Acute disease at Himalayas


What is Acute disease?

Acute disease is defined as a group of cerebral and pulmonary syndromes that can occur during a high-altitude trip. It is more common above 2500 meters but can be seen at lower altitudes, especially in sensitive people. Acute high altitude disease includes a wide range of syndromes known as “acute mountain sickness” (AMD), “high altitude cerebral edema” and “high altitude pulmonary edema.” There are several interventions to treat this condition, both pharmacological and non-pharmacological interventions; however, their beneficial and harmful effects are highly uncertain.





High altitude is arbitrarily classified as tall (1500 to 3500 meters), very high (3500 to 5500 meters), and final (above 5500 meters) . At high altitude, there is a drop in barometric pressure, which causes a decrease in the partial pressure of oxygen at Himalayan regions. In most cases, this hypobaric hypoxia triggers physiological responses that help the individual tolerate and adapt to the low oxygen conditions. However, in other cases, there are abnormal responses, that in turn cause one of three forms of acute altitude illness/acute disease: acute mountain sickness (AMS), high altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE) .

Acute high altitude illness is more common above 2500 meters but can be seen at lower elevations, especially in susceptible people. The factors such as the rate of ascent, the absolute change in altitude and individual physiology are the primary determinants as to whether HAI will develop or not. People going to heights over 4000 meters, females, people younger than mid‐adulthood, and people with a history of a migraine are at higher risk of suffering from altitude sickness.



Description of the condition

High altitude illness ( HAI )

The potential medical problems associated with a high altitude excursion are many, and terminology has sometimes confused their classification. For this review, upper altitude illness (HAI) is defined as a group of cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 meters (Luks 2014). HAI includes syndromes covered by the terms ‘acute mountain sickness‘ (AMS), ‘high altitude cerebral edema‘ (HACE), and ‘high altitude pulmonary edema‘ (HAPE). The risk categories for acute mountain sickness are shown in Appendix. HAI is considered an essential cause of mountain mortality.

Other medical problems that may be encountered at high altitudes include acute hypoxia, cerebrovascular syndromes, peripheral edema, retinopathy, retinal haemorrhage, thromboembolism, sleep disorders and periodic breathing, high altitude pharyngitis and bronchitis, ultraviolet exposure and keratitis (snow blindness) and exacerbation of pre‐existing illness (CATMAT; Palmer; Schoene); however these will not be considered in review.



Acute Mountain Sickness (AMS) & High Altitude Cerebral Edema ( HACE )

AMS is a neurological disorder characterized by a headache, anorexia, nausea and sometimes vomiting, light‐headedness, insomnia, and fatigue or loss of energy. A headache is the most prevalent symptom. In contrast, HACE is a potentially fatal neurologic disorder that is characterized by altered consciousness or ataxia, or both. If left untreated, HACE can result in death after brain herniation. HACE is widely viewed as the end stage of AMS and usually is preceded by symptoms of AMS, which suggests that they result from a similar pathophysiologic process. Both syndromes are characterized by edematous brain swelling, and intracranial hypertension. The severity of AMS can be graded using the Lake Louise Questionnaire, Environmental Symptoms Questionnaire, or by the use of a simple analog scale.

The pathophysiology involves an interaction of multiple physiological responses to hypoxia (ventilation, cerebral vasculature, autonomic nervous system, and nociceptive thresholds), and anatomical factors such as the compensatory capacity for cerebrospinal fluid, and the size of venous outflow

High altitude pulmonary edema ( HAPE )

HAPE is non‐cardiogenic pulmonary edema. It is characterized by a cough, progressive dyspnea with exertion, and decreased exercise tolerance, generally developing within two to four days after arrival at high altitude. The HAPE is rare after one week of acclimatization at a particular height. Hypoxia is the trigger that results in a complex cascade of events leading to HAPE. Essentially, HAPE is due to a “persistent imbalance between the forces that drive water into the airspace and the biologic mechanisms for its removal”. The hallmark of this condition is hypoxic pulmonary hypertension, which may be mediated via at least three potential mechanisms: defective pulmonary nitric oxide synthesis; exaggerated endothelin‐1 synthesis; and excessive sympathetic activation. A defect in alveolar transepithelial sodium transport has also been suggested.


