sildenafil-citrate and Altitude-Sickness

After ascent to high altitude (≥2500 m), the inability of the human body to adapt to the hypobaric and hypoxia environment can induce tissue hypoxia, then a series of high altitude illnesses including acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE) would develop. Symptoms of AMS include headache, dizziness, nausea, and vomiting; HAPE is characterized by orthopnea, breathlessness at rest, cough, pink frothy sputum, and results in obvious pulmonary edema that poses significant harm to people; HACE is characterized by ataxia and decreased consciousness, leading to coma and brain herniation which would be fatal if not treated promptly. This review article provides a current understanding of the pathophysiology of these three forms of high altitude illness and elaborates the current prevention and treatment measures of these diseases.

Topics: Acetazolamide; Acute Disease; Altitude Sickness; Calcium Channel Blockers; Carbonic Anhydrase Inhibitors; Cytokines; Dexamethasone; Endothelin-1; Hemodynamics; Humans; Hypertension, Pulmonary; Inflammation Mediators; Nifedipine; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Alveoli; Sildenafil Citrate

High altitude illness can be life-threatening if left untreated. Acute mountain sickness and high altitude pulmonary hypertension are two syndromes of high altitude illness. Recent clinical studies showed the beneficial effects of phosphodiesterase type 5 (PDE-5) inhibitors on the treatment of pulmonary hypertension. In this report, we performed a meta-analysis to evaluate the clinical efficacy of PDE-5 inhibitors on high altitude hypoxia and its complications.. Randomized controlled trials evaluating the efficacy of PDE-5 inhibitor in the setting of high altitude were identified by searching Cochrane Central Register of Controlled Trials (September 2013), PubMed (from 1990 to September 2013), and EMBASE (from 1990 to September 2013). Extracted outcomes from selected studies for meta-analysis included arterial oxygen saturation, pulmonary artery systolic pressure, heart rate, and Lake Louise Consensus AMS symptom score. Weighted mean differences with 95% confidence intervals were presented for the continuous outcomes.. Five clinical trials that met the selection criteria were identified for the meta-analysis. All of these studies used sildenafil as the PDE-5 inhibitor. A total of 60 subjects received sildenafil, and 72 subjects were given placebo. In accordance with previous report, short-term treatment with sildenafil (1-2 days) significantly reduced pulmonary artery systolic pressure at rest (MD -4.53; 95% CI -6.72, -2.34; p<0.0001). However, treatment with sildenafil (1-2 days) did not improve oxygen saturation after exposure to high altitude (MD 0.07; 95% CI -1.26, 1.41; p=0.91). Moreover, no significant difference was observed in heart rate between sildenafil and placebo-treated group (MD 6.95; 95% CI -3.53, 17.43; p=0.19). AMS score did not improve after treatment at different time points.. Short-term treatment with sildenafil can attenuate the altitude-induced high pulmonary systolic arterial pressure, but has no significant beneficial effects on arterial oxygen saturation, heart rate, and acute mountain sickness.

Topics: Altitude; Altitude Sickness; Heart Rate; Humans; Hypertension, Pulmonary; Hypoxia; Oxygen; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones

Exposure to high altitude causes alveolar hypoxia and induces pulmonary hypertension (PH) with consequent limitation of exercise capacity. To assess the impact of sildenafil on haemodynamic and clinical parameters, and on aerobic performance, 12 young healthy unacclimatised subjects were studied (6 received sildenafil 40 mg t.i.d. and 6 received placebo) at sea level and high altitude. Systolic pulmonary artery pressure increased at high altitude, but normalised with sildenafil. The altitude-induced decrease in maximal O2 consumption was significantly smaller with sildenafil than with placebo. Enhancing pulmonary circulation with sildenafil safely protects against the high altitude-induced PH and improves gas exchange.

Topics: Altitude; Altitude Sickness; Humans; Hypoxia; Piperazines; Purines; Sildenafil Citrate; Sulfones

