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A randomized trial of dexamethasone and acetazolamide for acute mountain sickness prophylaxis
A Randomized Trial of Dexamethasone and Acetazolamide for Acute Mountain Sickness Prophylaxis
ALLAN J. ELLSWORTH, Pharm.D. ERIC B. LARSON, M.D., M.P.H. DANIEL STRICKLAND, Ph.D. Seattle,
Forty-seven climbers participated in a double-blind, randomized trial comparing acetazolamide 250 mg, dexamethasone 4 mg, and placebo every eight hours as prophylaxis for acute mountain sickness during rapid, active ascent of Mount Rainier (elevation 4,392 m). Forty-two subjects (89.4 percent) achieved the summit in an average of 34.5 hours after leaving sea level. At the summit or high point attained above base camp, the group taking dexamethasone reported less headache, tiredness, dizziness, nausea, clumsiness, and a greater sense of feeling refreshed (p _<0.05). In addition, they reported fewer problems of runny nose and feeling cold, symptoms unrelated to acute mountain sickness. The acetazolamide group differed significantly (p 10.05) from other groups at low elevations (1,300 to 1,800 m), in that they experienced more feelings of nausea and tiredness, and they were less refreshed. These drug side effects probably obscured the previously established prophylactic effects of acetazolamide for acute mountain sickness. Separate analysis of an acetazolamide subgroup that did not experience side effects at low elevations revealed a prophylactic effect of acetazolamide similar in magnitude to the dexamethasone effect but lacking the euphoric effects of dexamethasone. This study demonstrates that prophylaxis with dexamethasone can reduce the symptoms associated with acute mountain sickness during active ascent and that acetazolamide can cause side effects that may limit its effectiveness as prophylaxis against the disease.
Washington
From the Schools of Pharmacy, Medicine, and Public Health, University of Washington, Seattle, Washington. Requests for reprints should be addressed to Dr. Allan Ellsworth, Department of Family Medicine, RF-30, University of Washington, Seattle, Washington 98195. Manuscript submitted May 18, 1987, and accepted August 13, 1987.
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Acute mountain sickness is a syndrome characterized by headache, nausea, excessive fatigue, loss of appetite, breathlessness, and insomnia [ 11. It is most likely to occur after rapid ascent to elevations higher than 3,000 m above sea level [ 1,2]. Although the precise pathophysiology of the disorder is unclear, it is part of a continuum of altitude-induced illnesses including high altitude pulmonary edema and high altitude cerebral edema, all presumably reflecting a common underlying physiologic response to hypoxia [3,4]. Although acute mountain sickness is generally benign and self-limited, impaired judgment and physical ability may compromise the enjoyment and safety of those visiting high altitudes [5]. Slow, staged ascent to altitude is effective in preventing acute mountain sickness, but is not always practical, especially in mountain rescue and military activities [6]. Prophylactic therapy with acetazolamide has been shown to reduce symptoms and symptom severity in subjects whether they achieve high altitude actively or passively [2,7-121. In a recent study of sedentary subjects exposed to simulated high altitude (4,570 m), prophylactic therapy with dexamethasone significantly decreased both cerebral and respiratory symptoms of acute mountain
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sickness [ 131. Betamethasone and dexamethasone have also been used to treat serious acute symptoms [ 1,14,15]. No investigators have assessed the efficacy of prophylactic dexamethasone during active ascent and its efficacy relative to acetazolamide, the accepted prophylactic agent [16], in randomized trials. Mount Rainier (4,392 m), climbed by more than 8,000 people per year, is a proven laboratory for the study of prophylactic drug regimens under actual climbing conditions [7,17]. We performed a double-blind, randomized trial comparing dexamethasone, acetazolamide, and placebo during standard weekend climbs of Mount Rainier.
SUBJECTS AND METHODS Subjects. The study group consisted of 47 volunteer climbers in five climbing parties, aged 18 to 52 years (43 men, four women) who normally resided at or near sea level. All were in good health with no previous history of acid-peptic disease or psychiatric disease. All gave informed consent. The Climb. Subjects drove from sea level to a trailhead at either 1,300 m on the northeast side or 1,600 m on the south side of Mount Rainier. Active ascent to a base camp at approximately 3,000 m averaged 6.8 hours. The ascent to the summit (4,392 m) began in the early morning (between 1 A.M. and 2 A.M.) on the second day, and was followed by return to road’s end the same day. The Randomized Trial. The study employed a doubleblind, placebo-controlled design. Using a random numbers table, subjects were assigned to receive identical-appearing pink capsules of either acetazolamide 250 mg (Lederle Laboratories lot 770), dexamethasone 4 mg (Merck Sharpe & Dohme lot 1OS-SSS), or lactose placebo every eight hours beginning 24 hours before ascent. Concomitant use of additional medications was recorded but unrestricted. Packets containing study medication, data collection forms, and instruction sheets were distributed at orientation sessions several days before each ascent. During these sessions, subjects were informed of study and climb details and were instructed in data collection methods. One of the investigators (A.E.) accompanied all climbing parties to validate and verify symptomatology and data collection. Assessment of Acute Mountain Sickness. A combined, abbreviated version of the Environmental Symptoms Questionnaire [ 181 and the General High-Altitude Questionnaire [ 191 was used to assess symptoms of acute mountain sickness [7,17]. Thirty symptoms were rated on 0- to 5 point Likert scales (0, not at all; 1, slight; 2, somewhat; 3, moderate; 4, quite a bit; and 5, extreme). Questionnaires were completed at 1,300 m or 1,600 m (trailhead), 3,000 m (base camp), 4,392 m (summit) or high point attained above base camp, and 3,000 m (base camp) on descent. The data collected at the trailhead after subjects had taken the first four doses of medication permitted post-hoc detection of a drug side effect. Based on a trial [7] conducted under similar conditions, acute mountain sickness was originally and arbitrarily defined as headache rated 2 or greater, nausea rated 1 or greater, or both on the symptom scales. However, this definition resulted in an incidence of the
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syndrome at the summit that was much higher than expected (placebo, 80 percent; acetazolamide, 78.8 percent; dexamethasone, 41.2 percent) [7] and did not agree with our clinical observations on the mountain. Also, 20 percent of climbers taking acetazolamide reported nausea at low elevation (1,300 to 1,600 m) compared with none of the climbers in the other two treatment groups, representing a drug side effect confounding symptoms of acute mountain sickness. Therefore, several symptoms (dizziness, tiredness, headache, and clumsiness) prominent in our subjects with acute mountain sickness and similar to symptoms used in other trials [1,2] were combined to define an acute mountain sickness index. The acute mountain sickness index was the mean of a subject’s scores for these symptoms at the high point. Acute mountain sickness was defined when individuals had scores of 2 or greater on this Oto &point scale. Nausea that occurred at low elevations as a side effect of acetazolamide was deliberately excluded from the index. Thus, the acute mountain sickness index does not include adverse effects of acetazolamide but still allows acetazolamide-treated climbers with nausea at low elevation and acute mountain sickness symptoms at higher elevations to be classified. Averaged cerebral and respiratory severity scores were also utilized to compare the degree of acute mountain sickness in experimental groups [ 131. Cerebral symptoms were divided into positive and negative clusters [20]. The positive cerebral average (C-pos) contained the “symptoms” satisfied, refreshed, happy, active, and energetic. The negative cerebral average (C-neg) represented the symptoms dizzy, tired, drowsy, lazy, sleepy, and trouble sleeping at altitude. The respiratory average (Resp) included shortness of breath, tired, lazy, and palpitations. Statistical Analysis. Subjective symptom scores were compared for each drug group by two complementary methods: First, the mean rank of the scores was computed and evaluated for differences by drug categories by Kruskal-Wallis one-way analysis of variance. These same scores were then categorized into two groups, using “2” as a cutoff point for significant symptoms (0 to 1, 2 to 5), and analyzed by drug group using contingency table techniques. An alpha level of p 10.05 was used in estimating sample size and as a criterion for statistical significance [21,22]. A beta error of 0.20 (power = 0.80) was selected as a basis for detecting false-negative results.
