High-altitude illness

What is high-altitude illness?^{1 2}

At higher altitudes, the inspired partial pressure of oxygen is reduced. Given time, humans are able to acclimatise to increasing altitude by:

• Increasing ventilation (via carotid body hypoxic ventilatory response).

• Haemoconcentration:

  • Short term: by reduction of plasma volume by diuresis, through suppression of antidiuretic hormone (ADH) and aldosterone.

  • Longer term: by increasing red blood cell production (via erythropoietin).

• Increasing tissue perfusion by increasing cardiac output.

At any point 1-5 days following ascent to altitudes of 2500 metres or more, individuals are at risk of developing one of three forms of acute altitude illness:

• Acute mountain sickness (AMS): a syndrome of nonspecific symptoms including headache, lassitude, dizziness and nausea.

• High-altitude cerebral oedema (HAPE or HAPO): a potentially fatal illness characterised by ataxia, decreased consciousness and characteristic changes on MRI.

• High-altitude pulmonary oedema (HACE or HACO): a non-cardiogenic form of pulmonary oedema resulting from excessive hypoxic pulmonary vasoconstriction which can be fatal if not recognised and treated promptly.

Medical problems are caused by hypobaric hypoxia stimulating hypoxia-inducible factor (HIF) release. As a result, impairment of the central nervous system, circulation and respiratory system occurs.

• AMS: consists of a number of nonspecific symptoms, including headache, loss of appetite, and nausea. If not treated, may lead to potentially life-threatening high altitude pulmonary oedema and high-altitude cerebral oedema.

• More severe forms include HACE and HAPE: these may lead to coma and death if left untreated.

• AMS and HACE are caused by hypoxia-induced changes in the blood-brain barrier, leading to cerebral oedema and brain swelling.

• In HAPE, hypoxic pulmonary arteriolar vasoconstriction leads to increased vascular permeability, probably due to patchy flow and sheer stress forces on capillary walls.

• AMS usually precedes development of HACE, whereas HAPE develops during the first 2-4 days at high altitude and is not always preceded by AMS.

People at increased risk of high-altitude illness include those with cardiac or pulmonary disease. It is possible for patients with stable coronary heart disease, hypertension or asthma to attain high altitudes; however, patients with chronic obstructive pulmonary disease, interstitial pulmonary disease or pulmonary hypertension are at greater risk and may need to avoid high altitude or use supplementary oxygen.³ Those with heart failure, severe anaemia and sickle cell disease are also best advised to avoid high altitude.⁴

Risk factors⁴

• Rapid ascent.

• Climbing to higher altitudes, starting ascent at higher altitudes and sleeping at higher altitudes.

• Continued ascent with symptoms of AMS is a risk factor for HACE.

• Individual susceptibility and history of high-altitude sickness. (Not invariable, however - even Sir Edmund Hillary developed altitude sickness on a subsequent visit to Nepal many years after successfully climbing Mt Everest.)

• Physical exertion at high altitudes.

• Permanent residence at low altitudes (below 900 metres).

• Latitude. (Higher risk at same altitude with increasing distance from equator due to reduced barometric pressure and PO₂.)

• High-altitude dwellers returning from a brief period at low altitude. This is race-dependent - rarely occurs, for example, in Sherpas and Tibetans, who have adapted to high altitude dwelling.^{5 6}

• Early hypoxaemia (as measured with a pulse oximeter).

• Age less than 50 years.

• Neck irradiation or surgery.

• Upper respiratory tract infections or bronchitis.

• Exertion, low temperatures and cardiopulmonary circulation abnormalities are predisposing factors for HAPE.

Acute mountain sickness

• Typically, occurs at altitudes greater than 2500 metres.

• The incidence of AMS increases with absolute height attained and with the rate of ascent. It has been described as affecting from 25% to up to 85% of travellers to high altitude, depending on location and rate of ascent.⁷

• It is not related to the level of physical fitness, other than potentially those who are more physically fit may unwisely ascend at a more rapid rate.

• Symptoms may take days to develop or may occur within hours, depending on the rate of ascent and the altitude attained:
  

  • Initial symptoms have been described as similar to a hangover, with headache the cardinal symptom, associated with fatigue, appetite loss and nausea or vomiting.

  • Irritability, insomnia, and dizziness may also occur.

  • Visual disturbances may be experienced at higher altitudes.

• May be self-limiting but can progress to peripheral oedema, retinal haemorrhages, dyspnoea at rest, altered consciousness and ataxia, and cerebral and pulmonary oedema.

