Moving the Debate Forward: Are Normobaric and Hypobaric Hypoxia Interchangeable in the Study of Altitude?

Introduction A point:counterpoint series (15,23,24,27,28) sparked much debate among altitude researchers about the existence of different physiological responses between normobaric hypoxia (hypoxia caused by lowering ambient air concentration of oxygen while at sea level air pressure [NH]) and hypobaric hypoxia (hypoxia caused by low ambient air pressure which results in low levels of oxygen absorbed by the blood [HH]) exposure. High altitude exposure above 2100 m results in hypoxemia. Even after acclimatization, baseline tissue oxygenation decreases (31), heart rate increases (1), respiration increases (41), acid-base status is altered (22), plasma volume decreases (21), and reversible brain edema can be induced (7,26). The outcome of this debate will affect numerous fields and populations ranging from recreational and professional athletes, workers at altitude, military acclimatization strategies, and intermittent hypoxia or hypobaric medical treatments. Therefore, understanding differences in NH and HH can have a large and important impact. Since the recent debate, a flurry of new research comparing the two environments and their relationship to real altitude exposure has been performed. There is evidence of differences in nitric oxide metabolism (11,16), fluid balance (19), oxidative stress (6,11,32), performance (2,4,13,35Y37), altitude sickness (9), cardiac function (8), and ventilation (18) between NH and HH. Küpper et al. (17) argued that any physiological differences between NH and HH are too small to be deemed clinically relevant, but the increased number of studies recently published may prove otherwise. Unfortunately, the body of evidence grows slowly. To improve this rate, not deter researchers from pursuing this field of study, and enhance the current understanding, the fundamentals of science and peer review may need to be refreshed among our community. Few research facilities are capable of creating HH due to the requirement of a pressurized chamber, and expeditions to real altitude can be both costly and confounded by factors like weather conditions and mode of ascent. This makes NH an attractive surrogate for studying altitude as it is more accessible both logistically and financially. Since resources such as hyperbaric chambers are scarce, only a small group of researchers can contribute to this field. Therefore, sharing of facilities should be encouraged among our peers so that various scientific voices can be heard. Along these lines, we need multiple groups performing the same procedures under the same conditions to determine if there are, in fact, differences between NH and HH. Repeatability is a cornerstone of science. An example of consistent procedures producing the same results comes from the work of three groups studying acute mountain sickness (AMS). AMS is associated with headache, anorexia, nausea, vomiting, insomnia, lassitude, and/or malaise (30). Symptoms can progress to life-threatening high altitude cerebral or pulmonary edema. AMS can occur in both HH and NH (33), and traditionally, AMS has been thought to be primarily the result of hypoxia. Emerging data, though, suggest that not only hypoxia, but the hypobaria of high altitude contributes to the development of AMS, such that both the prevalence and severity of AMS are greater in HH compared with NH (9). Roach et al. (34) found that AMS severity was higher in HH than in NH in a small sample of nine subjects after a 9-h exposure. A larger study involving 36 subjects by DiPasquale et al. (9) found that symptom severity was 1.6 times higher in HH than NH after an 8-h exposure. Not only that, HH led to significantly increasing AMS severity over time, regardless of the exercise duration, while NH only did so in combination with longer exercise (9). Additionally, symptoms contributing most to AMS were different in NH (namely, feeling sick and shortness of breath) compared with HH (characterized most by feeling faint, appetite loss, light headedness, and dim vision) (10). However, there was no difference in surrogate markers of cerebral perfusion, cerebral edema or intracranial pressure between NH and HH (7). Conversely, Richard et al. (33) found no difference in AMS severity between HH and NH in 12 subjects during a shorter 6-h exposure; in this study, not only was there a shorter exposure, but very INVITED COMMENTARY