Paris
13
, AP-HP, Bobigny, France
4
, EA
23
6
3
, ARPE, Université Paris
13
, Bobigny, France
5
, ARPE,
Bobigny, France6.
Acute exposure to high altitude (HA) induces pulmonary hypertension (PHT) which may lead
to life threatening conditions. In a double-blind placebo-controlled study, we examined the effects
of oral sildenafil, an inhibitor of phosphodiesterase type 5, which selectively decreases pulmonary
artery pressure (PAP), on HA-induced PHT and gas exchange in normal subjects. Twelve male
subjects (sildenafil, SIL n=6; placebo, PLA n=6) were exposed for 6 days at 4,350m. Treatment
(3 x 40mg sildenafil / day) was started 6 to 8 hours after arrival from sea level (SL) to HA and
maintained for 6 days. Systolic PAP (echocardiography) increased at HA before treatment (+29%
vs SL, P<0.01), then normalized in SIL (-6% vs SL, ns) and remained elevated in PLA (+ 21% vs
SL, P<0.05, P<0.05 PLA vs SIL). Right ventricle/left ventricle diameter increased by 12% in
PLA and decreased by 8% in SIL (P<0.05). Pulmonary vascular resistance increased by 143% in
PLA vs 35% in SIL (P<0.05). Cardiac output and systemic blood pressures increased at HA then
decreased similarly in both groups. PaO2 was higher and alveolar-arterial difference in O2 lower
in SIL than in PLA at rest and exercise (P<0.05). The HA-induced decrease in VO2max was
smaller in SIL than in PLA (P<0.05). All subjects suffered from Acute Mountain Sickness, with a
tendency for SIL to recover more rapidly than PLA. Sildenafil treatment was well tolerated. In
conclusion, sildenafil protects against the development of altitude-induced PHT and ameliorates
gas exchange. It can be a potential medication for further investigation to limit the unwanted
effects of high altitude. With grant from Pfizer S.A. France.
193.
ACETAZOLAMIDE: A TREATMENT FOR CHRONIC MOUNTAIN SICKNESS. Jean-Paul
Richalet
1
, Maria Rivera
2
, Patrick Bouchet
3
, Eduardo Chirinos
2
, Igor Onnen
4
, Olivier Petitjean
5
,
Françoise Lasne6, Stéphane Moutereau7, Fabiola León-Velarde
2
. EA
23
6
3
, ARPE, Université
Paris
13
, Bobigny, France
1
, Laboratorio de Transporte de Oxígeno, Universidad Peruana Cayetano
Heredia, Lima, Peru
2
, INSERM U
2
80, Lyon, France
3
, Hopital Avicenne, AP-HP, Bobigny,
France
4
, Service de Pharmacie, hôpital Avicenne, AP-HP, Bobigny, France
5
, Laboratoire
National de dépistage du dopage, Chatenay-Malabry, France6, Laboratoire de Biochimie, hôpital
Henri Mondor, AP-HP, Créteil, France7.
Chronic mountain sickness is characterized by an excessive polycythemia in high altitude
dwellers, with a prevalence of 5 to 18 % above 3,200 m. To date, no pharmacological treatment is
available. We evaluated the effects of a 3-week treatment with acetazolamide (ACZ) in a double
blind placebo-controlled study, in three groups of patients residing at Cerro de Pasco, Peru (4,300
m) with placebo (n=10), 250 mg (n=10) and 500 mg (n=10) of acetazolamide, daily. A group
(n=10) of healthy residents of Cerro de Pasco was used as control. ACZ decreased hematocrit by
7.1% and 6.7%, serum EPO by 67% and 50%, serum soluble transferrin receptors by.11.1%
and.3.4% and increased serum ferritin by 540% and 134% for 250 and 500 mg ACZ,
respectively. These variations clearly evidence a blunted erythropoiesis via diminished
production of EPO. ACZ increased mean nocturnal SaO2 by 4.3% and 5.1% for 250 and 500 mg
ACZ, respectively and plasma ferritin concentration, decreased mean nocturnal heart rate and the
number of apnea/hypopnea during sleep. After treatment, the distribution curves of nocturnal
SaO2 for patients treated with ACZ were displaced to the right and superimposed to control
values, while the placebo group remained centered on lower values of SaO2. The treatment was
well tolerated. The overall decrease in EPO induced by the treatment was estimated to be due
partly to an indirect effect of ACZ via the increase in ventilation and SaO2, and partly to a direct
inhibitory effect of ACZ on EPO secretion. Acetazolamide is the first efficient pharmacological
treatment of chronic mountain sickness without adverse effects, probably by reducing nocturnal
hypoventilation. Its low cost may allow a wide development with a considerable positive impact
on public health in high altitude regions.
194.
INTERMITTENT VS. CONTINUOUS HYPOXIA: CARDIOVASCULAR VARIABLES AND
BIOLOGICAL MARKERS. George Rodway
1
, Mark Sanders
1
, Jigme Sethi
1
, Leslie Hoffman
1
,
