Table 1. American College of Chest Physicians (ACCP) classification scheme for grading evidence and recommendations in clinical guidelinesGrade Description Benefits vs risks and burdens Methodological quality of

supporting evidence

1A Strong recommendation, high-quality evidence

Benefits clearly outweigh risks and burdens or vice versa

RCTs without important limitations or overwhelming evidence from observational studies

1B Strong recommendation, moderate-quality evidence

Benefits clearly outweigh risks and burdens or vice versa

RCTs with important limitations or exceptionally strong evidence from observational studies

1C Strong recommendation, low-quality or very low quality evidence

Benefits clearly outweigh risks and burdens or vice versa

Observational studies or case series

2A Weak recommendation, high-quality evidence

Benefits closely balanced with risks and burdens

RCTs without important limitations or overwhelming evidence from observational studies

2B Weak recommendation, moderate-quality evidence

Benefits closely balanced with risks and burdens

RCTs with important limitations or exceptionally strong evidence from observational studies

2C Weak recommendation, low-quality or very low quality evidence

Uncertainty in the estimates of benefits, risks and burden; benefits, risk and burden may be closely balanced

Observational studies or case series

RCT, randomized controlled trial.Source: Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines; report from an American College of Chest Physicians task force. Chest. 2006;129:174–181.

Supplementary Evidence Table 2. AMS/HACE Prevention Studies (listed in alphabetical order by first author)

Reference

Setup Intervention Outcomes Overall assessment of quality

Setting/ Study design

Eligibility criteria

Interventions

Primary outcome measure

Sample size

Numbers Effect size (primary outcomes)

Basnyat et al. Aceta-zolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol 2006. 1

Prospective double-blind randomized controlled trial of trekkers ascending between 3440 m and 4928 m. (Khumbu Valley, Nepal)

Healthy non-Nepali subjects 18-65 years old, with no acute infection, history of cardiac, pulmonary or other chronic diseases; and who had not slept above 2700 m or taken acetazolamide in previous 2 weeks.

Subjects randomized to receive acetazolamide 125 mg BID (low dose), acetazolamide 375 mg BID (high dose) or placebo.

Composite incidence and severity of AMS measured by Lake Louise Score(AMS defined as LLS≥3 including headache and at least one other symptom). Composite results reflect patients reporting AMS at either the midpoint or endpoint assessments.

222 subjects enrolled; 204 subjects (88%) completed the study protocol.

Low dose: 74 subjects; High dose: 82 subjects; placebo: 66 subjects.

Composite incidence of AMS 24% in low dose group vs. and 21% in high dose group and 51% in placebo group. No significant difference between the low and high dose groups regarding AMS scores but the high dose group had more parasthesias than the low-dose group.

A randomized trial showing that low dose acetazolamide is as effective as higher doses with fewer side effects. Groups are well matched and those lost to follow-up had similar demographics to study subjects. The study is limited by recruitment of subjects at 3440 m and loss of those who might develop AMS below that elevation.

Beidlema Prospecti Healthy Over 30 AMS-C 11 11 Statistical Rigorous

n BA et al. Effect of six days of staging on physiologic adjustments and acute mountain sickness during ascent to 4300 m. High Alt Med Biol 2009. 2

ve, unblinded, non-randomized cross-over study examiningAMS-C scores and physiologic parameters following acute exposure to 4300 m in a hypobaric chamber and following ascent to terrestrial 4300 m after 6 days of staging at 2200 m. (Pikes Peak, Colorado)

lowland residents without exposure to >1500 m for at least 2 months.

days following assessments in the hypobaric chamber (acute ascent), subjects spent 6 days at terrestrial 2200 m before ascending to terrestrial 4300 m (staged ascent). Two hour submaximal bicycle ergometry performed after resting assessments completed in the hypobaric chamber and at terrestrial high altitude.

scores, resting end-tidal CO2, arterial blood gases, oxygen saturation, heart rate and mean arterial pressure.

subjects subjects completed the study protocol.

ly significant decrease in AMS scores at 4300 m following staged ascent compared to acute ascent in a hypobaric chamber (p<0.005). End-tidal and arterial CO2 were lower and oxygen saturation was higher at 4300 m following staged ascent than with acute ascent. Resting heart rate and mean arterial pressure did not change in any of the test conditions.

study with careful control of experimental conditions. Aided by the fact that subjects served as their own controls. Questions remain about the feasibility of this strategy for AMS prevention for many high altitude sojourners.

Bloch KE et al. Effect of ascent protocol on acute mountain sickness and success on Muztagh

Prospective, randomized controlled trial examining the effect of ascent rate on acute

Healthy individuals with prior mountaineering exper-ience. Excluded individuals with cardiac or respiratory disease,

Subjects randomized to ascent protocols calling for reaching the summit after 15 (fast) or

AMS-C scores assessed at 5533 m, 6265 m, 6865 m and 7546 m, and number of proceedi

34 climbers

Slow ascent: 16 climbers; Fast ascent: 18 climbers.

Higher AMS scores in “fast” ascent group at each evaluation point (P<0.008). Climbers in the

This is the only randomized study examining the effect of ascent rate on AMS incidence. The

Ata, 7546 m. High Alt Med Biol 2004. 3

mountain sickness score during an expedition to 7546 m .(Muztagh Ata, China)

regular use of any medications or prior history of severe AMS below 3500 m, HAPE or HACE

19 (slow) days of climbing.

ng climbers.

slow ascent group were able to ascend according to protocol without AMS for more days and were more successful at reaching the highest camp at 6865 m without AMS than climbers in the fast ascent group.

groups were well matched, but bad weather interfered with pre-defined ascent protocols such that mean ascent rates to the summit were similar for the two groups. The authors accounted for the ascent protocols in their analysis.

Chow et al. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial Arch Intern Med 2005. 4

Prospective double-blind randomized controlled trial comparing Ginkgo biloba and acetazolamide in the prevention of AMS with ascent from sea level to 3800 m. (White Mountains,

Unacclimatized adult volunteers (18-65 years old) whose primary residence was ≤1200 m. Exclusions included travel to >2400 m within 30 days, contraindications to high altitude exposure, pre-existing use of ginkgo biloba or acetazola-

Subjects randomized to Ginkgo 120 mg po BID, acetazolamide 250 mg po BID or placebo BID starting 5 days before ascent. The acetazolamide group received placebo for the 1st

4 days.

Lake Louise AMS scores and incidence of AMS (diagnosis required headache plus at least one other symptom and total score ≥3).

70 subjects2 excluded for residence above 1200 m;10 withdrew before ascent; 1 withdrew after ascent.

Ginkgo: 17 subjects; Acetazolamide: 20 subjects; Placebo: 20 subjects.

Median LLS score lower in acetazolamide group than placebo group but not in Ginkgo group. AMS occurred less frequently in the acetazolamide group (30%) than in the placebo group (65%)

Randomized controlled design. The study was underpowered to find 50% relative reduction in incidence of AMS, but median AMS scores were significantly different between acetazolamide and placebo

California)

mide. whereas there was no difference between Ginkgo group (60%) and the placebo group.

and essentially the same for Ginkgo compared to placebo. A useful strategy in this study in that Ginkgo used by subjects was obtained as most high altitude travelers would obtain it, by purchasing from a chain supplement store.

