High Altitude Cerebral Oedema: Causes, Symptoms, Treatment, and Prevention
High altitude cerebral oedema (HACE) is one of two life-threatening high-altitude illnesses affecting the central nervous system. The other illness is called high-altitude pulmonary oedema (HAPE). Little is known about the causes of either condition, and the two are likely related in some way.
However, this text only addresses HACE. It is important to understand the signs, symptoms, causes, treatment, and prevention of HACE because more and more young, healthy climbers are dying from it. HACE is often the result of developing a less severe and more common high-altitude illness called acute mountain sickness (AMS). Therefore, HACE is discussed in detail with other altitude illnesses.
Most people who suffer from HACE begin developing symptoms between 24 and 48 hours after reaching a higher altitude. The condition can occur if you climb to higher heights above 7,000 feet or 2,286 meters, especially if the ascent is rapid. HACE can also occur if rapid ascent is combined with concurrent heavy physical exertion and illness. The aetiology of HACE, like AMS, is related to altitude and the body's response to lower amounts of oxygen in the atmosphere.
The term "cerebral oedema" refers to swelling of the brain because of excess extracellular fluid, increased intracellular fluid, or more commonly a mixture of the two. It is important not to delay recognition or the start of treatment for someone suspected of having HACE. Detection of the illness is something that all climbers and those who travel to high altitudes must become familiar with.
Definition and Overview
High altitude cerebral oedema (HACE) is a potentially fatal condition that can develop as the body copes with exposure to high altitudes or upon ascent to elevations above 2,500 m. High altitude can be defined as any elevation above 6,500 ft (2,500 m). Altitude exposure with quick ascents plus physical and psychogenic stress are cumulative in terms of triggering HACE.
The primary feature of this condition is the development of cerebral oedema or fluid-related swelling of the brain's tissues. This disruption results in a variety of functional deficits, including the capacity of neurons to communicate with one another and with other organs. Symptoms and signs develop very rapidly in patients; at the time of diagnosis, the protective mechanisms of the body are usually not effective, and severe neurological impairment has occurred.
A hallmark of this condition is the development of cerebellar ataxia, but in severe cases, a multitude of associated symptoms and signs may be present. These injuries are more easily induced and take longer to resolve once the pressure inside the skull increases even by a small amount, as is the case with sea-level cerebral edema. The population at highest risk for HACE is the one that rapidly ascends compared to one that acclimatizes at one altitude before ascent.
Symptoms start within the first six days after arrival at altitude; the majority of HACE symptoms begin to develop after the first 48 hours of arrival at altitude, despite a significant number of cases developing symptoms on the same day of arrival, which can complicate the diagnosis of symptoms from acute mountain sickness. Since cerebral blood flow is the initiator of blood flow to this portion of the brain and the ascending symptom of HACE is cerebral oedema alongside swelling, brain cell death occurs in areas of the brain where blood flow has been compromised, which is partly the reason for the possibility of permanent damage due to HACE.
At 5,000 m in Denver, in a non-linear fashion based on heart rate, there is an initial decrease in brain blood flow that lasts for days. However, the brain blood flow increases in a linear relationship above heart rates of 85 and even more significantly at heart rates of 100, known as cerebral vasodilatation with associated cerebral oedema. A certain amount of cerebral oedema is a normal adaptation to high-altitude exposure, which occurs over 3 to 5 days of acclimatization, usually without any symptoms.
Historical Background
High-altitude cerebral oedema (HACE) has become recognized by the broad medical community only in the past few decades, although it was likely recognized by early travellers in the high mountains. In the early days of mountain exploration, many of the symptoms of altitude illness were either misunderstood, attributed to unrelated illnesses, or dismissed as exaggerated complaints.
The landmark research expedition to Pikes Peak culminated in the only available review of mountaineers suffering from HACE for nearly a half-century. Many of the most important early studies of altitude sickness included the type of detailed observations of the victims that provide the data from which diagnoses can be inferred. The reluctance of the victims to submit to careful examination or descend for help left that as the only data available.
The next significant advance in altitude medicine that touched on the history of HACE was a landmark report from an ill-fated expedition. Qualitative recognition of CO2 narcotic effects of high altitudes and shockingly low barometric pressures at death from fatal HACE did not prevent confusion about the cause of HAPO, conflating HACO with a pulmonary embolus. The strong tendency to attribute poor outcomes at high altitudes to subjects' failure to obey safe principles persisted, notwithstanding evidence of acute mountain sickness in climber-observers and accumulated observation of headaches among successful commercial clients who heeded health care advice as best they could.
