A Treatment for Chronic Mountain Sickness
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《美国呼吸和危急护理医学》
Laboratoire Reponses Cellulaires et Fonctionnelles a l'Hypoxie, Universite Paris 13, Bobigny
Service de Physiologie et Explorations Fonctionnelles, and Service de Pharmacie, Hpital Avicenne, AP-HP, Bobigny
INSERM U280, Lyon
Laboratoire National de Depistage du Dopage, Chatenay-Malabry
Laboratoire de Biochimie, Hpital Henri Mondor, AP-HP, Creteil, France
Laboratorio de Transporte de Oxígeno, Universidad Peruana Cayetano Heredia, Lima, Peru
ABSTRACT
Rationale: Chronic mountain sickness or Monge's disease is characterized by an excessive polycythemia in high-altitude dwellers, with a prevalence of 5 to 18% above 3,200 m. To date, no pharmacologic treatment is available.
Objectives: We evaluated the efficacy of acetazolamide in the treatment of chronic mountain sickness and the importance of nocturnal hypoxemia in its pathophysiology.
Methods: A double-blind placebo-controlled study was performed in three groups of patients from Cerro de Pasco, Peru (4,300 m), treated orally for 3 weeks with placebo (n = 10), 250 mg of acetazolamide (n = 10), or 500 mg of acetazolamide (n = 10), daily.
Results: Acetazolamide decreased hematocrit by 7.1% (p < 0.001) and 6.7% (p < 0.001), serum erythropoietin by 67% (p < 0.01) and 50% (p < 0.001), and serum soluble transferrin receptors by 11.1% (p < 0.05) and 3.4% (p < 0.001), and increased serum ferritin by 540% (p < 0.001) and 134% (p < 0.001), for groups treated with 250 and 500 mg of acetazolamide, respectively. Acetazolamide (250 mg) increased nocturnal arterial O2 saturation by 5% (p < 0.01) and decreased mean nocturnal heart rate by 11% (p < 0.05) and the number of apnea–hypopnea episodes during sleep by 74% (p < 0.05). The decrease in erythropoietin was attributed mainly to the acetazolamide-induced increase in ventilation and arterial O2 saturation.
Conclusions: Acetazolamide, the first efficient pharmacologic treatment of chronic mountain sickness without adverse effects, reduces hypoventilation, which may be accentuated during sleep, and blunts erythropoiesis. Its low cost may allow wide development with a considerable positive impact on public health in high-altitude regions.
Key Words: altitude erythropoietin hypoxia nocturnal ventilation soluble transferrin receptors
Chronic mountain sickness (CMS) or Monge's disease is a disease encountered in 5 to 18% of the population residing at and above 3,200 m on the Altiplano of South America (1, 2) and on the Tibetan plateau (3). First described by Carlos Monge Medrano in 1925, its main feature is an excessive polycythemia (hemoglobin concentration above 21 g/dl) associated with chronic hypoxemia. This condition leads to cardiac failure and/or neurologic disorders (4). Clinical signs include headache, fatigue, sleep disturbances, dyspnea, and digestive complaints. The clinical status becomes progressively incapacitating, leading to social exclusion and psychological degradation. It is a severe public health problem for Andean countries because several million residents of the Altiplano may be at risk.
Despite some trials with medroxyprogesterone (5, 6), enalapril (7, 8), or almitrine (9), to date, no pharmacologic treatment is used to impede this progressive loss of adaptation to chronic hypoxia. The only management is repetitive blood letting or displacement of residence to lower altitudes (10). The latter has an important negative social and economic impact on the development of high-altitude regions and may have dramatic psychological and familial consequences.
The physiopathology of CMS is still largely debated (1, 4, 11, 12). Alveolar hypoventilation may play a central role in the overstimulation of erythropoiesis, leading to increased red cell mass and blood viscosity, systemic and pulmonary hypertension, and cardiac failure (13, 14). Hypoventilation could worsen during sleep in high-altitude residents, further aggravating excessive erythropoiesis (3, 5, 15–17). Moreover, periodic breathing is frequent in sea-level residents exposed to altitude hypoxia (18), and has also been described in high-altitude residents (3, 6, 15, 16).
Acetazolamide (ACZ), an inhibitor of carbonic anhydrase, decreases the reabsorption of bicarbonates in the proximal tubule of the kidney (19, 20). ACZ promotes diuresis, increases cerebral blood flow, and stimulates ventilation via metabolic acidosis (20). ACZ has been shown helpful in reducing central apneas in high-altitude mountaineers (21, 22) or in patients with sleep-related breathing disorders at sea level (23) but has never been evaluated in subjects chronically exposed to altitude hypoxia such as those suffering from CMS. Moreover, ACZ reduces erythropoietin (EPO) secretion (24, 25), either by its inhibitory action on reabsorption in the proximal tubule of the kidney (25) or through a rightward shift of the oxyhemoglobin dissociation curve due to acidosis (24).
Our hypothesis is that subjects who develop excessive polycythemia at high altitude 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. We propose that ACZ reduces EPO production principally by stimulating ventilation and reducing the level of nocturnal hypoxemia, and possibly by an indirect effect on the renal site of EPO production. Moreover, we propose to evaluate the efficiency of the treatment, not only by hematocrit 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 (26). Some of the results of this study have been previously reported in the form of an abstract (27).