Ellsworth et al. A randomized trial of dexamethasone and acetazolamide for acute mountain sickness prophylaxis Am J Med 1987. 5

Prospective double-blind randomized trial of acetazolamide and dexamethasone in the prevention of AMS in climbers ascending to 4392 m . (Mt. Rainier, Washington)

Healthy volunteer who resided at or near sea level and who lacked history of peptic ulcer … or psychi-atric disease.

Subjects randomized to receive acetazolamide 250 mg po, dexamethasone 4 mg po or placebo every 8 hours beginning 24 hours before ascent.

Combined abbreviated version of ESQ and a “General High-Altitude Questionnaire modified post-hoc to exclude confounding symptoms (primarily nausea caused by acetazola

47 climbers

Acetazolamide: 15 subjectsDexametha-sone: 17 subjectsPlacebo: 15 subjects.

At summit or high point achieved, dexamethasone group had less headache and several other symptoms than placebo (p<0.05). Acetazolamide patients had nausea and fatigue at lower elevations

Small study with well matched groups. 9 subjects, 6 of whom were taking dexamethasone spent an extra day at 3000 m, which may have affected acclimatization. AMS measure was modified post hoc.

mide prior to ascent).

(1300-1600 m) that likely obscured prophylactic effects. With exclusion of subjects with acetazolamide side effects at low elevations, acetazolamide had similar magnitude benefit on symptoms as dexamethasone.

Although the study was blinded 57% of acetazolamide group, 24% of dexamethasone group and 64% of placebo group guessed study drug correctly.

Ellsworth et al. Aceta- zolamide or dexamethasone use versus placebo to prevent acute mountain sickness on Mount Rainier West J Med 1991.6

Prospective randomized, double-blind, placebo-controlled crossover trial examining role of dexamethasone and acetazolamide in prevention of AMS in climbers making two ascents to 4392 m. (Mt. Rainier, Washingt

Climbers making separate ascents to 4392 m at least two weeks apart. Subjects normally resided at sea level, had no exposure to high altitude within 3 weeks of study, were free of cardiorespiratory disease, diabetes, sulfa allergy, peptic ulcer disease or

Subjects randomized to receive acetazolamide 250 mg po, dexamethasone 4 mg po or placebo every 8 hours on 2 separate ascents of Mt. Rainier starting 24 hours before ascent and continuing until descent. Each climber

AMS-C (cerebral) and AMS-R (respiratory) scores from the Environmental Symptoms Questionnaire.

18 climbers

Acetazolamide: 8 subjectsDexamethasone: 10 subjectsEach climber received placebo on their other climb.

AMS-C and AMS-R scores and incidence of AMS while taking dexamethasone were significantly lower than for acetazolamide (p=0.025) and placebo (p=0.025). 8 of 10 subjects in dexamethasone group preferred

Small study but subjects served as their own controls with the groups well matched for age, gender, previous ascents of Mt. Rainier and past history of AMS. Unclear why acetazolamide lacked benefit in this study compared to earlier

on) psych-iatric illness.

received placebo on 1 ascent and one of the study drugs on the other ascent. Order of drug versus placebo was random.

the drug climb to the placebo climb compared to only three of eight subjects in the acetazolamide group.

study by this group on Mt. Rainier but may reflect small sample size, large standard deviations of AMS scores, and the fact that acetazolamide side effects are similar to symptoms of AMS.

Forwand et al. Effect of acetazolamide on acute mountain sickness N Engl J Med 1968. 7

Prospective double-blind randomized controlled trial of acetazolamide in the prevention of AMS in subjects transported rapidly from sea level to 3900 m.

Healthy male soldiers without recent disease or history of serious pul-monary disease.

Subjects randomized to receive acetazolamide 250 mg po TID or placebo for 32 hours before and 40 hours after rapid transport to 3900 m.

Symptoms as assessed by 2 questionnaires and physicians’ daily histories; arterial blood gases.

43 male subjects

Aceta-zolamide: 21 subjects; Placebo: 22 subjects.

Headache frequency and severity were less in the acetazolamide group on days 1-5 at 3900 m. Upper-gastrointestinal tract symptoms and insomnia were less in the acetazolamide group on days 1-3 and 2-3 respectively. Acetazolamide treated patients had greater

One of the earliest randomized trials on this issue. Group demographics are not documented, but are likely well matched in the two groups. Study population is narrow and limits generalizability of the results but subsequent studies in broader populations have shown

increase in ventilation and alveolar oxygen tension and greater decrease in carbon dioxide and bicarbonate than controls.

similar benefit.

Gertsch et al. Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT) BMJ 2004. 8

Prospective double-blind randomized, placebo controlled trial examining use of Ginkgo biloba and acetazolamide for prevention of AMS in trekkers during ascent between 4280 or 4358 m and 4928 m. (Khumbu Valley, Nepal)

Healthy non-Nepali trekkers 18-65 yrs of age. Excluded if they had known cardiac, pulmonary or other chronic disease, AMS, significant active infection or had slept above 4500 m or used Ginkgo biloba or acetazolamide in prior two weeks.

Subjects randomized to receive Ginkgo biloba 120 mg po, acetazolamide 250 mg po, ginkgo biloba 120 mg po + acetazolamide 250 mg po or placebo twice daily.

Incidence and severity of AMS (defined as Lake Louise Score ≥3 with headache and at least 1 other symptom).

614 trekkers enrolled. 487 completed the study.

Ginkgo biloba: 124 subjects; acet-azolamide: 118 subjects; aceta-zolamide + ginkgo biloba: 126 subjects; placebo: 119 subjects.

In intention to treat analysis, incidence of AMS was 34% in placebo group, 12% in acetazolamide group (OR compared to placebo 3.76), 35% in Ginkgo biloba group (OR 0.95, P=NS) and 14% in acetazolamide + Ginkgo biloba group (OR 3.04).Incidence of severe AMS (LLS ≥ 5) significantly lower than

Very large trial but 21% of enrolled participants broke protocol or were lost to follow-up. Groups, including the group that did not complete the study, were similar in age, sex and ascent profiles. Adequately powered to detect statistically significant difference between groups at expected incidence of AMS.

placebo in acetazolamide and acetazolamide + Ginkgo biloba groups but not lower than placebo in the ginkgo biloba group.

The study is limited by recruitment of subjects at 4280 or 4358 m and loss of those who might develop AMS below those elevations.

Gertsch et al. Prospective, double-blind, randomized, placebo-controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: the Headache Evaluation at Altitude Trial (HEAT) Wilderness Environ Med 2010. 9

Prospective, double-blind, randomized placebo controlled trial comparing use of ibuprofen and acetazolamide for prevention of high altitude headache and AMS in trekkers ascending between 4280 or 4358 m and 4928 m. (Khumbu Valley, Nepal)

Healthy non-Nepali trekkers 18-65 yrs of age. Excluded if they had any headache, diagnosis of AMS or significant acute infection, had slept > 4500 m or taken NSAIDs or acetazolamide in prior 3 days.

Subjects randomized to receive acetazolamide 85 mg po, ibuprofen 600 mg po or placebo three times daily. Subjects took three doses at baseline before resuming trek.

Incidence of headache assessed by Lake Louise Questionnaire; headache severity assessed by visual analog scale; incidence of AMS.

