Thin Air Resulting in High Pressure: Mountain Sickness and Hypoxia-Induced Pulmonary Hypertension

Table 2

Clinical studies of potential treatments for high altitude PH.

Trial [reference]	Design	Study population ()	Location (altitude)	Treatments	Main hemodynamic results
Antezana et al. 1998 [44]	Uncontrolled, open-label trial with case-control analysis (high versus low baseline Hb and PASP; responders versus nonresponders)	Native residents at high altitude ( [14 with PH])	La Paz, Bolivia (3500–4100 m)	Nifedipine 10 mg (1–3 doses at 30 min intervals; sublingual)	Two-thirds of participants overall showed response to nifedipine (>20% decrease in PASP), but systemic systolic blood pressure showed greater decrease in nonresponders than responders
Manier et al. 1988 [45]	Uncontrolled, open-label trial	Native residents at high altitude ( [3 with PH])	La Paz, Bolivia (3600–4200 m)	Isovolemic hemodilution	Isovolemic hemodilution led to an increase from baseline in CO but had no consistent effect on mean PAP in participants with high altitude PH
Aldashev et al. 2005 [46]	Double-blind, randomized, placebo-controlled trial	Patients with high altitude PH ()	Naryn region, Kyrgyzstan (2500–4000 m)	Sildenafil 25 or 100 mg or placebo every 8 h for 12 weeks (tablets)	Sildenafil had a significant treatment effect versus placebo in terms of mean PAP (−6.7 mm Hg [95% CI: −11.6 to −1.8]; ) and 6MWD (+43.5 m [95% CI 13.4 to 72.6]; )
Jin et al. 2010 [47]	Meta-analysis of randomized, controlled trials	Patients with high altitude PH (8 [in 10 trials])	(>2500–5400 m)	PDE5 inhibitors	PDE5 inhibitors had a significant treatment effect versus control in terms of PASP at rest (weighted mean difference −7.5 mm Hg [95% CI: −10.9 to −4.2]; ), and no significant effect on systolic blood pressure and heart rate at rest and during exercise
Andrews et al. 2016 [48]	Open-label trial (hemodynamics evaluated during incremental exercise tests before and after administration of study drug)	Volunteers ( not reported)	Simulated altitude of ~4600 m	Riociguat 1 mg (single oral dose)	Riociguat led to a decrease in PAP and PVR at all levels of exercise intensity
Richalet et al. 2008 [49]	Double-blind, randomized, placebo-controlled trial, followed by an open-label trial after a 4-week washout period	Patients with CMS ()	Cerro de Pasco, Peru (4300 m)	Randomized phase: acetazolamide 250 mg or placebo daily for 12 weeks (oral); Open-label phase: acetazolamide 250 mg daily for 12 weeks (oral)	Randomized phase: acetazolamide had no significant effect on echocardiographic measures of high altitude PH compared with placebo; Open-label phase: acetazolamide led to significant improvements from baseline in CO (original placebo and acetazolamide groups both +1 L/min []) and PVR (original placebo group: −0.12 WU []; original acetazolamide group: −0.19 WU [])
Kojonazarov et al. 2012a [50]	Double-blind, randomized, placebo-controlled, crossover trial	Patients with high altitude PH ()	Tien-Shan Mountains, Kyrgyzstan (3200–3600 m)	Fasudil hydrochloride hydrate 30 mg or placebo (IV infusion)	Fasudil infusion led to improvements from baseline in PASP (−10 mm Hg) and CO (+0.5 L/min), whereas placebo infusion did not ( for fasudil versus placebo)
Seheult et al. 2009 [51]	Double-blind, randomized, placebo-controlled, crossover trial	Nonacclimatized volunteers ()	White Mountains, CA, USA (3800 m)	Bosentan 125 mg or placebo twice daily for 5 days before ascent and 2 days at high altitude (oral)	After ascent to high altitude, PASP increased from sea-level baseline to a greater extent with bosentan (+15 mm Hg) than with placebo (+8 mm Hg)
Kojonazarov et al. 2012b [52]	Uncontrolled, open-label trial	Patients with high altitude PH ()	Tien-Shan Mountains, Kyrgyzstan (2500–3800 m)	Bosentan 125 mg (single oral dose)	Bosentan led to a decrease in PASP from 46 to 37 mm Hg after 3 h, while CO remained stable
Pham et al. 2012 [53]	Double-blind, randomized, placebo-controlled, crossover trial	Volunteers ()	Acute (90 min) normobaric hypoxia equivalent to altitude of ~4300 m	Bosentan 250 mg or placebo (single oral dose)	Compared with placebo, bosentan blunted the hypoxia-induced rise in PASP by 6.4 mm Hg () and 5.2 mm Hg () in participants with and without a history of high altitude pulmonary edema, respectively
Kortekaas et al. 2009 [54]	Double-blind, randomized, placebo-controlled, crossover trial	Volunteers ()	Dhaulagiri, Nepal (5050 m)	Iloprost 5 g or placebo (single inhaled dose) at sea level and after 14-day trek to high altitude	TAPSE and tricuspid inflow peak velocities were decreased after trekking from sea level to high altitude, suggesting impaired right ventricular systolic and diastolic dysfunction; a single dose of inhaled iloprost did not reverse these changes
Smith et al. 2009 [55]	Two double-blind, randomized, placebo-controlled trials, one in healthy volunteers and one in patients with CMS (the latter also had a crossover phase)	Native sea level volunteers (); Native high altitude residents with CMS ()	Cerro de Pasco, Peru (4340 m)	Sea level volunteers: Fe(III)-hydroxide sucrose 200 mg or placebo (IV infusion) on third day after ascent to high altitude by road; Patients with CMS: isovolemic hemodilution followed by Fe(III)-hydroxide sucrose 400 mg or placebo (IV infusion)	Sea level volunteers: at high altitude, iron infusion reduced PASP by 6 mm Hg (95% CI: 4 to 8; ); Patients with CMS: iron depletion by hemodilution increased PASP from baseline by 9 mm Hg (95% CI: 4 to 14 mm Hg; ); subsequent iron replacement had no acute effect on PASP

6MWD: 6-minute walking distance; CI: confidence interval; CMS: chronic mountain sickness; CO: cardiac output; Hb: hemoglobin; IV: intravenous; PAP: pulmonary arterial pressure; PASP: pulmonary arterial systolic pressure; PDE: phosphodiesterase; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; TAPSE: tricuspid annular plane systolic excursion.