Treatment of chronic mountain sickness: Critical reappraisal of an old problem

Respiratory Physiology & Neurobiology 158 (2007) 251–265

Treatment of chronic mountain sickness: Critical reappraisal of an old problem Mar´ıa Rivera-Ch a,∗ , Fabiola Le´on-Velarde a , Luis Huicho b,c,d a

Departamento de Ciencias Biol´ogicas, Facultad de Ciencias y Filosof´ıa, Instituto de Investigaciones de Altura, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, Lima LI 31, Peru b Departamento Acad´ emico de Pediatr´ıa, Universidad Nacional Mayor de San Marcos, Lima LI 5, Lima, Peru c Departamento Acad´ emico de Pediatr´ıa, Universidad Peruana Cayetano Heredia, LI 5, Lima Peru d Instituto de Salud del Ni˜ no, 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 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 initiated 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

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Corresponding author. Tel.: +51 1 93488786; fax: +51 1 3190019. E-mail addresses: [email protected] (M. Rivera-Ch), [email protected] (F. Le´on-Velarde), [email protected] (L. Huicho). 1569-9048/$ – see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2007.05.003

policies. He stubbornly taught us that basic science is fundamental 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 country, 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; LeonVelarde 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

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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 consensus as a clinical syndrome occurring to natives or long-life residents above 2500 m, characterized by excessive erythrocytosis, 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 reappear after return to high altitude. It also proposes a CMS score based on clinical symptoms and Hb concentration for grading the severity of the disease, which use should allow better comparability of future studies. Subjects with chronic respiratory diseases or those with any underlying chronic condition that worsens hypoxemia are excluded from this CMS definition. 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 vessels. 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 estimated prevalence of this condition is 15.6% (Leon-Velarde and Arregui, 1994; Leon-Velarde et al., 1994) on the basis of a crosssectional 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 saturation (SaO2 ), and low peak expiratory flow. This study also revealed that chronic respiratory diseases may increase high altitude 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 substantial 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 (LeonVelarde, 2003). Kyrgyzstan health authorities have also called for an increased support to research related to CMS and underscored the importance of paying more attention to pulmonary

hypertension and cor pulmonale in Kyrgyzstan and China (LeonVelarde, 2003). Aging, worsened hypoventilation during sleep and periodic breathing are all been proposed as aggravating factors (LeonVelarde 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 accelerate the development of CMS (Frisancho, 1988; Monge-C et al., 1992). In this regard, it is interesting that mean Hb concentration 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 populations 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 agreement 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, systemic 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 (Le´on-Velarde et al., 2003a). Studies were carried out to examine the plasticity of chemoreflexes to both short- and long-term changes in blood gas tensions of chronically hypoxic high altitude natives with blunted respiratory 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 discrepancy in previous studies with regard to HVR. The basic notion remaining is that chronic alveolar hypoventilation in susceptible 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

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oxygen delivery to several organs including the brain. Paradoxically, 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 interventions 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 control 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 baroreceptor 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 orthostatic 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 manifestations of chronic hypoxia, that is, stimulation of erythropoiesis and stimulation of pulmonary hypertension, respectively. In many CMS patients, both manifestations are present simultaneously (Penaloza and Sime, 1971; Penaloza et al., 1971). However, occasionally CMS patients may have little or no elevation of pulmonary artery pressure or resistance beyond the normal increase at high altitude (Antezana et al., 1998). Alternatively, 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

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strategies, one aimed at improving pulmonary hypertension and its clinical consequences, and the other at seeking effective treatments 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 phenotype 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 Ethiopians 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 conferring greater reproductive success among women estimated with high probability to have genotypes for high percent of oxygen 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 developing 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 discussed 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 strategies 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 comparability 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

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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 susceptible 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 (LeonVelarde 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 individual randomized controlled trials, non-randomized controlled trials, case-series, case-reports, consensus/expert opinion, animal studies, or from basic studies addressing physiological and pathophysiological aspects. Systematic reviews of randomized controlled trials and well-designed individual randomized controlled 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 recommendation 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 outcomes 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 nonpharmacologically 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 efficacy of this therapy. Performing such a clinical trial would face formidable practical challenges. Case-series and casereports 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 ventilationperfusion 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 therapeutic 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