343 subjects recruited; 265 subjects provided data at endpoint of study. 48 participants deviated from study protocol and were excluded from intent to treat analysis.

Intent to treat analysis: acetazolamide: 97 subjects; ibuprofen: 103 subjectsPlacebo: 65 subjects.

No difference in incidence of headache between ibuprofen and acetazolamide (27.5 % vs. 27.1%); Headache incidence lower in both groups than in placebo; Headache severity no different between ibuprofen, acetazolamide and placebo groups. No difference in incidence of AMS between

Large trial with groups well matched for age, sex. Study had a large incidence of protocol violations and authors had to rely on intent to treat analysis. The study is limited by recruitment of subjects at 4280 or 4358 m and loss of those who might develop AMS below those elevations

ibuprofen and acetazolamide (13.7% vs. 18.8%, p=NS).

or those who might have used ibuprofen at lower elevations.

Gertsch et al. Altitude Sickness in Climbers and Efficacy of NSAIDs Trial (ASCENT): randomized, controlled trial of ibuprofen versus placebo for prevention of altitude illness Wilderness Environ Med 2012. 10

Prospective, double-blind, randomized placebo controlled trial examining use of ibuprofen for prevention of AMS in trekkers ascending between 4280 or 4358 m and 4928 m. (Khumbu Valley, Nepal)

Healthy, non-Nepali trekkers 18-65 yrs of age. Excluded if they had known AMS, significant active infection or had slept above 4500 m or used ibuprofen or acetazolamide in prior 3 days.

Subjects randomized to receive ibuprofen 600 mg po TID or placebo. Subjects took three doses at baseline before resuming trek.

Incidence and severity of AMS (defined as Lake Louise Score ≥3 with headache and at least 1 other symptom).

295 subjects recruited; 183 completed the study. 62 lost to follow-up and 49 broke trial protocol. 232 participants included in intent to treat analysis.

For intent to treat analysis: Ibuprofen: 123 subjects Placebo: 109 subjects.

For analysis excluding those who broke protocol: Ibuprofen: 110 subjectsPlacebo: 73 subjects.

In intent to treat analysis; incidence of AMS less with ibuprofen than with placebo (24% vs. 40% p=0.01).

In analysis of participants who completed the study, incidence of AMS was not significantly different between ibuprofen and placebo (17% vs. 25% p=0.13) .

Participants who broke protocol had higher incidence of AMS than fully compliant subjects.

Large trial with groups well matched for age, sex and ascent profile. The study had a high dropout rate (21%) and benefit only seen in intent to treat analysis. The study is limited by recruitment of subjects at 4280 or 4358 m and loss of those who might develop AMS below those elevations or those who might have used ibuprofen at lower elevations. No comparis

on with acetazolamide.

Hackett PH et al. The incidence, importance, and prophylaxis of acute mountain sickness Lancet 1976.11

Retrospective study of trekkers traveling through 4243 m. (Khumbu Valley, Nepal)

“Unacclimatized hikers” going above Pheriche.

Trekkers – who had either trekked from Kathmandu or first flew to Lukla (2800 m) -- were administered questionnaires in Pheriche. Subjects were advised on how to avoid AMS. Subsegment of study population also participated in a prospective randomized trial of AMS prevention, receiving either acetazolamide (250 mg po BID) or placebo. Those taking no tablets labeled as controls.

AMS symptom score ≥2 (study predates Lake Louise Score).

330 questionnaires distributed. 278 completed and included in the analysis.52 of 330 (16%) lost to follow-up.

Survey data: 117 trekkers walked from Kathmandu; 161 trekkers flew to 2800 m.

Prevention trial: Acetazolamide: 71 subjects; Placebo: 49 subjects; Control: 158 subjects.

For overall study population, incidence of AMS was 42% in those who trekked from Kathmandu versus 60% in those who flew to Lukla (p<0.001). In control group (no medications) 47% of trekkers from Kathmandu developed AMS vs. 85% of those who flew to Lukla (p<0.01). Lowest incidence of AMS (14%) was in those who flew to Lukla and took acetazolamide (p<0.01).

Important early study on a major trekking circuit. Although limited by lack of information regarding how well matched the subjects were in each group, the effect sizes were large and clearly established the benefit of slow ascent. Study results are affected by selection bias as subjects who turned back before Pheriche are not included in the analysis.

Lipman et al. Ibuprofen

Prospective double-

Healthy 18-65 yr old volunteers

Subjects randomized to

Incidence and severity

89 subjects recruited

Ibuprofen: 44 subjects:

Fewer participants in the

Small study with

prevents altitude illness: a randomized controlled trial for prevention of altitude illness with nonsteroidal anti-inflammatories Ann Emerg Med 2012. 12

blind randomized placebo controlled trial examining use of ibuprofen for prevention of AMS individuals ascending from 1240 m to 3810 m. (White Mountains, California)

residing at <1240 m without recent altitude exposure. Excluded if they had history of HACE or HAPE, were pregnant, had been > 1240 m in past week or had used NSAIDs, steroids or acetazolamide in week prior to study.

receive ibuprofen 600 mg po or placebo TID starting 6 hours before ascent.

of AMS (defined as Lake Louise Score ≥3 with headache and at least 1 other symptom).

. All completed study but 3 excluded post hoc by predetermined criteria.

Placebo: 42 subjects.

ibuprofen group developed AMS compared with the placebo group (43 vs. 69%; OR 0.3, number needed to treat: 3.9). AMS severity was also higher in the placebo group .

groups well matched for age sex and home altitude. Study powered to detect reduction in AMS of 20%. Ibuprofen did not achieve the determined clinically significant difference (> 2 points) in Lake Louise score relative to placebo.No comparison with acetazolamide.

Moraga et al. Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollague (3696 m) in northern Chile Wilderness Environ

Prospective double-blind randomized, controlled trial comparing Ginkgo biloba and acetazolamide for prevention of AMS during and after ascent to

University students residing at sea level. Exclusion criteria: previous experience ≥1500 m, history of seizure or recent pneu-monia.

Subjects randomized to receive EGb761 (Ginkgo biloba) 80 mg po or acetazolamide 250 mg po or placebo every 12 hours starting 24 hours before ascent and

Incidence of AMS (defined as Lake Louise Score > 3) ; oxygen saturation.

50 subjects screened. Thirteen excluded for prior altitude exposure and 2 excluded for seizure and recent pneumonia. 36 participants (all male)

Acetazolamide: 12 subjects;Ginkgo biloba: 12 subjects; Placebo: 12 subjects.

Incidence of AMS lower with Ginkgo biloba (0%) than acetazolamide (36% p<0.05) and placebo (56% p<0.05). Incidence with acetazolamide lower

Small study with groups well matched for age, weight, height and BMI.Total LLS score and constituent scores by symptoms are reported as mean ±

Med 2007.13

3696 m (Ollagüe, northern Chile)

continuing for 3 days at 3696 m.

made the ascent.

than placebo (p<0.05); Oxygen saturation with ginkgo biloba similar to that seen with acetazolamide but higher than placebo.

SD rather than as total AMS scores. 0% incidence in Ginkgo biloba group seems too low to be a true result, particularly in comparison to rates seen in other studies.

