Frontiers of hypoxia research

Acute mountain sickness Many hundreds of studies of AMS over the past two centuries have examined the contributions of ventilation, pulmonary gas exchange and fluid balance to the pathophysiology of AMS. Unfortunately, the traditional paradigm that invoked these peripheral responses to acute hypobaric hypoxia to explain AMS failed to substantially advance our understanding. Therefore, this review departs from the traditional paradigm and instead focuses on the responses of the central nervous system (CNS) to reveal new and perhaps fundamental information about the pathophysiology of AMS. Our justification for focusing on the CNS is (i) that the symptoms of AMS are largely neurological (Hackett, 1980), (ii) that high-altitude cerebral edema (HACE), considered to be the end-stage of severe AMS, has recently been identified as a vasogenic edema (Hackett et al., 1998), opening the door for a role for blood–brain barrier (BBB) permeability in AMS, (iii) that new, non-invasive techniques make measurement of brain water levels and cerebral blood volume (CBV) possible and (iv) that the available experimental evidence and theoretical arguments support a significant role for brain swelling in the pathophysiology of AMS. This review expands on concepts first explored in the literature by Krasney (Krasney, 1994), Hackett (Hackett, 1999) and Hackett and Roach (Hackett and Roach, 2001) (Fig. 1). AMS occurs in those that go too high, too fast. The most common symptoms are headache, nausea, anorexia, insomnia, fatigue/lassitude, vomiting and dizziness (Singh et al., 1969; Hackett et al., 1976; Hackett and Roach, 2000). Today’s ability to travel rapidly to high altitudes results annually in millions of people being exposed to the risk of AMS worldwide. The medical risks and costs are significant since as many as 5 % of cases can develop life-threatening highaltitude cerebral edema (HACE) (Hackett and Roach, 2000). Further understanding of the pathophysiology of the highaltitude illnesses could enhance our understanding of other illnesses involving oxygen deprivation. For example, increased knowledge of the mechanisms of high-altitude headache or BBB opening induced by hypoxia could contribute insight into similar pathophysiological processes occurring in patients at sea level. In addition, identification of the mechanisms of, and a role for, brain swelling in the pathophysiology of AMS could also affect the clinical care and management of acute high-altitude illness by providing 3161 The Journal of Experimental Biology 204, 3161–3170 (2001) Printed in Great Britain © The Company of Biologists Limited 2001 JEB3294