The RADICAL Trial was a prospective, double-blind, randomized, non-inferiority trial evaluating reduced dose (62.5 mg twice daily) vs. standard dose (125 mg twice daily) of acetazolamide for the prevention of acute mountain sickness in adults trekking to Everest Base Camp in Nepal.(1).
Background:
The current standard pharmacologic prophylaxis for acute mountain sickness (AMS) is acetazolamide 250 mg daily divided into two doses (2). The proposed mechanism is via acetazolamide’s inhibition of carbonic anhydrase, which at higher doses (250 to 500 mg daily), preferentially inhibits renal carbonic anhydrase leading to bicarbonate diuresis and a mild metabolic acidosis. At significant elevations, there is increased minute ventilation and respiratory alkalosis in response to hypoxemia. The metabolic acidosis that is induced by acetazolamide counters this respiratory alkalosis and allows an increased ventilatory response to facilitate acclimatization. Many studies have determined 250 mg daily to be the lowest effective dose for the prevention of AMS (3,4,5,6,7,8).
Although acetazolamide may be beneficial, there are multiple undesirable side effects that may deter its use, most notably:
- Paresthesias – especially undesirable for alpine climbers and mountaineers who often rely on tactile sensation
- Altered sensation of taste especially of carbonated beverages (and who doesn’t enjoy a cold beer after summiting a peak or a long day of trekking)
- Mild diuresis – can interrupt activities and sleep
Some mountaineers have used doses lower than 250 mg for AMS prophylaxis, but these lower doses have not been previously studied.
What They Did:
A prospective, double-blind, randomized, non-inferiority trial evaluating reduced dose of acetazolamide 62.5 mg twice daily vs. 125 mg twice daily for the prevention of acute mountain sickness in adults trekking to Everest Base Camp in Nepal.
P - Population Inclusion: Adults ≥ 18 year of age trekking to Everest Base Camp in Nepal Exclusion: **Planned ibuprofen use was not used as an exclusion criteria because the two studies that examined NSAIDs for preventing AMS were published after the study started (10,11). Read about it in a previous post here.
I - Intervention Reduced dose of acetazolamide 62.5 mg twice daily.
C - Comparison Standard dose of acetazolamide of 125 mg twice daily
O - Outcomes Primary Outcome: Incidence of AMS, defined as a Lake Louise Score (LLS) of 3 or more (9). Secondary Outcomes: Mild headache Moderate headache Severe headache, incapacitating 1 2 3 Poor appetite or nausea Moderate nausea or vomiting Severe nausea & vomiting, incapacitating 1 2 3 Mild fatigue / weakness Moderate fatigue / weakness Severe fatigue / weakness, incapacitating 1 2 3 Mild dizziness Moderate dizziness Severe dizziness, incapacitating 1 2 3 Did not sleep as well as usual Woke up many times, poor night’s sleep Unable to sleep 1 2 3 *Roach RC et al. (9)
Lake Louise Symptom Score
Symptoms
Severity
Points
Headache
No headache
0
Gastrointestinal symptoms
No gastrointestinal symptoms
0
Fatigue and / or weakness
Not tired or weak
0
Dizziness / lightheadedness
Not dizzy
0
Difficulty sleeping
Slept as well as usual
0
Results:
- 130 total enrolled: 96 in Nepal, 34 in Alaska
- Data from Alaska participants was excluded from analysis as insufficient altitude reached
- 73 participants included in analysis
- No difference in overall incidence of mild or severe AMS
- No difference in mean LLS between the reduced-dose and standard-dose groups
- No difference in frequency or severity of side effects (urination, change in beverage taste, toe tingling, and finger tingling)
- In patients reporting ibuprofen use, mean LLS was significantly higher than those who had not used it. However, this more likely reflects participants using ibuprofen to treat symptoms of AMS rather than as prophylaxis.
