High Altitude Cerebral Edema: Pathophysiological mechanisms and treatments associated with HACE

GUJHS. 2003 Aug; Vol. 1, No. 1

Jennifer Taillie*


Every year thousands of people go climbing in the Rockies, trekking in the world famous Himalayas, and skiing in the Alps in search of the ultimate adrenaline rush.1The explosion of recreational “extreme sports” such as snowboarding; mountain climbing and trekking; skateboarding; and mountain biking and the subsequent injuries sustained in these sports, have precipitated a need for further research in the extreme sport arena.2 It is estimated that during the year 1984, 34 million people, including travelers and indigenous populations, traversed terrain above 7,500 ft with numbers increasing each year thereafter.  Of this group, 25% of those reaching elevations above 8,500 ft developed manifestations of high-altitude illness.1 The incidence of acute mountain sickness (AMS) is increasing due to modern society’s ability to travel rapidly to high altitudes.13 Travelers need to be educated on the risk associated with high altitudes since as many as 5% of cases of AMS can develop life-threatening high altitude cerebral edema (HACE).3

Sudden exposure to high altitudes causes an array of signs and symptoms first noted sometime between 37 and 32 BC by a Chinese government official who observed “a man’s face turns pale, his head aches and he begins to vomit” when crossing the Himalayan Kilak Pass.4 This region later became known as “Big Headache and Little Headache Mountains.”5 It wasn’t until roughly 1975 that the term ‘high altitude cerebral edema’  (HACE) was recognized in medical and mountaineering literature.  It was used to describe the condition of severe altitude illness caused by complex pathophysiological mechanisms with serious neurological manifestations.6 The severity of this illness typically requires pharmacological treatments to either prophylactically prevent the illness or to resolve the symptoms once the illness has manifested.

Acute Mountain Sickness

Originally thought to be separate disorders, HACE is now largely considered to be the end-stage of severe acute mountain sickness (AMS).3 High altitude is generally defined as anywhere higher than 5,280 ft above sea level.  At such high elevations, AMS affects almost everyone to some degree.  Effects vary for each individual, but the most classic initial symptoms include headache, insomnia, anorexia, nausea, and dizziness.4 High altitude headache (HAH) is the most prominent symptom in AMS.3


AMS is best characterized as feeling “hung over.”4 The medical risks and costs for AMS are significant since as many as 5% of these cases develop life-threatening HACE.3 AMS and HACE are best described as being on a continuum, based on a common underlying pathophysiologic process in an unacclimatized individual at high altitude.5

High Altitude Cerebral Edema


There are several published hypotheses of the cause of HACE.  In 1975, Houston and Dickinson proposed that hypoxia might impair cell membrane ion-channel active transport of sodium by impairing ATP supply, thereby leading to cell swelling.7 According to Severinghaus, 1995 however, “HACE occurs at levels of tissue oxygenation compatible with relatively normal cerebral functioning, whereas, in experimental hypoxia, ATP depletion occurs only long after all neuronal activity has been lost.”7 Also that year, Lassen and Harper hypothesized that the elevated capillary pressure due to hypoxic vasodilation and high cerebral blood flow (CBF) caused hydrostatic capillary leak.  This theory is problematic due to the normally unique impermeability of brain capillaries.7

These previous theories were consistent with present thinking in that the main contributor to high altitude illness is hypoxia.  Hypoxemia is explained through a series of signals that ultimately cause brain swelling due to cerebral edema and elevated cerebral blood volume. Cellular and molecular responses signal hypoxemia that may modify endothelial permeability (vascular endothelial growth factor) or protect the endothelium against oxygen-derived free radical damage.  Hypoxemia is also associated with the upregulation of nitric oxide synthase and nitric oxide has been linked to the pathophysiology of headache and blood brain barrier permeability.  Additionally, hypoxemia can elevate circulating arginine vasopressin levels through peripheral chemoreceptor activation, which consequently causes anti-diuresis and increased extracellular water levels.