Roncin et al. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure Aviat Space Environ Med 1996 .14

Prospective, randomized double blind, placebo-controlled trial examining role of EGb761 (Ginkgo biloba) on prevention of AMS in subjects ascending to 5400 m .(Nepal)

Male expedition members with history of AMS during a previous expedition (based on AMS score > 2).

Subjects randomized to receive Ginkgo biloba 80 mg po BID or placebo.

AMS score by ESQ (AMS-C and AMS-R).

44 subjects

Ginkgo biloba: 22 subjects; Placebo: 22 subjects.

Subjects receiving Ginkgo biloba had a lower incidence of altitude illness compared to placebo subjects when assessed by AMS-C scores (0% versus 41%, p=0.0014) and AMS-R scores (14% vs. 82%, p<0.001).

Small study with well-matched groups. The Ginkgo group had 2 current and 3 ex-smokers, while the placebo group was all non-smokers.

van Patot et al. Prophylactic low-dose acetazolamide

Prospective double-blind, randomized controlle

Healthy subjects residing between 1400 and 1600 m. Exclusions

Subjects randomized to receive acetazolamide 125 mg PO

Incidence and severity of AMS based on AMS-C score and

44 subjects

Acetazolamide: 22 subjects Placebo: 22 subjects

Lower incidence of AMS in the acetazolamide group

Although a small study compared to trials in Nepal, the groups

reduces the incidence and severity of acute mountain sickness High Alt Med Biol 2008.15

d trial of low-dose acetazolamide in prevention of AMS with ascent from 1600 m to 4300 m over 2 hours. (Pikes Peak, Colorado)

included pregnancy, history of cardiac/pulmonary disease (except asthma), alcohol consumption <24 h prior to ascent, current viral illness or travel above 2000 m within past 2 weeks.

BID or placebo, starting 3 days prior to ascent, and continuing for 24 hours at high altitude.

Lake Louis Score. AMS diagnosis based on AMS-C ≥ 0.7 and LLS ≥ 3 plus presence of headache.

(14% vs. 45%, p=0.02). AMS-C and Lake Louise scores were lower in acetazolamide group.

were well matched and the effect sizes are large. All subjects were residents of moderate altitude, which is a difference from other trials.

AbbreviationsAMS Acute Mountain SicknessAMS-C cerebral AMS scoreAMS-R respiratory AMS scoreESQ Environmental Symptom QuestionnaireOR odds ratio

1. Basnyat B, Gertsch JH, Holck PS, et al. Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol. 2006;7(1):17-27.

2. Beidleman BA, Fulco CS, Muza SR, et al. Effect of six days of staging on physiologic adjustments and acute mountain sickness during ascent to 4300 meters. High Alt Med Biol. 2009;10(3):253-260.

3. Bloch KE, Turk AJ, Maggiorini M, et al. Effect of ascent protocol on acute mountain sickness and success at Muztagh Ata, 7546 m. High Alt Med Biol. 2009;10(1):25-32.

4. Chow T, Browne V, Heileson HL, Wallace D, Anholm J, Green SM. Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial. Arch Intern Med. 2005;165(3):296-301.

5. Ellsworth AJ, Larson EB, Strickland D. A randomized trial of dexamethasone and acetazolamide for acute mountain sickness prophylaxis. Am J Med. 1987;83(6):1024-1030.

6. Ellsworth AJ, Meyer EF, Larson EB. Acetazolamide or dexamethasone use versus placebo to prevent acute mountain sickness on Mount Rainier. West J Med. 1991;154(3):289-293.

7. Forwand SA, Landowne M, Follansbee JN, Hansen JE. Effect of acetazolamide on acute mountain sickness. N Engl J Med. 1968;279(16):839-845.

8. Gertsch JH, Basnyat B, Johnson EW, Onopa J, Holck PS. Randomised, double blind, placebo controlled comparison of ginkgo biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT). BMJ. 2004;328(7443):797.

9. Gertsch JH, Lipman GS, Holck PS, et al. Prospective, double-blind, randomized, placebo-controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: the Headache Evaluation at Altitude Trial (HEAT). Wilderness Environ Med. 2010;21(3):236-243.

10. Gertsch JH, Corbett B, Holck PS, et al. Altitude Sickness in Climbers and Efficacy of NSAIDs Trial (ASCENT): randomized, controlled trial of ibuprofen versus placebo for prevention of altitude illness. Wilderness Environ Med. 2012;23(4):307-315.

11. Hackett PH, Rennie D, Levine HD. The incidence, importance, and prophylaxis of acute mountain sickness. Lancet. 1976;2(7996):1149-1155.

12. Lipman GS, Kanaan NC, Holck PS, Constance BB, Gertsch JH. Ibuprofen prevents altitude illness: a randomized controlled trial for prevention of altitude illness with nonsteroidal anti-inflammatories. Ann Emerg Med. 2012;59(6):484-490.

13. Moraga FA, Flores A, Serra J, Esnaola C, Barriento C. Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollague (3696 m) in northern Chile. Wilderness Environ Med. 2007;18(4):251-257.

14. Roncin JP, Schwartz F, D'Arbigny P. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure. Aviat Space Environ Med. 1996;67(5):445-452.

15. van Patot MC, Leadbetter G, 3rd, Keyes LE, Maakestad KM, Olson S, Hackett PH. Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness. High Alt Med Biol. 2008;9(4):289-293.

Supplementary Table 3. AMS/HACE Treatment Studies (listed in alphabetical order by first author)

Reference Setup Intervention Outcomes Overall assessment of quality

Setting/ Study design

Eligibility criteria

Interventions

Primary outcome measure

Sample size

Numbers Effect size (primary outcomes)

Bärtsch, P., et al. Treatment of acute mountain sickness by simulated descent: a randomised controlled trial BMJ 1993. 1

Randomized control trial conducted over two seasons assessing the effectiveness of hyperbaric therapy at 4559 m (Capanna Margherita, Italy)

Ascent by foot to 4559 m, stayed at altitude for 12 hrs, and signs of AMS (defined as headache and an additional symptom). Individuals with signs or symptoms of HAPE or who had taken aceta-zolamide or nifedipine were excluded.

One hour of hyperbaric treatment at a pressure of 193 mbar (equivalent to descent of 2250 m) or a pressure of 23 mbar (equivalent to 300 m) in the first season (16 mbar (equivalent to a descent of 200 m) or bed rest were used controls in the second season.)

AMS-C score, clinical score by interview and physical examination and oxygen saturation assessed before, immediately after and 12 hrs after treatment

71 mountaineers (35 in the first season, 36 in the second)

High pressure: 31 subjects; Low pressure: 23 subjects (23 mbar in first season, 16 mbar in second season); Bed rest: 10 (Seven patients were excluded due to inadvertent treatment at the wrong pressure)

Oxygen saturation rose to 90% during hyperbaric treatment but returned to 72% after 12 hrs. No changes were seen in oxygen saturation in controls. AMS-C scores and clinical scores were decreased in the hyperbaric therapy group relative to pre-treatment levels immediately following treatment (p<0.005) but returned to levels comparable to the controls after 12

High quality randomized, controlled study with relatively large sample size demonstrating limited temporal benefit of hyperbaric treatment. The effect of repeated treatments was not assessed. The control groups were treated differently between the two seasons in which the study was conducted but the small difference in administered pressures is likely of little

hrs. clinical significance.