RESULTS Group Description. Table I shows study group comparisons. The only difference (duration of ascent) is accounted for by the fact that nine subjects in climbing group one (six of whom received dexamethasone) spent an extra day at 3,000 m to review glacier travel and crevasse rescue. Weather conditions were generally fair with minimal wind and no precipitation during all climbs. Forty-two subjects (89.4 percent) attained the summit. Three subjects in the placebo group failed to reach the summit because of acute mountain sickness. One did not leave the base camp, and the other two stopped at approximately 4,000 m because of symptoms including
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TABLE I
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Group ComparIsonsi
Age (years) Sex, male, (percent) Prior Mt. Rainier ascents (percent) Past history of acute mountain sickness (percent) Time, base camp to summit (hours) Total time to summit (hours) Attained summit (percent) Study drug taken (doses) Additional medications Analgesics (percent) Sedatives (percent) Guessed study drug correctly (percent) Mean and SEM, t p I 0.05.
TABLE II
Dexamethasone (n = 17)
29.3
33.3
f 9.1 86.7 26.7 40.0
8.1 f 29.9
f
7.6 f
f 11.5 88.2 47.1
Placebo (n = 15) 30.1 f 9.0 100 53.3
35.3
0.4 0.9
66.7
7.4 f 0.3 39.8
93.8
f
3.0+
8.2 f 32.1
94.1 0.2
7.1 f
40 13.3 57.1
except
l
Acetazolamide (n = 15)
headache, nausea and/or vomiting, and malaise. Of the two subjects receiving active drug who failed to reach the summit, the climber taking acetazolamide (highest elevation 3,810 m) turned back because of fatigue but did not have symptoms of acute mountain sickness. The climber receiving dexamethasone (highest elevation 3,353 m) turned back because of symptoms of acute mountain sickness. Symptoms of Acute Mountain Sickness. Symptom scores were different between experimental groups at the trailhead (1,300 or 1,600 m) before the group was at risk for acute mountain sickness. As expected, the climbers receiving acetazolamide reported increased urinary frequency more often (acetazolamide-60 percent versus dexamethasone- 11.8 percent, placebo-26.7 percent; p 50.05). However, four unexpected symptoms were associated with acetazolamide at low elevations: nausea (frequency: acetazolamide-20 percent versus dexamethasone- percent, placebo-0 percent; p 50.05); tired (frequency: acetazolamide-66.7 percent versus dexamethasone- 11.8 percent, placebo-33.3 percent; p 50.05); sleepy (symptom scores: acetazolamide-1.87 versus dexamethasone-0.53, placebo-1.07; p 10.05);
f
0.7 2.9
78.6 0.3
7.6 f
29.4 11.8 23.5
0.2
53.3 13.3 64.3
as noted.
Symptoms on the Summit or Highest Altitude Attained Above Base Camp Frequency Dexamethasone (n = 17)
Symptom Positive symptoms Satisfaction Refreshed Happy Energetic Active Thinking clearly Negative symptoms Shortness of breath Urinary frequency Dizziness Tired Drowsy Laziness Irritable Palpitations Headache Nausea Sleepy Difficulty sleeping Clumsy
(percent)
of Significant* Placebo (n = 14)
Symptoms Acetazolamide (n = 15)
Dexamethasone (n = 17)
Mean Symptom Scoresf Placebo (n = 14)
f SEM Acetazofamide (n = 15)
94 63f5 88 53 53 100
77 31 77 21 29 79
80 27 80 20 27 87
3.7 2.3 3.8 1.6 1.9 3.7
f f f f f f
0.4 0.435 0.4 0.3 0.3 0.2
3.0 1.0 2.9 0.8 1.1 2.9
f f f f f f
0.5 0.4 0.5 0.2 0.3 0.4
2.7 1.0 2.9 0.8 0.8 2.9
f f f f f f
0.4 0.3 0.4 0.3 0.3 0.4
59 13 24t 81 56 41 24 47 24 12 53 65 411:
71 14 64 100 86 64 42 64 57 43 70 93 85
67 33 2ot 93 67 60 47 50 33 33 67 4ot 67
1.9 0.6 0.9 2.8 1.9 1.6 1.0 1.6 0.9 0.6 1.9 2.6 1.5
f f f f f f f f f f f f f
0.3 0.2 0.2$ 0.3$ 0.4 0.4 0.3 0.3 0.31 0.3$ 0.4 0.5 0.3$
2.6 0.4 2.1 4.4 2.9 2.6 1.3 2.1 2.3 1.7 2.5 3.6 2.7
f f f f f f f f f f f f f
0.4 0.2 0.5 0.2 0.4 0.5 0.4 0.4 0.5 0.5 0.5 0.4 0.4
2.1 1.1 0.9 3.5 2.2 2.5 1.3 1.6 1.3 1.0 2.3 1.3 2.1
f f f f f f f f f f f f f
0.3 0.4 0.3* 0.3 0.5 0.4 0.3 0.4 0.2 0.3 0.4 0.4’ 0.4
* Significant symptoms = symptom severity rated by subjects as at least “somewhat” (22) on a 0- to 5-point Likert scale. Statistical differences by drug group were analyzed using contingency table techniques. t indicates no symptoms, 1 slight, 2 somewhat, 3 moderate, 4 quite a bit, and extreme. Symptom scores given for illustrative purposes only. Statistical comparisons were based upon mean rank scores utilizing Kruskal-Wallis analysis of variance. * p 10.05, compared with placebo. 5 p 10.05, compared with acetazolamide.
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TABLE III
Symptoms
on the Summit Frequency
Symptom Positive symptoms Satisfaction Refreshed
Happy Energetic Active ’ Thinking clearly Negative symptoms Shortness of breath Urinary frequency Dizziness Tired Drowsy Laziness Irritable Palpitations Headache Nausea Slyw Difficulty sleeping Clumsy * Significant symptoms = differences by drug group 7 0 indicates no symptoms, only. Statistical comparisons t p I 0.05, compared with * p I 0.05, compared with
Dexamethasone (n = 17)
or Highest
(percent)
Altitude
Attained
Above
SICKNESS
Mean Symptom Scorest f Dexamethasone (n = 17)
SEM Acetazolamide Sick Well (n = 7) (n = 8)
Placebo (n = 14)
88
f f f f f f
0.4 0.4@ 0.4 0.3 0.39 0.2
3.0 1.0 2.9 0.8 1.1 2.9
f f f f f: f
0.5 0.4 0.5 0.2 0.3 0.4
2.4 0.7 2.7 0.4 0.4 3.0
f f f f f f
0.5 0.2 0.6 0.3 0.2 0.6
3.0 1.3 3.1 1.1 1.1 2.9
f 0.7 f 0.5 f 0.6 f 0.5 f 0.4 f 0.5
63 25 13t 88 50 50 13i§ 38 38 13x9 38 505 63
1.9 0.6 0.9 2.8 1.9 1.6 1.0 1.6 0.9 0.6 1.9 2.6 1.5
f f f f f f f f f f f f f
0.3 0.2 0.21 0.3x* 0.4 0.4 0.3 0.3 0.3$ 0.35 0.4 0.5 0.3$
2.6 f 0.4 f 2.1 f 4.4 f 2.9 f 2.6 f 1.3 f 2.1 f 2.3 f 1.7 f 2.5 f 3.6f0.4 2.7 f
0.4 0.2 0.5 0.2 0.4 0.5 0.4 0.4 0.5 0.5 0.5
2.4 1.6 1.3 4.0 3.3 3.3 2.1 2.2 1.4 1.7 3.3 1.1 2.6
f 0.6 f 0.6 f 0.5 f 0.4 f 0.7 f 0.6 f 0.5 f 0.7 f 0.3 f 0.5 f 0.4 f0.6’ f 0.6
1.9 0.6 0.6 3.0 1.3 1.8 0.6 1.3 1.1 0.4 1.4 1.4 1.8
f f f f: f f f f f f f f f
77 31 77 21 29 79
86 0 86 14 0 86
75 sots 75 25 50
59 13 24% 81 56 41 24* 47 24 12$§ 53 65t 41
72 14 64 100 86 64 42 64 57 43 70 93 85
71 43 29 100 86 71 86 67 29 57 100 29z 71
symptom severity rated by subjects as at least “somewhat” were analyzed using contingent table techniques. 1 slight, 2 somewhat, 3 moderate, 4 quite a bit, and 5 extreme. were based upon mean rank scores utilizing Kruskal-Wallis placebo. acetazolamide/sick.