METHODS
Patients and Procedure
Thirty male patients suffering from CMS and 10 normal subjects living at Cerro de Pasco (4,300 m) gave their informed consent to participate in this randomized double-blind placebo-controlled study, which was approved by the ethics committee of the Universidad Peruana Cayetano Heredia (Lima, Peru). All subjects were high-altitude natives (> 3,000 m) and were residing permanently at Cerro de Pasco, except for occasional travels to low altitude (< 3,000 m). None of the subjects had been traveling for more than 1 mo at low altitude in the preceding 6 mo. A complete clinical evaluation was made and the CMS clinical score was calculated. The CMS score is based on the following symptoms: breathlessness, sleep disturbance, cyanosis, paresthesias, headache, and tinnitus (28). Systemic arterial pressure was measured by sphygmomanometry after a 15-minute rest in the supine position. All patients had a hematocrit at or above 63%, except one subject with 60% but who presented clear clinical signs of CMS. An evaluation of ventilatory function was performed before inclusion in the study to exclude subjects with pulmonary diseases. Forced vital capacity (FVC) and forced expired volume in 1 s (FEV1) were measured by spirometry (Hill Med-Specialist, Miami, FL). All values were within normal limits corrected for age, height, and body weight. Resting values of end-tidal PO2 and PCO2 were measured during daytime, using a fast gas analyzer (Normocap Oxy; Datex-Ohmeda Division, Instrumentarium, Hatfield, UK). Plasma bicarbonate was measured in venous blood using a CO2_L ADVIA chemistry reagent (Bayer Diagnostics, Puteaux, France). pH was estimated by assuming that PETCO2 is equivalent to PaCO2 and using the Henderson-Hasselbalch equation: pH = 6.1 + log[)].
Subjects were all nonsmokers except for one subject (placebo) who had been smoking fewer than five cigarettes per day for 10 years. Allocation to treatment was done randomly through computer-generated random numbers balanced between the three treatment groups (n, age in years, weight in kilograms, and height in centimeters):
Patients with CMS treated with placebo: n = 10, 44 ± 9, 63 ± 3, 1.58 ± 0.05
Patients with CMS treated with 250 mg of ACZ daily (D250): n = 10, 43 ± 9, 65 ± 9, 1.62 ± 0.08
Patients with CMS treated with 500 mg of ACZ daily (D500): n = 10, 41 ± 6, 67 ± 10, 1.60 ± 0.05
A group of normal subjects (n = 10; age, 39 ± 9 years; weight, 64 ± 7 kg; height, 1.60 ± 0.05 m) living at the same altitude, with no apparent disease at examination and with a hematocrit at or below 55%, served as control subjects. All measurements were made at the Instituto de Investigacion de Altura (Cerro de Pasco) on two occasions, before and after 21 d of treatment. Subjects were asked to come to the institute every morning to take their medication with a glass of water, under the control of a physician. Active and placebo tablets were identical in appearance. Treatment was double blind.
Night Recordings
We monitored nocturnal breathing and arterialized O2 saturation (SaO2) with a Poly-Mesam MAP recording system (ResMed [Mnchengladbach, Germany] and MAP Medizin-Technologie GmbH [Martinsried, Germany]), using thoracic and abdominal strain gauges for recording of ventilation, nasal thermistors for nasal flux, and transcutaneous oximetry at the finger tip for continuous measurement of SaO2. Heart rate was obtained through electrocardiographic recording via three precordial electrodes. No electroencephalographic recording was made to analyze sleep stages. We assumed that nocturnal recordings correspond mainly to sleep conditions. However, wakening periods cannot be excluded, but may be considered as part of a usual night of a patient with CMS at high altitude. Analysis of nocturnal respiration included detection of apneas, hypopneas (central and obstructive), and periods of desaturation. In fact, only apneas and hypopneas of central origin were found: all episodes of reduction in nasal flux were accompanied by thoracic and abdominal reductions in ventilation. Basal ventilation was obtained from a normal quiet 5-min resting period while in bed, 5 min after extinction of light in the bedroom, thus presumably before induction of sleep. Apnea and hypopnea events were defined as a decrease in ventilation of more than 80 and 50% from basal value, respectively. Index of apneas plus hypopneas (apnea–hypopnea index, AHI) was calculated as the mean number of events per hour of night recording. A value of AHI above 5 has been considered as pathologic and a risk factor for cardiovascular diseases (29).
Hematologic Status
A venous blood sample was obtained via an antecubital vein in the supine position, immediately when subjects woke up in the morning after the night of sleep recording. Hematocrit was obtained by centrifugation (Microcentrifuge IEC; Thermo Electron, Waltham, MA). Soluble transferrin receptor (sTfR) and ferritin levels in serum were determined with Nichols Advantage soluble transferrin receptor and ferritin reagent cartridges (Nichols Institute Diagnostics, San Clemente, CA), respectively, as previously described in detail (30). Serum concentration of EPO was measured in duplicate by enzyme-linked immunosorbent assay (ELISA) (Quantikine IVD kit; R&D Systems, Minneapolis, MN).
Statistical Analysis
Data are expressed as means and SD. Data were compared by Student t test for paired (effect of treatment) or unpaired (comparison of groups) samples, except for AHI, for which nonparametric tests were used (Mann-Whitney for comparison of groups, Wilcoxon for effect of treatment).
RESULTS
Two patients (one in the D250 group and one in the D500 group) left the study for personal reasons and were not available for the posttreatment measurements.
Characteristics of Patients with CMS
When compared with the control group, patients with CMS (n = 28, pooled placebo, D250, and D500 groups before treatment) showed a higher hematocrit, higher serum EPO and soluble transferrin receptor concentrations, similar serum ferritin, lower nocturnal arterial oxygen saturation, a higher nocturnal heart rate, a similar apnea–hypopnea index (AHI), a higher systolic and diastolic arterial pressure, and a higher CMS clinical score (Table 1).
