cardiovascular and cerebrovascular con-
trol aspects in affected subjects (Hainsworth et al., 2007). This
review quotes studies performed in high altitude natives with and
without CMS. One of these studies showed that affected subjects
have impaired autonomic control of cardiovascular and cerebral
function, particularly in aspects related to peripheral vascular
resistance and cerebral blood flow autoregulation (Claydon et al.,
2005). Peripheral vascular resistance, the major mechanism for
the control of blood pressure was studied through measurement
of responses of forearm vascular resistance to carotid barorecep-
tor stimulation in high altitude residents with and without CMS,
both at their altitude of residence and shortly after descent to
sea level (Moore et al., 2006). Results showed that baroreflex
sensitivity was similar in both groups and at both locations. At
high altitude the “set point” was higher in the CMS group but,
within a day of exposure to normoxia, it was reset to a lower
pressure which was similar to that of healthy subjects (Moore et
al., 2006). In another study, cerebral autoregulation was assessed
through the correlation between flow and pressure during ortho-
static stress. The results showed impairment of cerebrovascular
autoregulation in CMS patients (Claydon et al., 2005).
1.6. High altitude pulmonary hypertension and CMS
Finally, it must be emphasized that CMS and high altitude
pulmonary hypertension (HAPH) represent separate manifesta-
tions of chronic hypoxia, that is, stimulation of erythropoiesis
and stimulation of pulmonary hypertension, respectively. In
many CMS patients, both manifestations are present simul-
taneously (Penaloza and Sime, 1971; Penaloza et al., 1971).
However, occasionally CMS patients may have little or no ele-
vation of pulmonary artery pressure or resistance beyond the
normal increase at high altitude (Antezana et al., 1998). Alterna-
tively, particularly in children and young adults, life-threatening
HAPH may occur with little or no increase in Hb (Anand and Wu,
2004; Ge and Helun, 2001; Lin and Wu, 1974; Sui et al., 1988).
Therefore, two separate pathophysiologies have been proposed
for these altitude-related illnesses, with the recognition that in a
given patient they may or may not coexist (Leon-Velarde et al.,
2005). This separation has clinical implications. We need to pay
particular emphasis to the development of separate treatment
253
strategies, one aimed at improving pulmonary hypertension and
its clinical consequences, and the other at seeking effective treat-
ments for CMS with excessive polycythemia. Thus later in this
review we will also discuss briefly the potential of various agents
in the treatment of HAPH.
1.7. Genetic adaptations and CMS
Adding to the complexity of the pathophysiology of CMS,
there are genetic differences in the response of high altitude
populations to chronic hypoxia. Andeans display a pheno-
type characterized by enhanced erythrocytosis (Monge, 1978;
Winslow and Monge, 1978) that may even lead to CMS
(Winslow and Monge, 1978), a condition whose hallmark is
excessive erythrocytosis and low SaO2 . Tibetans show instead
normal erythropoiesis and low SaO2 (Beall, 2000, 2006).
Recently, a third pattern of adaptation was described in Ethiopi-
ans native to high altitude settings without evidence of iron
deficient anemia, hemoglobinopathy, or chronic inflammatory
conditions. They showed Hb concentration and SaO2 values
similar to those found at sea level (Beall et al., 2002). It seems
that natural selection has favored the presence and persistence
of genes for a low erythropoietic response and of genes for
higher oxygen saturation (Beall et al., 1994, 1997, 2004), and
conferred to Ethiopians a better degree of adaptation to high
altitude hypoxia (Beall et al., 2004). It appears therefore that
high-altitude hypoxia acts as an agent of natural selection con-
ferring greater reproductive success among women estimated
with high probability to have genotypes for high percent of oxy-
gen saturation (Beall et al., 2004). The implication is that if this
pattern persists, then the frequency of the high saturation allele
will increase (Beall et al., 2004).
Thus it seems that CMS is not always an unavoidable final
result of the responses to chronic hypoxia. Better understanding
the role of genetic basis of such responses and of modifying
factors such as life style, environmental and indoor pollution
and chronic respiratory conditions will pave the way for devel-
oping future preventive and therapeutic interventions for CMS.
Fig. 1 shows the proposed pathophysiological events leading to
CMS and/or pulmonary artery hypertension and sites that can be
influenced by pharmacological agents. This conceptual model
does not include the responses to chronic hypoxia occurring at
the cellular and molecular level. These responses have been dis-
cussed in detail elsewhere (Hochachka, 1986; Hochachka et al.,
1998) and are beyond the scope of this review.
2. Therapeutic approaches proposed:
pathophysiological and clinical rationale
For a better understanding of the different therapeutic strate-
gies proposed ever since the first description of CMS, we will
try to offer the corresponding underlying pathophysiological
rationale. For assessing efficacy of treatments, we first need to
have an agreement on a set of conditions allowing comparabil-
ity of studies and a rigorous evaluation of study methodologies.
Such conditions include a clear definition of CMS, an integrated
pathophysiological framework taking into account all relevant
254 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265

Fig. 1. Proposed pathophysiology of CMS and HAPH. Determinant (genetic) and modifying/risk factors in the response to hypoxia are showed and sites for possible
therapeutic interventions are signaled by arrows denoting stimulatory (+) or inhibitory effects (−). Andean, Tibetan and Ethiopian populations are showed as examples
of different genetic patterns of adaptation, which determine the responses to chronic hypoxia that may de modulated by modifying/risk factors. Depending on genetic
and modifying factors, high-altitude hypoxia raises different responses that involve regulatory actions of central and peripheral system nervous on the cardiovascular
and respiratory systems, which in turn modify the oxygen transport that may be impaired in those predisposed, leading eventually to excessive erythrocytosis and CMS.
Alternatively or simultaneously, hypoxia may lead to HAPH. Modifying/risk factors may increase the risk of CMS and/or HAPH, accelerate their development or
increase their severity. CNS: central nervous system; NS: nervous system; HAPH: high altitude pulmonary hypertension; HPV: hypoxic pulmonary vasoconstriction;
EPO: erythropoietin; IGF-1: insulin-like growth factor 1; Ac-SDKP: N-acetyl-seryl-aspartyl-lysyl-proline.

