Sildenafil Increased Exercise Capacity during Hypoxia at Low Altitudes and at Mount Everest Base Camp

Context Alveolar hypoxia causes pulmonary hypertension. Sildenafil causes pulmonary vasodilatation in patients subjected to acute hypoxia at sea level. These observations have generated hypotheses about using sildenafil in acute mountain sickness and for treating pulmonary hypertension in patients with chronic respiratory insufficiency. Contribution Sildenafil reduced hypoxic pulmonary hypertension at rest and with exercise and increased maximum exercise capacity and cardiac output in 14 mountain climbers who received sildenafil and placebo in random order at low altitude while breathing hypoxic gas and again at an elevation of 5400 m. Cautions The results of this small study are preliminary. Sildenafil's role in the management of acute mountain sickness is unclear. The Editors Acute and chronic hypoxia are well-characterized causes of pulmonary hypertension (1, 2). Exercise capacity is reduced during severe alveolar hypoxia, regardless of whether the condition is due to environmental factors such as high altitude or to various respiratory diseases. The extent to which hemodynamic constraints related to enhanced right ventricular afterload contribute to limited exercise capacity during hypoxia and pulmonary hypertension remains unknown. High-altitude pulmonary edema and acute mountain sickness are serious complications that can occur during ascent to high altitudes. Individual susceptibility plays a major role in development of these conditions (3, 4), and the association of high-altitude pulmonary edema with an exaggerated pulmonary hypertensive response to hypoxia and increased vascular leakage is well documented (5, 6). Several factors are thought to cause hypoxia-related exercise limitation. First, alveolar hypoxia leads to systemic hypoxemia, which in itself may cause early fatigue of the peripheral muscles under exercise (mild to moderate hypoxia) or even at rest (severe hypoxia). Second, general hypoxia may cause nonhomogeneous vasoconstriction and compromise gas exchange. Third, pulmonary hypertension may limit right ventricular performance, resulting in inadequate adaptation of cardiac output to the peripheral demand. Researchers are unsure how much each of these factors contributes to overall exercise limitation in hypoxia. The selective phosphodiesterase-5 inhibitor sildenafil was originally approved for treatment of erectile dysfunction. Recently, sildenafil was found to reduce pulmonary vascular resistance in different forms of precapillary pulmonary hypertension (7-10) and also mimicked features of a selective pulmonary vasodilator. In a previous study (10), we examined patients with lung fibrosis and pulmonary hypertension who were known to be susceptible to increased gas-exchange disturbances after vasodilator treatment. In these patients, sildenafil reduced pulmonary hypertension, leaving the systemic arterial pressure unchanged, and simultaneously improved gas exchange (10). These effects were probably attributable to preferred vasodilatation in well-ventilated lung areas (intrapulmonary selectivity). Similar results were seen in patients with chronic thromboembolic pulmonary hypertension and ventilationperfusion mismatch (11). Sildenafil has also been shown to reduce pulmonary hypertensive response to acute hypoxia in healthy participants at sea level (12). However, its impact on high-altitude pulmonary hypertension and exercise capacity under hypoxic conditions is unknown. We examined the influence of oral sildenafil on pulmonary hemodynamics and exercise tolerance during hypoxia-induced pulmonary hypertension in healthy volunteers who were not susceptible to high-altitude pulmonary edema. We performed the study during acute hypoxic challenge at sea level and during long-term exposure to hypoxia at the base camp on Mount Everest. The study aimed to characterize differences in pulmonary hemodynamics, gas-exchange properties, and exercise limitations during acute hypoxia (without adaptation at low altitude) and after adaptation to prolonged hypoxia (at high altitude). Methods Participants Fourteen healthy volunteers (12 men and 2 women) were enrolled in the study. Eight participants were experienced mountaineers who repeatedly performed alpine-style climbing to altitudes higher than 6000 m. The other 6 participants were healthy, well-trained, experienced trekkers who had repeatedly traveled to altitudes above 3500 m. No participants had a history of high-altitude pulmonary edema. The median age, height, and weight of participants were 36.5 years (95% CI, 33.0 to 44 years), 175 cm (CI, 172.5 to 178 cm), and 72.3 kg (CI, 66.0 to 77.0 kg), respectively. Laboratory and clinical testing confirmed the absence of renal, hepatic, or hematologic disorders in all participants. The University Hospital Giessen Ethics Committee approved the study, and each participant gave written informed consent before inclusion. Design All participants underwent