Effect of Treatment with ACZ
Treatment with ACZ decreased hematocrit by 7.1 and 6.7% (Figure 1A), serum EPO by 67 and 50% (Figure 2A), and serum soluble transferrin receptors by 11.1 and 3.4% (Figure 2B) and increased serum ferritin by 540 and 134% (Figure 2C) for groups receiving 250 and 500 mg of ACZ, respectively. These variations clearly evidence a blunted erythropoiesis via diminished EPO production. No dose effect was found, the changes being similar with the two doses of ACZ. This suggests that the Emax (dose for maximal effect) has already been reached with 250 mg. The CMS clinical score decreased by 56, 50, and 52% with placebo and 250 and 500 mg of ACZ, respectively (Figure 1B). Diurnal PETO2 was increased by 6.5 and 4.5% with 250 and 500 mg of ACZ, respectively, whereas PETCO2 decreased by about 14% in both treated groups, suggesting a positive effect of acetazolamide on minute ventilation (Table 2). Evaluation of plasma bicarbonate and pH clearly shows that ACZ induced metabolic acidosis (Table 2). The treatment increased mean nocturnal SaO2 by 4.3 and 5.1% (Figure 3A) and decreased mean nocturnal heart rate by 11 and 4% (Figure 4A) for 250 and 500 mg of ACZ, respectively. Mean AHI decreased only in the group treated with 250 mg of ACZ (Figure 3B). The number of subjects with an AHI above 5 was reduced from 3 to 0 with 250 mg of ACZ and not modified in the other groups. Both systolic and diastolic systemic arterial pressure measured during daytime decreased with ACZ treatment, but also with placebo (Figures 4B and 4C). Before treatment, the distribution of nocturnal SaO2 in patients with CMS was shifted to lower values when compared with the control group (Figure 5). After treatment, the distribution curves of 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. Treatment with placebo had no effect on biological parameters and on physiological parameters measured during sleep. Tolerance to the medication was good; the only mentioned adverse effects were slightly increased diuresis (three, three, and five subjects in placebo, D250, and D500 groups, respectively), paresthesias (two, four, and eight subjects in placebo, D250, and D500 groups, respectively), and altered taste of gaseous beverages (two, one, and no subjects in placebo, D250, and D500 groups, respectively).
Mechanisms of Action
Variation of EPO with SaO2 was linear and parallel (same slope) before and after treatment (Figure 6). Using the regression equation for values obtained before treatment (pooled 250- and 500-mg values), we calculated the decrease in EPO induced by a decrease in SaO2 equivalent to that observed by treatment (arrow from point B along the "before" regression equation; see Figure 6). The rest of the EPO decrease to attain the mean value of EPO after treatment was then considered as independent of SaO2 (vertical arrow to point A; see Figure 6). Thus, 53% of the overall decrease in EPO induced by the treatment was estimated to be due to an indirect effect of ACZ via the increase in ventilation and SaO2, and 47% was due to another mechanism, probably related to a renal effect of ACZ on EPO secretion.
DISCUSSION
Monge's disease or chronic mountain sickness is an excessive polycythemia, frequent among high-altitude residents. In Bolivia, about 3 million persons live between 3,000 and 5,500 m of altitude. In La Paz (Bolivia), 1 million inhabitants live between 3,200 and 4,050 m. The prevalence of CMS in this population has been estimated at 5.2% (31). Therefore considering only the town of La Paz and its suburbs, about 50,000 persons may benefit from a treatment reducing their hematocrit. In Cerro de Pasco (4,300 m, Peru; 80,000 inhabitants), the mean prevalence of excessive polycythemia (hemoglobin exceeding 21.3 g/dl) has been estimated at 18.2% (32) or 14.8% (33), suggesting that treatment with ACZ may be relevant for 12,000 to 15,000 inhabitants of this town.
In the present study, patients with CMS showed, by definition, a high CMS clinical score and a high hematocrit. They presented a higher systemic blood pressure, and were more hypoxemic during sleep than control subjects. Similarly, during sleep at 3,658 m in Lhasa, Tibet, patients with CMS spent two-thirds of their night with SaO2 values less than 70% (3). Nocturnal heart rate was higher in patients with CMS, probably because of this exacerbated hypoxemia. Only 8 of 38 subjects showed a significant pattern of periodic breathing during sleep (AHI > 5) and no difference was evidenced between subjects with CMS and normal subjects, similar to what was found by others in Andeans (16, 17) but not in Chinese (3).
The hematologic status of patients with CMS included increased erythropoiesis, with high early morning EPO and increased sTfR, witness to the permanent overstimulation of bone marrow (26). Mean ferritin levels were normal, although some subjects showed low levels (< 20 μg/L), probably related to insufficient iron stores in the face of enhanced erythropoiesis. Conversely, decreased iron stores may limit red cell formation in spite of high EPO production (34). The present study is the first evaluating sTfR in normal and polycythemic high-altitude residents. Values of sTfR for patients with CMS were about twofold those of control subjects, the latter being slightly above those of sea level residents (26).
The physiopathology of CMS has been attributed to the following sequence: blunted respiratory response to hypoxia, hypoventilation, excessive hypoxemia, and excessive erythropoiesis. Ageing and loss of regulation of red cell production within the bone marrow may also facilitate the occurrence of this disease in high-altitude residents (1, 4, 12, 14).
Patients with CMS are usually more hypoxemic than normal high-altitude dwellers, in part because of hypoventilation, both during awake and sleep states (13). Nocturnal hypoventilation, inducing a lower SaO2 during sleep, might aggravate the stimulation of erythropoiesis (17). In fact, serum EPO was related to nocturnal hypoxemia (16) but not to the level of blood hemoglobin (35) in CMS subjects residing at 4,300 m. However, the short half-life of EPO may lead to underestimation of night production of this hormone when blood sampling is performed during daytime. In the present study, we did find a correlation, although weak, between nocturnal SaO2 and serum EPO, probably because blood sampling was done immediately after wake-up in the early morning. Moreover, if nocturnal hypoxemia enhances erythropoiesis, then measurement of daytime SaO2 will underestimate the hypoxic stimulation of EPO production.
Although the beneficial effects of ACZ on ventilation and SaO2 had already been shown in subjects acutely exposed to hypoxia (21, 22), the present study is the first to evaluate the effect of ACZ on nocturnal SaO2 and erythropoiesis in chronic hypoxia. We evidenced a clear beneficial effect of ACZ on the hematologic status of patients with CMS. Three weeks of treatment with ACZ was sufficient to inhibit the erythropoiesis of these patients, as evidenced by a decrease in hematocrit and sTfR. The decrease in hematocrit may have been hindered by the diuretic effect of ACZ leading to a slight hemoconcentration. Ferritin levels were markedly increased with the treatment, probably by a resetting of iron turnover after a sudden blunting of iron use for red cell formation. Considering the short half-life of ACZ in humans (about 90 min), a double (morning and evening) dose of ACZ would probably have been more efficient in treating nocturnal hypoxemia. However, to ensure the highest acceptance of the protocol by the subjects, we avoided making them come twice to the hospital and provoking nocturnal diuresis.