Despite three decades of increasing medical attention to altitude research, blown-off weather windows led to continued deaths and disfigurements that shocked the public, embarrassed researchers and energized new studies. High-altitude physicians still debate their priorities. Medical care of victims is best guided by reports from survivors, who universally regretted their confusion. The condition is fatal unless rapidly recognized and treated with oxygen and/or descent to a safe altitude.
Physiological Responses to High Altitude
Human beings evolved at low altitudes where the atmospheric composition leads to adequate oxygenation of tissues. Discoveries of artefacts at hypoxic, high-altitude sites indicate that humans have been intermittently occupying such places for thousands of years, even before the development of past civilizations. Physiological adaptations and responses in humans occur when they ascend to high-altitude environments, often referred to as acclimatization, even though permanent biological modifications are termed genetic adaptation.
Acclimatization is most successfully induced by moderate, sustained hypobaric hypoxic exposure undertaken for weeks, whereas "residential" hypoxia can partly protect against high-altitude illness. Several factors determine an individual's inability to further ascend to extreme altitudes. Reduced barometric pressure of air at high altitudes is directly related to the level of altitude for volume, humidity, and pressure regulation.
Health risks when travelling to high-altitude locations are thus related to the reduced partial pressures of inspired oxygen. The daily day and night cycle at high altitudes is unlikely to significantly alter ventilatory responses, and the small fall in arterial oxygen at night does not usually impair the performance of metabolic processes. The main pulmonary acclimatization is to recruit pulmonary arteriovenous anastomoses, which is modulated more by arterial oxygen saturation than by ventilation or increases in cardiac function.
One of the three main altitude-related conditions is acute mountain sickness, whose causes appear similar to high-altitude pulmonary oedema. Cognitive performance remains unaffected by high altitude, except in unacclimatized subjects. Since ascent to altitude occurs frequently around the world, acute mountain sickness can undermine not just travellers but also military personnel, mountaineers, and rescue teams, leading to altered human behaviour and poor decision-making.
Acute mountain sickness also increases susceptibility to developing severe conditions, including those that may result in death. High-altitude leucopenia sets in about 12 hours after the appearance of altitude-related oedema. Acute mountain sickness is the most common acute disorder of high altitude, affecting around 25% of travellers ascending very quickly above 2,500 m. Acute mountain sickness is defined as a headache with at least one other symptom. High altitude pulmonary oedema commonly begins as acute mountain sickness and rapidly aggravated dyspnea occurs in almost 25% of acute mountain sickness sufferers not receiving acetazolamide.
High-altitude cerebral oedema: In the mid-1970s, information from recent studies suggested that high-altitude pulmonary oedema was associated with an accumulation of fluid in the brain, and it was postulated that an increase in the brain itself might set the stage for altitude sickness. In 1988, a physician proposed that acute mountain sickness and high-altitude pulmonary oedema are related and that acute mountain sickness sufferers may be susceptible to the causation of either acute mountain sickness or high-altitude pulmonary oedema, concluding that one condition should therefore not be used to replace the other. The term "high-altitude cerebral oedema" was proposed to describe the development of cerebral swelling in association with acute mountain sickness symptoms.
Acute Mountain Sickness
Acute Mountain Sickness (AMS) is the most common form of altitude distress presenting itself at high altitude and is characterized by the following symptoms:
headache,
loss of appetite,
nausea and sometimes vomiting,
dizziness,
fatigue,
a bad mood,
difficulties in sleeping.
It originates in the superficial layers of the brain. The onset of these symptoms gradually increases over a few hours to a day after the ascent to altitudes greater than 2500 m. It is the most common result after a sudden ascent to high altitudes after a brief stay at oxygen levels equivalent to those at sea level. AMS serves as a precursor to a more severe form of altitude-induced brain function impairment known as high-altitude cerebral oedema.
A headache together with one or more of the following symptoms is an initial sign of altitude distress:
another symptom listed above,
large pulse pressure,
appetite loss,
nausea,
vomiting,
persistent difficulty in sleeping.
The main risk factors for developing AMS are rapid ascent to high altitudes and lack of acclimatization.
AMS occurs because of the swelling of the brain in response to decreased oxygen levels. To the same altitude, people from different backgrounds may experience varying effects of acclimatization. In many cases, milder symptoms of AMS occur. AMS does not necessarily lead to HACE.
