American Alpine Jounrna and Accidents in North American Climbing

Mountain Medicine, A Review of High-Altitude Cerebral Edema

  • Feature Article
  • Climb Year:
  • Publication Year: 1999

Mountain Medicine

A review of High-Altitude Cerebral Edema

by Geoffrey Tabin, M.D.

The week before Jeff Colovis and I went to climb the Black Dike on Cannon Cliff in New Hampshire, he broke four toes in an accident at his construction job. I suggested we delay our ice climb. He replied with an innocent, “Why?”

“Because it will hurt your foot,” I said.

“Well, that would be my foot’s problem,” he shot back. “I want to climb.”

After the ascent, I asked Jeff how he was doing. He answered, “Great! My foot hurts, but I had a fine day.”

At least somewhere, in even the most reptilian human brain, we are aware of sensations in our bodies. When we are cold, hot, short of breath, or in pain, a signal is sent via our nerves to the brain, which interprets the signals and tells us how we are doing. Things become more difficult, however, when it is the brain itself that is suffering. Often, the brain is unaware of its own difficulties, being either oblivious or too sick to assess its own symptoms. The result can be impaired judgment and the ignoring of serious deficits in function. In mountaineering, this condition is seen in the progression from Acute Mountain Sickness (AMS) into High Altitude Cerebral Edema (HACE).

HACE can progress rapidly from impaired judgment to disorientation, coma, and death. This year’s mountaineering medicine review will focus on HACE. We will review what is known about the symptoms of and treatment for HACE and explain new research that is shedding light on the pathophysiology of what is happening in our brains when we go too high too fast.

High Altitude Cerebral Edema has long been considered a severe form of high altitude illness resulting from swelling in and around the brain. The brain is the keeper of consciousness and initiator of commands to all other organs. The human anatomy has protected the brain in a rigid, bony, strong but inflexible vault. Being rigid, the skull allows no room for expansion. Thus, any swelling inside it has the effect of compressing the brain itself.

The brain is nourished continuously with blood from the heart that carries life-sustaining oxygen and glucose. Anything that disturbs the flow affects the brain and will cause rapid loss of consciousness. The brain is only 2% of the body by weight, but utilizes 15% of the body’s oxygen. Any decrease in the oxygen flow to the brain has immediate effects.

The brain is also protected internally by a modification to the brain capillary wall called the blood brain barrier. Unlike other capillaries (the small tubes that carry oxygenated blood to tissues), the brain capillary consists of a continuous wall of crescent-shaped endothelial cells that overlap in “tight junctions” to minimize formation of open pores. Surrounding the endothelial cells are additional protective layers: a basement membrane and partial coating of glial cells. Substances leaving the blood plasma must penetrate several membrane layers before entering the extra-cellular brain fluid. Differences in the transport mechanisms and permeability among molecules effectively allow the blood brain barrier to act as a selective filter, allowing oxygen and glucose to reach hungry neurons, but preventing leakage of plasma fluid.

Previously, when high-altitude sojourners experienced such symptoms as headache, dizziness, appetite loss, nausea, and even changing consciousness, it was believed that the physiologic disturbances were neurological in origin. Some experts concluded that hypoxia (low oxygen) interfered with energy production—in particular, production of adenosine triphosphate (ATP) in brain cells. ATP is present in all cell types and permits a finely adjusted use of energy. Without adequate ATP, researchers concluded, brain cells could no longer work properly.

In the last decade, it has become clear that ATP in the brain is not adversely affected by the degree of hypoxia that occurs at high altitude. Unlike the condition that occurs with high-altitude hypoxia, when ATP is depleted, unconsciousness is immediate. Therefore, another mechanism must be responsible for the initiation of Acute Mountain Sickness.

A number of plausible explanations have been proposed. One likely candidate was the brain’s “transmission system,” which is composed of chemicals called neurotransmitters. It is the effect of hypoxia on neurotransmitters, for example, that causes muddled thinking and slow reaction times at altitudes of about 5500 meters or more. But these symptoms are quite different from those of Mountain Sickness, which include a feeling of listlessness, low energy, lack of appetite, and mild headache.