steps and factors in the development of CMS that are suscepti-
ble to intervention and modification, and finally explicit criteria
for a formal assessment of the validity and applicability of the
different therapeutic studies.
We will use as reference for our analyses the definition of
CMS agreed on the International Consensus Statement (Leon-
Velarde et al., 2005). In addition, we will consider whether
the evidence-base for each particular treatment comes from
systematic reviews of randomized controlled trials, from indi-
vidual randomized controlled trials, non-randomized controlled
trials, case-series, case-reports, consensus/expert opinion, ani-
mal studies, or from basic studies addressing physiological and
pathophysiological aspects. Systematic reviews of randomized
controlled trials and well-designed individual randomized con-
trolled trials will be ranked as those with the highest level of
evidence (Harbour and Miller, 2001), whereas basic studies will
be considered as preliminary evidence waiting for appropriate
clinical testing in humans. In addition to the quality of evidence,
whenever we make judgments about the strength of a recom-
mendation on CMS treatment, we will also consider the balance
between benefits and harms, translation of the evidence into
specific circumstances, the certainty of the baseline risk, and
resource utilization (Atkins et al., 2004). Clinical relevant out-
comes taken into account for judging the quality of the studies
on treatment of CMS will include CMS score and quality of life.
Changes in Hb concentration, SaO2 , baseline ventilation, HVR,
and pulmonary artery pressure will be considered as relevant
surrogate outcomes.
We broadly classify the therapeutic approaches of CMS
in those aimed at reducing pharmacologically or non-
pharmacologically the increased red blood cell mass and in
those directed to stimulate ventilation for increasing SaO2 and
therefore to reduce the increased erythropoietic response that
characterizes CMS.
2.1. Non-pharmacologic reduction of erythremia:
blood-letting
Blood-letting is used in patients with CMS for the purpose
of reducing red cell mass volume and Hb concentrations at least
to values considered normal for the altitude of residence. We
did not find randomized controlled trials on safety and effi-
cacy of this therapy. Performing such a clinical trial would
face formidable practical challenges. Case-series and case-
reports have shown that blood-letting with or without isovolemic
hemodilution reduces hematocrit values, improves oxygenation
and leads to improvement of symptoms (Cruz et al., 1979; Klein,
1983; Sedano et al., 1988; Sedano and Zaravia, 1988; Winslow
et al., 1985; Wu, 1979). Blood-letting also decreases ventilation-
perfusion mismatching and improves PaO2 (Manier et al., 1988).
Although adverse events such as severe iron deficiency in most
treated patients have been observed with the use of this therapeu-
tic procedure in other conditions (Barenbrock et al., 1993), they
failed to be reported in a systematic way in the case-series and
case-reports published to date in the treatment of CMS. Of note,
in one study where before- and after-therapy measurements were
performed in three subjects with CMS, hematocrit decreased in
all, but no improvement of symptoms was observed 24 h after
bleeding (Monge-C et al., 1966). It is a common observation
that if the patient stays at high altitude, hematocrit reaches again
pre-treatment values and symptoms reappear within a few days
to weeks. Measurements after treatment in the reported studies
 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265
were performed, but the authors did not report in a systematic
way whether changes in quantitative measurements and in symp-
toms along specific periods of time after the institution of therapy
were evaluated. Thus we do not know with certainty how long the
beneficial effects last. It is claimed that blood-letting along with
isovolemic hemodilution is safer than phlebotomy without vol-
ume replacement (Klein, 1983) and that it allows a long-lasting
improvement of symptoms (Sedano and Zaravia, 1988). How-
ever, we did not find solid findings from well designed clinical
studies supporting such statements.
High altitude residents, in particular those from the Andean
region, frequently express concern on being deprived of part of
their blood, and thus the acceptance of blood-letting may be quite
low, although this issue has not been systematically investigated.
Due to its transient effects, to invasive nature of the therapy,
and to acceptance problems, the conduction of future random-
ized controlled trials with blood-letting, alone or in combination
with isovolemic hemodilution, seems unlikely. Currently, blood-
letting is practiced on a very limited scale.
2.2. Pharmacologic reduction of erythremia
The main growth factor that promotes production of blood red
cells in hematopoietic organs is erythropoietin (EPO). Unequiv-
ocal evidence for the existence of EPO was provided by Erslev in
the middle of the 20th century (Erslev, 1953). Shortly afterwards,
pioneer studies demonstrated erythropoietic activity in plasma
and urine from anemic animals (Borsook et al., 1954; Gordon
et al., 1954; Hodgson and Toha, 1954). Human EPO was suc-
cessfully purified in 1977 (Miyake et al., 1977). The primary
site of EPO production has been localized in kidneys (Jacobson
et al., 1957). More specifically EPO is produced mainly by
peritubular cells of the kidney (Lacombe et al., 1988). It has
been documented that liver and other extra-renal cells such as
macrophages are also able to produce EPO (Jelkmann, 1992).
A lowered oxygen capacity, a reduced oxygen partial pressure
and an increased O2 -Hb affinity are all factors that stimulate the
production of erythropoietin (Jelkmann, 1992).
2.2.1. Angiotensin-converting enzyme inhibitors
Various findings preceded the essay of ACE inhibitors in the
treatment of CMS. First, a certain proportion of kidney trans-
planted patients developed post-transplant erythropoiesis (PTE)
through enhanced erythropoiesis mediated by an altered regula-
tion in EPO production (Thevenod et al., 1983), and transplanted
patients receiving ACE inhibitors had anemia as a side-effect
(Lamperi and Carozzi (1985)), suggesting that drugs able to
inhibit erythropoiesis could be useful in the treatment of PTE.
In addition, a positive association was found between renin-
angiotensin system activation and elevated red blood cell mass
in diverse clinical conditions (Bourgoignie et al., 1968; Hudgson
et al., 1967; Labeeuw et al., 1992; Onoyama et al., 1989, 1995;
Volpe et al., 1994; Vlahakos et al., 1991, 1999). At least two
systems participate in the pathogenesis of PTE in addition of
EPO, namely, the renin-angiotensin system, and endogenous
androgens (Vlahakos et al., 2001, 2003). Furthermore, other
erythropoiesis-stimulating factors might play a contributing
255
role, including the oligopeptide N-acetyl-seryl-aspartyl-lysyl-
proline (Ac-SDKP), a natural inhibitor of the pluripotent stem
cell whose catabolism is increased by ACE inhibitors (Azizi et
al., 1996), and the growth factor insulin-like growth factor 1
(IGF-1) (Blahakos et al., 2003; Congote et al., 1991; Glicklich
et al., 2001).