AMS may also occur at the time of acute mountain sickness. Migraines can be present without any symptoms, but AMS is present even with these complaints. If you develop such complaints, you must immediately descend to a lower altitude as a precaution. A cure should be sought if you start to deteriorate as soon as you return to a lower altitude.
High Altitude Pulmonary Oedema
High altitude pulmonary oedema (HAPE) is another important illness linked to high altitude. It is characterized by fluid accumulation in the alveoli of the lungs as well as interstitial lung tissue. This results in the abnormal movement of fluid from the pulmonary circulation into the alveoli and interstitium. This results in severe hypoxemia, the most important and fatal problem that results from this situation. Individuals suffering from HAPE rapidly become breathless.
An abnormal sound of breathing in the chest, commonly called 'rales,' can be heard with a stethoscope, but this may be absent in the early stage. These individuals have a persistent cough which initially may produce white and frothy sputum. They may also have a feeling of breathlessness, chest tightness, and a sense of smothering. Symptoms are usually worse at night and with exertion. Initially, these individuals have rapid shallow breathing which may change to extreme difficulty in breathing or respiratory failure if not treated promptly.
The risk of developing HAPE may vary from person to person. Many people may have underlying problems that make them more susceptible to it, such as a previous history of HAPE or living at sea level. However, all these individuals have one common factor: they are ascending faster than their bodies can adapt to the decreasing amount of oxygen with increasing altitude.
Also, younger people and relatively stronger and fitter individuals are perhaps more likely to develop HAPE than those who are older and who may not have a similar level of strength and fitness. A thorough understanding of the underlying physiological principles has shown that the best way to prevent HAPE is not to ascend within 24 hours. Despite best efforts, HAPE may still develop in some individuals. Sustained physical exertion after the first symptom – breathlessness – or the development of chest tightness may result in serious consequences.
Anyone showing the symptoms of HAPE should seek healthcare immediately. It is vitally important to keep in mind that if there is one person in the group showing this symptom, others may also be at high risk of developing the condition. HAPE and HACE seem to share a common basis or mechanism which may explain why they often occur together in the same individual. In summary, it is important to remember that illnesses occur in high-altitude settings which can be dangerous and result in death. HAPE exemplifies the role of high altitude in initiating such medical conditions.
Pathophysiology of High Altitude Cerebral Edema
High Altitude Cerebral Edema (HACE) is a pathological condition that predominantly develops after 48 hours of exposure to a high altitude at which the average barometric pressure falls below 500 hPa. Although the pathophysiology of HACE is not well understood, it is certainly associated with brain fluid disturbances. At high altitudes, a lack of oxygen, or hypoxia, can develop when the blood's oxygen delivery is insufficient to meet the metabolic needs due to lower inspired partial pressure, reduced cardiac output, lower arterial oxygen saturation, or their combination.
The brain consumes about one-fifth of total body oxygen at rest, and this requirement can be approximately doubled during maximal exercise. Clinical and animal studies have identified that the presence of hypoxia is associated with increased blood-brain barrier (BBB) permeability. The BBB, a dynamic structure formed by cerebral endothelial cells supported by astrocytes, excludes many substances from the brain, contributing to the preservation of a stable internal environment required for the function of the central nervous system and the generation of signals by electrical impulses. BBB disruption is usually an early event in HACE development, which often occurs, hence further leading to cerebral oedema.
Recent studies showed that the inflammatory response may play a role in BBB disruption. Hypoxia-associated hyperemia and congestion are linked to mechanical stressing of the BBB due to perivascular cell squeezing, leading to its physical and metabolic compromising of its endothelial, distortion of astrocyte, and neuronal function.
Altitude-induced HACE pathogenesis involves complex systems operating in a hyper-reflex manner. In response to hypoxia at high altitudes, the human body goes through various physiological adjustments starting from the initiation of the hypoxia reflex cascade involving the chemoreceptors in the arterial region. This cascade leads to an increase in pulmonary arterial pressure to improve oxygen exchange, as well as an increase in heart rate and contractility.
Continued exposure to hypoxia at high altitudes can lead to increases in both cardiac and vascular dimensions, and hence, improvements in stroke volume and peripheral oxygen transport, respectively. Since the rates of adaptation to altitude itself and re-adaptation to sea level on descent are highly variable among individuals, HACE prevention and prophylactic treatment are quite important. In addition, understanding the putative mechanisms underlying causes, symptoms, and treatment of altitude illness is recommended to provide healthcare providers with adequate knowledge and competence in handling affected persons who present with acute neurological manifestations during or after a sojourn.