Exposure to high altitudes especially with rapid ascent may induce hypoxic pulmonary vasoconstriction (HPV) and pulmonary hypertension (PH) possibly leading to life-threatening high-altitude pulmonary edema (HAPE). The aim of the study was to evaluate the incidence of PH on a 1-day rapid ascent up Mount Fuji (3775 m) in recreational climbers and also to determine the effectiveness of sildenafil for this rapid ascent-induced PH as measured by echocardiography.. Twenty-five subjects who climbed Mount Fuji showed significantly increased pulmonary artery systolic pressure (PASP) from 22.3 ± 5.3 mmHg at sea level to 29.4 ± 8.7 mmHg at 3775 m. Five subjects showed PASP >35 mmHg (35.6-46.2 mmHg, average 42.0 ± 3.9 mmHg) and took oral sildenafil 50 mg after which PASP decreased significantly to 24.5 ± 4.6 mmHg (18.7-31.0 mmHg) after 30 minutes.. One-day rapid ascent of Mount Fuji may induce mild-to-moderate PH and intervention with sildenafil can reduce this PH, suggesting that the therapeutic use of sildenafil would be more reasonable for the relatively infrequent occurrence of altitude-induced PH than its prophylactic use.

Topics: Adult; Aged; Altitude; Altitude Sickness; Antihypertensive Agents; Echocardiography; Female; Humans; Hypertension, Pulmonary; Incidence; Japan; Male; Middle Aged; Mountaineering; Risk Factors; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Acute mountain sickness (AMS) is a common problem among visitors at high altitude, and may progress to life-threatening pulmonary and cerebral oedema in a minority of cases. International consensus defines AMS as a constellation of subjective, non-specific symptoms. Specifically, headache, sleep disturbance, fatigue and dizziness are given equal diagnostic weighting. Different pathophysiological mechanisms are now thought to underlie headache and sleep disturbance during acute exposure to high altitude. Hence, these symptoms may not belong together as a single syndrome. Using a novel visual analogue scale (VAS), we sought to undertake a systematic exploration of the symptomatology of AMS using an unbiased, data-driven approach originally designed for analysis of gene expression. Symptom scores were collected from 292 subjects during 1110 subject-days at altitudes between 3650 m and 5200 m on Apex expeditions to Bolivia and Kilimanjaro. Three distinct patterns of symptoms were consistently identified. Although fatigue is a ubiquitous finding, sleep disturbance and headache are each commonly reported without the other. The commonest pattern of symptoms was sleep disturbance and fatigue, with little or no headache. In subjects reporting severe headache, 40% did not report sleep disturbance. Sleep disturbance correlates poorly with other symptoms of AMS (Mean Spearman correlation 0.25). These results challenge the accepted paradigm that AMS is a single disease process and describe at least two distinct syndromes following acute ascent to high altitude. This approach to analysing symptom patterns has potential utility in other clinical syndromes.

Topics: Acute Disease; Adult; Altitude; Altitude Sickness; Antioxidants; Bolivia; Expeditions; Fatigue; Female; Headache; Humans; Male; Mountaineering; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sleep Wake Disorders; Sulfones; Surveys and Questionnaires; Syndrome; Tanzania; Vasodilator Agents; Visual Analog Scale; Young Adult

Sildenafil improves oxygen delivery and maximal exercise capacity at very high altitudes (≥ 4,350 m), but it is unknown whether sildenafil improves these variables and longer-duration exercise performance at moderate and high altitudes where competitions are more common. The purpose of this study was to determine the effects of sildenafil on cardiovascular hemodynamics, arterial oxygen saturation (SaO(2)), peak exercise capacity (W (peak)), and 15-km time trial performance in endurance-trained subjects at simulated moderate (MA; ~2,100 m, 16.2% F(I)O(2)) and high (HA; ~3,900 m, 12.8% F(I)O(2)) altitudes. Eleven men and ten women completed two HA W (peak) trials after ingesting placebo or 50 mg sildenafil. Subjects then completed four exercise trials (30 min at 55% of altitude-specific W (peak) + 15-km time trial) at MA and HA after ingesting placebo or 50 mg sildenafil. All trials were performed in randomized, counterbalanced, and double-blind fashion. Sildenafil had little influence on cardiovascular hemodynamics at MA or HA, but did result in higher SaO(2) values (+3%, p < 0.05) compared to placebo during steady state and time trial exercise at HA. W (peak) at HA was 19% lower than SL (p < 0.001) and was not significantly affected by sildenafil. Similarly, the significantly slower time trial performance at MA (28.1 ± 0.5 min, p = 0.016) and HA (30.3 ± 0.6 min, p < 0.001) compared to SL (27.5 ± 0.6 min) was unaffected by sildenafil. We conclude that sildenafil is unlikely to exert beneficial effects at altitudes <4,000 m for a majority of the population.