ACE inhibitors or angiotensin II receptors antagonists have
proved to be effective in the treatment of PTE (Gaston et al.,
1994), very likely through increase of renal blood flow, inhi-
bition of sodium reabsorption in renal tubular cells with a
consequent fall in oxygen consumption leading eventually to
an enhanced erythropoietin production, and blockade of a direct
effect of angiotensin II on erythropoiesis (Cole et al., 2000; Mrug
et al., 1997; Perazella and Bia, 1993), possibly mediated by
an up-regulation of angiotensin type 1 receptors on erythroid
precursors.(Gupta et al., 2000). The accumulation of Ac-SDKP
induced by ACE inhibitors could also decrease directly the EPO
production independently of effects mediated by angiotensin II
(Azizi et al., 1996).
An excessively increased Hb concentration as a result of
enhanced erhythropoiesis as a hallmark of CMS (Morrone et al.,
1997; Dainiak et al., 1989; Leon-Velarde et al., 1991; Winslow
et al., 1989) and the development of proteinuria and chronic
renal disfunction in a proportion of affected patients (Monge-M
and Monge-C, 1966; Rennie et al., 1971) led to the assessment
of possible beneficial effects of ACE inhibitors in high altitude
polycythemia.
The prophylactic and therapeutic effects of enalapril were
assessed in experimental chronic hypobaric hypoxia in mice
(Gamboa et al., 1997). Treated mice showed significantly
reduced hematocrit values compared with those of controls when
enalapril was administered after exposure to hypoxia. In a pre-
liminary non-controlled and non-randomized study, seven males
and three females with CMS native to Cerro de Pasco were
treated with enalapril during 30 days (Vargas et al., 1996). Hema-
tocrit decreased after the second week of therapy and CMS score
also decreased, but the results were not consistent in all par-
ticipants. This was the first clinical study on the therapeutic
role of an ACE inhibitor in CMS, but definitive conclusions on
safety and efficacy could not be derived due to its methodological
drawbacks.
The main clinical evidence on efficacy of ACE inhibitors in
the treatment of CMS comes from the only randomized trial
performed to date (COMGAN, 2002). Twenty-six consecutive
patients with altitude polycythemia and persistent proteinuria
were randomly assigned to receive either enalapril (5 mg/day) or
no treatment and were followed for 2 years. The study was open
to doctors and patients. The primary endpoint was the effect of
enalapril on packed cell volume, Hb concentration, and urinary
protein excretion rate. Secondary endpoints were the relations
between packed cell volume and Hb concentration and urinary
protein excretion rate at study entry, and between reduction in
packed cell volume or Hb concentration and reduction in uri-
nary protein excretion rate during treatment. All patients were
of mixed Indian and European, mostly Spanish, ethnic origin,
were born at altitudes of 3200–4000 m, and had lived in La Paz
(3600 m) for at least 1 year. Diagnosis of altitude polycythemia
256 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265
and persistent proteinuria was made on the basis of packed cell
volume greater than or equal to 55%, and urinary protein excre-
tion rate greater than or equal to 150 mg/24 h, measured on two
or more occasions, 2 months apart, in otherwise healthy peo-
ple. Patients were advised to restrict their dietary sodium and to
eat 0.6–0.8 g protein per kg body weight daily. Other antihyper-
tensive drugs but not ACE inhibitors or angiotensin II receptor
antagonists were allowed. The sample size of the study was pow-
ered to detect a mean 6.74% decrease in packed cell volume in
treated patients and none in controls.
In study patients but not in controls, mean packed cell volume,
Hb concentration, and proteinuria fell significantly. At 12 and 24
months of follow-up, packed cell volume, Hb concentration, and
proteinuria differed significantly between the groups. In study
patients, follow-up changes in packed cell volume or Hb con-
centration and proteinuria were strongly correlated. Enalapril
was well tolerated by all patients.
In addition to the above discussed mechanisms, possible path-
ways accounting for the beneficial effect of enalapril observed in
this study include a direct and indirect effect on erythropoiesis.
Enalapril is known to increase renal blood flow and decrease
sodium tubular reabsorption, which in turn lead to increased
oxygen availability at the level of erythropoietin-producing cells.
The study hypothesis was that in altitude polycythemia,
increased production of erythrocytes sustained by erythropoi-
etin, being at least in part dependent on angiotensin II (Morrone
et al., 1997), could be limited by inhibition of production of
angiotensin II. The fact that the extent and temporal pattern of
reductions in packed cell volume and Hb concentration induced
by ACE inhibition were almost identical in these disorders
(Perazella and Bia, 1993; Montanaro et al., 2000) corroborated
such hypothesis. The decrease in packed cell volume and Hb
concentration was progressive and linear, suggesting that com-
plete recovery from polycythemia might just be a function of
time.
A progressive and time-dependent reduction of proteinuria
was also shown, that in some cases decreased to undetectable
levels. This reduction was clearly a specific effect of treatment
as controls showed progressive increase. Enalapril may have
decreased proteinuria by improving the sieving properties of the
glomerular barrier (Remuzzi et al., 1990, 1991). But ameliora-
tion of the effects of polycythemia might have partly contributed
to reduction in proteinuria, as there was a positive correlation
in the study patients between changes in packed cell volume (or
Hb concentration) and proteinuria.
Finally, the authors state that reductions in both packed
cell volume and proteinuria should have an additive effect in
decreasing the cardiovascular and renal complications of alti-
tude polycythemia, and in the long term, should substantially
reduce morbidity and mortality. As baseline packed cell vol-
ume and Hb concentration were positively correlated with blood
pressure, serum creatinine, blood urea nitrogen, and protein-
uria, polycythemia is likely an independent risk factor for renal
and cardiovascular disease in high altitude natives. In controls
blood pressure and proteinuria increased throughout the study
along with Hb concentration and packed cell volume. This sug-
gests that high altitude polycythemia could also contribute to the
development and progression of chronic renal dysfunction, very
likely through increased blood pressure, blood viscosity or both
(Winterborn et al., 1987), although chronic hypoxia might also
directly cause renal disease (Fine et al., 2000).