Epidemiology of acute high altitude illness ( HAI )

It has been estimated that 25% of people at moderate altitude are affected by acute mountain sickness (AMS), and 50% to 85% of travelers at 4000 meters or more. The incidence of high altitude cerebral edema and high altitude pulmonary edema is much lower than for AMS, with estimates in the range of 0.1% to 4.0%. Rapid ascent, poor acclimatization, physical exertion at altitude, young age, and history of prior altitude illness are major risk factors to develop HAI. Other risk factors are permanent residence lower than 900 meters; obesity; and coronary heart disease.



Description of the intervention

Interventions for treating HAI can be broadly classified as pharmacological and non‐pharmacological. Several statements and guidelines have been published in this area. Some of them have been issued by the Wilderness Medical Society; the Committee to Advise on Tropical Medicine and Travel statement (CATMAT); and the Centers for Disease Control and Prevention (CDC).


A) Non‐pharmacological interventions

  1. Descent
  2. Hyperbaric chamber
  3. Portable pressure bag or Gamow bag
  4. Breathing system designed to conserve oxygen supplies at high altitude
  5. Positive airway pressure and other therapies


B) Pharmacological interventions

  1. Oxygen
  2. Carbonic anhydrase inhibitors: acetazolamide
  3. Glucocorticosteroids: dexamethasone
  4. Non‐steroidal anti‐inflammatory drugs (NSAIDs): ibuprofen
  5. Selective 5‐hydroxytryptamine
  6. Inhaled nitric oxide.
  7. Anticonvulsant drugs: gabapentin
  8. Diuretics: furosemide
  9. Calcium channel blockers: nifedipine
  10. Non‐selective phosphodiesterase inhibitor (theophylline or aminophylline)
  11. Magnesium


How the intervention might work?


Both pharmacological and non‐pharmacological

Invasions are used to treat acute high altitude illness; however, immediate descent or evacuation to a lower altitude is lifesaving and the treatment of choice for patients with fully developed severe high altitude illness . Treatments other than descent are considered when descent is not possible due to bad weather, terrain or other logistical factors.

Some of the ways the pharmacological and non‐pharmacological treatments might work are as follows.


A) Acute mountain sickness (AMS) and high altitude cerebral edema ( HACE )

  1. Carbonic anhydrase inhibitors (acetazolamide, methazolamide) inhibit carbonic anhydrase in the kidneys, resulting in bicarbonaturia and metabolic acidosis. This results in hyperventilation to compensate through a respiratory alkalosis, and thus this drug causes improvements in ventilation to respond more fully to hypoxic stimuli at altitude. Acetazolamide can also cause pulmonary vasodilation unrelated to carbonic anhydrase inhibition.
  2. Steroids (dexamethasone and medroxyprogesterone): dexamethasone blocks hypoxia‐induced endothelial dysfunction; and medroxyprogesterone acts as a respiratory stimulant.
  3. Furosemide: this diuretic drug would reduce pulmonary extravascular fluid accumulation; however, diuretics have no role in high altitude pulmonary edema (HAPE) treatment particularly because many HAPE patients have concurrent intravascular volume depletion.
  4. Non‐steroidal anti‐inflammatory drugs (NSAIDs) (ibuprofen, paracetamol, aspirin): a prostaglandin‐mediated increase in cerebral microvascular permeability may contribute to the pathophysiology of AMS, and treatment with prostaglandin synthetase inhibitors may reduce this response.
  5. Selective 5‐hydroxytryptamine (1) receptor agonists (sumatriptan) are selective cerebral vasoconstrictors.
  6. Anticonvulsant drugs (gabapentin): Gabapentin is an anticonvulsant drug with analgesic properties.
  7. Hyperbaric therapy (chambers, manual air pump, fabric pressure bags or Gamow bags) simulate descent and gives symptomatic improvement within a few hours as a temporary measure while awaiting descent.