Topics: Adult; Altitude; Altitude Sickness; Bicycling; Cardiovascular System; Double-Blind Method; Exercise; Female; Hemodynamics; Humans; Male; Physical Endurance; Piperazines; Purines; Resistance Training; Rest; Sildenafil Citrate; Sulfones

Exaggerated hypoxic pulmonary vasoconstriction is a key factor in the development of high altitude pulmonary edema (HAPE). Due to its effectiveness as a pulmonary vasodilator, sildenafil has been proposed as a prophylactic agent against HAPE. By conducting a parallel-group double blind, randomized, placebo-controlled trial, we investigated the effect of chronic sildenafil administration on pulmonary artery systolic pressure (PASP) and symptoms of acute mountain sickness (AMS) during acclimatization to high altitude. Sixty-two healthy lowland volunteers (36 male; median age 21 years, range 18 to 31) on the Apex 2 research expedition were flown to La Paz, Bolivia (3650 m), and after 4-5 days acclimatization ascended over 90 min to 5200 m. The treatment group (n=20) received 50 mg sildenafil citrate three times daily. PASP was recorded by echocardiography at sea level and within 6 h, 3 days, and 1 week at 5200 m. AMS was assessed daily using the Lake Louise Consensus symptom score. On intention-to-treat analysis, there was no significant difference in PASP at 5200 m between sildenafil and placebo groups. Median AMS score on Day 2 at 5200 m was significantly higher in the sildenafil group (placebo 4.0, sildenafil 6.5; p=0.004) but there was no difference in prevalence of AMS between groups. Sildenafil administration did not affect PASP in healthy lowland subjects at 5200 m but AMS was significantly more severe on Day 2 at 5200 m with sildenafil. Our data do not support routine prophylactic use of sildenafil to reduce PASP at high altitude in healthy subjects with no history of HAPE. TRIALS REGISTRATION NUMBER: NCT00627965.

Topics: Adolescent; Adult; Altitude; Altitude Sickness; Blood Pressure; Double-Blind Method; Echocardiography; Female; Humans; Hypertension, Pulmonary; Hypoxia; Intention to Treat Analysis; Male; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Systole; Vasodilator Agents; Young Adult

Exposure to high altitude induces pulmonary hypertension that may lead to life-threatening conditions. In a randomized, double-blind, placebo-controlled study, the effects of oral sildenafil on altitude-induced pulmonary hypertension and gas exchange in normal subjects were examined. Twelve subjects (sildenafil [SIL] n = 6; placebo [PLA] n = 6) were exposed for 6 days at 4,350 m. Treatment (3 x 40 mg/day) was started 6 to 8 hours after arrival from sea level to high altitude and maintained for 6 days. Systolic pulmonary artery pressure (echocardiography) increased at high altitude before treatment (+29% versus sea level, p < 0.01), then normalized in SIL (-6% versus sea level, NS) and remained elevated in PLA (+21% versus sea level, p < 0.05). Pulmonary acceleration time decreased by 27% in PLA versus 6% in SIL (p < 0.01). Cardiac output and systemic blood pressures increased at high altitude then decreased similarly in both groups. Pa(O(2)) was higher and alveolar-arterial difference in O(2) lower in SIL than in PLA at rest and exercise (p < 0.05). The altitude-induced decrease in maximal O(2) consumption was smaller in SIL than in PLA (p < 0.05). Sildenafil protects against the development of altitude-induced pulmonary hypertension and improves gas exchange, limiting the altitude-induced hypoxemia and decrease in exercise performance.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Altitude Sickness; Blood Pressure; Cardiac Output; Double-Blind Method; Echocardiography; Exercise Tolerance; Humans; Hypertension, Pulmonary; Hypoxia; Lung; Male; Oxygen Consumption; Phosphodiesterase Inhibitors; Piperazines; Placebos; Pulmonary Diffusing Capacity; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones

This study explored phosphodiesterase type 5 (PDE5) inhibition as a strategy for treating high altitude pulmonary arterial hypertension (HAPH).. 689 subjects (313 men) of mean (SD) age 44 (0.6) years living above 2500 m were screened for HAPH by medical examination and electrocardiography, and 188 (27%) met the criteria for right ventricular hypertrophy. 44 underwent cardiac catheterisation and 29 (66%) had a resting mean pulmonary artery pressure (PAP) above 25 mmHg. 22 patients with a raised mean PAP were randomised to receive sildenafil (25 or 100 mg) or matching placebo taken 8 hourly for 12 weeks.. At 3 months, patients on sildenafil 25 mg 8 hourly (n = 9) had a significantly (p = 0.018) lower mean PAP (-6.9 mmHg) at the end of the dosing interval than those on placebo (n = 8) (95% CI -12.4 to -1.3). The treatment effect for sildenafil 100 mg 8 hourly (n = 5) compared with placebo was -6.4 mm Hg (95% CI -12.9 to 0.1). Both doses improved 6 minute walk distance, the lower dose by 45.4 m (95% CI 11.5 to 79.4; p = 0.011) and the higher dose by 40.0 m (95% CI 0.2 to 79.8; p = 0.049). Sildenafil was well tolerated. Necroscopic lung specimens from three subjects with HAPH showed abundant PDE5 in the muscular coat of remodelled pulmonary arterioles.. PDE5 is an attractive drug target for the treatment of HAPH and a larger study of the long term effects of PDE5 inhibition in HAPH is warranted.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adolescent; Adult; Aged; Aged, 80 and over; Altitude Sickness; Cyclic Nucleotide Phosphodiesterases, Type 5; Double-Blind Method; Electrocardiography; Female; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Middle Aged; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones

Both acute hypoxia and sildenafil may influence autonomic control through transient cardiovascular effects. In a double-blind study, we investigated whether sildenalfil (Sil) could interfere with cardiovascular effects of hypoxia. Twelve healthy men [placebo (Pla) n = 6; Sil, n = 6] were exposed to an altitude of 4,350 m during 6 days. Treatment was continuously administered from 6 to 8 h after arrival at altitude (3 x 40 mg/day). The autonomic control on the heart was assessed by heart rate variability (HRV) during sleep at sea level (SL) and between day 1-2 and day 5-6 in hypoxia. Arterial pressure (AP) and total peripheral resistances (TPR) were obtained during daytime. There was no statistical difference between groups in HRV, AP, and TPR throughout the study. Hypoxia induced a decrease in R-R interval and an increase in AP in both groups. Low frequency-to-high frequency ratio increased at day 1-2 (Pla, P = 0.04; Sil, P = 0.02) and day 5-6 (Pla and Sil, P = 0.04) vs. SL, whereas normalized high-frequency power decreased only in Pla (P = 0.04, day 1-2 vs. SL). Normalized low-frequency power increased at high altitude (Pla and Sil, P = 0.04, day 5-6 vs. SL). TPR decreased at day 2 in Pla (P = 0.02) and tended to normalize at day 6 (P = 0.07, day 6 vs. day 2). Acute hypoxia induced a decrease in parasympathetic and increase in sympathetic tone, which tended to be reversed with acclimatization. Sil had no deleterious effects on the cardiovascular response to high-altitude exposure and its control by the autonomic nervous system.

Topics: Acclimatization; Adult; Altitude Sickness; Autonomic Nervous System; Blood Pressure; Cardiovascular System; Heart; Heart Rate; Humans; Hypoxia; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Topics: Altitude; Altitude Sickness; Humans; Hypoxia; Phosphodiesterase 5 Inhibitors; Phosphoric Diester Hydrolases; Sildenafil Citrate; Treatment Outcome

Topics: Altitude Sickness; Humans; Hypertension, Pulmonary; Japan; Mountaineering; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

The purpose of this study was to review the patient characteristics and management of 56 cases of high altitude pulmonary edema at the Pheriche Himalayan Rescue Association Medical Aid Post, and to measure the use of medications in addition to descent and oxygen.. In a retrospective case series, we reviewed all patients diagnosed clinically with high altitude pulmonary edema during the 2010 Spring and Fall seasons. Nationality, altitude at onset of symptoms, physical examination findings, therapies administered, and evacuation methods were evaluated.. Of all patients, 23% were Nepalese, with no difference in clinical features compared with non-Nepalese patients; 28% of all patients were also suspected of having high altitude cerebral edema. Symptoms developed in 91% of all patients at an altitude higher than the aid post (median altitude of onset of 4834 m); 83% received oxygen therapy, and 87% received nifedipine, 44% sildenafil, 32% dexamethasone, and 39% acetazolamide. Patients who were administered sildenafil, dexamethasone, or acetazolamide had presented with significantly lower initial oxygen saturations (P ≤ .05). After treatment, 93% of all patients descended; 38% descended on foot without a supply of oxygen.. A significant number of patients presenting to the Pheriche medical aid post with high altitude pulmonary edema were given dexamethasone, sildenafil, or acetazolamide in addition to oxygen, nifedipine, and descent. This finding may be related to perceived severity of illness and evacuation limitations. Although no adverse effects were observed, the use of multiple medications is not supported by current evidence and should not be widely adopted without further study.