Another proposed mechanism for the physiology of Acute Mountain Sickness was that hyperventilation by the lungs in an attempt to bring more oxygen into the system leads to blowing off excess CO2, which changes the body’s pH in a manner known as respiratory alkalosis. This acid base imbalance can lead to nausea and lack of appetite. A third idea was that increased blood flow to the brain causes pressure and headaches. The brain attempts to keep its oxygen level steady. When there is less oxygen per volume of blood, the brain reacts by redirecting more blood flow to itself, causing an increase in the volume of blood inside the rigid skull, and thus, pressure. This would explain the pounding headache one feels in the temples with each heartbeat with early mountain sickness. Dr. Charlie Houston, the godfather of high-altitude research, believes that “all or most signs and symptoms at altitude, and from many other causes of hypoxia, are fundamentally mediated by the central nervous system, whether it be via the brain or its neurons.” If this is correct, then AMS is a mild form of HACE.

Other clues to understanding AMS came from the very sickest climbers, those who developed full-blown High-Altitude Cerebral Edema. Their symptoms pointed to swelling of the brain itself as a likely cause for the more mild AMS as well. Inder Singh, an Indian military physician, described the effects experienced by thousands of Indian soldiers who were rushed from a relatively low altitude to a very high one when the Chinese attacked their border in the Himalaya. Singh measured the pressure of the soldiers’ cerebral spinal fluid by doing spinal taps. He found it was higher when the soldiers were severely ill. He also did a biopsy on the brain of a soldier who died of presumed altitude illness that showed marked edema. Since the symptoms of these soldiers with cerebral edema were essentially exaggerated symptoms of AMS, Singh logically assumed AMS to be due to increased intracranial pressure resulting from swelling of the brain.

It is because of Singh’s studies as well as autopsies conducted by other researchers on trekkers and climbers who had died as a result of severe brain swelling that the extreme form of AMS came to be known as High-Altitude Cerebral Edema. Still, important questions remain unanswered: What exactly causes cerebral edema? Is it really a physiologic extension of AMS? Why are some susceptible and others not?

Three theories were used to explain the swelling in the brain. The first was the so-called Cytotoxic theory. In cytotoxic edema, lack of oxygen to the brain causes a slowing of an essential oxygen-dependent mechanism that pumps fluid out of cerebral cells. The result is that individual brain cells swell, increasing the volume of tissue in the skull. A second theory was the Vasogenic theory, which suggests the pathophysiologic cause to be an extravasation of fluid from the blood vessels caused by a leaking of the blood brain barrier. Finally, a combination of both mechanisms plus the increase in cerebral blood flow was deduced to be an overall method of expanding the volume in the skull and placing pressure on the brain.

Until recently, there were no sensitive ways to view the brain inside the skull of a living human or to determine the degree of swelling that might or might not be present. With the advent of computed tomography (CT scanning) and Magnetic Resonance Imaging (MRI), researchers could finally obtain brain images of persons who became ill at high altitudes. Location of the edema in the brain could give clues to its cause, and comparison of brain images across a range of illness could explain the relationship of AMS to HACE. Unfortunately, however, CT and MRI machines are expensive and cumbersome and cannot be taken up on the mountain.

Peter Hackett, M.D., worked from 1981 to 1989 on Denali, frequently treating victims of Acute Mountain Sickness. Several of his patients were evacuated from Denali to a hospital in Anchorage, and Hackett obtained MRI scans of these victims. Hackett’s findings show that plasma was leaking from blood vessels and forming pools between brain cells, particularly in an area of the white matter known as the corpus callosum (which consisted of fibers that unite the two cerebral hemispheres). The brain cells themselves did not appear swollen. This exact image had never before been seen in any condition.