B) High altitude pulmonary edema ( HAPE )

  1. Calcium channel blockers (e.g., nifedipine) reduce pulmonary vascular resistance.
  2. Nitric oxide is an endothelium‐derived relaxing factor which attenuates the pulmonary vasoconstriction produced by hypoxia.
  3. Non‐selective phosphodiesterase inhibitor (theophylline or aminophylline): the antihypoxia and antioxidation effects of aminophylline may reduce periodic breathing, cerebral and pulmonary microvascular permeability. and also pulmonary artery pressure.
  4. Positive airway pressure and other therapies: breathing against a positive expiratory pressure improves arterial oxygen saturation .


Why it is essential to do HAI review

Conducting this systematic review for some reasons is necessary. First, many people travel to recreational areas located at high altitude, and with rapidly increasing levels of world travel, this trend is increasing. Second, there is considerable uncertainty about the actual effectiveness of the many approaches to treating acute, and their clinical efficacy and safety must be assessed. This is especially important, considering that travelers may be falsely reassured that they will be safe going to high altitudes, as believe they have an adequate remedy in their rucksacks in case they get ill.

A systematic review, including a rigorous assessment of the risk of bias, of the most up‐to‐date evidence will help clinicians make informed decisions on the use of non‐pharmacological and pharmacological interventions for treating acute HAI.


Types of studies

We included Randomized Controlled Trials (RCTs) irrespective discovery status (trials may be unpublished or published as an article, an abstract or a letter). We applied no language and no country limitation. We did not enforce restrictions concerning periods of follow‐up. We excluded studies about chronic mountain sickness or Monge’s syndrome. We excluded quasi‐randomized studies and prospective observational studies for evaluating clinical effectiveness.


Types of participants

We included trials involving people with high altitude Illness (acute mountain sickness/high altitude cerebral edema, or high altitude pulmonary edema, or both), with or without a history of high altitude Illness. We did not apply any restriction by age and gender.

Types of interventions

A) Non‐pharmacological interventions

  1. Descent
  2. Hyperbaric chamber
  3. Portable pressure bag or Gamow bag
  4. Breathing system designed to conserve oxygen supplies at high altitude
  5. Positive airway pressure

B) Pharmacological interventions

  1. Oxygen
  2. Carbonic anhydrase inhibitors (e.g., acetazolamide)
  3. Glucocorticosteroids: dexamethasone and medroxyprogesterone
  4. Non‐steroidal anti‐inflammatory drugs (NSAIDs) and paracetamol: ibuprofen, aspirin, and paracetamol
  5. Selective 5‐hydroxytryptamine (1) receptor agonist: sumatriptan
  6. Inhaled nitric oxide
  7. Anticonvulsant drugs (e.g., gabapentin)
  8. Diuretics (e.g. furosemide)
  9. Calcium channel blockers: nifedipine
  10. Magnesium



Types of outcome measures

Primary outcomes

  1. All‐cause mortality: we assessed this outcome through three approaches.
  2. The number of deaths from any cause divided by the number of participants in each group.
  3. To determine how many deaths were caused by HAPE or HACE: the number of deaths from high altitude pulmonary edema (HAPE) or high altitude cerebral edema (HACE) divided by the number of participants in each group.
  4. To determine how lethal HAPE or HACE were: the number of deaths by HAPE or HACE divided by the number of participants affected by HAPE or HACE in each group.
  5. Complete relief of acute mountain sickness symptoms: defined as the complete absence of severe mountain sickness symptoms by the end of the study.

Secondary outcomes:

Reduction in illness severity scores of acute mountain syndrome (headache, nausea, insomnia, and dizziness; alone or in any combination) evaluated by the Lake Louise Questionnaire, Environmental Symptoms Questionnaire, or any other validated scale. Because these different scales are not directly comparable, we analyzed the results for each range separately.


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