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were performed, but the authors did not report in a systematic way whether changes in quantitative measurements and in symptoms 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 volume replacement (Klein, 1983) and that it allows a long-lasting improvement of symptoms (Sedano and Zaravia, 1988). However, 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 randomized controlled trials with blood-letting, alone or in combination with isovolemic hemodilution, seems unlikely. Currently, bloodletting 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). Unequivocal 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 successfully 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 transplanted patients developed post-transplant erythropoiesis (PTE) through enhanced erythropoiesis mediated by an altered regulation 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 reninangiotensin 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

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role, including the oligopeptide N-acetyl-seryl-aspartyl-lysylproline (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, inhibition 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 preliminary 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). Hematocrit decreased after the second week of therapy and CMS score also decreased, but the results were not consistent in all participants. 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 urinary 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

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and persistent proteinuria was made on the basis of packed cell volume greater than or equal to 55%, and urinary protein excretion rate greater than or equal to 150 mg/24 h, measured on two or more occasions, 2 months apart, in otherwise healthy people. Patients were advised to restrict their dietary sodium and to eat 0.6–0.8 g protein per kg body weight daily. Other antihypertensive drugs but not ACE inhibitors or angiotensin II receptor antagonists were allowed. The sample size of the study was powered 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 concentration and proteinuria were strongly correlated. Enalapril was well tolerated by all patients. In addition to the above discussed mechanisms, possible pathways 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 erythropoietin, 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 complete 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 amelioration 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 altitude polycythemia, and in the long term, should substantially reduce morbidity and mortality. As baseline packed cell volume and Hb concentration were positively correlated with blood pressure, serum creatinine, blood urea nitrogen, and proteinuria, 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 suggests 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 outcomes 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 subjects 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 differentiated 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 (LeonVelarde et al., 2005). Thus the study could not assess the efficacy of enalapril in patients with defined clinical and laboratory criteria 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 clinical improvement and quality of life as primary outcomes, and a standardized definition of CMS including clinical and laboratory 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 erythropoietin (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 pentoxifylline 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 oxygenation (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 stimulate adenylate cyclase, activated by micromolar concentrations of adenosine (Ueno et al., 1988). Under hypoxic conditions,

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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). Pentoxifylline 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 intermittent 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 transplanted 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 exposure 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 oxygendependent 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 noncontrolled 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 reduction 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 releasing several neuromodulators among them dopamine, which shows an elevated concentration (Peguignot et al., 1987). Modulations of dopaminergic pathways may contribute to the

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time-dependent changes in ventilation observed during acclimatization 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 system 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; LeonVelarde 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 chemosensitvity 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 controls 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 isocapnic 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 pathophysiologic 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 controlled 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-

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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 administration 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 protocol, 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 therapeutic 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 interconversion between CO2 and H2 CO3 , or any of its ionic species (Maren, 1967). Modulation of carbonic anhydrase activity provides 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 therapeutic 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 cytoplasmic and its primary role is the modulation of CO2 transport and excretion. The process of CO2 transport begins with molecular CO2 diffusing out of the tissues and into the circulation and then into the red blood cells along its partial pressure gradient. 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 cerebral 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). However, it has never been evaluated in subjects chronically exposed to altitude hypoxia such as those suffering from CMS. Moreover, acetazolamide reduces EPO secretion (Miller et al., 1973; Eckardt et al., 1989), either by its inhibitory action on reabsorption 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 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. It was a randomized, double-blind placebo-controlled study of acetazo-

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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 acetazolamide (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 hypoventilation, 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 kidney (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. Moreover, 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 pressure 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 concomitant 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 hypoventilation 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 breathing, may contribute to nocturnal desaturation, but do not appear to be determining factors because they were not particularly

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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 sideeffects. 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 different from CMS. In fact, there is evidence pointing to increased pulmonary vascular resistance secondary to hypoxia induced pulmonary vasoconstriction and vascular remodeling of pulmonary arterioles (Aldashev et al., 2002; Ge and Helun, 2001; Heath, 1989; Heath et al., 1990). Treatment options for pulmonary 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 represent potential targets for therapeutic intervention (Maggiorini and Leon-Velarde, 2003). The biochemical pathways underlying 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 concentrations 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 antiproliferative effects which are mediated by cyclic GMP (Ignarro et al., 1999). Cyclic GMP is hydrolysed by phosphodiesterases