Few previous studies have tried to use respiratory stimulants to reduce high-altitude polycythemia. No change in hematocrit was observed in five subjects with polycythemia studied in Leadville, Colorado (3,100 m) before and after treatment for 7–10 d with medroxyprogesterone acetate (MPA) at 30 mg/day (6). In the same study, mean nocturnal SaO2 increased from 79 to 83% with MPA, although MPA had no effect on periodic breathing. With more prolonged treatment (10 wk, MPA at 60 mg/d), hematocrit decreased from 60 to 52%, and diurnal SaO2 increased from 84 to 90% in 17 patients with polycythemia. However, the main adverse effect of MPA was the loss of libido, probably through a decrease in testosterone (5). This effect prevented the use of this drug by male Andean populations (9). Almitrine, a respiratory stimulant, has been used for 4 weeks in 12 patients with CMS and induced a decrease in hematocrit from 65.2 to 62%, without change in diurnal ventilation or blood gases (9). Enalapril, an angiotensin-converting enzyme inhibitor (10 mg/day for 30 days), decreased mean hematocrit from 66 to 64% in 10 residents from Cerro de Pasco (7). Similarly, enalapril at 5 mg/day for 2 years decreased hematocrit from 63.5 to 56.8% in 13 patients from La Paz (8). However, both studies had no controlled placebo-treated group. None of these pharmacologic procedures have been implemented in high-altitude regions, because of insufficient proof of efficacy or adverse effects or high cost. A monthly treatment with ACZ would cost about 5.3 (6.4 US$), compared with 26 (31 US$) for enalapril. The most common treatment of CMS is blood letting, a technique that has transient effects (4, 10). In fact, a number of patients must move their residency to sea level, although this has a considerable negative impact on their family organization and socioeconomic status.
The mechanisms by which ACZ is efficient in the treatment of CMS may be identified as due partly to the ventilatory stimulant effect of ACZ and partly to another mechanism, probably a renal effect on EPO production, independent of SaO2 (Figure 6). EPO is produced by peritubular cells in the kidney (36). An inhibitory effect of ACZ on EPO production has been observed in humans (24) and in mice (although with much higher doses [25]) exposed to hypoxia. ACZ, and no other diuretics, inhibits the production of EPO. It acts specifically on the proximal tubule by inhibiting sodium reabsorption, which is the main determinant of renal oxygen consumption. Moreover, serum EPO has been inversely correlated to the level of renal tissue oxygenation at high altitude (34). Thus, by reducing reabsorption activity, ACZ would locally lower oxygen consumption and increase oxygen pressure within the tissue, thereby reducing the hypoxic signal that triggers EPO production (25). The acid–base status of the subjects was estimated from the resting diurnal values of end-tidal PO2 and PCO2 and the venous plasma bicarbonate concentration (Table 2). As expected, ACZ 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 oxyhemoglobin dissociation curve). Factors other than oxygen transport could interfere with EPO secretion, such as blood volume status. An acute 5% reduction in plasma volume induced by plasmapheresis (with no change in red cell mass) resulted in a slight increase in serum EPO (by 5.4 mU/ml) in humans (37). Therefore, the ACZ-induced decrease in EPO found in the present study could have been limited by a concomitant decrease in blood volume.
The positive effect of ACZ on mean nocturnal SaO2 and frequency distribution of nocturnal SaO2 suggests that nocturnal hypoventilation is an important factor in the excessive erythropoiesis in CMS. Thus our study gives, for the first time, not only a perspective on mass treatment of CMS but also a clue as to its pathophysiology. Breathing disturbances during sleep, such as periodic breathing, may contribute to nocturnal desaturation, but do not appear to be determining factors because they were not particularly frequent in patients with CMS and are not markedly modified by ACZ. Low ventilatory response to hypoxia in high-altitude residents, and especially in patients with CMS, has been put forward as responsible for this low ventilation (5, 13, 16).
The placebo effect observed in the present study is evident from the clinical CMS score and the diurnal measurement of arterial blood pressure, both parameters that could be influenced by the mental status of patients. Similarly, some adverse effects were mentioned with equal frequency by the placebo- and acetazolamide-treated groups. It is well known that any subjective symptom scoring system is potentially vulnerable to a placebo effect. However, no such effect was found in biological parameters (hematocrit, sTfR, ferritin, and EPO) or in physiologic parameters measured during sleep (heart rate and SaO2). The absence of any available treatment for this incapacitating disease has created great frustration among high-altitude residents. Any new clinical trial generates intense hope that may explain the desire to contribute to the proof of its efficiency and the desire to please the physician promoting the study.
In conclusion, this study helps to better characterize the clinical and biological status of CMS and gives some evidence about its pathophysiology, mainly nocturnal hypoventilation. We propose acetazolamide (250 mg daily) as a low-cost treatment for this disease. Large-scale trials are now necessary to evaluate the feasibility of implementation of this procedure in the Andean or Tibetan region.
Acknowledgments
The authors thank Gentiane Rouffet, Ludovic Abuaf, and Robert Langer (ResMed and MAP Medizin-Technologie GmbH) for use of the Poly-Mesam recording system, and Rosario Tapia Ramirez, Jose Antonio Palacios Linares, and Flor Raymundo for their help in Cerro de Pasco. We thank Theraplix (Aventis SA) for providing acetazolamide.