Ferrazzini, G. et al, Successful treatment of acute mountain sickness with dexamethasone. BMJ 1987. 2

Randomized, double-blind, placebo controlled trial of dexamethasone in the treatment of AMS at 4559 m(Capanna Margherita, Italy)

Climbers planning to stay the night at 4559 m with AMS (> 3 points on a scale incorporating symptoms and clinical examination); Subjects with frank HAPE or HACE were excluded.

Dexamethasone (8 mg po followed by 4mg po at 6 and 12 hrs) or placebo.

AMS symptom score, oxygen saturation, forced vital capacity, forced expiratory volume in one second, minute ventilation, retinal vessel diameter. Assessment before and 12-16 hrs after receiving treatment.

35 climbers

Dexamethasone: 17 patients; Placebo: 18 patients.

The AMS symptom score improved by 4.1 points in the dexamethasone group vs. 0.4 points in the placebo group (p<0.001). Saturation improved in the dexamethasone group from 75.5 to 82% while the placebo went from 76.2 to 77.8 % (p<0.01). Forced vital capacity and forced expiratory volume in one second showed modest improvements in the treatment group while no differences were observed in minute

Randomized, placebo-controlled data showing improvements in AMS symptoms and oxygen saturation following treatment with dexamethasone. The study has a larger sample size than the study by Grissom et al. There is little insight into the effect on symptoms more than 12-16 hours after treatment.

ventilation or retinal diameter.

Grissom, CK et al. Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange. Ann Intern Med 1992. 3

Randomized double-blind, placebo controlled study assessing the efficacy of aceta-zolamide in the treatment of AMS at 4200 m.(Mt. McKinley, Alaska)

Climbers with symptoms of AMS as defined by a score of >2 on the AMS symptom questionnaire. Climbers were included within 24 hours of the onset of symptoms and were excluded if they had signs or symptoms of HAPE or HACE or had used acetazolamide within the previous week.

Acetazolamide 250 mg po or placebo every 8 hours. One subject with history of sulfa-allergy was assigned non-randomly to the placebo group.

AMS symptom questionnaire score, oxygen saturation, forced vital capacity, peak expiratory flow, end-tidal carbon dioxide (ET-CO2), arterial blood gas. Alveolar-arterial oxygen

difference was measured for 3 patients in the treatment group and all patients in the placebo group.

12 climbers

Aceta-zolamide: 6 patientsPlacebo: 6 patients

After 24 hours, 5 of 6 patients in the acetazolamide group had scores < 2 on the AMS symptom questionnaire, while all of the placebo group still had scores > 2. Individual metrics indicated that the acetazolamide group experienced fewer symptoms (p=0.097), higher PaO2 (p=0.045), and lower alveolar arterial oxygen difference (p=0.024). No significant differences were noted in PaCO2 (p=0.12) .

Randomized, placebo controlled data showing the efficacy of acetazolamide in the treatment of AMS both in terms of improving symptoms and shortening the time course of the disease. The study is limited by the small sample size and the lack of control for how long individuals spent reaching 4200 m. There was no information provided regarding symptom development upon ascent to higher elevation.

Hackett, PH, et al. Dexamethasone for prevention and treatment of acute mountain sickness Aviat Space Environ Med. 1988. 4

Observational study assessing efficacy of dexamethasone for treatment of AMS at 4400m Conducted in conjunction with a randomized, placebo-controlled study looking at the role of dexamethasone in AMS prevention.(Mt. McKinley, Alaska)

Participants included active duty soldiers who developed AMS following rapid transport (< 1hr) from sea level to 4400 m. The subjects were participants in a study of dexamethasone for AMS prophylaxis as part of their ascent to 4400 m were, otherwise healthy, took no other medication, and had no travel to altitude in preceding 3 wks.

All subjects who developed AMS in the prevention study were administered dexamethasone 4 mg po or intramuscular every 6 hours.

Examination (body weight, minute ventilation, forced vital capacity, peak expiratory flow, oxygen saturation) and symptom scores (self-report questionnaire, environmental symptom questionnaire, AMS-C and AMS-R). Measurements were taken 12 hours after arrival and every 24 hrs for three days during the treatment trial.

11 soldiers received treatment for AMS with dexamethasone.

Symptoms improved within two treatment doses with eight subjects no longer meeting AMS criteria. Oxygen saturation increased from 73.1% to 81.4% after 36 hrs (p<0.05). Peak expiratory flow increased from 495.5 to 560 l/min at 36 hours (p<0.01). With cessation of treatment after 5 doses, one soldier had a return of AMS after 12 hrs and four had AMS by the second day off treatment.

Treatment efficacy data limited by the small number of subjects, lack of a placebo arm and the fact that treated soldiers did not receive similar therapy in the preceding prevention study. Observed improvement on dexamethasone did not seem to be attributable to the self-limiting nature of AMS given that 6 of the 11 experienced symptom rebound after stopping the drug.

Keller, HR, et al. Simulated descent v

Randomized trial comparing

Individuals who ascended to 4559

One hour hyperbaric treatment

Lake Louise score, clinical

31 climbers

Hyperbaric therapy: 15; Dexameth

After 1 hour, portable hyperbari

Well conducted, randomiz

dexamethasone in treatment of acute mountain sickness: a randomised trial. BMJ 1995. 5

dexamethasone and simulated descent via portable hyperbaric chamber. In individuals with acute mountain sickness at 4559 m. (Capanna Margherita, Italy)

m, planned to stay overnight had clinical score > 3 for AMS. Patients with frank clinical signs of HAPE were excluded.

(of 193 mbar, equivalent to descent of 2250 m) or oral dexamethasone (8mg po followed by 4mg po every 6 hours).

score, AMS-C score, and oxygen saturation before, 1 hr following and 11 hrs after treatment.

asone: 16. c therapy was superior to dexamethasone scores by 2.1 points for the Lake Louise score, 2.5 points for the clinical score, and 0.7 points for the AMS-C score. After 11 hours, the dexamethasone treatment was superior to pressurization by 5.4 points for Lake Louise, 3.1 points for clinical exam, and 1.3 points for AMS-C (p<0.001). Oxygen saturation was 2% higher one hour following hyperbaric therapy compared to dexamethasone treatment while 11 hours

ed trial with clear outcomes indicating that hyperbaric treatment provides more immediate relief of symptoms, while dexamethasone yields more enduring benefits. The experimental design did not include groups receiving neither or both interventions. While dexamethasone provided more benefit 11 hours following treatment, the study did not provide insight into the overall duration of effect.

after treatment, oxygen saturation was higher in the dexamethasone treated group (p<0.01)

Levine, BD et al. Dexamethasone in the treatment of acute mountain sickness NEJM 1989. 6

Randomized, double-blind, placebo controlled, cross over study of the effect of dexamethasone on subjects with AMS in a hypobaric chamber (equivalent altitude 3700 m).

No specific eligibility criteria: subjects were healthy adult volunteers.

Subjects exposed to hypobaric hypoxia equivalent to 3700 m for 48 hours on two occasions separated by 4 weeks. Those individuals developing AMS received dexamethasone (4 mg every 6 hours or placebo.

Environmental symptoms questionnaire administered at baseline (600m), hypoxic baseline (3700m), and 4 times daily during hypobaric hypoxia. Physical assessment involving psychometric testing, cardiopulmonary monitoring, chest radiography, respiratory sleep patterns, and blood panels.