Strengths:
- First prospective RCT to evaluate reduced dose of acetazolamide (lower than 125 mg BID) for AMS prophylaxis
- Study was adequately powered
- All demographic variables were well matched between treatment arms
- Participants and investigators were blinded to study assignments
- Study medications made and packaged to appear identical in appearance
- Study medications were prepared by a separate, third party that packaged medications to appear identical
- Ascent rates in both groups (average of 524±232 meters/day in the reduced dose group and 488±224 meters/day in the standard dose group) were sufficient to cause AMS
- Participants were enrolled at lower altitudes, which follows current guidelines
- Relatively low number of dropouts
Limitations:
- Without a placebo arm, they were unable to factor in underlying AMS incidence (previous studies with placebo groups reported similar rates of AMS as study, but more recent studies have shown lower rates)
- Participants were allowed to ascend at their own pace (sometimes times more slowly), which may have in itself protected trekkers from developing AMS
- Analysis excluded participants with <25% compliance with medications, which may have masked a potential difference in incidence or severity of side effects as these may have been deterrents for participants’ continued compliance
Discussion:
- The results support the possibility of using lower acetazolamide dosing than what has been previously recommended
- However, reducing the dose did not protect from related side effects
- Participants who reported using ibuprofen had higher LLS; the medications may have been taken to treat symptoms rather than for prevention of AMS (it was not known at the time of the study that ibuprofen can be potentially used for AMS prevention)
- There were higher rates of overall incidence of AMS, perhaops attributable to more frequent LLS assessments rather than inefficacy of medication
Bottom Line:
In patients with ascent rates averaging around 524 meters per day, a reduced dose of acetazolamide 62.5 mg twice daily may be noninferior to current standard dose of 125 mg twice daily. However, the lower dose was not shown to reduce side effects, which are the usual deterrents of compliance.
References:
- McIntosh SE, Hemphill M, McDevitt MC, et al. Reduced acetazolamide dosing in countering altitude illness: A comparison of 62.5 vs 125 mg (the RADICAL trial). Wilderness Environ Med. 2019; 00(00):1-10
- Luks AM, McIntosh SE, Grissom CK, Auerbach PS, Rodway GW, Schoene RB, et al. Wilderness Medical Society practice guidelines for the prevention and treatment of acute altitude illness: 2014 update. Wilderness Environ Med. 2014;25(4 suppl):S4-S14.
- Reid LD, Carter KA, Ellsworth A. Acetazolamide or dexamethasone for prevention of acute mountain sickness: a meta-analysis. Wilderness Environ Med. 1994;4(5):34–48.
- Dumont L, Mardirosoff C, Tramer MR. Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review. BMJ. 2000;321(7256):267–72.
- Seupaul RA, Welch JL, Malka ST, Emmett TW. Pharmacologic prophylaxis for acute mountain sickness: a systematic shortcut review. Ann Emerg Med. 2012;59(4):307–17.
- Kayser B, Dumont L, Lysakowski C, Combescure C, Haller G, Tramer MR. Reappraisal of acetazolamide for the prevention of acute mountain sickness: a systematic review and meta-analysis. High Alt Med Biol. 2012;13 (2):82–92.
- Low EV, Avery AJ, Gupta V, Schedlbauer A, Grocott MP. Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. BMJ. 2012;345:e6779.
- Nieto Estrada VH, Molano Franco D, Medina RD, Gonzalez Garay AG, Marti-Carvajal AJ, Arevalo-Rodriguez I. Interventions for preventing high altitude illness: Part 1. Commonly-used classes of drugs. Cochrane Database Syst Rev. 2017;6 CD009761.
- Roach RC, Bartsch P, Oelz O, Hackett PH. Lake Louise AMS Scoring Consensus Committee. The Lake Louise acute mountain sickness scoring system. In: Sutton JR, Coates G, Houston CS, eds. Hypoxia and Molecular Medicine. Burlington, VT: Queen City Press; 1993:272-4.
- Kanaan NC, et al. Prophylactic acetaminophen or ibuprofen result in equivalent acute mountain sickness incidence at high altitude: A prospective randomized trial. Wilderness Environ Med. 2017 Jun;28(2):72-78.
Christianna Sim
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- Can a lower dose of acetazolamide prevent acute mountain sickness? - March 29, 2019
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