FOOTNOTES
Originally Published in Press as DOI: 10.1164/rccm.200505-807OC on August 26, 2005
Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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Roberts D, Smith DJ, Donnelly S, Simard S. Plasma-volume contraction and exercise-induced hypoxaemia modulate erythropoietin production in healthy humans. Clin Sci 2000;98:39–45.(Jean-Paul Richalet, Maria Rivera, Patric)
Service de Physiologie et Explorations Fonctionnelles, and Service de Pharmacie, Hpital Avicenne, AP-HP, Bobigny
INSERM U280, Lyon
Laboratoire National de Depistage du Dopage, Chatenay-Malabry
Laboratoire de Biochimie, Hpital Henri Mondor, AP-HP, Creteil, France
Laboratorio de Transporte de Oxígeno, Universidad Peruana Cayetano Heredia, Lima, Peru
ABSTRACT
Rationale: Chronic mountain sickness or Monge's disease is characterized by an excessive polycythemia in high-altitude dwellers, with a prevalence of 5 to 18% above 3,200 m. To date, no pharmacologic treatment is available.
Objectives: We evaluated the efficacy of acetazolamide in the treatment of chronic mountain sickness and the importance of nocturnal hypoxemia in its pathophysiology.
Methods: A double-blind placebo-controlled study was performed in three groups of patients from Cerro de Pasco, Peru (4,300 m), treated orally for 3 weeks with placebo (n = 10), 250 mg of acetazolamide (n = 10), or 500 mg of acetazolamide (n = 10), daily.
Results: Acetazolamide decreased hematocrit by 7.1% (p < 0.001) and 6.7% (p < 0.001), serum erythropoietin by 67% (p < 0.01) and 50% (p < 0.001), and serum soluble transferrin receptors by 11.1% (p < 0.05) and 3.4% (p < 0.001), and increased serum ferritin by 540% (p < 0.001) and 134% (p < 0.001), for groups treated with 250 and 500 mg of acetazolamide, respectively. Acetazolamide (250 mg) increased nocturnal arterial O2 saturation by 5% (p < 0.01) and decreased mean nocturnal heart rate by 11% (p < 0.05) and the number of apnea–hypopnea episodes during sleep by 74% (p < 0.05). The decrease in erythropoietin was attributed mainly to the acetazolamide-induced increase in ventilation and arterial O2 saturation.
Conclusions: Acetazolamide, the first efficient pharmacologic treatment of chronic mountain sickness without adverse effects, reduces hypoventilation, which may be accentuated during sleep, and blunts erythropoiesis. Its low cost may allow wide development with a considerable positive impact on public health in high-altitude regions.
Key Words: altitude erythropoietin hypoxia nocturnal ventilation soluble transferrin receptors
Chronic mountain sickness (CMS) or Monge's disease is a disease encountered in 5 to 18% of the population residing at and above 3,200 m on the Altiplano of South America (1, 2) and on the Tibetan plateau (3). First described by Carlos Monge Medrano in 1925, its main feature is an excessive polycythemia (hemoglobin concentration above 21 g/dl) associated with chronic hypoxemia. This condition leads to cardiac failure and/or neurologic disorders (4). Clinical signs include headache, fatigue, sleep disturbances, dyspnea, and digestive complaints. The clinical status becomes progressively incapacitating, leading to social exclusion and psychological degradation. It is a severe public health problem for Andean countries because several million residents of the Altiplano may be at risk.
Despite some trials with medroxyprogesterone (5, 6), enalapril (7, 8), or almitrine (9), to date, no pharmacologic treatment is used to impede this progressive loss of adaptation to chronic hypoxia. The only management is repetitive blood letting or displacement of residence to lower altitudes (10). The latter has an important negative social and economic impact on the development of high-altitude regions and may have dramatic psychological and familial consequences.
The physiopathology of CMS is still largely debated (1, 4, 11, 12). Alveolar hypoventilation may play a central role in the overstimulation of erythropoiesis, leading to increased red cell mass and blood viscosity, systemic and pulmonary hypertension, and cardiac failure (13, 14). Hypoventilation could worsen during sleep in high-altitude residents, further aggravating excessive erythropoiesis (3, 5, 15–17). Moreover, periodic breathing is frequent in sea-level residents exposed to altitude hypoxia (18), and has also been described in high-altitude residents (3, 6, 15, 16).
Acetazolamide (ACZ), an inhibitor of carbonic anhydrase, decreases the reabsorption of bicarbonates in the proximal tubule of the kidney (19, 20). ACZ promotes diuresis, increases cerebral blood flow, and stimulates ventilation via metabolic acidosis (20). ACZ has been shown helpful in reducing central apneas in high-altitude mountaineers (21, 22) or in patients with sleep-related breathing disorders at sea level (23) but has never been evaluated in subjects chronically exposed to altitude hypoxia such as those suffering from CMS. Moreover, ACZ reduces erythropoietin (EPO) secretion (24, 25), either by its inhibitory action on reabsorption in the proximal tubule of the kidney (25) or through a rightward shift of the oxyhemoglobin dissociation curve due to acidosis (24).
Our hypothesis is that subjects who develop excessive polycythemia at high altitude 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. We propose that ACZ reduces EPO production principally by stimulating ventilation and reducing the level of nocturnal hypoxemia, and possibly by an indirect effect on the renal site of EPO production. Moreover, we propose to evaluate the efficiency of the treatment, not only by hematocrit 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 (26). Some of the results of this study have been previously reported in the form of an abstract (27).