This open randomized controlled clinical trial was adequately
powered to detect a clinically relevant decrease of primary out-
comes in treated subjects. Clear inclusion and exclusion criteria
were also stated. The results are quite convincing, as packed
cell volume, Hb concentration, and particularly proteinuria fell
significantly in a sustained way along the treatment period. The
authors acknowledge that economic constraints led them to use a
fixed small dose of enalapril and that higher doses of enalapril or
combination with other inhibitors of angiotensin activity, such
as angiotensin II receptor antagonists, might be more effective
and rapid in treatment of polycythemia. Other drawbacks of the
study include lack of clinical data for defining whether study sub-
jects suffered also from symptoms attributable to CMS, besides
eryhtrocytosis and proteinuria. Lack of assessment of clinical
symptoms and of quality of life is an important limitation of the
study, as CMS affects profoundly the performance of patients
in their daily routine. Subjects with packed cell volume greater
than or equal to 55% were included in the study, but there is no
information on male to female ratio, whereas gender differenti-
ated thresholds of Hb ≥21 and ≥19 g/dL have been proposed in
men and women, respectively, for determining the existence of
excessive eryhtrocytosis as part of the definition of CMS (Leon-
Velarde et al., 2005). Thus the study could not assess the efficacy
of enalapril in patients with defined clinical and laboratory cri-
teria of CMS, particularly in those with higher red cell mass and
more severe symptoms. Future larger studies are needed to assess
the safety and efficacy of enalapril and other ACE inhibitors
and of angiotensin II receptor antagonists in the treatment of
CMS with and without proteinuria. They should include clini-
cal improvement and quality of life as primary outcomes, and
a standardized definition of CMS including clinical and labora-
tory data should be used to allow comparability (Leon-Velarde
et al., 2005).
2.2.2. Methylxanthines
Erythrocytosis occurs in 6.8–17.3% of kidney transplanted
patients (Oymak et al., 1995). The polycythemia arising after
kidney transplant is associated with increased levels of ery-
thropoietin (EPO) (Oymak et al., 1995; Thevenod et al., 1983;
Gaciong et al., 1996). Increased serum levels of EPO have
also been observed in patients with high altitude polycythemia
(Dainiak et al., 1989; Leon-Velarde et al., 1991; Winslow et
al., 1989). Methylxanthines, including teophylline and pentoxi-
fylline have been used for treating eryhtrocytosis associated with
renal diseases such as in patients who developed polycythemia
after kidney transplant (Bakris et al., 1990; Ward and Clissold,
1987). It has also been reported that pentoxifylline reduces blood
viscosity and thus may improve blood flow and tissue oxy-
genation (Bacher et al., 2005; Porter et al., 1982; Strano et al.,
1984). Adenosine is a cellular messenger that exerts its action
through A1 and A2 adenosine receptors. A2 receptors stimu-
late adenylate cyclase, activated by micromolar concentrations
of adenosine (Ueno et al., 1988). Under hypoxic conditions,
 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265
increased micromolar concentrations of adenosine stimulate A2
receptors resulting in an increase of cAMP, a second messenger
that is involved in renal EPO production (Fisher, 1988). Pen-
toxifylline antagonizes the A2 receptors, so it may produce a
reduction in the levels of cAMP and EPO. On the basis of
such physiologic and pharmacologic evidence, animal studies
were conducted in order to assess the effects of methylxantines
on the polycythemia associated to chronic hypoxia exposure.
Pentoxifylline blunted significantly the hematocrit increase in
mice when administered prior to exposure to chronic inter-
mittent hypobaric hypoxia (Gamboa et al., 1997). The same
results were not seen when the drug was administered after
mice had developed hypoxic polycythemia. We were not able to
find randomized clinical trials performed to assess the effects of
theophylline or pentoxifylline in patients with chronic mountain
sickness. Moreover, the beneficial effects of methylxantines and
in particular of theophylline on polycythemia in kidney trans-
planted patients were not confirmed in a recent randomized,
open labeled, crossover trial study (Trivedi and Lal, 2003).
2.2.3. Adrenergic blockers and dopaminergic antagonists
The sympathetic nervous system plays an important role
in the regulation of EPO production in animals exposed to
hypoxia (Fink and Fisher, 1977). Renal nerve activity facilitates
EPO secretion during hypobaric hypoxia through a mechanism
that involves norepinephrine. Norepinephrine seems to exert
its effects by activating either ␣-adrenergic or ␤-adrenergic
receptors. Based on this rationale, prazosin, an ␣-adrenergic
antagonist used as an anti-hypertensive drug, was administered
for up to 28 days in mice with eryhtrocytosis resulting from expo-
sure to hypobaric hypoxia and in controls, to assess its effects on
both EPO production and the rate of eryhthropoiesis (Izaguirre
et al., 1994). The drug inhibited the rate of erythropoiesis, as
measured by red blood cell iron59 uptake, with a decrease of
hematocrit from the third day. It also inhibited the oxygen-
dependent secretion of EPO. The researchers postulated that
the drug may exert its modulating effects on erythropoiesis by
reducing the peripheral vascular resistance seen during hypoxia,
producing an increase of renal blood flow, thus improving the
renal oxygen supply, which drives erythropoietin formation. We
did not find any clinical trial in humans to assess prazosin safety
and efficacy in the treatment of CMS.
As it is known that hypoxia also activates the ␤-adrenergic
system, which stimulates red blood cell production, a non-
controlled study was performed to assess the effect of adrenergic
␤-receptor inhibition with propranolol on fuid volumes and
the polycythemic response (Grover et al., 1998). The study
was designed to test the hypothesis that altitude polycythemia
might be sustained by increased adrenergic activity. No reduc-
tion in hematocrit or Hb concentration occurred in response to
␤-adrenergic blockade in 11 unacclimatized men exposed to
4300 m for 3 weeks (Grover et al., 1998). There are not published
studies with propranolol in high altitude natives with CMS.
Carotid bodies respond to hypoxia synthesizing and releas-
ing several neuromodulators among them dopamine, which
shows an elevated concentration (Peguignot et al., 1987).