6 male volunteers started the study; 5 developed AMS and were included in the analysis.

5 subjects developed AMS in both decompression periods and received both dexamethasone and placebo. One subject did not develop symptoms.

Dexamethasone improved AMS-C component score by 63% (p<0.05) after 12 hrs compared with a 23% improvement in the placebo group that was not statistically significant. No significant difference in oxygen saturation or pulse rate was found between dexamethasone and placebo.

This study had a rigorous experimental design with thoroughly assessed patients but is limited by the small sample size. Dexamethasone (4 mg every 6 hours at the onset of symptoms) effectively relieved symptoms of AMS.

Taber, RL. Protocols for the use of portable hyperbari

Observational study of the time course of portable hyperbari

Patients presenting to a clinic at 4240 m with HAPE or HACE

All patients received oxygen (when available) and

Symptom assessment at 10-15 min intervals in the bag and after

25 patients

AMS: 10 patients; HAPE 9 patients; HACE : 6 patients.

Improvement in symptoms noted in all groups of patients

While this observational study shows that

c chambers for the treatment of high altitude disorders. J of Wilderness Medicine 1990. 7

c treatment of patients with AMS HAPE or HACE at 4240 m. (Pheriche, Nepal)

who could not be evacuated to lower elevation as well as patients with AMS. AMS defined as headache, nausea/vomiting and loss of appetite; HAPE defined as dyspnea at rest, tachypnea and rales; HACE defined as loss of fine motor coordination, slurred speech, disorienta-tion and ataxia.

dexamethasone (8 mg IV/po then 4 mg every 6 hr) as indicated by individual symptoms in addition to medications taken before arrival at the clinic. All patients then received portable hyperbaric therapy (~ 550 Torr for varying durations).

leaving the bag.

with AMS patients requiring on average 2 hours for symptom improvement, HAPE patients requiring 4 hours and HACE patients 6 hours.

hyperbaric therapy leads to symptom improvement in AMS, HAPE and HACE, methodological issues limit the conclusions that can be drawn from the study. In addition to the small sample sizes in each group, the authors did not control for events leading up to clinic presentation such as amount of descent prior to clinic arrival and use of adjunctive medications. Monitoring time for possible rebound after treatment also varied from case

to case while not all patients received supplemental oxygen.

1. Bärtsch P, Merki B, Hofstetter D, Maggiorini M, Kayser B, Oelz O. Treatment of acute mountain sickness by simulated descent: a randomised controlled trial. BMJ. 1993; 306:1098 –1101.

2. Ferrazzini G, Maggiorini M, Kriemler S, Bartsch P, Oelz O. Successful treatment of acute mountain sickness with dexamethasone. Br Med J (Clin Res Ed). 1987;294: 1380–1382.

3. Grissom CK, Roach RC, Sarnquist FH, Hackett PH. Acetazolamide in the treatment of acute mountain sickness: clinical efficacy and effect on gas exchange. Ann Intern Med. 1992;116:461– 465.

4. Hackett PH, Roach RC, Wood RA, et al. Dexamethasone for prevention and treatment of acute mountain sickness. Aviat Space Environ Med. 1988;59:950 – 954.

5. Keller HR, Maggiorini M, Bartsch P, Oelz O. Simulated descent v dexamethasone in treatment of acute mountain sickness: a randomised trial. BMJ. 1995;310: 1232–1235.

6. Levine BD, Yoshimura K, Kobayashi T, Fukushima M, Shibamoto T, Ueda G. Dexamethasone in the treatment of acute mountain sickness. N Engl J Med. 1989;321: 1707–1713.

7. Taber RL. Protocols for the use of portable hyperbaric chambers for the treatment of high altitude disorders. J Wild Med. 1990;1:181–192.

Supplementary Evidence Table 4. HAPE Prevention or Treatment Studies (listed in alphabetical order by first author)

Reference

Setup Intervention Outcomes Overall assessment of quality

Setting/ Study design

Eligibility criteria

Interventions

Primary outcome measure

Sample size

Numbers Effect size (primary outcomes)

Baggish et al. The impact of moderate-altitude staging on pulmonary arterial hemodynamics after ascent to high altitude. High Alt Med Biol 2010.1

Prospective, unblinded, non-randomized cross-over study examiningpulmonary artery pressure responses following acute exposure to 4300 m in a hypobaric chamber and following ascent to terrestrial 4300 m after 7 days of staging at 2200 m. (Pikes Peak, Colorado)

Healthy, young active duty military males, resident at low altitude

Over 7 weeks following assessments in the hypobaric chamber (direct ascent), subjects spent 7 days at terrestrial 2200 m before ascending to terrestrial 4300 m (staged ascent)

Pulmonary artery pressure measured by echocardio-graphy following direct ascent to 4300 m and 90 minutes and 4 days following staged ascent to the same elevation

10 10 subjects completed the entire study protocol.

Mean pulmonary artery pressure at 4300 m was lower following staged ascent to 4300 m compared to direct ascent to the same elevation (25 + 4 mm Hg vs. 37 + 8 mm Hg). Estimated pulmonary artery pressure remained unchanged after 4 days of high altitude residence.

While this high- quality study demonstrates that staged ascent decreases pulmonary vascular responses to acute hypoxia, the study does not provide evidence regarding prevention of HAPE in known susceptible individuals. The optimal regimen for staged ascent is not clear based on this study.

Bärtsch P, et al. Prevention of high altitude pulmonary edema by nifedipine. N Engl J Med 19912

Prospective, randomized, placebo controlled, double blind study examining nifedipine in

History of radiographically documented HAPE and continued alpine climbing after a prior episode of HAPE.

Affected individuals received nifedipine 20 mg slow release preparation po or placebo every 8 hours

Diagnosis of HAPE by SpO2, clinical examination, and chest radiography.

21 subjects

Nifedipine group: 10 subjects; Placebo group: 11 subjects

Only 10% of subjects receiving nifedipine developed HAPE, while 64% of subjects receiving placebo developed HAPE. Those

Important early, high quality study in HAPE-susceptible patients that demonstrated effective prevention of HAPE

treatment of HAPE. Subjects ascended in less than 22 hours from 1130 m to 4559 m. Ascent by cable car to 3200 m, then climbing for 1.5 hrs to 3611 m for overnight stay, then climbing for 4 hrs to 4559 m (Capanna Margherita, Italy)

starting the day before ascent and during ascent to 4559 m and for three days following arrival at 4559 m

subjects receiving nifedipine had lower pulmonary artery systolic pressure by echocardiography and lower alveolar-arterial oxygen difference.

with nifedipine by lowering pulmonary artery pressure.

Deshwal R, et al. Nifedipine for the treatment of high altitude pulmonary edema. Wilderness Environ Med 2012.3

Open label randomized trial examining efficacy of nifedipine in treatment for individuals with HAPE evacuated from a mean altitude of 3,581 m to a hospital at 1,370 m and

Indian soldiers diagnosed with HAPE based on Lake Louise Criteria.

Affected individuals received nifedipine 30 mg sustained release BID or placebo. Treatments were administered in an alternating manner in addition to oxygen and bed rest for all patients.

Time to normalization of oxygen saturation, resolution of radiographic infiltrates and resolution of lung crepitation, and duration of hospital stay.