METHODS
Patients and Procedure
Thirty male patients suffering from CMS and 10 normal subjects living at Cerro de Pasco (4,300 m) gave their informed consent to participate in this randomized double-blind placebo-controlled study, which was approved by the ethics committee of the Universidad Peruana Cayetano Heredia (Lima, Peru). All subjects were high-altitude natives (> 3,000 m) and were residing permanently at Cerro de Pasco, except for occasional travels to low altitude (< 3,000 m). None of the subjects had been traveling for more than 1 mo at low altitude in the preceding 6 mo. A complete clinical evaluation was made and the CMS clinical score was calculated. The CMS score is based on the following symptoms: breathlessness, sleep disturbance, cyanosis, paresthesias, headache, and tinnitus (28). Systemic arterial pressure was measured by sphygmomanometry after a 15-minute rest in the supine position. All patients had a hematocrit at or above 63%, except one subject with 60% but who presented clear clinical signs of CMS. An evaluation of ventilatory function was performed before inclusion in the study to exclude subjects with pulmonary diseases. Forced vital capacity (FVC) and forced expired volume in 1 s (FEV1) were measured by spirometry (Hill Med-Specialist, Miami, FL). All values were within normal limits corrected for age, height, and body weight. Resting values of end-tidal PO2 and PCO2 were measured during daytime, using a fast gas analyzer (Normocap Oxy; Datex-Ohmeda Division, Instrumentarium, Hatfield, UK). Plasma bicarbonate was measured in venous blood using a CO2_L ADVIA chemistry reagent (Bayer Diagnostics, Puteaux, France). pH was estimated by assuming that PETCO2 is equivalent to PaCO2 and using the Henderson-Hasselbalch equation: pH = 6.1 + log[)].
Subjects were all nonsmokers except for one subject (placebo) who had been smoking fewer than five cigarettes per day for 10 years. Allocation to treatment was done randomly through computer-generated random numbers balanced between the three treatment groups (n, age in years, weight in kilograms, and height in centimeters):
Patients with CMS treated with placebo: n = 10, 44 ± 9, 63 ± 3, 1.58 ± 0.05
Patients with CMS treated with 250 mg of ACZ daily (D250): n = 10, 43 ± 9, 65 ± 9, 1.62 ± 0.08
Patients with CMS treated with 500 mg of ACZ daily (D500): n = 10, 41 ± 6, 67 ± 10, 1.60 ± 0.05
A group of normal subjects (n = 10; age, 39 ± 9 years; weight, 64 ± 7 kg; height, 1.60 ± 0.05 m) living at the same altitude, with no apparent disease at examination and with a hematocrit at or below 55%, served as control subjects. All measurements were made at the Instituto de Investigacion de Altura (Cerro de Pasco) on two occasions, before and after 21 d of treatment. Subjects were asked to come to the institute every morning to take their medication with a glass of water, under the control of a physician. Active and placebo tablets were identical in appearance. Treatment was double blind.
Night Recordings
We monitored nocturnal breathing and arterialized O2 saturation (SaO2) with a Poly-Mesam MAP recording system (ResMed [Mnchengladbach, Germany] and MAP Medizin-Technologie GmbH [Martinsried, Germany]), using thoracic and abdominal strain gauges for recording of ventilation, nasal thermistors for nasal flux, and transcutaneous oximetry at the finger tip for continuous measurement of SaO2. Heart rate was obtained through electrocardiographic recording via three precordial electrodes. No electroencephalographic recording was made to analyze sleep stages. We assumed that nocturnal recordings correspond mainly to sleep conditions. However, wakening periods cannot be excluded, but may be considered as part of a usual night of a patient with CMS at high altitude. Analysis of nocturnal respiration included detection of apneas, hypopneas (central and obstructive), and periods of desaturation. In fact, only apneas and hypopneas of central origin were found: all episodes of reduction in nasal flux were accompanied by thoracic and abdominal reductions in ventilation. Basal ventilation was obtained from a normal quiet 5-min resting period while in bed, 5 min after extinction of light in the bedroom, thus presumably before induction of sleep. Apnea and hypopnea events were defined as a decrease in ventilation of more than 80 and 50% from basal value, respectively. Index of apneas plus hypopneas (apnea–hypopnea index, AHI) was calculated as the mean number of events per hour of night recording. A value of AHI above 5 has been considered as pathologic and a risk factor for cardiovascular diseases (29).
Hematologic Status
A venous blood sample was obtained via an antecubital vein in the supine position, immediately when subjects woke up in the morning after the night of sleep recording. Hematocrit was obtained by centrifugation (Microcentrifuge IEC; Thermo Electron, Waltham, MA). Soluble transferrin receptor (sTfR) and ferritin levels in serum were determined with Nichols Advantage soluble transferrin receptor and ferritin reagent cartridges (Nichols Institute Diagnostics, San Clemente, CA), respectively, as previously described in detail (30). Serum concentration of EPO was measured in duplicate by enzyme-linked immunosorbent assay (ELISA) (Quantikine IVD kit; R&D Systems, Minneapolis, MN).
Statistical Analysis
Data are expressed as means and SD. Data were compared by Student t test for paired (effect of treatment) or unpaired (comparison of groups) samples, except for AHI, for which nonparametric tests were used (Mann-Whitney for comparison of groups, Wilcoxon for effect of treatment).
RESULTS
Two patients (one in the D250 group and one in the D500 group) left the study for personal reasons and were not available for the posttreatment measurements.
Characteristics of Patients with CMS
When compared with the control group, patients with CMS (n = 28, pooled placebo, D250, and D500 groups before treatment) showed a higher hematocrit, higher serum EPO and soluble transferrin receptor concentrations, similar serum ferritin, lower nocturnal arterial oxygen saturation, a higher nocturnal heart rate, a similar apnea–hypopnea index (AHI), a higher systolic and diastolic arterial pressure, and a higher CMS clinical score (Table 1).