electrocardiography, lung function testing, and measurement of peripheral arterial oxygen saturation. Systolic pulmonary artery pressure was measured by using a portable Doppler echocardiography device (ACUSON Cypress, Siemens Medical Solutions USA, Inc., Malvern, Pennsylvania), according to previously evaluated techniques (13, 14). Recordings were stored on a magneto-optical disc and were analyzed by the study investigator and by 2 independent investigators who were unaware of the study procedures. Cardiac output was assessed noninvasively by using a gas-rebreathing technique and a commercially available device (Innocor, Innovision, Odense, Denmark) (15, 16). The indicator gas mixture contained 1% sulfur hexafluoride, 5% nitrous oxide, and 50% oxygen in nitrogen. After correction for system volume changes using the sulfur hexafluoride, cardiac output was calculated from the rate of uptake of nitrous oxide by using an infrared photoacoustic gas analyzer (AMIS 2001, Innovision). This device allowed reproducible assessments of cardiac output, as reported elsewhere (15, 16). However, the device's measurement of cardiac output at maximum exercise capacity depended strongly on participants' accurate adherence to the required breathing pattern. To determine adherence, we repeatedly trained participants in the use of the device before obtaining study measurements. Exercise capacity was quantified on a cycle ergometer while participants were in a half-supine position. Exercise was started at 25 W and was increased stepwise every 2 minutes by 25 W until maximum tolerance was reached. Echocardiography was performed at rest and throughout exercise, in parallel with measurements of peripheral oxygen saturation and electrocardiogram readings. Cardiac output was assessed by the rebreathing technique at rest and at maximum exercise capacity. During the first period of measurements at low altitude in Giessen (171 m above sea level), all participants were examined while breathing room air, at rest and during exercise. After they had fully recovered from the physical effort of the initial exercise session ( 6 hours of rest), participants were exposed to a hypoxic gas mixture with 10% fraction of inspired oxygen (corresponding to approximately 70 mm Hg of partial pressure of oxygen in the inspired gas) for 2 hours. The gas mixture was administered through masks that tightly covered participants' noses and mouths throughout the investigation period. The masks were connected to a reservoir to compensate for breathing-related changes in participants' inspiratory flow, especially during effort on the cycle ergometer. After the first hour, the participants were assigned to receive placebo or sildenafil, 50 mg. Before the study, an independent pharmacy packed the study medication, which consisted of unlabeled blue diamond-shaped pills, in numbered envelopes that were then administered according to a computerized randomization procedure. The study's crossover design (Figure 1) allowed intraindividual comparison of drug effects. We chose the sildenafil dose on the basis of our experience treating various forms of pulmonary hypertension and after consulting pharmacokinetic and pharmacodynamic data from studies of erectile dysfunction (7, 10, 17, 18). We considered carryover effects to be unlikely because of sildenafil's short half-life and the accordingly chosen washout period of at least 24 hours between investigations. Figure 1. Flow of participants through the study. After 2 hours, while maintaining participants' exposure to the hypoxic atmosphere, we performed echocardiographic assessment at rest. Next, participants again underwent exercise testing, following the previously described protocol. During the next study day, participants repeated the hypoxic challenge following the identical protocol as during the first study day, receiving either placebo or sildenafil in a crossover manner. The next phase of the study took place on Mount Everest. All participants ascended from Kathmandu, Nepal, to the base camp at Mount Everest in 8 days. The ascent involved a flight from Kathmandu (elevation, 1330 m) to Lukla (elevation, 2880 m) on the first day, with an overnight stay in Phakding (elevation, 2652 m). On the second day, the group ascended to Namche Bazar (elevation, 3440 m) and stayed for 2 nights. Participants continued the ascent to Tengboche (elevation, 3867 m) on day 4 and to Pheriche (elevation, 4240 m) on day 5. On day 6, the participants reached Lobuche (elevation, 4930 m), then ascended to Gorak Shep (elevation, 5150 m) on day 7 and to the base camp (elevation, 5245 m) on day 8. Although the fraction of inspired oxygen at this altitude is the same as at low altitude (21%), the partial pressure of oxygen was similar to the partial pressure experienced during hypoxic exposure at low altitude because the overall atmospheric pressure was lower (50% of values at sea level). After 6 days of acclimatization, we obtained baseline high-altitude measurements and tested participants during