• The Lake Louise AMS score can be used for assessing the severity of AMS. A score of 3 or greater should be considered to be AMS.⁸

High-altitude cerebral oedema

• Incidence is around 1-2% in those who ascend rapidly to 4500 metres.⁹

• Usually it occurs 2-4 days after ascent and presents with features of moderate to severe AMS but also:

  • Hallucinations, disorientation, confusion, ataxia, drowsiness and decreasing level of consciousness.

  • Seizures, blurred speech and double vision are less common.

  • Focal and nonfocal manifestations of raised intracranial pressure (severe headache, papilloedema, vomiting, IIIrd or VIth cranial nerve palsies), retinal haemorrhages and focal neurological deficits - eg, cranial nerve palsy.

• It may progress rapidly to coma and death if untreated. Death can occur within 24 hours of developing ataxia if immediate descent does not occur.¹⁰

• It is usually associated with HAPE.

High-altitude pulmonary oedema

• The incidence of HAPE at 2500 metres is around 0.01% but it rises to 1.9% at 3600 metres and 2.5-5.0% at 4300 metres.¹¹

• Risk factors for HAPE include the rate of ascent, intensity of exercise and the absolute altitude. It has been recognised that some individuals are more susceptible.

• Usually it occurs 2-4 days after ascent:
  

  • Symptoms and signs are typical of pulmonary oedema, including dyspnoea at rest, cough (initially dry from interstitial oedema and then productive of frothy sputum which may be bloodstained in later stages), chest tightness, poor exercise tolerance and eventually cyanosis.

  • Pulmonary crepitations are found in at least one lung field, along with central cyanosis, tachycardia, and tachypnoea.

  • Other signs include mild fever, and orthopnoea.

• HAPE can occur with or without AMS or HACE and can lead to death. It is the leading cause of death related to altitude illness.⁷

Investigations

These may be limited in mountain environments but where facilities exist, the following may be helpful:

• Pulse oximetry reflects expected hypoxia at altitude - helpful in HAPE but doesn't correlate well with severity of AMS or HACE. There is much in the literature about the possible value of baseline pulse oximetry in predicting AMS.¹²

• Arterial blood gases and CXR (unilateral or bilateral fluffy infiltrates) in HAPE.

• CT/MRI scan in HACE to rule out cerebrovascular accident/transient ischaemic attack (TIA).

Differential diagnosis¹⁰

• Dehydration.

• Exhaustion.

• Hypoglycaemia.

• Hyponatraemia.

• Anxiety.

• Hypothermia.

• Other causes of respiratory distress - eg, pneumonia.

• Other causes of central neurological dysfunction - eg, brain tumour, TIA, stroke.

High-altitude illness treatment and management^{1 10 13}

The most important factor in treatment is acclimatisation, avoiding any further ascent and rest or beginning descent. Oxygen supplementation, and pharmacological intervention, and, if available, a portable hyperbaric chamber are important. Some time can be bought with the use of oxygen or hyperbaric bags but they should not delay descent when it is at all possible.

A Cochrane review concluded that there is limited available evidence to determine the effects of non-pharmacological and pharmacological interventions in treating acute high altitude illness. Low-quality evidence suggests that dexamethasone and acetazolamide might reduce AMS score compared to placebo. However, the clinical benefits and harms related to these potential interventions remain unclear. Overall, the evidence is of limited practical significance in the clinical field.¹⁴

Because of the popularity of high-mountain sports and tourism, better education is essential.

Symptom control

• Analgesics and antiemetics.

• Ibuprofen, which is more effective than aspirin for relieving high-altitude headache.

Mild AMS

• Rest and avoiding further ascent until symptoms improve.

Moderate to severe cases of AMS

• Descent is required if symptoms are not improving or are getting worse with rest at the same altitude.

• Supplementary oxygen therapy.

• Acetazolamide (250 mg bd) and/or dexamethasone (8 mg stat then 4 mg qds), especially if descent is not possible. (Acetazolamide is more effective for prophylaxis than for treatment - dexamethasone may be the effective option when it comes to treatment.)

HACE

• Descent with supplementary oxygen. Descent should be immediate, even at night if possible, as it may be life-saving.

• Dexamethasone to relieve symptoms and aid descent, or in situations where descent is not possible.

• Hyperbaric therapy (in portable hyperbaric chambers such as the Gamow Bag®) can improve symptoms sufficiently to aid actual descent - eg, bring an individual out of a coma or improve ataxia; it can be life-saving when descent is not possible and oxygen is unavailable.

• If symptoms persist after descent, treatment with oxygen and dexamethasone should be continued.