The end result of this combination of peripheral responses reaches the brain and influences blood brain barrier permeability, cerebral edema and cerebral blood volume, causing an increase in intracranial pressure.3 HACE is likely the result of increased cerebral edema, caused by increased cerebral blood flow5 due to the increased permeability of cerebral endothelium when expose to hypoxia.3 Increased cerebral blood flow results in increased intracranial pressure, which is responsible for many of the clinical manifestations of HACE.5

Hypoxia is the body’s primary response to rapid ascent to a high-altitude environment.  The lowered barometric pressure of the ambient atmosphere results in diminished alveolar oxygen tension and as a consequence, arterial partial pressure of oxygen (PaO2) drops dramatically.4


While normal PaO2 at sea level is around 90-95 mm Hg, it plummets to around 35 mm Hg at 20,140 feet above sea level.1 In addition to dramatic decreases in PaO2, higher altitudes also trigger a greater decrease in oxygen saturation, thus putting the body in further jeopardy.  The decrease in PaO2 is the most significant environmental change caused by high altitude, thus the high altitude environment is commonly referred to as one of hypobaric hypoxia.5

During ascent to altitude, chemoreceptors in the carotid body detect the decrease in PaO2and stimulate the hypoxic ventilatory response (HVR).  A state of hypoxia in the body causes hyperventilation or an increase in minute ventilation.  Increase in ventilation results in water loss, increased PaO2 and decreased PaCO2.  Increased PaO2 caused by hyperventilation is an example of the body’s protective mechanisms it used to fight off the detrimental effects of increasing altitude.1 A crucial problem arises however, because the decreased PaCO2 in the alveoli produces respiratory alkalosis, which partly masks the ventilatory reaction to hypoxia by suppressing the chemoreceptor signal that detects the dangerous decrease in PaO2.8 This HVR is genetically predetermined and is closely related to an individual’s ability to acclimatize to a hypoxic environment and to his/her capacity for exercise at high altitude.  Individuals with the greatest increase in minute ventilation in response to high altitude are least likely to develop respiratory alkalosis and become symptomatic.5

Because of the rapid ventilatory response to the drop in PaO2, there is an increase in both the respiration rate and diuresis.  Bicarbonate diuresis resulting from respiratory alkalosis combined with increased respiration rate, causes an increase in body fluid loss, which ultimately leads to dehydration.4 2,3-Diphosphoglutamate (a phosphate compound normally present in blood in different concentrations under different conditions9) production increases, which shifts the oxygen-hemoglobin dissociation curve to the right, favoring oxygen release at the tissue level.5


Figure 1.  Normal Oxygen Hemoglobin Dissociation Curve

As adapted from http://perfline.com/student/curve.html9

This shift, however, is negated by the extreme leftward shift of the curve owing to respiratory alkalosis, favoring the hemoglobin-oxygen affinity at the lung.  This leftward shift may initially appear to be beneficial because it makes it easier for hemoglobin to bind to oxygen, but favoring the hemoglobin-oxygen affinity at the lung makes it harder to release.5

Since the PaO2 is low due to atmospheric hypoxia and the blood volume is low because of dehydration, circulating levels of catecholamines increase, creating an increased heart rate, blood pressure and venous tone.1 Other changes include increased sympathetic nervous system activity, increased heart rate, pulmonary artery vasoconstriction, increased pulmonary artery pressure and increased cerebral blood flow.5

Hypoxia resulting from exposure to high altitudes also plays an important role in angiogenesis.  Angiogenesis is the process by which growing ischemic or hypoxic tissues stimulate the in-growth of capillaries.  Tissue hypoxia and/or ischemia up-regulates a series of active proteins that initiate the angiogenic process by attacking and disintegrating capillary basement membrane, weakening capillaries and permitting plasma and/or blood leakage.7 The angiogenic response, via the active proteins, attracts macrophages that release a variety of growth factors and cytokines, leading to a loss of endothelial integrity.10