Effect of Treatment with ACZ
Treatment with ACZ decreased hematocrit by 7.1 and 6.7% (Figure 1A), serum EPO by 67 and 50% (Figure 2A), and serum soluble transferrin receptors by 11.1 and 3.4% (Figure 2B) and increased serum ferritin by 540 and 134% (Figure 2C) for groups receiving 250 and 500 mg of ACZ, respectively. These variations clearly evidence a blunted erythropoiesis via diminished EPO production. No dose effect was found, the changes being similar with the two doses of ACZ. This suggests that the Emax (dose for maximal effect) has already been reached with 250 mg. The CMS clinical score decreased by 56, 50, and 52% with placebo and 250 and 500 mg of ACZ, respectively (Figure 1B). Diurnal PETO2 was increased by 6.5 and 4.5% with 250 and 500 mg of ACZ, respectively, whereas PETCO2 decreased by about 14% in both treated groups, suggesting a positive effect of acetazolamide on minute ventilation (Table 2). Evaluation of plasma bicarbonate and pH clearly shows that ACZ induced metabolic acidosis (Table 2). The treatment increased mean nocturnal SaO2 by 4.3 and 5.1% (Figure 3A) and decreased mean nocturnal heart rate by 11 and 4% (Figure 4A) for 250 and 500 mg of ACZ, respectively. Mean AHI decreased only in the group treated with 250 mg of ACZ (Figure 3B). The number of subjects with an AHI above 5 was reduced from 3 to 0 with 250 mg of ACZ and not modified in the other groups. Both systolic and diastolic systemic arterial pressure measured during daytime decreased with ACZ treatment, but also with placebo (Figures 4B and 4C). Before treatment, the distribution of nocturnal SaO2 in patients with CMS was shifted to lower values when compared with the control group (Figure 5). After treatment, the distribution curves of 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. Treatment with placebo had no effect on biological parameters and on physiological parameters measured during sleep. Tolerance to the medication was good; the only mentioned adverse effects were slightly increased diuresis (three, three, and five subjects in placebo, D250, and D500 groups, respectively), paresthesias (two, four, and eight subjects in placebo, D250, and D500 groups, respectively), and altered taste of gaseous beverages (two, one, and no subjects in placebo, D250, and D500 groups, respectively).
Mechanisms of Action
Variation of EPO with SaO2 was linear and parallel (same slope) before and after treatment (Figure 6). Using the regression equation for values obtained before treatment (pooled 250- and 500-mg values), we calculated the decrease in EPO induced by a decrease in SaO2 equivalent to that observed by treatment (arrow from point B along the "before" regression equation; see Figure 6). The rest of the EPO decrease to attain the mean value of EPO after treatment was then considered as independent of SaO2 (vertical arrow to point A; see Figure 6). Thus, 53% of the overall decrease in EPO induced by the treatment was estimated to be due to an indirect effect of ACZ via the increase in ventilation and SaO2, and 47% was due to another mechanism, probably related to a renal effect of ACZ on EPO secretion.
DISCUSSION
Monge's disease or chronic mountain sickness is an excessive polycythemia, frequent among high-altitude residents. In Bolivia, about 3 million persons live between 3,000 and 5,500 m of altitude. In La Paz (Bolivia), 1 million inhabitants live between 3,200 and 4,050 m. The prevalence of CMS in this population has been estimated at 5.2% (31). Therefore considering only the town of La Paz and its suburbs, about 50,000 persons may benefit from a treatment reducing their hematocrit. In Cerro de Pasco (4,300 m, Peru; 80,000 inhabitants), the mean prevalence of excessive polycythemia (hemoglobin exceeding 21.3 g/dl) has been estimated at 18.2% (32) or 14.8% (33), suggesting that treatment with ACZ may be relevant for 12,000 to 15,000 inhabitants of this town.
In the present study, patients with CMS showed, by definition, a high CMS clinical score and a high hematocrit. They presented a higher systemic blood pressure, and were more hypoxemic during sleep than control subjects. Similarly, during sleep at 3,658 m in Lhasa, Tibet, patients with CMS spent two-thirds of their night with SaO2 values less than 70% (3). Nocturnal heart rate was higher in patients with CMS, probably because of this exacerbated hypoxemia. Only 8 of 38 subjects showed a significant pattern of periodic breathing during sleep (AHI > 5) and no difference was evidenced between subjects with CMS and normal subjects, similar to what was found by others in Andeans (16, 17) but not in Chinese (3).
The hematologic status of patients with CMS included increased erythropoiesis, with high early morning EPO and increased sTfR, witness to the permanent overstimulation of bone marrow (26). Mean ferritin levels were normal, although some subjects showed low levels (< 20 μg/L), probably related to insufficient iron stores in the face of enhanced erythropoiesis. Conversely, decreased iron stores may limit red cell formation in spite of high EPO production (34). The present study is the first evaluating sTfR in normal and polycythemic high-altitude residents. Values of sTfR for patients with CMS were about twofold those of control subjects, the latter being slightly above those of sea level residents (26).
The physiopathology of CMS has been attributed to the following sequence: blunted respiratory response to hypoxia, hypoventilation, excessive hypoxemia, and excessive erythropoiesis. Ageing and loss of regulation of red cell production within the bone marrow may also facilitate the occurrence of this disease in high-altitude residents (1, 4, 12, 14).
Patients with CMS are usually more hypoxemic than normal high-altitude dwellers, in part because of hypoventilation, both during awake and sleep states (13). Nocturnal hypoventilation, inducing a lower SaO2 during sleep, might aggravate the stimulation of erythropoiesis (17). In fact, serum EPO was related to nocturnal hypoxemia (16) but not to the level of blood hemoglobin (35) in CMS subjects residing at 4,300 m. However, the short half-life of EPO may lead to underestimation of night production of this hormone when blood sampling is performed during daytime. In the present study, we did find a correlation, although weak, between nocturnal SaO2 and serum EPO, probably because blood sampling was done immediately after wake-up in the early morning. Moreover, if nocturnal hypoxemia enhances erythropoiesis, then measurement of daytime SaO2 will underestimate the hypoxic stimulation of EPO production.