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3.7 2.3 3.8 1.6 1.9 3.7
94 631s 88 53 53 100
and refreshed (symptom scores: acetazolamide-2.13 versus dexamethasone-2.94, placebo-3.71; p 10.05). Tsible II shows symptoms at the high point attained above base camp. Climbers taking dexamethasone reported less tiredness, headache, nausea, and clumsiness than those taking placebo (p 50.05). Climbers taking dexamethasone were more refreshed and reported being dizzy less frequently than either of the other two groups. Two other symptoms (feeling cold and runny nose) unrelated to acute mountain sickness were significantly improved by dexamethasone compared with acetazolamide and placebo. Subjects receiving acetazolamide had significantly less difficulty sleeping at altitude than did the placebo subjects. Because symptoms developed in the acetazolamide group that might be associated with acute mountain sickness before additional analgesic medication was initiated by subjects and at low elevations, it was assumed that these symptoms represented a drug side effect that could confound detection of a prophylactic effect of acetazolamide at higher elevations. Thus, the acetazolamide group was divided into two groups, acetazolamide/sick (n = 7), and acetazolamide/well (n = 8), based on the presence or absence of nausea at the trailhead. In this
PROPHYLAXIS-ELLSWORTH
Base Camp
bf Significant*
Placebo (n = 14)
Symptoms Acetazolamide Well Sick (n = 7) (n = 8)
MOUNTAIN
(22)
0.4
on a 0- to S-point
Symptom scores given analysis of variance.
Likert
0.4 0.4 0.3% 0.4t 0.4t 0.5 0.3 0.6 0.3 0.3% 0.6 0s 0.4
scale.
Statistical
for illustrative
purposes
comparison, the prophylactic effect of dexamethasone compared with placebo was unchanged. However, when the climbers with drug side effects due to acetazolamide at low elevation are grouped in a separate subgroup, the remaining climbers (the acetazolamide/well group) experienced a prophylactic effect with significantly less tiredness, drowsiness, dizziness, nausea, and irritability. This group was generally comparable to the dexamethasone group for amelioration of negative symptoms. The dexamethasone group experienced higher levels of positive symptoms (Table III). Using the acute mountain sickness index described earlier (acute mountain sickness present if the mean of scores for dizzy, tired, headache, and clumsy is greater than or equal to 2) revealed that 25 percent of the dexamethasone group and 76.9 percent of the placebo group had the syndrome at the high point. In the aggregate, 53.3 percent of the acetazolamide group had acute mountain sickness. When the acetazolamide group was divided, 25 percent of the acetazolamide/well subgroup and 85.7 percent of the acetazolamide/sick subgroup had acute mountain sickness (dexamethasone versus placebo, p 50.05; acetazolamide/well versus placebo, p 50.05).
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4
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A ~DEXAMETH
m~cETn20~
~PLACEBO
1 3
2 2 8 2’ 5 k0 I > cn
c-POS AMS
1B
a
n
C-NEG SYMPTOM CLUSTERS
DEXLMETH HACUWELL
q
ACLISIW
RESP
q
PL&ZEBO
lz3 r 2
2 c-POS
AMS
C-NEG SYMPTOM CLUSTERS
RESP
Figure 1. A, effects of prophylactic dexamethasone (DEXAMETH), n = 17, compared with ace&o/amide (ACETAZOL), n = 15, and placebo, n = 15 on the severity of averaged acute mountain sickness (AMS) symptoms. * p I 0.05 for comparisons with placebo; t p -< 0.05 for cornparisons with acetazolamide. B, effects of prophylactic dexamethasone (DEXAMETH), n = 17, acetazolamide, and placebo,. n = 15, on the severity of averaged acute moufi tain sickness (AMS) symptoms as in Figure 1A except the acetazolamide group has been subdivided into two groups: those without side effects (ACZ/WfLL), n = 8, and those with side effects (ACZ/SICK). n = 7. * p I 0.05 for comparisons with placebo group; 7 p -< 0.1 for comparisons with acetazolamide/sick subgroup. C-pos, C-neg, and Resp rep resent averages of cerebral (C-pos, C-neg) and respiratory (Resp) symptoms derived from the Environmental Symptoms Questionnaire [ 781 and the General High-Altitude Questionnaire [ 191. C-pos is satisfied, refreshed, happy, active, and energetic. C-neg is dizzy, tired, drowsy, lazy, sleepy, and difficulty sleeping. Resp is shortness of breath, tired, lazy, and palpitations.