The angiogenic capillary breakdown and the resulting edema most likely occur only after many hours of sustained hypoxia.  Either process may lead to tissue ischemia by compression of capillaries and further hypoxic insult.  Other contributing factors to the leakage through damaged permeable, incompetent capillary walls include the increased cerebral blood flow caused by hypoxia or periodic bursts of high blood pressure caused by exertion, fear or sudden severe hypoxia.7 A study released by Shlim et al.11 in 1991 reported the sudden manifestation of brain tumors in three apparently normal subjects going to high altitude in Nepal.  The study theorized the “hypoxia may have resulted in swelling in an already compromised intracranial volume because of an increased capillary permeability associated with tumor angiogenesis.”11


Figure 2.  Pathophysiology of Acute Mountain Sickness

“This schema emphasizes a role for blood­brain barrier opening (BBB), brain

swelling and cerebrospinal compliance (CSC). Although highly speculative at

present, new non-invasive and sensitive techniques will allow measurement of

the variables necessary to evaluate this hypothesis (see text for more detail).

pCap, cerebral capillary perfusion pressure; cCSF, cranial cerebrospinal fluid;

ICP, intracranial pressure; CBV, cerebral blood volume; CBF, cerebral blood flow.”

Roach and Hackett, 2001.


Because initial symptoms of acute mountain sickness rapidly progress to more serious high altitude illness, it is imperative to start treatment immediately.5 Above all, descent is the most successful treatment for HACE5, with the goal of reaching the lowest possible altitude.6 Additionally, any further ascent within 24 hours should be avoided in order to allow for acclimatization at that altitude.5

Pharmacotherapy can be used either prophylactically or as a treatment for HACE. Acetazolamide is traditionally used as a preventive measure for all types of altitude sickness.  This type of treatment is especially important for those travelers approaching 10,000 ft.4 Commonly known as DiamoxÓ, acetazolamide is a sulfonamide carbonic anhydrase inhibitor6 that enhances renal excretion of bicarbonate, producing a mild acidosis.5 This reverses the bicarbonate diuresis resulting from the respiratory alkalosis from hypoxia.  Ventilation increases in response to acidosis, mimicking the process of acclimatization.  Acetazolamide may also work by lowering the cerebral spinal fluid volume and pressure5 by increasing the minute ventilation oxygen saturation and decreasing periodic breathing at night.4 “Pharmacological acclimatization” is usually avoided by a majority of mountaineers whilst the “package trekker”, or one who is less experienced, generally welcomes any relief from altitude illness.6

The traditional method of treating altitude sickness is by the administration of dexamethasone.  A synthetic glucocorticoid, it is primarily used to treat cerebral symptoms.  Its exact mechanism of action is uncertain, though it does produce profound euphoric effects, which may play a role in the improvement of symptoms.5 It has been hypothesized that dexamethasone may have the ability to decrease fluid leaks from the mircovasculature.4 Additionally, it acts to relieve nausea5, though prochloperazine may also be used.4

Though effective, dexamethasone is now rarely used prophylactically due to the significant dysphoria and the likelihood of a rebound case of altitude illness occurring with discontinued use of the drug.5 Nowadays it has a valuable role as an adjunctive therapy in the treatment of HACE.  Johnson et al.12 theorized that dexamethasone may stabilize cerebral vascular integrity, thereby reducing vasogenic edema and lowering intracranial pressure, processes that both contribute to the clinical entity of HACE.12


High altitude cerebral edema (HACE) is a severe high altitude illness with serious neurological manifestations.  The symptoms associated with HACE may not only physiologically threaten the health of an individual, but also the specific neurological implications may impair his or her mental state, leading to impaired perception and judgment, further compromising the health of the individual.  The pathophysiological mechanisms of HACE are complex and often disputed but there is general agreement that hypoxia is the underlying cause of the subsequent physiologic responses.  Due to the increased number of people participating in high altitude activities as well as an increase in access to such activities, it is imperative that the signs and symptoms of HACE and other forms of high altitude illness are effectively communicated.  Proper high altitude health promotion will help reduce the incidence as well as the mortality associated with HACE and other forms of high altitude illness, even as the number of people exposed to higher elevations continues to rise.

*Georgetown University School of Nursing and Health Studies, 3700 Reservoir Rd. NW, Washington, DC. 20057. tailliej@georgetown.edu


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