Clinical Presentation and Symptoms
HACE can initially present unilaterally, but due to ensuing oedema, it frequently results in the same outcome bilaterally. Due to early predilection of the frontal region, the examination could elicit an unreflective smile as the main indicator of HACE formation. Ataxia has been noted early on in the evolution of HACE, as opposed to the evolving form of symptoms characteristic of severe AMS or the gradual monotonous slope of the ataxia.
The acuity and degree of impairment may range from an altered mental status to a more perplexing manifestation of dementia. The degree of change immediately precedes significant point changes in mentation and may precipitously transition to a coma with little warning.
Patients have deteriorated from a conversational baseline state and were found stuporous with exposure to severe insults and tasks. Once profound disease has set in, both the physical and psychological nature of the patient, point-of-care stratification becomes minutely granular and the lines separating the patient categories are further blurred.
Owing to these elements encountered in the clinical workplace, more nuanced acute care management of these patients, some of whom display AMS while others evolve to have concomitant cerebrospinal fluid abnormalities, comes into play. Advanced settings may elucidate signs of both forms of HACE or combinations of HAPE, HACE, and AMS along with High-Altitude Pulmonary Oedema.
It is important to be alerted to the existence of severe neurologic AMS at 17.5% and 9.7% of detected HACE at advanced altitude camps, allowing for early decisions concerning evolution, activity, and descent meticulously.
Diagnosis and Differential Diagnosis
HACE is diagnosed with the aid of signs, symptoms, and a thorough clinical examination to indicate and assess impaired levels of consciousness. For studies that require specific quantification, the scoring system can be applied with the assessment of ataxia and the response to simple questions about today's date, based on the score of "3" out of their 4 questions wrong, and the assessment of altered mental status using a scale or another such test. To prevent inappropriate treatment and imaging, HACE should be differentiated from Acute Mountain Sickness and High Altitude Pulmonary Edema.
HACE can be diagnosed if there is no reliable history of a rapid altitude gain, in those known to live at an altitude, or a history of recent use of certain medications. Conversely, AMS is diagnosed if the patient was acutely exposed (during the last 7 days) to an elevation higher than 2,500 m above sea level, with a headache plus one of the symptoms listed above.
Despite the stereotypical pronouncements, the actual rates of decline in the parameters are surprisingly modest and were insensitive to the initial rates of rise. Nevertheless, it is important to recognize clinical HACE where the history of AMS might be lacking when emergency measures have to be implemented, and the gold standard for the diagnosis of HACE remains the development of ataxia or mental status change in people who are ill.
While neuroimaging has been suggested as a routine for diagnosing or excluding HACE, its limited portability and feasibility render it of limited use in the diagnosis of this condition where clinical diagnosis remains the best strategy.
Treatment Approaches
If any patient is suspected of having altitude sickness or any other form of acute mountain sickness, immediate descent to lower altitudes is the treatment of choice and the most effective way to reverse symptoms rapidly. Time to safe descent is based on the severity of the cerebral oedema and the risk of further high-altitude exposure.
Pharmacological therapy is often started as soon as a diagnosis is suspected and continued through descent while monitoring for improvement. In the case of increased intracranial pressure, medications to decrease that pressure or decrease oedema formation are utilized. Dexamethasone, however, has been shown to help reverse and prevent the worsening of cerebral oedema, though it takes hours to days to start making a significant clinical change.
Many other non-pharmacological treatment modalities have also been proposed, but the most clinically effective options are oxygen, hyperbaric treatment, and slow descent. High-flow oxygen administered via face mask has a much lesser effect, as most symptoms associated with altitude sickness are hypoxic in origin.
The severity of altitude sickness will predict the necessary therapy for optimal results. Patients with severe signs and symptoms require immediate descent to the lowest altitude, and they may require additional assistance. A person with a past medical history of altitude sickness and reinjury at high elevation may also need prophylaxis by descent.
Patients who are descending without therapy may require additional time at safe altitudes before reascending. Pharmacologic treatment utilizing dexamethasone, a corticosteroid, helps to decrease inflammation and reduce brain oedema. Diuretics are often discussed as an ancillary type of pharmacologic therapy to decrease cerebral oedema; their use is still debated. The mildest altitude sickness can be treated simply with descent.