In the analysis of the positive and negative cerebral (Cpos, C-neg) and respiratory (Resp) symptom scores [13,20], dexamethasone improved C-pos (2.68 f 1.2) compared with both acetazolamide (1.65 f 1.0) and placebo(l.74f 1.2;p10.05).BbthC-neg(1.94f 1.2) and Resp (1.93 f 0.9) were significantly reduced by dexamethasone compared with placebo (3.0 f 1.1, 2.93 f 1.1; p 5 0.05) but were not significantly changed from the acetazolamide group (2.1 f 1.1, 2.5 f 1.1). Figure 1A depicts these indices and again shows that dexameth1028
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asone is effective prophylaxis in all comparisons with placebo. The data (Figure 1 B) also suggest that acetazolamide, in the absence of side effects, improves respiratory and negative cerebral symptoms but not positive cerebral symptoms. There was a highly significant correlation between our acute mountain sickness index and the averaged cerebral and respiratory indices (correiation coefficient with C-pos, -0.44, p = 0.002; .with Gneg, 0.80, p
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perature variations) [23] probably contribute to its prophylactic efficacy when efficacy is judged by subjective scales [ 131. Since supplemental oxygen on ascent prevents symptoms, most investigators have assumed that hypoxia is the cause of acute mountain sickness. However, the failure of oxygen to bring total relief suggests that the signs and symptoms of acute mountain syndrome are caused by compensatory changes initiated by hypoxia [24]. Several authors have shown that on ascent to high altitude, cerebral blood flow increases, taking six to 36 hours to reach maximum, and then gradually decreasing toward normal over five to six days [1,25]. The time course of the increase and decline in cerebral blood flow is accompanied by vasodilatory changes in retinal blood flow [13] and is similar to the time course of acute mountain sickness. Other studies support this line of reasoning. Measures that would reduce cerebral blood flow are effective in amelioration of headache due to acute mountain sickness [26]. Forced hyperventilation reduces cerebral blood flow through decreased hypoxic vasodilation and increased vasoconstriction [24]. Headache and other symptoms of the disease are increased by supplemental carbon dioxide [27]. More recently, the headache occurring at high altitude could not be attributed to increases in cerebral blood flow when measured by Doppler ultrasound, even though the headaches tended to occur in association with the most severe hypoxemia [28]. Hence, alternative pathophysiologic explanations must be considered such as an altitude effect on cerebral venous pressure, cerebral spinal fluid dynamics, or an increase in permeability. Whatever the underlying mechanism, vasogenic cerebral edema occurs with exposure to high altitude in association with hyperfiltration through microcirculation [24,29]. Although this study does not elucidate the precise mechanism by which dexamethasone exerts a prophylactic effect, one logical explanation is that dexamethasone prevents symptoms by minimizing edema formation. Dexamethasone is associated with reduced retinal artery vasodilation [ 131. Thus, dexamethasone could be associated with reduced cerebral blood flow [24] and improved microcirculatory integrity [30], thereby reducing edema by decreasing filtration through the microcirculation. The drug is known to improve vasogenic cerebral edema by this mechanism [30]. Climbers in our study taking acetazolamide reported less difficulty sleeping at altitude. Periodic breathing dur-
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ing sleep, a common cause of frequent awakening, is almost universal at altitude [31] and is eliminated by acetazolamide. Whether the prophylactic effect of acetazolamide on acute mountain sickness is due to improved sleep or some other mechanism (increased ventilation, mild diuretic effects, decreased production of cerebrospinal fluid, or a combination of these) is not known. The adverse effects reported with use of acetazolamide include paresthesias, polyuria, nausea and vomiting, drowsiness, and lethargy [25]. Although nausea has not been reported as an adverse effect in previous trials, it is commonly seen in clinical practice (ophthalmology) [32] and in the field (personal communication, Peter Hackett, M.D.). Since this particular side effect overlaps significantly with the symptoms of acute mountain sickness, one must be cautious in advising prophylactic therapy with acetazolamide for all persons ascending to altitude. This situation also highlights the importance of a placebo in clinical trials comparing the efficacy of medications for acute mountain sickness. CONCLUSlONS We have shown that dexamethasone can prevent the symptoms of acute mountain sickness in fit climbers involved in active ascent to an altitude of 4,392 m on Mount Rainier at least as effectively as acetazolamide and apparently with fewer side effects. Although no adverse effects were associated with this short, albeit, high-dose course of dexamethasone, only 25 cases have been reported and thus we urge caution and cannot yet recommend widespread use of dexamethasone prophylaxis [33]. Most cases of acute mountain sickness are selflimiting. Additional experience is necessary to completely evaluate this promising but potentially toxic therapy. Acetazolamide is still considered the drug of choice for chemoprophylaxis of acute mountain sickness. Dexamethasone might be considered in the situation of a forced rapid ascent to a very high altitude (i.e., flying to above 14,000 feet on an overnight rescue). As demonstrated in this study, side effects are important when considering drug prophylaxis for acute mountain sickness. ACKNOWLEDGMENT We would like to thank Kenneth A. Myrabo, R.R.T., M.M., Respiratory Care Services, and Theodore T. Taniguchi, R.Ph., MSc., Pharmacy Services, for their technical assistance; both are from University Hospital, University of Washington, Seattle, Washington.
REFERENCES 1. 2.
Singh I, Khanna PK, Srivastava MC, et al: Acute mountain sickness. N Engl J Med 1969; 280: 175-184. Hackett PH. Rennie D, Levine HD: The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 1976; II: 1149-1154.
December
3. 4. 5.
1987
Houston CS: ifestations. Hultgren HN: 1979; 131: McLennan J,
The American
High altitude illness: disease with protean manJAMA 1976; 236: 2193-2195. High altitude medical problems. West J Med 18-23. Ungersma J: Mountaineering accidents in the
Journal
of Medicine
Volume
93
1029
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6.
7.
a.
9.
10. 11.
12. 13. 14. 15. 16. 17.
18.
19.
1030
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ET AL
Sierra Nevada. Am J Sports Med 1983; 11: 160-163. Stamoer DA, Sterner RT, Robinson SM: Evaluation of an acute mountain sickness questionnaire: effects of intermediate-altitude staging upon subjective symptomatology. Avait Space Environ Med 1980; 51: 379-387. Larson EB, Roach RC, Schoene RB, Hornbein TF: Acute mountain sickness and acetazolamide: clinical efficacy and effect on ventilation. JAMA 1982; 248: 328-332. Birmingham Medical Research Expeditionary Society Mountain Sickness Group: Acetazolamide in the control of acute mountain sickness. Lancet 1981; I: 180-183. Evans WO, Robinson SM, Horstman OH, et al: Amelioration of the symptoms of acute mountain sickness by staging and acetazolamide. Avait Space Environ Med 1976; 47: 512-516. Gray GW, ‘Bryan AC, Frayser R, et al: Control of acute mountain sickness. Aerospace Med 1971; 42: 81-84. Forwand SA, Landowne M, Follansbee JN, Hansen JE: Effect of acetazolamide on acute mountain sickness. N Engl J Med 1968; 279: 839-845. Cain SM, Dunn JE: Low doses of acetazolamide to aid accommodation of men to altitude. J Appl Physiol 1966; 21: 1195-1200. Johnson TS, Rock PB, Fulco CS, et al: Prevention of acute mountain sickness by dexamethasone. N Engl J Med 1984; 310: 683-686. Ferreira P, Grundy P: Dexamethasone in the treatment of acute mountain sickness (letter). N Engl J Med 1985; 312: 1390. Houston CS, Dickinson J: Cerebral form of high altitude illness. Lancet 1975; II: 758-761. Acetazolamide for acute mountain sickness. FDA Drug Bulletin 1983; 13: 27. Roach RC, Larson EB, Hornbein TF, et al: Acute mountain sickness, antacids, and ventilation during rapid, active ascent of Mount Rainier. Avait Space Environ Med 1983; 541397-40 1. Sampson JB, Cymerman A, Burse RL, et al: Procedures for the measurement of acute mountain sickness. Avait Space Environ Med 1983; 54: 1063-1073. Stamper DA, Sterner RT, Kinsman RA: Symptomatology
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subscales for the measurement of acute mountain sickness. Percept Mot Skills 1971; 33: 735-742. Wohns RNW, Colpitts M, Clement T, et al: Phenytoin and acute mountain sickness on Mount Everest. Am J Med 1986; 80: 32-36. Norusis MJ: SPSS/PC+TM for the IBM PC/XT/AT. Chicago: SPSS, 1986. Dixon WJ: BMDP statistical software. Berkley: University of California Press, 1985. Haynes RC, Muran F: Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of adrenocortical steroid biosynthesis. In: Gilman AG, Goodman LS, Rail TW, Muran F, eds. Goodman and Gilman’s the pharmacological basis of therapeutics 7th ed. New York: Macmillan, 1985; 1470-1471. Severinghaus JW, Chiodi H, Eger El, et al: Cerebral blood flow in man at high altitude. Circ Res 1966; 19: 274-282. Hackett PH, Rennie D: Acute mountain sickness. Semin Res Med 1983; 5: 132-140. Carson R, Evans W: Symptomatology, pathophysiology and treatment of acute mountain sickness. Fed Proc 1969; 28: 1085-1091. Maher JT, Cymerman A, Reeves JT, et al: Acute mountain sickness: increased severity in eucapnic hypoxia. Avait Space Environ Med 1975; 46: 826-829. Reeves JT, Moore LG, McCullough RE, et al: Headache at high altitude is not related to internal carotid arterial blood vefocity. J Appl Physiol 1985; 59: 909-915. Lassen NA: The brain: cerebral blood flow. In: Sutton JR, Jones NL, Houston CS, eds. Hypoxia: man at altitude. New York: Thieme-Stratton, 1982. Gutin PH: Corticosteroid therapy in patients with cerebral tumors: benefits, mechanisms, problems, practicalities. Semin Oncol 1975; 2: 49-56. Sutton JR, Houston CS, Mansell AL, et al: Effect of acetazolamide on hypoxemia during sleep at high altitude. N Engl J Med 1979; 301: 1329-1331. Havener WH: Secretory inhibitors. In: Ocular Pharmacology, 4th ed. St. Louis: CV Mosby, 1978; 475-496. Shlim DR: Treatment of Acute Mountain Sickness (letter). N Engl J Med 1985; 313: 891-892.