Modulations of dopaminergic pathways may contribute to the
257
time-dependent changes in ventilation observed during acclima-
tization to hypoxia (Tatsumi et al., 1995; Huey et al., 2000a;
Huey and Powell, 2000). Pre- and post-synaptic dopamine D2
receptors in the carotid bodies and in the central nervous sys-
tem modulate the respiratory response to hypoxia (Huey et
al., 2000b). Thus domperidone, a D2 dopaminergic antagonist
receptor has been tried in animal and human experiments to
assess its effect on ventilation and to test the hypothesis that
blunting of the respiratory response to hypoxia may be due to
increased levels of dopamine (Gamboa et al., 2003a,b; Leon-
Velarde et al., 2003b).
In the animal experiment, 18 chronically hypoxic rats were
studied with and without domperidone treatment (Gamboa et al.,
2003a,b). Acute and prolonged treatment significantly increased
poikilocapnic ventilatory response to hypoxia and decreased Hb
concentration from 21.6 to 18.9 g/dL. The results suggest that the
stimulant effect of D2 receptor blockade on ventilatory response
to hypoxia may compensate the blunted peripheral chemosen-
sitvity after chronic exposure and this in turn may decrease Hb
concentration.
In the human study, domperidone (single oral dose of 40 mg)
was administered to five patients with CMS and to five con-
trols without CMS, all high altitude natives and living at 4300 m
(Leon-Velarde et al., 2003b). A control set of experiments was
performed on 5 native adults at sea level who also received the
same single oral dose of domperidone. The slope of isocap-
nic ventilation as function of SaO2 increased significantly after
domperidone administration in all three groups. These results
confirm the previous findings in chronically hypoxic rats and
suggest that domperidone could be assessed in formal clinical
trials for determining its safety and efficacy in the treatment of
CMS.
2.3. Central or peripheral ventilation stimulants
Since hypoventilation seems to be a prominent pathophysio-
logic feature leading to hypoxemia and eryhtrocytosis in patients
with CMS, agents aimed to stimulate central or peripheral
control of ventilation seem natural candidates for performing
clinical studies on their efficacy in CMS.
2.3.1. Central stimulants: medroxyprogesterone
Kryger et al. performed a randomized-placebo con-
trolled study of the effects of medroxypogesterone acetate
(20–60 mg/day) in subjects with excessive polycythemia at high
altitude (Kryger et al., 1978). Medroxypogesterone is a hormone
that exerts stimulant effects on central control of ventilation.
Some patients were treated for up to 5 years. After 10 weeks
of treatment, subjects showed improvement of tidal volume and
minute ventilation, lowered PaCO2 , and raised PaO2 and SaO2 ,
and decreased hematocrit that reached values normal for 3100
altitude, as well as virtual elimination of CMS symptoms. The
major adverse event reported by some patients was decrease of
interest in sex that is probably related to a reduced androgen
production. The small sample size of the study did not allow a
reliable assessment of clinical outcomes. Although the results
of this trial are encouraging, the decrease of libido is an impor-
258 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265
tant consideration that may have impaired medroxyprogesterone
acceptance, as most affected patients are males.
2.3.2. Peripheral stimulants: almitrine
Almitrine is a substance that stimulates the aortic and carotid
chemoreceptors (Laubie and Diot, 1972; Laubie and Schmitt,
1980) and thus a clinical assessment of its possible beneficial
effects in patients with CMS was warranted. Two double-blind,
placebo controlled trials were conducted in 40 subjects with
hematocrit values over 57% living in La Paz (3600–4000 m).
They were reported in a single publication (Villena et al., 1985).
The first one aimed at assessing the ventilatory response and
the variation in PaO2 immediately after the acute administra-
tion of oral almitrine (3 mg/kg/day) or placebo. Twenty subjects
were randomly assigned to almitrine and 20 subjects to placebo.
Three hours later there was a significant increase in PaO2 , pH
and respiratory rate, although the increase in ventilation was
not significant. In the second protocol, patients were randomly
assigned to oral almitrine (1 mg/kg/day) for 4 weeks (n = 10) or
to placebo (n = 10). Measurements were taken every week. There
was a slight but significant reduction in hematocrit (−3.5%) in
treated patients, but all the remaining measurements (ventilation,
PaCO2 , pH, oxygen consumption, CO2 production) remained
constant. The authors implied therefore that the reduction of
hematocrit was not due to an increase in diurnal PaO2 but instead
to an improvement of pulmonary ventilation during sleep. There
were not significant side-effects, except for one patient who
reported dyspnea. This complaint was related to a particularly
strong respiratory effect, as the ventilation increased from 7.5 to
14.4 L/min in this subject. There is no information on inclusion
and exclusion criteria, on the power of sample size in each pro-
tocol, on clinical features of included subjects, on concomitant
treatment allowed, and whether or not subjects were randomly
assigned to active treatment or to placebo.
Additional and adequately designed studies of almitrine are
needed before reaching a definitive conclusion on its safety and
efficacy in the treatment of CMS. In particular, longer therapeu-
tic schemes are needed, including nocturnal assessments of SaO2
and ventilation, along with the evaluation of clinical features
and well-being perception of patients, as well as compliance
assessment.
3. Acetazolamide: a new promising therapeutic agent
3.1. Physiological rationale
Carbonic anhydrase was discovered in 1932 (Meldrum and
Roughton, 1933). Maren defined it as a catalyst in the intercon-
version between CO2 and H2 CO3 , or any of its ionic species
(Maren, 1967). Modulation of carbonic anhydrase activity pro-
vides a mean to regulate the rate of HCO3 − transport (Sterling
et al., 2001). The family of mammalian carbonic anhydrases
consists of at least 10 members with both cytosolic forms and
forms with catalytic site anchored to the extracellular surface
of the cell (Geers and Gros, 2000; Kivela et al., 2000). The
enzyme has many physiological roles, including CO2 transport,
acid–base regulation, nitrogen metabolism, fluid secretion and
absorption, and ventilatory control and thus when considering
the physiological effects and clinical implication of the thera-
peutic use of an inhibitor of carbonic anhydrase, the ubiquity of
the enzyme in the body should always be considered (Swenson,
1998). In the red blood cells the enzyme is strictly cytoplas-
mic and its primary role is the modulation of CO2 transport and
excretion. The process of CO2 transport begins with molecu-
lar CO2 diffusing out of the tissues and into the circulation and
then into the red blood cells along its partial pressure gradi-
ent. In the red blood cells CO2 is hydrated into bicarbonate and
a proton; a process catalyzed by carbonic anhydrase (Esbaugh
and Tufts, 2006). The bicarbonate ion is then shuttled out of the
cell, while the proton is buffered by either Hb or non-carbonic
acid buffers. These processes remove both end products of CO2
hydration from the red blood cells, allowing a maximal amount
of CO2 to be loaded into the blood (Esbaugh and Tufts, 2006).