Topics: Acetazolamide; Altitude Sickness; Dexamethasone; Emergency Treatment; Female; Humans; Hypertension, Pulmonary; Male; Mountaineering; Nepal; Nifedipine; Oxygen Inhalation Therapy; Piperazines; Purines; Retrospective Studies; Seasons; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

To provide guidance to clinicians about best practices, the Wilderness Medical Society (WMS) convened an expert panel to develop evidence-based guidelines for the prevention and treatment of acute mountain sickness (AMS), high altitude cerebral edema (HACE), and high altitude pulmonary edema (HAPE). These guidelines present the main prophylactic and therapeutic modalities for each disorder and provide recommendations for their roles in disease management. Recommendations are graded based on the quality of supporting evidence and balance between the benefits and risks/burdens according to criteria put forth by the American College of Chest Physicians. The guidelines also provide suggested approaches to the prevention and management of each disorder that incorporate these recommendations.

Topics: Acetazolamide; Acute Disease; Albuterol; Altitude Sickness; Brain Edema; Carbolines; Dexamethasone; Humans; Mountaineering; Nifedipine; Piperazines; Pulmonary Edema; Purines; Salmeterol Xinafoate; Sildenafil Citrate; Societies; Sulfones; Tadalafil; Wilderness Medicine

Topics: Acetazolamide; Acute Disease; Altitude Sickness; Canada; Dexamethasone; Humans; Methazolamide; Nifedipine; Piperazines; Purines; Sildenafil Citrate; Sleep Wake Disorders; Sulfones; Travel

High altitude pulmonary edema (HAPE) is the leading cause of death from altitude illness and rapid descent is often considered a life-saving foundation of therapy. Nevertheless, in the remote settings where HAPE often occurs, immediate descent sometimes places the victim and rescuers at risk. We treated 11 patients (7 Nepalese, 4 foreigners) for HAPE at the Himalayan Rescue Association clinic in Pheriche, Nepal (4240 m), from March 3 to May 14, 2006. Ten were admitted and primarily treated there. Seven of these (6 Nepalese, 1 foreigner) had serious to severe HAPE (Hultgren grades 3 or 4). Bed rest, oxygen, nifedipine, and acetazolamide were used for all patients. Sildenafil and salmeterol were used in most, but not all patients. The duration of stay was 31 +/- 16 h (range 12 to 48 h). Oxygen saturation was improved at discharge (84% +/- 1.7%) compared with admission (59% +/- 11%), as was ultrasound comet-tail score (11 +/- 4 at discharge vs. 33 +/- 8.6 at admission), a measure of pulmonary edema for which admission and discharge values were obtained in 7 patients. We conclude it is possible to treat even serious HAPE at 4240 m and discuss the significance of the predominance of Nepali patients seen in this series.

Topics: Acetazolamide; Adult; Albuterol; Altitude; Altitude Sickness; Bed Rest; Emergency Treatment; Female; Humans; Male; Middle Aged; Mountaineering; Nepal; Nifedipine; Oxygen Inhalation Therapy; Piperazines; Pulmonary Edema; Purines; Salmeterol Xinafoate; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Altitude Sickness; Erectile Dysfunction; Heart Diseases; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Raynaud Disease; Sildenafil Citrate; Stroke; Sulfones; Vasodilator Agents

Topics: Altitude Sickness; Humans; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Edema; Purines; Sildenafil Citrate; Sulfones

Topics: Aerospace Medicine; Altitude; Altitude Sickness; Barotrauma; Humans; Male; Physical Fitness; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

High-altitude pulmonary edema reflects a potentially life-threatening condition affecting susceptible persons in the second night after ascent to altitudes above 2500 m. Currently, nifedipine is the only pharmacological intervention approved for both, prevention and treatment of high-altitude pulmonary edema. We evaluated the application of the phosphodiesterase-V inhibitor sildenafil combined with the non-selective phosphodiesterase-inhibitor theophylline as preventive agents. In theory, the proposed regimen can impede the two main pathophysiological features of high-altitude pulmonary edema: the deleteriously high pulmonary artery pressure (sildenafil's task) on the one hand, and the activation of an inflammatory cascade (theophylline's task) on the other hand. We suggest that these orally applicable phosphodiesterase inhibitors might be useful in the prevention of high-altitude pulmonary edema.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Altitude Sickness; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Edema; Purines; Sildenafil Citrate; Sulfones; Theophylline