20. 21.
22. 23.
24. 25. 26. 27. 28.
29.
30. 31.
32. 33.
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ALLAN J. ELLSWORTH, Pharm.D. ERIC B. LARSON, M.D., M.P.H. DANIEL STRICKLAND, Ph.D. Seattle,
Forty-seven climbers participated in a double-blind, randomized trial comparing acetazolamide 250 mg, dexamethasone 4 mg, and placebo every eight hours as prophylaxis for acute mountain sickness during rapid, active ascent of Mount Rainier (elevation 4,392 m). Forty-two subjects (89.4 percent) achieved the summit in an average of 34.5 hours after leaving sea level. At the summit or high point attained above base camp, the group taking dexamethasone reported less headache, tiredness, dizziness, nausea, clumsiness, and a greater sense of feeling refreshed (p _<0.05). In addition, they reported fewer problems of runny nose and feeling cold, symptoms unrelated to acute mountain sickness. The acetazolamide group differed significantly (p 10.05) from other groups at low elevations (1,300 to 1,800 m), in that they experienced more feelings of nausea and tiredness, and they were less refreshed. These drug side effects probably obscured the previously established prophylactic effects of acetazolamide for acute mountain sickness. Separate analysis of an acetazolamide subgroup that did not experience side effects at low elevations revealed a prophylactic effect of acetazolamide similar in magnitude to the dexamethasone effect but lacking the euphoric effects of dexamethasone. This study demonstrates that prophylaxis with dexamethasone can reduce the symptoms associated with acute mountain sickness during active ascent and that acetazolamide can cause side effects that may limit its effectiveness as prophylaxis against the disease.
Washington
From the Schools of Pharmacy, Medicine, and Public Health, University of Washington, Seattle, Washington. Requests for reprints should be addressed to Dr. Allan Ellsworth, Department of Family Medicine, RF-30, University of Washington, Seattle, Washington 98195. Manuscript submitted May 18, 1987, and accepted August 13, 1987.
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Acute mountain sickness is a syndrome characterized by headache, nausea, excessive fatigue, loss of appetite, breathlessness, and insomnia [ 11. It is most likely to occur after rapid ascent to elevations higher than 3,000 m above sea level [ 1,2]. Although the precise pathophysiology of the disorder is unclear, it is part of a continuum of altitude-induced illnesses including high altitude pulmonary edema and high altitude cerebral edema, all presumably reflecting a common underlying physiologic response to hypoxia [3,4]. Although acute mountain sickness is generally benign and self-limited, impaired judgment and physical ability may compromise the enjoyment and safety of those visiting high altitudes [5]. Slow, staged ascent to altitude is effective in preventing acute mountain sickness, but is not always practical, especially in mountain rescue and military activities [6]. Prophylactic therapy with acetazolamide has been shown to reduce symptoms and symptom severity in subjects whether they achieve high altitude actively or passively [2,7-121. In a recent study of sedentary subjects exposed to simulated high altitude (4,570 m), prophylactic therapy with dexamethasone significantly decreased both cerebral and respiratory symptoms of acute mountain
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sickness [ 131. Betamethasone and dexamethasone have also been used to treat serious acute symptoms [ 1,14,15]. No investigators have assessed the efficacy of prophylactic dexamethasone during active ascent and its efficacy relative to acetazolamide, the accepted prophylactic agent [16], in randomized trials. Mount Rainier (4,392 m), climbed by more than 8,000 people per year, is a proven laboratory for the study of prophylactic drug regimens under actual climbing conditions [7,17]. We performed a double-blind, randomized trial comparing dexamethasone, acetazolamide, and placebo during standard weekend climbs of Mount Rainier.
SUBJECTS AND METHODS Subjects. The study group consisted of 47 volunteer climbers in five climbing parties, aged 18 to 52 years (43 men, four women) who normally resided at or near sea level. All were in good health with no previous history of acid-peptic disease or psychiatric disease. All gave informed consent. The Climb. Subjects drove from sea level to a trailhead at either 1,300 m on the northeast side or 1,600 m on the south side of Mount Rainier. Active ascent to a base camp at approximately 3,000 m averaged 6.8 hours. The ascent to the summit (4,392 m) began in the early morning (between 1 A.M. and 2 A.M.) on the second day, and was followed by return to road’s end the same day. The Randomized Trial. The study employed a doubleblind, placebo-controlled design. Using a random numbers table, subjects were assigned to receive identical-appearing pink capsules of either acetazolamide 250 mg (Lederle Laboratories lot 770), dexamethasone 4 mg (Merck Sharpe & Dohme lot 1OS-SSS), or lactose placebo every eight hours beginning 24 hours before ascent. Concomitant use of additional medications was recorded but unrestricted. Packets containing study medication, data collection forms, and instruction sheets were distributed at orientation sessions several days before each ascent. During these sessions, subjects were informed of study and climb details and were instructed in data collection methods. One of the investigators (A.E.) accompanied all climbing parties to validate and verify symptomatology and data collection. Assessment of Acute Mountain Sickness. A combined, abbreviated version of the Environmental Symptoms Questionnaire [ 181 and the General High-Altitude Questionnaire [ 191 was used to assess symptoms of acute mountain sickness [7,17]. Thirty symptoms were rated on 0- to 5 point Likert scales (0, not at all; 1, slight; 2, somewhat; 3, moderate; 4, quite a bit; and 5, extreme). Questionnaires were completed at 1,300 m or 1,600 m (trailhead), 3,000 m (base camp), 4,392 m (summit) or high point attained above base camp, and 3,000 m (base camp) on descent. The data collected at the trailhead after subjects had taken the first four doses of medication permitted post-hoc detection of a drug side effect. Based on a trial [7] conducted under similar conditions, acute mountain sickness was originally and arbitrarily defined as headache rated 2 or greater, nausea rated 1 or greater, or both on the symptom scales. However, this definition resulted in an incidence of the
MOUNTAIN
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ET AL
syndrome at the summit that was much higher than expected (placebo, 80 percent; acetazolamide, 78.8 percent; dexamethasone, 41.2 percent) [7] and did not agree with our clinical observations on the mountain. Also, 20 percent of climbers taking acetazolamide reported nausea at low elevation (1,300 to 1,600 m) compared with none of the climbers in the other two treatment groups, representing a drug side effect confounding symptoms of acute mountain sickness. Therefore, several symptoms (dizziness, tiredness, headache, and clumsiness) prominent in our subjects with acute mountain sickness and similar to symptoms used in other trials [1,2] were combined to define an acute mountain sickness index. The acute mountain sickness index was the mean of a subject’s scores for these symptoms at the high point. Acute mountain sickness was defined when individuals had scores of 2 or greater on this Oto &point scale. Nausea that occurred at low elevations as a side effect of acetazolamide was deliberately excluded from the index. Thus, the acute mountain sickness index does not include adverse effects of acetazolamide but still allows acetazolamide-treated climbers with nausea at low elevation and acute mountain sickness symptoms at higher elevations to be classified. Averaged cerebral and respiratory severity scores were also utilized to compare the degree of acute mountain sickness in experimental groups [ 131. Cerebral symptoms were divided into positive and negative clusters [20]. The positive cerebral average (C-pos) contained the “symptoms” satisfied, refreshed, happy, active, and energetic. The negative cerebral average (C-neg) represented the symptoms dizzy, tired, drowsy, lazy, sleepy, and trouble sleeping at altitude. The respiratory average (Resp) included shortness of breath, tired, lazy, and palpitations. Statistical Analysis. Subjective symptom scores were compared for each drug group by two complementary methods: First, the mean rank of the scores was computed and evaluated for differences by drug categories by Kruskal-Wallis one-way analysis of variance. These same scores were then categorized into two groups, using “2” as a cutoff point for significant symptoms (0 to 1, 2 to 5), and analyzed by drug group using contingency table techniques. An alpha level of p 10.05 was used in estimating sample size and as a criterion for statistical significance [21,22]. A beta error of 0.20 (power = 0.80) was selected as a basis for detecting false-negative results.