110 Indian soldiers with HAPE.

All patients were treated with descent, oxygen, and bed rest.

Those patients treated with nifedipine in addition to oxygen and bedrest did not have improved outcomes.

Adjunctive treatment with nifedipine adds no incremental benefit to HAPE patients already treated with descent and oxygen. The study does not allow any conclusions about the role of nifedipine in the

treated with oxygen at 4-6 l/min and bed rest (India).

treatment of patients who are unable to descend and/or receive supplemental oxygen.

Hackett PH, et al. The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema: a comparison. Int J Sports Med 1992.4

Case series of treatment of HAPE with oxygen, pulmonary vasodilators, or both conducted on patients with HAPE on Mt. McKinley (4300 m) or at a Colorado ski resort (2835 m).

HAPE diagnosed according to clinical findings and hypoxemia as assessed by pulse oximetry.

Affected individuals received supplemental oxygen, nifedipine (10 mg sublingual), hydralazine (10-20 mg IV), phentolamine (1mg/min for 10 minutes then 0.5 mg/min for 20 minutes IV), or phentolamine plus oxygen.

Change from baseline in pulmonary artery pressure measured by echocardio-graphy.

HAPE subjects: 16; Controls: 10

Oxygen was administered to 10 HAPE subjects and 6 control subjects. Nifedipine given to 10 HAPE subjects and 6 controls. Hydralazine was given to 3 HAPE subjects. Phentolamine was given to 6 HAPE subjects and 5 controls.

All agents reduced pulmonary artery pressure, with the greatest effect seen with combined administration of oxygen and phentolamine.

This study, which is limited by the lack of randomization and unequal number of subjects in each treatment group, demonstrates that several pulmonary vasodilators are effective in reducing pulmonary artery pressure in HAPE. These agents should be considered as potential adjunctive therapy to supplemental oxygen.

Leshem E, et al. Tadalafil and acetazolamide versus

Open label study of tadalafil and acetazolamide in

Healthy trekkers attempting a summit of Kiliman-jaro.

Subjects assigned to receive either Tadalafil 20 mg po

Development of severe high altitude illness defined as

Between 2006 and 2009, 68 climbers

Acetazolamide only: 27 subjects; Tadalafil plus acetazola

Incidence of HAPE was significantly lower in the tadalafil

Limitations to this study include a non-blinded and non-

acetazolamide for the prevention of severe high altitude illness. J Travel Med 2012.5

HAPE prevention in healthy trekkers climbing to 5895 m using an identical 6 day ascent profile.(Mt. Kilimanjaro, Africa).

QD and acetazolamide 125 mg po BID or acetazolamide 125 mg po BID beginning on day 3 of the ascent. Participants were allocated to either group according to their preference.

HAPE or HACE diagnosed using established criteria (HAPE defined by the 1991 International Hypoxia Symposium Criteria)

deemed eligible for study. 55 met inclusion criteria and 51 completed the study protocol.

mide: 24 subjects. 70% or participants were male.

plus acetazolamide group than in the acetazolamide only group (4.2 vs. 22.2%; p=0.03). All cases of HAPE diagnosed on summit day.

randomized study design. It does not support the use of acetazolamide for HAPE prevention and should be considered only as a hypothesis generating study supporting the need for a study comparing acetazolamide and other pulmonary vasodilators in HAPE prevention.

Maggiorini M, et al. Both tadalafil and dexamethasone may reduce the incidence of high altitude pulmonary edema. Ann Intern Med 2006.6

Prospective, randomized, placebo controlled, double blind study to assess efficacy of tadalafil and dexamethasone in prevention of HAPE. Subjects ascended in less than 24 hrs from

Prior history of HAPE.

Subjects randomized to receive tadalafil 10 mg po BID or dexamethasone 8 mg po BID, or placebo BID starting the morning of the day before ascent to high altitude.

Development of HAPE as assessed by clinical examination and chest radiography after the first and second nights at 4559 m or when HAPE or severe AMS occurred.

Dexamethasone: 10 subjects; Tadalafil: 10 subjects; Placebo: 9 subjects

2 participants receiving tadalafil developed severe AMS on arrival to 4559 m and withdrew from the study.

78% incidence of HAPE with placebo versus 12% with tadalafil (p<0.007) and 0% with dexamethasone (p<0.001). When two patients in tadalafil group who withdrew from the study are included in analysis, 30%

High quality study in HAPE-susceptible individuals demonstrating benefit of dexamethasone and tadalafil in HAPE prevention although outcome in the tadalafil group depends on how the two

490 m to 4559 m. Travel to 1130 m and then ascent by cable care to an 3200 m, climbing for 1.5 hrs to 3611 m for an overnight stay, then a 4 hr ascent to 4559 m for a two night stay at that elevation. (Capanna Margherita, Italy)

would be deemed as having incapacitating altitude illness. Both tadalafil and dexamethasone resulted in smaller increases in pulmonary artery systolic pressure compared to placebo.

subjects incapacitated with AMS are treated. With tadalafil there is a 10% incidence of HAPE or a 30% incidence of incapacitating altitude illness. Benefit with dexamethasone was an unexpected finding for which the mechanism remains unclear.

Oelz O, et al. Nifedipine for high altitude pulmonary oedema. Lancet 1989.7

Case control study at 4559 m comparing physiological parameters in HAPE patients treated with nifedipine with subjects who remained healthy at the same altitude following a similar

HAPE diagnosed by clinical signs, increased alveolar-arterial oxygen difference and chest radio-graphy.

Nifedipine 10 mg sublingual, repeated x 1 if SBP did not drop 10 mm Hg or more after 15 minutes, then nifedipine 20 mg slow release po every 6 hours.

In HAPE subjects, PaO2 SpO2, alveolar-arterial oxygen difference, PaCO2 and radiographic score at 1 hour, 14 to 16 hours, and 34 to 37 hours. HAPE subjects' baseline parameters were also compared to healthy subjects at the same altitude

6 male subjects with HAPE age 27 to 51.

Pulmonary artery systolic pressure measured by echocardiography significantly decreased with nifedipine therapy. In HAPE subjects, PaO2 and SpO2 did not significantly increase with nifedipine treatment, but

While the study suggests nifedipine is an effective adjunctive treatment for HAPE because it lowers pulmonary artery pressure, improves the alveolar arterial oxygen difference, and improves radiographic scores, overall

ascent profile. (Capanna Margherita, Italy)

without HAPE.

alveolar-arterial oxygen difference and radiographic score were significantly decreased. PaCO2

significantly increased in HAPE subjects treated with nifedipine. HAPE subjects were more hypoxemic than controls at altitude without HAPE.

study quality is limited, by the lack of a randomized controlled design comparing use of nifedipine versus placebo in individuals with HAPE.

Sartori C, et al. Salmeterol for the prevention of high altitude pulmonary edema. N Engl J Med 2002.8

Prospective, randomized, placebo controlled, double blind study examining use of salmeterol for prevention of HAPE. Subjects ascended in less than 22 hours from 1130 m to 4559 m. Ascent by cable

At least one radiographically documented episode of HAPE within the prior four years.

Subjects randomized to receive inhalation of 125 mcg of salmeterol or placebo every twelve hours starting the morning before the day of ascent to high altitude.

