title: Design and conduct of 'Xtreme Alps': a double-blind, randomised controlled study of the effects of dietary nitrate supplementation on acclimatisation to high altitude.
abstract: The study of healthy human volunteers ascending to high altitude provides a robust model of the complex physiological interplay that emulates human adaptation to hypoxaemia in clinical conditions. Nitric oxide (NO) metabolism may play an important role in both adaptation to high altitude and response to hypoxaemia during critical illness at sea level. Circulating nitrate and nitrite concentrations can be augmented by dietary supplementation and this is associated with improved exercise performance and mitochondrial efficiency. We hypothesised that the administration of a dietary substance (beetroot juice) rich in nitrate would improve oxygen efficiency during exercise at high altitude by enhancing tissue microcirculatory blood flow and oxygenation. Furthermore, nitrate supplementation would lead to measurable increases in NO bioactivity throughout the body. This methodological manuscript describes the design and conduct of the 'Xtreme Alps' expedition, a double-blind randomised controlled trial investigating the effects of dietary nitrate supplementation on acclimatisation to hypobaric hypoxia at high altitude in healthy human volunteers. The primary outcome measure was the change in oxygen efficiency during exercise at high altitude between participants allocated to receive nitrate supplementation and those receiving a placebo. A number of secondary measures were recorded, including exercise capacity, peripheral and microcirculatory blood flow and tissue oxygenation. Results from this study will further elucidate the role of NO in adaption to hypoxaemia and guide clinical trials in critically ill patients. Improved understanding of hypoxaemia in critical illness may provide new therapeutic avenues for interventions that will improve survival in critically ill patients.
authors.affiliation: UCL Centre for Altitude, Space and Extreme Environment Medicine, Portex Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; University College London, Division of Surgery and Interventional Science, 9th Floor, Royal Free Hospital, Pond Street, London NW3 2QG, UK. Electronic address: daniel.martin@ucl.ac.uk.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Martin
authors.forename: Edward T
authors.initials: ET
authors.lastname: Gilbert-Kawai
authors.forename: Paula M
authors.initials: PM
authors.lastname: Meale
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.forename: Alexandra
authors.initials: A
authors.lastname: Cobb
authors.forename: Maryam
authors.initials: M
authors.lastname: Khosravi
authors.forename: Kay
authors.initials: K
authors.lastname: Mitchell
authors.forename: Michael P W
authors.initials: MP
authors.lastname: Grocott
authors.forename: Denny Z H
authors.initials: DZ
authors.lastname: Levett
authors.forename: Michael G
authors.initials: MG
authors.lastname: Mythen
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
mesh_terms: D000064:Acclimatization / Q000187:drug effects*; D000328:Adult; D000532:Altitude Sickness / Q000188:drug therapy* / Q000503:physiopathology; D002302:Cardiac Output / Q000502:physiology; D002985:Clinical Protocols; D019587:Dietary Supplements; D004311:Double-Blind Method; D004452:Echocardiography / Q000187:drug effects; D015444:Exercise / Q000502:physiology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy; D007558:Italy; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry; D009566:Nitrates / Q000032:analysis / Q000097:blood / Q000627:therapeutic use*; D010100:Oxygen / Q000032:analysis; D012463:Saliva / Q000737:chemistry; D013147:Spirometry; D055815:Young Adult
chemical_list: D009566:Nitrates; D010100:Oxygen
keywords: Critical care; Exercise; High altitude; Hypoxaemia; Hypoxia; Microcirculation; Nitric oxide