RESULTS Group Description. Table I shows study group comparisons. The only difference (duration of ascent) is accounted for by the fact that nine subjects in climbing group one (six of whom received dexamethasone) spent an extra day at 3,000 m to review glacier travel and crevasse rescue. Weather conditions were generally fair with minimal wind and no precipitation during all climbs. Forty-two subjects (89.4 percent) attained the summit. Three subjects in the placebo group failed to reach the summit because of acute mountain sickness. One did not leave the base camp, and the other two stopped at approximately 4,000 m because of symptoms including
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TABLE I
SICKNESS
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Group ComparIsonsi
Age (years) Sex, male, (percent) Prior Mt. Rainier ascents (percent) Past history of acute mountain sickness (percent) Time, base camp to summit (hours) Total time to summit (hours) Attained summit (percent) Study drug taken (doses) Additional medications Analgesics (percent) Sedatives (percent) Guessed study drug correctly (percent) Mean and SEM, t p I 0.05.
TABLE II
Dexamethasone (n = 17)
29.3
33.3
f 9.1 86.7 26.7 40.0
8.1 f 29.9
f
7.6 f
f 11.5 88.2 47.1
Placebo (n = 15) 30.1 f 9.0 100 53.3
35.3
0.4 0.9
66.7
7.4 f 0.3 39.8
93.8
f
3.0+
8.2 f 32.1
94.1 0.2
7.1 f
40 13.3 57.1
except
l
Acetazolamide (n = 15)
headache, nausea and/or vomiting, and malaise. Of the two subjects receiving active drug who failed to reach the summit, the climber taking acetazolamide (highest elevation 3,810 m) turned back because of fatigue but did not have symptoms of acute mountain sickness. The climber receiving dexamethasone (highest elevation 3,353 m) turned back because of symptoms of acute mountain sickness. Symptoms of Acute Mountain Sickness. Symptom scores were different between experimental groups at the trailhead (1,300 or 1,600 m) before the group was at risk for acute mountain sickness. As expected, the climbers receiving acetazolamide reported increased urinary frequency more often (acetazolamide-60 percent versus dexamethasone- 11.8 percent, placebo-26.7 percent; p 50.05). However, four unexpected symptoms were associated with acetazolamide at low elevations: nausea (frequency: acetazolamide-20 percent versus dexamethasone- percent, placebo-0 percent; p 50.05); tired (frequency: acetazolamide-66.7 percent versus dexamethasone- 11.8 percent, placebo-33.3 percent; p 50.05); sleepy (symptom scores: acetazolamide-1.87 versus dexamethasone-0.53, placebo-1.07; p 10.05);
f
0.7 2.9
78.6 0.3
7.6 f
29.4 11.8 23.5
0.2
53.3 13.3 64.3
as noted.
Symptoms on the Summit or Highest Altitude Attained Above Base Camp Frequency Dexamethasone (n = 17)
Symptom Positive symptoms Satisfaction Refreshed Happy Energetic Active Thinking clearly Negative symptoms Shortness of breath Urinary frequency Dizziness Tired Drowsy Laziness Irritable Palpitations Headache Nausea Sleepy Difficulty sleeping Clumsy
(percent)
of Significant* Placebo (n = 14)
Symptoms Acetazolamide (n = 15)
Dexamethasone (n = 17)
Mean Symptom Scoresf Placebo (n = 14)
f SEM Acetazofamide (n = 15)
94 63f5 88 53 53 100
77 31 77 21 29 79
80 27 80 20 27 87
3.7 2.3 3.8 1.6 1.9 3.7
f f f f f f
0.4 0.435 0.4 0.3 0.3 0.2
3.0 1.0 2.9 0.8 1.1 2.9
f f f f f f
0.5 0.4 0.5 0.2 0.3 0.4
2.7 1.0 2.9 0.8 0.8 2.9
f f f f f f
0.4 0.3 0.4 0.3 0.3 0.4
59 13 24t 81 56 41 24 47 24 12 53 65 411:
71 14 64 100 86 64 42 64 57 43 70 93 85
67 33 2ot 93 67 60 47 50 33 33 67 4ot 67
1.9 0.6 0.9 2.8 1.9 1.6 1.0 1.6 0.9 0.6 1.9 2.6 1.5
f f f f f f f f f f f f f
0.3 0.2 0.2$ 0.3$ 0.4 0.4 0.3 0.3 0.31 0.3$ 0.4 0.5 0.3$
2.6 0.4 2.1 4.4 2.9 2.6 1.3 2.1 2.3 1.7 2.5 3.6 2.7
f f f f f f f f f f f f f
0.4 0.2 0.5 0.2 0.4 0.5 0.4 0.4 0.5 0.5 0.5 0.4 0.4
2.1 1.1 0.9 3.5 2.2 2.5 1.3 1.6 1.3 1.0 2.3 1.3 2.1
f f f f f f f f f f f f f
0.3 0.4 0.3* 0.3 0.5 0.4 0.3 0.4 0.2 0.3 0.4 0.4’ 0.4
* Significant symptoms = symptom severity rated by subjects as at least “somewhat” (22) on a 0- to 5-point Likert scale. Statistical differences by drug group were analyzed using contingency table techniques. t indicates no symptoms, 1 slight, 2 somewhat, 3 moderate, 4 quite a bit, and extreme. Symptom scores given for illustrative purposes only. Statistical comparisons were based upon mean rank scores utilizing Kruskal-Wallis analysis of variance. * p 10.05, compared with placebo. 5 p 10.05, compared with acetazolamide.