Although the beneficial effects of ACZ on ventilation and SaO2 had already been shown in subjects acutely exposed to hypoxia (21, 22), the present study is the first to evaluate the effect of ACZ on nocturnal SaO2 and erythropoiesis in chronic hypoxia. We evidenced a clear beneficial effect of ACZ on the hematologic status of patients with CMS. Three weeks of treatment with ACZ was sufficient to inhibit the erythropoiesis of these patients, as evidenced by a decrease in hematocrit and sTfR. The decrease in hematocrit may have been hindered by the diuretic effect of ACZ leading to a slight hemoconcentration. Ferritin levels were markedly increased with the treatment, probably by a resetting of iron turnover after a sudden blunting of iron use for red cell formation. Considering the short half-life of ACZ in humans (about 90 min), a double (morning and evening) dose of ACZ would probably have been more efficient in treating nocturnal hypoxemia. However, to ensure the highest acceptance of the protocol by the subjects, we avoided making them come twice to the hospital and provoking nocturnal diuresis.
Few previous studies have tried to use respiratory stimulants to reduce high-altitude polycythemia. No change in hematocrit was observed in five subjects with polycythemia studied in Leadville, Colorado (3,100 m) before and after treatment for 7–10 d with medroxyprogesterone acetate (MPA) at 30 mg/day (6). In the same study, mean nocturnal SaO2 increased from 79 to 83% with MPA, although MPA had no effect on periodic breathing. With more prolonged treatment (10 wk, MPA at 60 mg/d), hematocrit decreased from 60 to 52%, and diurnal SaO2 increased from 84 to 90% in 17 patients with polycythemia. However, the main adverse effect of MPA was the loss of libido, probably through a decrease in testosterone (5). This effect prevented the use of this drug by male Andean populations (9). Almitrine, a respiratory stimulant, has been used for 4 weeks in 12 patients with CMS and induced a decrease in hematocrit from 65.2 to 62%, without change in diurnal ventilation or blood gases (9). Enalapril, an angiotensin-converting enzyme inhibitor (10 mg/day for 30 days), decreased mean hematocrit from 66 to 64% in 10 residents from Cerro de Pasco (7). Similarly, enalapril at 5 mg/day for 2 years decreased hematocrit from 63.5 to 56.8% in 13 patients from La Paz (8). However, both studies had no controlled placebo-treated group. None of these pharmacologic procedures have been implemented in high-altitude regions, because of insufficient proof of efficacy or adverse effects or high cost. A monthly treatment with ACZ would cost about 5.3 (6.4 US$), compared with 26 (31 US$) for enalapril. The most common treatment of CMS is blood letting, a technique that has transient effects (4, 10). In fact, a number of patients must move their residency to sea level, although this has a considerable negative impact on their family organization and socioeconomic status.
The mechanisms by which ACZ is efficient in the treatment of CMS may be identified as due partly to the ventilatory stimulant effect of ACZ and partly to another mechanism, probably a renal effect on EPO production, independent of SaO2 (Figure 6). EPO is produced by peritubular cells in the kidney (36). An inhibitory effect of ACZ on EPO production has been observed in humans (24) and in mice (although with much higher doses [25]) exposed to hypoxia. ACZ, and no other diuretics, inhibits the production of EPO. It acts specifically on the proximal tubule by inhibiting sodium reabsorption, which is the main determinant of renal oxygen consumption. Moreover, serum EPO has been inversely correlated to the level of renal tissue oxygenation at high altitude (34). Thus, by reducing reabsorption activity, ACZ would locally lower oxygen consumption and increase oxygen pressure within the tissue, thereby reducing the hypoxic signal that triggers EPO production (25). The acid–base status of the subjects was estimated from the resting diurnal values of end-tidal PO2 and PCO2 and the venous plasma bicarbonate concentration (Table 2). As expected, ACZ 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 oxyhemoglobin dissociation curve). Factors other than oxygen transport could interfere with EPO secretion, such as blood volume status. An acute 5% reduction in plasma volume induced by plasmapheresis (with no change in red cell mass) resulted in a slight increase in serum EPO (by 5.4 mU/ml) in humans (37). Therefore, the ACZ-induced decrease in EPO found in the present study could have been limited by a concomitant decrease in blood volume.
The positive effect of ACZ on mean nocturnal SaO2 and frequency distribution of nocturnal SaO2 suggests that nocturnal hypoventilation is an important factor in the excessive erythropoiesis in CMS. Thus our study gives, for the first time, not only a perspective on mass treatment of CMS but also a clue as to its pathophysiology. Breathing disturbances during sleep, such as periodic breathing, may contribute to nocturnal desaturation, but do not appear to be determining factors because they were not particularly frequent in patients with CMS and are not markedly modified by ACZ. Low ventilatory response to hypoxia in high-altitude residents, and especially in patients with CMS, has been put forward as responsible for this low ventilation (5, 13, 16).
The placebo effect observed in the present study is evident from the clinical CMS score and the diurnal measurement of arterial blood pressure, both parameters that could be influenced by the mental status of patients. Similarly, some adverse effects were mentioned with equal frequency by the placebo- and acetazolamide-treated groups. It is well known that any subjective symptom scoring system is potentially vulnerable to a placebo effect. However, no such effect was found in biological parameters (hematocrit, sTfR, ferritin, and EPO) or in physiologic parameters measured during sleep (heart rate and SaO2). The absence of any available treatment for this incapacitating disease has created great frustration among high-altitude residents. Any new clinical trial generates intense hope that may explain the desire to contribute to the proof of its efficiency and the desire to please the physician promoting the study.
In conclusion, this study helps to better characterize the clinical and biological status of CMS and gives some evidence about its pathophysiology, mainly nocturnal hypoventilation. We propose acetazolamide (250 mg daily) as a low-cost treatment for this disease. Large-scale trials are now necessary to evaluate the feasibility of implementation of this procedure in the Andean or Tibetan region.
Acknowledgments
The authors thank Gentiane Rouffet, Ludovic Abuaf, and Robert Langer (ResMed and MAP Medizin-Technologie GmbH) for use of the Poly-Mesam recording system, and Rosario Tapia Ramirez, Jose Antonio Palacios Linares, and Flor Raymundo for their help in Cerro de Pasco. We thank Theraplix (Aventis SA) for providing acetazolamide.
FOOTNOTES
Originally Published in Press as DOI: 10.1164/rccm.200505-807OC on August 26, 2005
Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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