202005231112Interventions for treating acute high altitude illness Cochrane


Cochrane Database Syst Rev. 2018 Jun; 2018(6): CD009567. Published online 2018 Jun 30. 
Acute high altitude illness is defined as a group of cerebral and pulmonary syndromes that can occur during travel to high altitudes. It is more common above 2500 metres, but can be seen at lower elevations, especially in susceptible people. Acute high altitude illness includes a wide spectrum of syndromes defined under the terms 'acute mountain sickness' (AMS), 'high altitude cerebral oedema' and 'high altitude pulmonary oedema'. There are several interventions available to treat this condition, both pharmacological and non‐pharmacological; however, there is a great uncertainty regarding their benefits and harms.

To assess the clinical effectiveness, and safety of interventions (non‐pharmacological and pharmacological), as monotherapy or in any combination, for treating acute high altitude illness.

Search methods
We searched CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science, CINAHL, Wanfang database and the World Health Organization International Clinical Trials Registry Platform for ongoing studies on 10 August 2017. We did not apply any language restriction.

Selection criteria
We included randomized controlled trials evaluating the effects of pharmacological and non‐pharmacological interventions for individuals suffering from acute high altitude illness: acute mountain sickness, high altitude pulmonary oedema or high altitude cerebral oedema.

Data collection and analysis
Two review authors independently assessed the eligibility of study reports, the risk of bias for each and performed the data extraction. We resolved disagreements through discussion with a third author. We assessed the quality of evidence with GRADE.
Main results
We included 13 studies enrolling a total of 468 participants. We identified two ongoing studies. All studies included adults, and two studies included both teenagers and adults. The 13 studies took place in high altitude areas, mostly in the European Alps. Twelve studies included participants with acute mountain sickness, and one study included participants with high altitude pulmonary oedema. Follow‐up was usually less than one day. We downgraded the quality of the evidence in most cases due to risk of bias and imprecision. We report results for the main comparisons as follows.
Non‐pharmacological interventions (3 studies, 124 participants)

All‐cause mortality and complete relief of AMS symptoms were not reported in the three included trials. One study in 64 participants found that a simulated descent of 193 millibars versus 20 millibars may reduce the average of symptoms to 2.5 vs 3.1 units after 12 hours of treatment (clinical score ranged from 0 to 11 ‒ worse; reduction of 0.6 points on average with the intervention; low quality of evidence). In addition, no complications were found with use of hyperbaric chambers versus supplementary oxygen (one study; 29 participants; low‐quality evidence).
Pharmacological interventions (11 trials, 375 participants)
All‐cause mortality was not reported in the 11 included trials. One trial found a greater proportion of participants with complete relief of AMS symptoms after 12 and 16 hours when dexamethasone was administered in comparison with placebo (47.1% versus 0%, respectively; one study; 35 participants; low quality of evidence). Likewise, when acetazolamide was compared with placebo, the effects on symptom severity was uncertain (standardized mean difference (SMD) −1.15, 95% CI −2.56 to 0.27; 2 studies, 25 participants; low‐quality evidence). One trial of dexamethasone in comparison with placebo in 35 participants found a reduction in symptom severity (difference on change in the AMS score: 3.7 units reported by authors; moderate quality of evidence). The effects from two additional trials comparing gabapentin with placebo and magnesium with placebo on symptom severity at the end of treatment were uncertain. For gabapentin versus placebo: mean visual analogue scale (VAS) score of 2.92 versus 4.75, respectively; 24 participants; low quality of evidence. For magnesium versus placebo: mean scores of 9 and 10.3 units, respectively; 25 participants; low quality of evidence). The trials did not find adverse events from either treatment (low quality of evidence). One trial comparing magnesium sulphate versus placebo found that flushing was a frequent event in the magnesium sulphate arm (percentage of flushing: 75% versus 7.7%, respectively; one study; 25 participants; low quality of evidence).

Authors' conclusions
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. High‐quality research in this field is needed, since most trials were poorly conducted and reported.
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 the purposes of this review, high altitude illness (HAI) is defined as a group of cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (Luks 2014). This includes syndromes covered by the terms 'acute mountain sickness' (AMS), 'high altitude cerebral oedema' (HACE),and 'high altitude pulmonary oedema' (HAPE). The risk categories for acute mountain sickness are shown in Appendix 1 (Luks 2010; Luks 2014). HAI is considered as an important cause of mountain mortality (Windsor 2009).

Other medical problems that may be encountered at high altitudes include acute hypoxia, cerebrovascular syndromes, peripheral oedema, 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 2007; Palmer 2010; Schoene 2008); however these will not be considered in this review.

Acute mountain sickness (AMS) and high altitude cerebral oedema (HACE)
AMS is a neurological disorder characterized by headache, anorexia, nausea and sometimes vomiting, light‐headedness, insomnia, and fatigue or loss of energy (Palmer 2010). Headache is the most prevalent symptom (Luks 2017). In contrast, HACE is a potentially fatal neurologic disorder that is characterized by altered consciousness or ataxia (Imray 2010), or both. If left untreated, HACE can result in death subsequent to brain herniation (Bailey 2009). HACE is widely viewed as the end stage of AMS, and is normally preceded by symptoms of AMS (Basnyat 2003), which suggests that they result from a similar pathophysiologic process (Palmer 2010). Both syndromes are characterized by oedematous brain swelling, and intracranial hypertension (Luks 2017). The severity of AMS can be graded using the Lake Louise Questionnaire, Environmental Symptoms Questionnaire, or by the use of a simple analogue scale (Imray 2010).

The pathophysiology apparently 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 capacity of venous outflow (Luks 2017).

High altitude pulmonary oedema (HAPE)
HAPE is a non‐cardiogenic pulmonary oedema (Smedley 2013). It is characterized by cough, progressive dyspnoea with exertion, and decreased exercise tolerance, generally developing within two to four days after arrival at high altitude (Hall 2011). HAPE is rare after one week of acclimatization at a particular altitude (Maggiorini 2010; Palmer 2010). Hypoxia is the trigger that results in a complex cascade of events leading to HAPE (Stream 2008). Essentially, HAPE is due to a "persistent imbalance between the forces that drive water into the airspace and the biologic mechanisms for its removal" (Scherrer 2010). 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 exaggerated sympathetic activation (Scherrer 2010). A defect in alveolar transepithelial sodium transport has also been suggested (Scherrer 2010). An extensive review of pulmonary hypertension induced by high altitude is reported by Pasha 2010.

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 travellers at 4000 meters or more (Eide 2012). The incidence of high altitude cerebral oedema and high altitude pulmonary oedema is much lower than for AMS, with estimates in the range of 0.1% to 4.0% (Luks 2010). Rapid ascent, poor acclimatization, physical exertion at altitude, young age, and history of prior altitude illness are major risk factors to develop HAI (Eide 2012). Other risk factors are permanent residence lower than 900 metres; obesity (Ri‐Li 2003); and coronary heart disease (Dehnert 2010).

(See Appendix 2 for a glossary of medical terms.)