With descent, the plasma, which is mostly water, apparently stopped leaking and was reabsorbed into the blood circulation, which explained why the severe symptoms were completely reversible. Hackett and his colleagues studied a total of nine High-Altitude Cerebral Edema victims; the findings were present in seven of them. The paper reporting these findings was published on December 9, 1998, in the Journal of the American Medical Association and concludes that the blood brain barrier is indeed the culprit in HACE. There are many hypotheses as to what may cause the brain’s blood vessels to leak at high altitudes. Further studies in humans and perhaps animal experiments using species that are susceptible to edema in the white matter may help resolve this question in the next few years.

Other recent research has focused on the role of nitric oxide (NO) as an important factor in hypoxia-reduced capillary leakage. NO is found in the inner lining of blood vessels. Its principal action is to cause relaxation of the muscles surrounding the capillaries, allowing the smaller vessels to dilate. NO also seems to decrease the effectiveness of clot formation in the bloodstream. The effects of decreased oxygen levels in the bloodstream have been postulated to include affecting NO production and thus increasing leaking from blood vessels while at the same time decreasing clotting to stop the extravasation of edema fluid. This research fits well with Dr. Hackett’s MRI findings.

Hackett’s findings also explain why there is a beneficial effect in the administration of steroids in altitude illness. Dexamethasone may work its effect by decreasing blood brain barrier permeability. Dexamethasone prevents the increase in permeability of cultured endothelial cell monolayers that are subjected to hypoxia. The finding also explains why this edema may resolve very quickly without permanent damage once a person retreats to lower altitude.

Hackett’s findings do not exclude an element of intracellular edema as well, but they clearly suggest that vasogenic edema is the major operant factor in the pathophysiology of HACE in the phase that it becomes clinically evident. The reason why certain individuals’ blood brain barriers may be more susceptible to leakage than others, and why certain people become more symptomatic than others, still remains a subject for further research. Genetic differences in the response of the blood brain barrier regulation and genetic differences in cerebral vascular leakage under hypoxic conditions are currently under investigation. It may also be that people who do well at high altitude have more room within their skull to accommodate the edematous fluid and do not have the same increase in pressure on the brain. This would support what many lay people have long hypothesized: people who climb frequently to high altitudes must have empty space in their skulls.

A few years ago I was in a panel discussion on high-altitude climbing. I was asked what were the most important attributes for doing hard routes in the Himalaya. My answer was, “A high pain tolerance and a very short memory.” The moderator next turned to Simon Parsons, an Australian climber, and asked his opinion. Simon replied, “What was the question?” Perhaps the answer should be a very small brain.


1. Hackett, P.H., and Roach, R.C. “High-Altitude Medicine.” In Wilderness Medicine, edited by Auerbach, P.A., 1-37. St. Louis: Mosby, 1995.

2. Hackett, P.H., Yarnell, P.R., Hill, R., Reynard, K., Heit, J., and McCormick, J. “High-Altitude Cerebral Edema Evaluated with Magnetic Resonance Imaging: Clinical Correlation and Pathophysiology.” In The Journal of American Medical Association 280, 1920-1925. 1998.

3. Krasney, J.A. “A Neurogenic Basis for Acute Altitude Illness.” In Medicine Science Sport Exercise 26, 195-208. 1994.

4. Hackett, P.H., and Shlim, D. “The High Life: Health and Sickness at High Altitude.” In 1997 Medical and Health Annual, edited by Bernstein, E., 24-41. Chicago: Encyclopedia Britannica, 1996.

5. Krasney, J. “Cerebral Hemodynamics and High-Altitude Cerebral Edema”. In Hypoxia: Women at Altitude, edited by Houston, C., and Coates, G., 254-268. Burlington, Vermont: Queen City Press, 1997.

For a complete bibliography, the most recent abstracts from the International Hypoxia Symposia, and links to mountain medicine web sites, see

This AAJ article has been reformatted into HTML. Please contact us if you spot an error.