At the respiratory surface, these reactions are reversed and CO2
is eliminated from the body along its partial pressure gradient
(Esbaugh and Tufts, 2006).
Carbonic anhydrase stimulates the reabsorption of HCO3 −
in the proximal tubules of the kidney, an effect that is inhibited
by agents such as acetazolamide (Clapp et al., 1963; Swenson,
1998). Acetazolamide also produces diuresis, increases cere-
bral blood flow, and stimulates ventilation through metabolic
acidosis (Swenson, 1998). Acetazolamide has been effective in
reducing central apneas in high altitude mountaineers (Hackett
et al., 1987; Sutton et al., 1979) or in patients with sleep-related
breathing disorders at sea level (DeBacker et al., 1995). How-
ever, it has never been evaluated in subjects chronically exposed
to altitude hypoxia such as those suffering from CMS. More-
over, acetazolamide reduces EPO secretion (Miller et al., 1973;
Eckardt et al., 1989), either by its inhibitory action on reabsorp-
tion in the proximal tubule of the kidney (Eckardt et al., 1989)
or through a rightward shift of the O2 -Hb affinity curve due
to acidosis (Miller et al., 1973). For such inhibitory effects on
various biological actions of carbonic anhydrase acetazolamide
was therefore a potential therapeutic agent in the treatment of
patients with CMS.
3.2. Clinical studies
Acetazolamide has recently been studied in a clinical trial as
a new pharmacologic therapy for CMS (Richalet et al., 2005).
The working hypothesis of this study was that subjects who
develop CMS have nocturnal hypoventilation, associated or not
with sleep apneas, leading to prolonged or repetitive episodes of
arterial O2 desaturation responsible for an excessive nocturnal
production of EPO and stimulation of erythropoiesis (Richalet et
al., 2005). It was proposed that acetazolamide would reduce EPO
production principally by stimulating ventilation and reducing
the level of nocturnal hypoxemia, and possibly by an indirect
effect on the renal EPO production. This study also aimed at
evaluating the efficiency of the treatment, not only by hemat-
ocrit or serum EPO, but also by serum ferritin, as an index of
available iron stores, and serum soluble transferrin receptors, as
an index of overall bone marrow erythropoietic activity. It was a
randomized, double-blind placebo-controlled study of acetazo-
 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265
lamide efficacy and safety in subjects with CMS from Cerro
de Pasco, Peru (4300 m). Subjects were randomly assigned
to receive daily during 3 weeks either oral placebo (n = 10),
250 mg of oral acetazolamide (n = 10), or 500 mg of oral acetazo-
lamide (n = 10). Acetazolamide decreased hematocrit by 7.1%
and 6.7%, serum erythropoietin by 67% and 50%, and serum
soluble transferrin receptors by 11.1% and 3.4%, and increased
serum ferritin by 540% and 134%, for groups treated with
250 and 500 mg of acetazolamide, respectively. Acetazolamide
(250 mg) increased nocturnal SaO2 by 5% and decreased mean
nocturnal heart rate by 11% and the number of apnea–hypopnea
episodes during sleep by 74%. All the changes were significantly
different. The decrease in erythropoietin was attributed mainly
to the acetazolamide-induced increase in ventilation and SaO2 .
It was concluded that acetazolamide showed efficacy and safety
in the treatment of CMS. Acetazolamide reduced hypoventi-
lation, which may be accentuated during sleep, and blunted
erythropoiesis.
According to the results of this study, it is proposed that the
mechanisms by which acetazolamide exert its beneficial effect
in subjects with CMS may include at least in part a ventilatory
stimulant effect and in part an inhibitory renal effect on EPO
production, independent of SaO2 .
The finding of a decreased resting PETCO2 in CMS patients
who received acetazolamide in the clinical trial we are discussing
here reinforce the possibility that the drug exerts a stimulatory
effect on ventilation and that this is the main mechanism, through
which the drug, at the dose used, is beneficial in patients with
CMS (Rivera-Ch, M., unpublished). On the other hand, it is
known that EPO is produced by peritubular cells in the kid-
ney (Lacombe et al., 1988) and that acetazolamide can inhibit
EPO production in humans (Miller et al., 1973) and in mice
(Eckardt et al., 1989) exposed to hypoxia. It acts specifically on
the proximal tubule by inhibiting sodium reabsorption, which
is the main determinant of renal oxygen consumption. More-
over, serum EPO has been inversely correlated to the level of
renal tissue oxygenation at high altitude (Richalet et al., 1994).
Thus, by reducing reabsorption activity, acetazolamide would
locally lower oxygen consumption and increase oxygen pres-
sure within the tissue, thereby reducing the hypoxic signal that
triggers EPO production (Eckardt et al., 1989). The acid–base
status of the subjects showed that acetazolamide had induced
metabolic acidosis that has certainly participated, not only in
the stimulation of ventilation but also in better oxygenation of
renal EPO-producing cells, through a rightward shift of the O2 -
Hb affinity curve. The acetazolamide-induced decrease in EPO
found in the clinical trial could have been limited by a con-
comitant decrease in blood volume (Richalet et al., 2005). The
positive effect of the drug on mean nocturnal SaO2 and frequency
distribution of nocturnal SaO2 suggests that nocturnal hypoven-
tilation is an important factor contributing to the development of
excessive erythropoiesis in CMS. Thus this study gives for the
first time, not only the potential possibility of mass treatment of
CMS but also a significant contribution to its pathophysiology.