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TABLE III
Symptoms
on the Summit Frequency
Symptom Positive symptoms Satisfaction Refreshed
Happy Energetic Active ’ Thinking clearly Negative symptoms Shortness of breath Urinary frequency Dizziness Tired Drowsy Laziness Irritable Palpitations Headache Nausea Slyw Difficulty sleeping Clumsy * Significant symptoms = differences by drug group 7 0 indicates no symptoms, only. Statistical comparisons t p I 0.05, compared with * p I 0.05, compared with
Dexamethasone (n = 17)
or Highest
(percent)
Altitude
Attained
Above
SICKNESS
Mean Symptom Scorest f Dexamethasone (n = 17)
SEM Acetazolamide Sick Well (n = 7) (n = 8)
Placebo (n = 14)
88
f f f f f f
0.4 0.4@ 0.4 0.3 0.39 0.2
3.0 1.0 2.9 0.8 1.1 2.9
f f f f f: f
0.5 0.4 0.5 0.2 0.3 0.4
2.4 0.7 2.7 0.4 0.4 3.0
f f f f f f
0.5 0.2 0.6 0.3 0.2 0.6
3.0 1.3 3.1 1.1 1.1 2.9
f 0.7 f 0.5 f 0.6 f 0.5 f 0.4 f 0.5
63 25 13t 88 50 50 13i§ 38 38 13x9 38 505 63
1.9 0.6 0.9 2.8 1.9 1.6 1.0 1.6 0.9 0.6 1.9 2.6 1.5
f f f f f f f f f f f f f
0.3 0.2 0.21 0.3x* 0.4 0.4 0.3 0.3 0.3$ 0.35 0.4 0.5 0.3$
2.6 f 0.4 f 2.1 f 4.4 f 2.9 f 2.6 f 1.3 f 2.1 f 2.3 f 1.7 f 2.5 f 3.6f0.4 2.7 f
0.4 0.2 0.5 0.2 0.4 0.5 0.4 0.4 0.5 0.5 0.5
2.4 1.6 1.3 4.0 3.3 3.3 2.1 2.2 1.4 1.7 3.3 1.1 2.6
f 0.6 f 0.6 f 0.5 f 0.4 f 0.7 f 0.6 f 0.5 f 0.7 f 0.3 f 0.5 f 0.4 f0.6’ f 0.6
1.9 0.6 0.6 3.0 1.3 1.8 0.6 1.3 1.1 0.4 1.4 1.4 1.8
f f f f: f f f f f f f f f
77 31 77 21 29 79
86 0 86 14 0 86
75 sots 75 25 50
59 13 24% 81 56 41 24* 47 24 12$§ 53 65t 41
72 14 64 100 86 64 42 64 57 43 70 93 85
71 43 29 100 86 71 86 67 29 57 100 29z 71
symptom severity rated by subjects as at least “somewhat” were analyzed using contingent table techniques. 1 slight, 2 somewhat, 3 moderate, 4 quite a bit, and 5 extreme. were based upon mean rank scores utilizing Kruskal-Wallis placebo. acetazolamide/sick.
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3.7 2.3 3.8 1.6 1.9 3.7
94 631s 88 53 53 100
and refreshed (symptom scores: acetazolamide-2.13 versus dexamethasone-2.94, placebo-3.71; p 10.05). Tsible II shows symptoms at the high point attained above base camp. Climbers taking dexamethasone reported less tiredness, headache, nausea, and clumsiness than those taking placebo (p 50.05). Climbers taking dexamethasone were more refreshed and reported being dizzy less frequently than either of the other two groups. Two other symptoms (feeling cold and runny nose) unrelated to acute mountain sickness were significantly improved by dexamethasone compared with acetazolamide and placebo. Subjects receiving acetazolamide had significantly less difficulty sleeping at altitude than did the placebo subjects. Because symptoms developed in the acetazolamide group that might be associated with acute mountain sickness before additional analgesic medication was initiated by subjects and at low elevations, it was assumed that these symptoms represented a drug side effect that could confound detection of a prophylactic effect of acetazolamide at higher elevations. Thus, the acetazolamide group was divided into two groups, acetazolamide/sick (n = 7), and acetazolamide/well (n = 8), based on the presence or absence of nausea at the trailhead. In this
PROPHYLAXIS-ELLSWORTH
Base Camp
bf Significant*
Placebo (n = 14)
Symptoms Acetazolamide Well Sick (n = 7) (n = 8)
MOUNTAIN
(22)
0.4
on a 0- to S-point
Symptom scores given analysis of variance.
Likert
0.4 0.4 0.3% 0.4t 0.4t 0.5 0.3 0.6 0.3 0.3% 0.6 0s 0.4
scale.
Statistical
for illustrative
purposes
comparison, the prophylactic effect of dexamethasone compared with placebo was unchanged. However, when the climbers with drug side effects due to acetazolamide at low elevation are grouped in a separate subgroup, the remaining climbers (the acetazolamide/well group) experienced a prophylactic effect with significantly less tiredness, drowsiness, dizziness, nausea, and irritability. This group was generally comparable to the dexamethasone group for amelioration of negative symptoms. The dexamethasone group experienced higher levels of positive symptoms (Table III). Using the acute mountain sickness index described earlier (acute mountain sickness present if the mean of scores for dizzy, tired, headache, and clumsy is greater than or equal to 2) revealed that 25 percent of the dexamethasone group and 76.9 percent of the placebo group had the syndrome at the high point. In the aggregate, 53.3 percent of the acetazolamide group had acute mountain sickness. When the acetazolamide group was divided, 25 percent of the acetazolamide/well subgroup and 85.7 percent of the acetazolamide/sick subgroup had acute mountain sickness (dexamethasone versus placebo, p 50.05; acetazolamide/well versus placebo, p 50.05).
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4
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A ~DEXAMETH
m~cETn20~
~PLACEBO
1 3
2 2 8 2’ 5 k0 I > cn
c-POS AMS
1B
a
n
C-NEG SYMPTOM CLUSTERS
DEXLMETH HACUWELL
q
ACLISIW
RESP
q
PL&ZEBO
lz3 r 2
2 c-POS
AMS
C-NEG SYMPTOM CLUSTERS
RESP
Figure 1. A, effects of prophylactic dexamethasone (DEXAMETH), n = 17, compared with ace&o/amide (ACETAZOL), n = 15, and placebo, n = 15 on the severity of averaged acute mountain sickness (AMS) symptoms. * p I 0.05 for comparisons with placebo; t p -< 0.05 for cornparisons with acetazolamide. B, effects of prophylactic dexamethasone (DEXAMETH), n = 17, acetazolamide, and placebo,. n = 15, on the severity of averaged acute moufi tain sickness (AMS) symptoms as in Figure 1A except the acetazolamide group has been subdivided into two groups: those without side effects (ACZ/WfLL), n = 8, and those with side effects (ACZ/SICK). n = 7. * p I 0.05 for comparisons with placebo group; 7 p -< 0.1 for comparisons with acetazolamide/sick subgroup. C-pos, C-neg, and Resp rep resent averages of cerebral (C-pos, C-neg) and respiratory (Resp) symptoms derived from the Environmental Symptoms Questionnaire [ 781 and the General High-Altitude Questionnaire [ 191. C-pos is satisfied, refreshed, happy, active, and energetic. C-neg is dizzy, tired, drowsy, lazy, sleepy, and difficulty sleeping. Resp is shortness of breath, tired, lazy, and palpitations.