Diagnosis of HAPE by SpO2, arterial blood gas, clinical examination, and chest radiography.

37 subjects

Salmeterol group = 18; Placebo group = 19

HAPE incidence 74% with placebo and 33% with salmeterol (P=0.02). The HAPE patients had higher radiographic scores, were more hypoxemic, and had higher mountain sickness scores. There was no difference in pulmonary artery pressure

High-quality study demonstrating that inhaled salmeterol is effective in preventing HAPE in HAPE-susceptible individuals. Two possible mechanisms are discussed, including, beta-adrenergic enhancement of alveolar

care to 3200 m, then climbing for 1.5 hrs to 3611 m for an overnight stay, then climbing for 4.5 hrs to 4559 m. (Capanna Margherita, Italy)

determined by echocardio-graphy.

fluid clearance by stimulation of transepithelial sodium transport and possible beta-adrenergic effect on hypoxic pulmonary vasoconstriction. Despite observed benefit, salmeterol still not used as monotherapy for prevention.

Scherrer U, et al. Inhaled nitric oxide for high altitude pulmonary edema. N Engl J Med 1996.9

Comparison of physiologic responses to inhaled nitric oxide in individuals with a history of HAPE and those resistant to the disorder. All subjects traveled to 1130 m, ascended by cable care to 3200 m,

HAPE-susceptible group: Radiographically documented HAPE within the prior 4 years; Control group: alpine mountaineers with repeated ascents over 4000 m and no history of HAPE.

Administration of nitric oxide inhalation (40 ppm with an FIO2 of 0.21) at 18 and 36 hours following arrival at 4559 m.

Comparison of pulse oximetry, arterial blood gas analysis and estimated pulmonary artery systolic pressure measured by echocardiography while breathing ambient air and during administration of inhaled nitric oxide.

36 subjects

HAPE prone group: 18 subjects. Control group: 18 subjects

After 18 to 36 hours at 4559 m, 56% of the HAPE-prone subjects developed HAPE while none of the control group developed HAPE.

Nitric oxide decreased pulmonary artery pressure more in HAPE-prone subjects than in control subjects. Nitric oxide improved oxygenation HAPE-prone subjects who developed HAPE and did not alter oxygenatio

While demonstrating that inhalation of nitric oxide improves arterial oxygenation in HAPE, this study is more useful in providing insight into disease pathophysiology rather than treatment. The complexity of administer

climbed for 1.5 hrs to 3611 m for an overnight stay, and then ascended over 4 hr to 4559 m. (Capanna Margherita, Italy)

n HAPE-prone subjects who remained healthy. Nitric oxide worsened oxygenation in HAPE-resistant subjects.

ing nitric oxide precludes common use for treatment of HAPE as compared to oxygen, which is more readily available and much less expensive.

Schoene RB, et al. High altitude pulmonary edema and exercise at 4,400 meters on Mount McKinley. Effect of expiratory positive airway pressure. Chest 1985.10

Case series of climbers with HAPE at 4400 m treated with expiratory positive airway pressure (EPAP)(Mt. McKinley, Alaska)

Clinical diagnosis of HAPE with hypoxemia by pulse oximetry,dyspnea, tachycardia, and crackles on lung auscul-tation

All subjects received EPAP applied with a tight fitting face mask at 5 and 10 cm H2O.

SpO2, end tidal carbon dioxide (ET-CO2) mm Hg, inspired minute ventilation (Vi) respiratory rate (RR), and heart rate (HR).

4 male subjects with HAPE, mean age 33 ±10 years, and mean SpO2, 54 ±11 %.

EPAP treatment led to significant increases in SpO2, (54% to 63%) decreased RR (23 to 13 bpm), increased ET-CO2. No changes observed in Vi and HR.

Application of EPAP improves clinical parameters in HAPE patients, but should be considered an adjunctive measure to descent. Although the improvement in oxygenation is significant, the HAPE patients remained severely hypoxemic relative to the expected SpO2, at that elevation and would still require descent or suppleme

ntal oxygen. Study quality limited by the small numbers of subjects and lack of a control group.

Zafren K, et al. Treatment of high altitude pulmonary edema by bed rest and supplemental oxygen. Wilderness Environ Med 1996.11

Case series from two primary care centers between 2650 and 2950 m.(Colorado)

Patients aged 16 to 69 years diagnosed with HAPE.

Selected HAPE patients received treatment with bed rest and supplemental oxygen rather than hospital admission.

Patients were considered improved on follow-up assessment if arterial oxygen saturation breathing ambient air increased by 10% or symptoms had improved compared to initial evaluation.

Of 58 patients with confirmed HAPE, 25 (43%) were treated by bed rest and supplemental oxygen and were seen on return visits to the clinic.

Comparison of baseline and follow-up parameters was performed in 25 HAPE patients.

On return visit (usually one day later) systolic blood pressure, heart rate, respiratory rate, and temperature all significantly decreased. Oxygen saturation breathing ambient air significantly increased.

While the study demonstrates that some patients with HAPE can be safely treated with supplemental oxygen as outpatients and remain at the same elevation, the study suffers from selection bias in that those patients chosen for outpatient treatment were probably less sick then those admitted to the hospital.

1. Baggish AL, Fulco CS, Muza S, et al. The impact of moderate-altitude staging on pulmonary arterial hemodynamics after ascent to high altitude. High Alt Med Biol. 2010;11(2):139-145.

2. Bärtsch P, Maggiorini M, Ritter M, Noti C, Vock P, Oelz O. Prevention of high altitude pulmonary edema by nifedipine. The New England journal of medicine. 1991;325:1284-1289.

3. Deshwal R, Iqbal M, Basnet S. Nifedipine for the treatment of high altitude pulmonary edema. Wilderness & environmental medicine. 2012;23(1):7-10.

4. Hackett PH, Roach RC, Hartig GS, Greene ER, BD. L. The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema, a comparison. Int J Sports med. 1992;13:S68-S71.

5. Leshem E, Caine Y, Rosenberg E, Maaravi Y, Hermesh H, Schwartz E. Tadalafil and acetazolamide versus acetazolamide for the prevention of severe high-altitude illness. Journal of travel medicine. 2012;19(5):308-310.

6. Maggiorini M, Brunner-La Rocca HP, Peth S, et al. Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial. Ann Intern Med. 2006;145(7):497-506.

7. Oelz O, Maggiorini M, Ritter M, Waber U, Jenni R. Nifedipine for high altitude pulmonary edema. Lancet. 1989;2:1241-1244.

8. Sartori C, Allemann Y, Duplain H, et al. Salmeterol for the prevention of high-altitude pulmonary edema. N Engl J Med. 2002;346(21):1631-1636.

9. Scherrer U., Vollenweider J., Delabays A., et al. Inhaled Nitric Oxide for High-altitude Pulmonary Edema. N Engl J. Med. 1996;334:624-629.

10. Schoene RB, Roach RC, Hackett PH, Harrison G, Mills WJ, Jr. High altitude pulmonary edema and exercise at 4,400 meters on Mount McKinley. Effect of expiratory positive airway pressure. Chest. 1985;87(3):330-333.

11. Zafren K, Reeves JT, Schoene R. Treatment of high-altitude pulmonary edema by bed rest and supplemental oxygen. Wilderness Environ Med. 1996;7(2):127-132.