Breathing disturbances during sleep, such as periodic breath-
ing, may contribute to nocturnal desaturation, but do not appear
to be determining factors because they were not particularly
259
frequent in patients with CMS and are not markedly modified
by acetazolamide. Low ventilatory response to hypoxia in high
altitude residents, and especially in patients with CMS, has been
advanced as responsible for this low ventilation (Kryger et al.,
1978; Severinghaus et al., 1966; Bernardi et al., 2003).
The results of this clinical trial are encouraging. It shows
beneficial effects in patients with CMS without important side-
effects. Its low cost may allow scaling-up the intervention with
substantial public health impact. There remain, however, several
points to be addressed in future studies. Sample sizes adequate
enough for inferring both primary and secondary endpoints will
add significantly to the strength of evidence. In addition, as
CMS is a lifelong condition, duration of treatment and follow-up
after discontinuation of the drug should be substantially longer,
so as to define clearly whether the best treatment approach is
an intermittent, periodic scheme, or a chronic, continuous one.
In addition, clinical relevant outcomes need to be taken into
account, including improvement of symptoms and perceived
quality of life.
4. Treatment of chronic high altitude pulmonary
hypertension (HAPH)
4.1. Pathophysiology
As we pointed out before, chronic high altitude pulmonary
hypertension is described in some but not all patients with
excessive polycythemia and CMS, and is characterized by right
ventricular enlargement and pulmonary hypertension that can
progress to heart failure and premature death (Maggiorini and
Leon-Velarde, 2003). This observation suggests that pulmonary
hypertension follows a pathophysiologic sequence quite differ-
ent from CMS. In fact, there is evidence pointing to increased
pulmonary vascular resistance secondary to hypoxia induced
pulmonary vasoconstriction and vascular remodeling of pul-
monary arterioles (Aldashev et al., 2002; Ge and Helun, 2001;
Heath, 1989; Heath et al., 1990). Treatment options for pul-
monary hypertension are therefore not necessarily the same that
were described for CMS.
The structural changes in the pulmonary vasculature that
occur in subjects with HAPH may be explained at least in part
by hypoxia associated smooth muscle cell proliferation. These
features along with the increased pulmonary vascular tone rep-
resent potential targets for therapeutic intervention (Maggiorini
and Leon-Velarde, 2003). The biochemical pathways underly-
ing HAPH are poorly understood, but modifications of nitric
oxide synthesis, metabolism and effects may have a role. In
animal studies the absence of endothelial nitric oxide synthase
increases susceptibility to this condition (Fagan et al., 2000). Of
note, it has been shown that indigenous Tibetans acclimatised
to life at 3600 m have two-fold higher nitric oxide concentra-
tions in exhaled breath than lowlanders (Beall et al., 2001), and
inhaled nitric oxide has been shown to have beneficial effects
on pulmonary hemodynamics in HAPH (Anand et al., 1998).
Nitric oxide is a potent vasorelaxant and has also antiprolif-
erative effects which are mediated by cyclic GMP (Ignarro et
al., 1999). Cyclic GMP is hydrolysed by phosphodiesterases
260 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265
(PDE). PDE5 is the major PDE subtype present in pulmonary
vasculature and is more abundant in the lung than in other tissues
(Thomas et al., 1990). These observations offered the possibil-
ity of relatively selective pulmonary vasodilatation with little
systemic hypotension. In fact, it was observed that agents with
PDE5 inhibitory activity reduce pulmonary artery pressure in
animal models (Itoh et al., 2004; Sebkhi et al., 2003; Schermuly
et al., 2004).
4.2. Clinical studies
A randomized, double blind, placebo-controlled trial for eval-
uating the effects of sildenafil in subjects living above 2500 m
with HAPH has been published recently (Aldashev et al., 2005).
Sildenafil is a PDE5 inhibitor. In this study, eligible patients
were randomized to receive sildenafil, 25 or 100 mg, or match-
ing placebo every 8 h for 12 weeks. The primary endpoint was the
change in mean pulmonary arterial pressure (Ppa) from baseline
(week 0) after 12 weeks of treatment. There was a statistically
significant difference between the three groups in changes from
baseline to week 12 in mean Ppa measured 8–10 h post-dose.
Also, both doses of sildenafil improved exercise capacity and
physical symptom score. Sildenafil was well tolerated. Necro-
scopic lung specimens from three subjects with HAPH showed
abundant PDE5 in the muscular coat of remodelled pulmonary
arterioles. The authors concluded that PDE5 is an attractive drug
target for the treatment of HAPH and a larger study of the long-
term effects of PDE5 inhibition in HAPH is warranted (Aldashev
et al., 2005).
Eligible subjects for this study had to be transferred to the
referral facility located at 760 m to undergo cardiac catheteri-
zation and thus one can wonder whether the Ppa measurements
at this low altitude reflected accurately the high altitude values,
although the authors argue that untreated increased pulmonary
arterial pressure remains high for several days after removal from
high altitude setting, as it has been verified in animals (Sebkhi et
al., 2003). In addition, only one in four subjects with electrocar-
diographic evidence of right ventricular hyperthrophy accepted
or were able to travel the distance to the hospital for protocol
studies and only 22 patients were able to repeat the hospital vis-
its required for the sildenafil component of the study. Thus the
study was underpowered to assess the full potential of sildenafil
in HAPH and to explore the dose–response relationship. How-
ever, sildenafil has several characteristics that make it attractive
for future larger clinical trials. It has a selective effect on pul-
monary arteries, has little effect on systemic blood pressure, and
it is well tolerated.
Nifedipine is a calcium channel-blocker that has been used
in subjects suffering from high altitude pulmonary edema
(Bärtsch et al., 1991), primary pulmonary hypertension (Rich
and Brundage, 1987) or pulmonary hypertension secondary to
chronic obstructive pulmonary disease (Simoneau et al., 1981;
Sajkov et al., 1993).