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(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 possibility 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 evaluating 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 matching 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. Necroscopic 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 longterm 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 catheterization 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 electrocardiographic 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 visits 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. However, sildenafil has several characteristics that make it attractive for future larger clinical trials. It has a selective effect on pulmonary 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 (B¨artsch 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 nonrandomized 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 difference in Ppa was observed between the low-Hb and high-Hb groups. Nifedipine induced a decrease of >20% in Ppa in twothirds 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 pulmonary 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 acetazolamide 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 inhibited 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 circulation. 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 kidney, this ventilatory stimulation was also demonstrated to be a consequence of vascular endothelial and central chemoreceptor carbonic anhydrase inhibition (Swenson, 1998). In a comprehensive review on carbonic anhydrase inhibitors and HPV, evidence is presented on the hypoxic response of the pulmonary circulation that may be useful in different conditions having HPV as a prominent pathogenic event (Swenson, 2006). Such conditions include high altitude pulmonary edema and high altitude cerebral edema, considered extremely severe forms or variations 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

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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 plausible 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 taking into account these and other contextual factors are needed to better define the burden of disease, time-course and severity 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 warranted. Surveillance of health impact resulting from corrective environmental interventions in mining cities and other settings with high prevalence of risk and modifying factors is necessary, 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 associated 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 acceptable 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. Acetazolamide 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.

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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 overemphasized. 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. References Aldashev, A.A., Sarybaev, A.S., Sydykov, A.S., Kalmyrzaev, B.B., Kim, E.V., Mamanova, L.B., Maripov, R., Kojonazarov, B.K., Mirrakhimov, M.M., Wilkins, M.R., Morrell, N.W., 2002. Characterization of high altitude pulmonary hypertension in the Kyrgyz: association with angiotensinconverting enzyme genotype. Am. J. Respir. Critl. Care. Med. 66, 396– 402. Aldashev, A.A., Kojonazarov, B.K., Amatov, T.A., Sooronbaev, T.M., Mirrakhimov, M.M., Morrell, N.W., Wharton, J., Wilkins, M.R., 2005. Phosphodiesterase type 5 and high altitude pulmonary hipertensi´on. Thorax 60, 683–687. Anand, I.S., Prasad, B.A.K., Chugh, S.S., Rao, K.R.M., Cornfield, D.N., Milla, C.E., Singh, N., Singh, S., Selvamurthy, W., 1998. Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema. Circulation 98, 2441–2445. Anand, I.S., Wu, T., 2004. Syndromes of subacute mountain sickness. High Alt. Med. Biol. 5, 156–170. Antezana, A.M., Antezana, G., Aparicio, O., Noriega, I., Velarde, F.L., Richalet, J.P., 1998. Pulmonary hypertension in high-altitude chronic hypoxia: response to nifedipine. Eur. Respir. J. 12, 1181–1185. Atkins, D., Best, D., Briss, P.A., Eccles, M., Falck-Ytter, Y., Flottorp, S., Guyatt, G.H., Harbour, R.T., Haugh, M.C., Henry, D., Hill, S., Jaeschke, R., Leng, G., Liberati, A., Magrini, N., Mason, J., Middleton, P., Mrukowicz, J., O’Connell, D., Oxman, A.D., Phillips, B., Sch¨unemann, H.J., Edejer, T.T., Varonen, H., Vist, G.E., Williams, J.W., Zaza, S., GRADE Working Group, 2004. Grading quality of evidence and strength of recommendations. Br. Med. J. 328, 1490. Azizi, M., Rousseau, A., Ezan, E., Guyene, T.T., Michelet, S., Grognet, J.M., Lenfant, M., Corvol, P., Menard, J., 1996. Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J. Clin. Invest. 97, 839–844. Bacher, A., Eggensperger, E., Koppensteiner, R., Mayer, N., Klimscha, W., 2005. Pentoxifylline attenuates the increase in whole blood viscosity after transfusion. Acta Anaesthesiol. Scand. 49, 41–46. Bakris, L., Sauter, E.R., Hussey, J.L., Fisher, J.W., Gaber, A.O., Winstt, R., 1990. Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation. N. Engl. J. Med. 323, 86–90. Bainton, C.R., Carcelen, A., Severinghaus, J.W., 1964. Carotid chemoreceptor insensitivity in Andean natives. J. Physiol. 177, 30–31. Barenbrock, M., Spieker, C., Rahn, K.H., Zidek, W., 1993. Therapeutic efficiency of phlebotomy in posttransplant hypertension associated with erythrocytosis. Clin. Nephrol. 40, 241–243. B¨artsch, P., Maggiorini, M., Rittert, M., Noti, C., Vock, P., Oelz, O., 1991. Prevention of high pulmonary oedema by nifedipine. N. Engl. J. Med. 325, 1284–1289.

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