HAPE

• Descent with supplementary oxygen if available; descent of even a few hundred metres may be enough.

• Nifedipine (30 mg bd of a slow-release product) can relieve symptoms and aid descent; or can be used in situations where descent is not possible.

• Phosphodiesterase inhibitors (sildenafil and tadalafil) have been used with success. There are no systematic reviews of their use for this indication.

• Hyperbaric therapy can be useful to aid descent or in situations where descent is impossible or oxygen is unavailable.

• If there are persistent symptoms after descent then the patient may require continued treatment with oxygen and nifedipine.

Prevention of high-altitude illness¹³

Prevention of altitude-related illness by slow ascent is the best approach but this is not always practical.

General advice¹⁰

• Gradual ascent allowing time for acclimatisation. A typical rate of ascent would be 500 metres (1,600 feet) per day with a rest day for every 1000 m (3,300 feet) ascent. Avoid going directly (eg, flying or driving) from low altitude to more than 2750 m (9,000 feet) if possible.

• Keep warm and well hydrated.

• Avoid alcohol, particularly in the first 48 hours.

• Mild exercise only for the first 48 hours.

• Visitors to altitude can monitor themselves for AMS using the Lake Louise AMS score.⁸

• Anyone who develops symptoms should not ascend further until the symptoms have settled. If they are getting worse then immediate descent is recommended.

Medication

• Prophylactic treatment with acetazolamide has been shown to be effective in reducing the symptoms of AMS. A systematic review in the BMJ showed that the lowest effective dose was 250 mg daily (usually given as 125 mg bd) and the number needed to treat to prevent AMS was six.¹⁵ The most common adverse effect of acetazolamide is paraesthesia; at this lower dose it is more likely to be tolerated.¹⁶

• Dexamethasone has evidence of benefit and the recommended adult doses are 2 mg every six hours or 4 mg every twelve hours. It should not be used for more than ten days to avoid adrenal suppression.

• There is no robust evidence that ginkgo biloba extract is effective in preventing AMS.

• Ibuprofen has been studied and found in some trials to be effective in preventing AMS at a dose of 600 mg tds compared to placebo.¹⁷ It has not yet been compared to acetazolamide.

• Nifedipine can be used prophylactically (30 mg bd of a slow-release preparation) for individuals with high risk or a previous history of HAPE.

• Tadalafil has been studied as a possible preventative treatment for HAPE in high-risk individuals but further studies are needed before it can be recommended.

Other high-altitude conditions⁷

• Peripheral oedema.

• High-altitude retinopathy.

• High-altitude pharyngitis and bronchitis.

• Chronic mountain sickness: polycythaemia which can develop after long periods of time at high altitude.

• Ultraviolet keratitis (snow blindness). This is corneal damage from ultraviolet radiation, causing foreign-body sensation, irritation, pain, photophobia, tearing, blepharospasm and decreased visual acuity 6-12 hours after the exposure. Prognosis is usually excellent with full recovery in 24-76 hours.

High-altitude and type 1 diabetes mellitus⁷

• Studies have not shown any difference in occurrence rates of AMS, HACE or HAPE between normal subjects and those with type 1 diabetes at altitudes ranging from 1,700 to 5,800 metres.

• Those with pre-existing diabetic retinopathy may be at higher risk for high-altitude retinal haemorrhage (HARH) and/or disease progression and it is recommended that such individuals have a dilated pupil ophthalmological examination and/or fluorescein angiogram before considering any trip involving exposure to high altitude.¹⁸

• People with diabetes should have close glucose monitoring and rapid access to a glucagon kit (and to ensure that at least one of their travelling companions can locate and knows how to use the kit in the case of an emergency). Altitude illness can trigger diabetic ketoacidosis. Those with diabetes should be aware of difficulties in managing complications of diabetes in remote situations.

• Both overestimation and underestimation of glycaemia and of standard glucose control solutions have been demonstrated at altitude. Glucometers may not function properly either due to cold or altitude and travellers with diabetes should be aware of this potential and alert to symptoms.

• Prolonged travel at high altitude is associated with significant anorexia and loss of body weight. Insulin injections should be carefully timed and titrated to ensure that they match actual nutrient ingestion.

• Average temperatures decrease by 2°C for every 300 metres of elevation, so temperatures at freezing point can be expected at >3,000 metres. Insulin should not be exposed to temperatures that are <2°C because of potential loss of bioactivity. Therefore, adequate protection of insulin from extremes of temperature, including carrying supplies next to the skin, are essential.¹⁸