There are no published randomized controlled studies of
calcium channel-blockers in patients with HAPH. In a non-
randomized comparative study, systolic pulmonary arterial
pressure (Ppa) was studied by Doppler echocardiography, at rest
and after sublingual nifedipine, in 31 asymptomatic residents
at 3600 m (Antezana et al., 1998). Individuals were separated
into two groups with high and low Ppa. Individuals were also
split into two groups according to Hb concentration: those with
normal Hb values for the altitude of residence and those with
abnormally high Hb values (above 18 g/dL). No significant dif-
ference in Ppa was observed between the low-Hb and high-Hb
groups. Nifedipine induced a decrease of >20% in Ppa in two-
thirds of the subjects. This response was correlated with higher
levels of basal Ppa and was inversely correlated with age in
the low-Hb group. Also, pulmonary vasoreactivity to nifedipine
was independent of the degree of Hb. The authors concluded
that mild to moderate pulmonary hypertension secondary to
chronic altitude hypoxia may be reversible, despite a possible
remodelling of the pulmonary arterioles. They suggest that this
intervention could possibly prevent the progression of the pul-
monary hypertension to heart failure. Limiting factors for an
extended use of calcium antagonists include the fact that they
have to be given in relatively high doses for obtaining an effect
on pulmonary artery pressure, lack specificity for the pulmonary
vascular bed and side effects such as ankle edema are quite
frequent (Hackett and Roach, 2001; Rich et al., 1992).
Acetazolamide has been used for decades as the drug of
choice for preventing and treating acute mountain sickness
(AMS) and very recently has shown encouraging effects in
patients with CMS, as it was discussed before. Preclinical animal
and human studies done in the 1950s had revealed that acetazo-
lamide was a moderate respiratory stimulant and that it exerts this
effect through the inhibition of renal carbonic anhydrase and the
generation of a mild metabolic acidosis secondary to an inhib-
ited renal reabsorption of bicarbonate (Maren, 1967). The first
report of hypoxic pulmonary vasoconstriction (HPV) inhibition
by acetazolamide was by Emery et al. (1977) in a study focused
on the effects of hypercapnia on hypoxia and the pulmonary cir-
culation. It was reported in this study that acetazolamide caused
partial inhibition of HPV in the isolated perfused lung. This
finding of a carbonic anhydrase inhibitor effect on a process
not thought to involve acid–base exchange or a pH transduction
signal went wholly unrecognized. As carbonic anhydrase was
discovered in many other tissues beyond the red cell and kid-
ney, this ventilatory stimulation was also demonstrated to be a
consequence of vascular endothelial and central chemoreceptor
carbonic anhydrase inhibition (Swenson, 1998). In a comprehen-
sive review on carbonic anhydrase inhibitors and HPV, evidence
is presented on the hypoxic response of the pulmonary circula-
tion that may be useful in different conditions having HPV as
a prominent pathogenic event (Swenson, 2006). Such condi-
tions include high altitude pulmonary edema and high altitude
cerebral edema, considered extremely severe forms or varia-
tions of AMS, HAPH, and primary pulmonary hypertension.
There are consistent data from pulmonary artery smooth muscle
cells, isolated perfused lungs, and live unanesthetized animals
all pointing to a potent reduction in HPV by acetazolamide. It is
extremely interesting that the efficacy of acetazolamide as a HPV
inhibitor does not appear to be related to carbonic anhydrase
inhibition, since other potent carbonic anhydrase inhibitors have
no effect on HPV (Swenson, 2006). Thus, besides its established
 M. Rivera-Ch et al. / Respiratory Physiology & Neurobiology 158 (2007) 251–265
effect in AMS and its potentially beneficial role in treatment
of CMS, the effects of acetazolamide on chronic HAPH also
deserve to be assessed.
5. Is it time for a shift to a preventive approach?
Obesity and chronic respiratory diseases seem to increase
the risk of developing CMS and the severity of the condition
(Leon-Velarde and Arregui, 1994; Leon-Velarde et al., 1994).
Addressing risk and aggravating factors for CMS seems a plau-
sible and potentially beneficial preventive approach for reducing
the burden of disease due to CMS. Although insufficiently
studied to date, factors amenable to preventive public health
interventions include westernized lifestyles such as sedentary
life, unhealthy feeding habits, heavy alcohol consumption and
smoking, as well as obesity, chronic respiratory conditions, and
environmental and indoor pollution. Comparative studies tak-
ing into account these and other contextual factors are needed
to better define the burden of disease, time-course and sever-
ity of CMS in different populations. In particular, comparisons
of populations living in areas relatively free of environmental
contamination such as mining activity with those living in high
altitude settings relatively free of such contaminants are war-
ranted. Surveillance of health impact resulting from corrective
environmental interventions in mining cities and other settings
with high prevalence of risk and modifying factors is neces-
sary, particularly for assessing changes in aspects related to high
altitude related diseases such as CMS. Advocating intermittent
exposure for high altitude residents susceptible of developing
CMS and particularly for those working in mining settlements
may reduce the negative effects of chronic hypoxia. Also, if
early exposure to chronic hypoxia demonstrates to be associ-
ated with an increased risk of CMS or other clinical expressions
of maladaptation later during adulthood, then there would be a
prospect for additional preventive measures during pregnancy
and infancy.
6. Conclusions
There is not yet a safe and effective therapeutic approach to
CMS for massive use. Descent to low altitudes is not accept-
able because of its disrupting effects on family life and on work
opportunities. Blood-letting has been reported to decrease only
transiently blood red cell mass, there are cultural barriers to
its massive use, and it is unacceptably invasive. Pharmacologic
blockade of erythropoiesis by agents such as methylxantines is
still in an experimental phase, and ␣- and ␤-adrenergic agents
have been only preliminary tested. Medroxypogesterone could
be used in older affected women, but it is unacceptable for most
male patients. Stimulants of peripheral chemoreceptors such
as almitrine have been tried only in one limited randomized
controlled study and thus they need further clinical trials. Aceta-
zolamide and ACE inhibitors are promising therapies, but before
advocating their massive use there are remaining issues that need
to be solved in future larger trials. Use of standard definitions of
CMS such as the recent consensus definition (Leon-Velarde et
al., 2005) will also improve comparability of studies.
261
Sildenafil and other agents whose effects are mediated in
some way via modification of nitric oxide pathway are aimed
mainly to reduction of the pulmonary artery pressure, which will
not necessarily have beneficial effects in patients with excessive
polycythemia and CMS.
Finally, the importance of changing the current paradigm to
one that privileges preventive interventions cannot be overem-
phasized. However, before health policy interventions based on
sound evidence are scaled-up, further systematic studies on the
role of risk and modifying factors of CMS are needed.
Acknowledgment
MSc. Adolfo Castillo polished up the grammar of former
versions of the manuscript and provided useful comments.
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