Returning to higher altitudes utilizes all of the same treatment modalities as those found helpful during acute treatment. Instead of additional interventions such as oxygen and slow ascent, emphasis should be placed on decreasing altitude as well as not pressing descent until a person has fully recovered.
Pharmacological Interventions
Pharmacological interventions consist of specialized treatments and critical medications to alleviate symptoms. This may consist of one or more compounds affecting the pathophysiology of the underlying illness. Dexamethasone is a cornerstone treatment for HACE with proven benefit from several case series showing full recovery.
Dexamethasone has anti-inflammatory properties, reduces cerebral blood flow, and thus has a direct role in reducing brain swelling. Pooled evidence from multisite intervention trials in mild to severe HACE has shown that the benefit is greatest in patients presenting with more severe disease. In contrast, acetazolamide is often used in HACE for its respiratory stimulus effect; it increases acclimatization and reduces the symptoms of AMS in addition to reducing intracranial pressure.
The choice of medications and whether one or more is indicated will depend on variables such as the severity of the condition and patient needs, which in turn may be influenced by the medications' dosage, side effects, and contraindications.
A bolus dose of 8 mg dexamethasone is advocated as first-line treatment in any patient with a suspected altitude illness to avoid permanent brain damage since even mild forms of brain swelling result in acute brain dysfunction with potentially neuropsychiatric and prosencephalic effects.
Data are limited for other groups among whom dexamethasone prophylaxis has been advised. Therefore, this evidence is increasingly becoming more specific and can inform pharmacological choices for healthcare providers in the management of HACE, pending outcomes of further multicenter trials. With the growing number of alpinists and trekkers who travel to high altitudes, further studies should be conducted to assess the efficacy of these drugs in more diverse populations.
Non-pharmacological Interventions
Immediate descent Immediate descent is the most important intervention for HACE. The use of medications should not interfere with the decision and commencement to descend, and medication should never replace the need for descent. Depending on the severity, the time it takes for symptoms to resolve after initiation of descent ranges from hours to days.
Supplemental oxygen therapy can be provided and is effective, especially in the early stages where HACE can progress to AMS. The aim is to achieve an arterial oxygen saturation of over 90%. Face masks or nasal cannulas with flow rates between 4 litres to 6 l/min at rest or higher during exercise increase oxygen availability.
Gradual acclimatization Gradual acclimatization of climbers to high-altitude environments over days may reduce the risk of HACE. The “climb high, sleep low” technique reduces a climber’s exposure to lower oxygen pressures during sleep. Rest/avoidance of heavy exercise Rest and avoidance of overexertion are recommended once the initial symptoms of HACE are apparent to hasten recovery.
Hydration Maintenance of proper hydration is important for any patient with HACE. Fluid requirements increase due to faster respiration, which can reduce body water and hyperventilation-induced diuresis. While adequate hydration is important, forced oral intake should be avoided in patients with impaired consciousness to prevent aspiration.
Avoiding rapid ascents in alpine environments is the most effective way of preventing HACE. Climbers at high altitudes who develop symptoms of severe headache, unsteady gait, increasing lethargy, and ataxia in particular should descend immediately. Prompt descent is more important and at least as effective as drug therapy.
Preventive Measures and Risk Factors
The occurrence of HACE, as well as the severity, depends on individual susceptibility and on certain risk factors. Rapid ascent, i.e., the speed and not the altitude gained, is the main risk factor as it does not give the organism enough time for acclimatization. Slow ascent, taking into account the general height of the area, will help prevent HACE.
People living and working in high-altitude areas will be somewhat better acclimatized; however, they will sooner or later get HACE if they do not adhere to the basic principles of acclimatization and ascend too quickly to higher levels. Those who are faster and stronger are more at risk since there might be a false feeling of being all right, as they feel less affected by their work or ascent.
Educating the climbers often serves as preventive, for there are innumerable instances where a climber descending from the mountains with HACE describes somebody high up with the description of the initial stage of HACE when the patient is still mobile. Suspicions of HACE keep the climber in the vicinity of the climber sick with HACE until enough evidence is received to warrant early evacuation. Group dynamics will determine when one feels one reasonably suspects HACE.
Evacuation may be started at an earlier level if professional high-altitude rescuers are available. The earlier the person is evacuated, the more his exercise plays a positive role in counteracting the active component of HACE. Any known medical disorder should be treated adequately before a person goes to high altitude. A person should be individually assessed and made aware of his expected tolerance to high altitude and any countermeasures short of medicines he should take according to his assessment.
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