In the analysis of the positive and negative cerebral (Cpos, C-neg) and respiratory (Resp) symptom scores [13,20], dexamethasone improved C-pos (2.68 f 1.2) compared with both acetazolamide (1.65 f 1.0) and placebo(l.74f 1.2;p10.05).BbthC-neg(1.94f 1.2) and Resp (1.93 f 0.9) were significantly reduced by dexamethasone compared with placebo (3.0 f 1.1, 2.93 f 1.1; p 5 0.05) but were not significantly changed from the acetazolamide group (2.1 f 1.1, 2.5 f 1.1). Figure 1A depicts these indices and again shows that dexameth1028
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asone is effective prophylaxis in all comparisons with placebo. The data (Figure 1 B) also suggest that acetazolamide, in the absence of side effects, improves respiratory and negative cerebral symptoms but not positive cerebral symptoms. There was a highly significant correlation between our acute mountain sickness index and the averaged cerebral and respiratory indices (correiation coefficient with C-pos, -0.44, p = 0.002; .with Gneg, 0.80, p
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ACUTE
perature variations) [23] probably contribute to its prophylactic efficacy when efficacy is judged by subjective scales [ 131. Since supplemental oxygen on ascent prevents symptoms, most investigators have assumed that hypoxia is the cause of acute mountain sickness. However, the failure of oxygen to bring total relief suggests that the signs and symptoms of acute mountain syndrome are caused by compensatory changes initiated by hypoxia [24]. Several authors have shown that on ascent to high altitude, cerebral blood flow increases, taking six to 36 hours to reach maximum, and then gradually decreasing toward normal over five to six days [1,25]. The time course of the increase and decline in cerebral blood flow is accompanied by vasodilatory changes in retinal blood flow [13] and is similar to the time course of acute mountain sickness. Other studies support this line of reasoning. Measures that would reduce cerebral blood flow are effective in amelioration of headache due to acute mountain sickness [26]. Forced hyperventilation reduces cerebral blood flow through decreased hypoxic vasodilation and increased vasoconstriction [24]. Headache and other symptoms of the disease are increased by supplemental carbon dioxide [27]. More recently, the headache occurring at high altitude could not be attributed to increases in cerebral blood flow when measured by Doppler ultrasound, even though the headaches tended to occur in association with the most severe hypoxemia [28]. Hence, alternative pathophysiologic explanations must be considered such as an altitude effect on cerebral venous pressure, cerebral spinal fluid dynamics, or an increase in permeability. Whatever the underlying mechanism, vasogenic cerebral edema occurs with exposure to high altitude in association with hyperfiltration through microcirculation [24,29]. Although this study does not elucidate the precise mechanism by which dexamethasone exerts a prophylactic effect, one logical explanation is that dexamethasone prevents symptoms by minimizing edema formation. Dexamethasone is associated with reduced retinal artery vasodilation [ 131. Thus, dexamethasone could be associated with reduced cerebral blood flow [24] and improved microcirculatory integrity [30], thereby reducing edema by decreasing filtration through the microcirculation. The drug is known to improve vasogenic cerebral edema by this mechanism [30]. Climbers in our study taking acetazolamide reported less difficulty sleeping at altitude. Periodic breathing dur-
MOUNTAIN
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PROPHYLAXIS-ELLSWORTH
ET AL
ing sleep, a common cause of frequent awakening, is almost universal at altitude [31] and is eliminated by acetazolamide. Whether the prophylactic effect of acetazolamide on acute mountain sickness is due to improved sleep or some other mechanism (increased ventilation, mild diuretic effects, decreased production of cerebrospinal fluid, or a combination of these) is not known. The adverse effects reported with use of acetazolamide include paresthesias, polyuria, nausea and vomiting, drowsiness, and lethargy [25]. Although nausea has not been reported as an adverse effect in previous trials, it is commonly seen in clinical practice (ophthalmology) [32] and in the field (personal communication, Peter Hackett, M.D.). Since this particular side effect overlaps significantly with the symptoms of acute mountain sickness, one must be cautious in advising prophylactic therapy with acetazolamide for all persons ascending to altitude. This situation also highlights the importance of a placebo in clinical trials comparing the efficacy of medications for acute mountain sickness. CONCLUSlONS We have shown that dexamethasone can prevent the symptoms of acute mountain sickness in fit climbers involved in active ascent to an altitude of 4,392 m on Mount Rainier at least as effectively as acetazolamide and apparently with fewer side effects. Although no adverse effects were associated with this short, albeit, high-dose course of dexamethasone, only 25 cases have been reported and thus we urge caution and cannot yet recommend widespread use of dexamethasone prophylaxis [33]. Most cases of acute mountain sickness are selflimiting. Additional experience is necessary to completely evaluate this promising but potentially toxic therapy. Acetazolamide is still considered the drug of choice for chemoprophylaxis of acute mountain sickness. Dexamethasone might be considered in the situation of a forced rapid ascent to a very high altitude (i.e., flying to above 14,000 feet on an overnight rescue). As demonstrated in this study, side effects are important when considering drug prophylaxis for acute mountain sickness. ACKNOWLEDGMENT We would like to thank Kenneth A. Myrabo, R.R.T., M.M., Respiratory Care Services, and Theodore T. Taniguchi, R.Ph., MSc., Pharmacy Services, for their technical assistance; both are from University Hospital, University of Washington, Seattle, Washington.
REFERENCES 1. 2.
Singh I, Khanna PK, Srivastava MC, et al: Acute mountain sickness. N Engl J Med 1969; 280: 175-184. Hackett PH. Rennie D, Levine HD: The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 1976; II: 1149-1154.
December
3. 4. 5.
1987
Houston CS: ifestations. Hultgren HN: 1979; 131: McLennan J,
The American
High altitude illness: disease with protean manJAMA 1976; 236: 2193-2195. High altitude medical problems. West J Med 18-23. Ungersma J: Mountaineering accidents in the
Journal
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6.
7.
a.
9.
10. 11.
12. 13. 14. 15. 16. 17.
18.
19.
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Sierra Nevada. Am J Sports Med 1983; 11: 160-163. Stamoer DA, Sterner RT, Robinson SM: Evaluation of an acute mountain sickness questionnaire: effects of intermediate-altitude staging upon subjective symptomatology. Avait Space Environ Med 1980; 51: 379-387. Larson EB, Roach RC, Schoene RB, Hornbein TF: Acute mountain sickness and acetazolamide: clinical efficacy and effect on ventilation. JAMA 1982; 248: 328-332. Birmingham Medical Research Expeditionary Society Mountain Sickness Group: Acetazolamide in the control of acute mountain sickness. Lancet 1981; I: 180-183. Evans WO, Robinson SM, Horstman OH, et al: Amelioration of the symptoms of acute mountain sickness by staging and acetazolamide. Avait Space Environ Med 1976; 47: 512-516. Gray GW, ‘Bryan AC, Frayser R, et al: Control of acute mountain sickness. Aerospace Med 1971; 42: 81-84. Forwand SA, Landowne M, Follansbee JN, Hansen JE: Effect of acetazolamide on acute mountain sickness. N Engl J Med 1968; 279: 839-845. Cain SM, Dunn JE: Low doses of acetazolamide to aid accommodation of men to altitude. J Appl Physiol 1966; 21: 1195-1200. Johnson TS, Rock PB, Fulco CS, et al: Prevention of acute mountain sickness by dexamethasone. N Engl J Med 1984; 310: 683-686. Ferreira P, Grundy P: Dexamethasone in the treatment of acute mountain sickness (letter). N Engl J Med 1985; 312: 1390. Houston CS, Dickinson J: Cerebral form of high altitude illness. Lancet 1975; II: 758-761. Acetazolamide for acute mountain sickness. FDA Drug Bulletin 1983; 13: 27. Roach RC, Larson EB, Hornbein TF, et al: Acute mountain sickness, antacids, and ventilation during rapid, active ascent of Mount Rainier. Avait Space Environ Med 1983; 541397-40 1. Sampson JB, Cymerman A, Burse RL, et al: Procedures for the measurement of acute mountain sickness. Avait Space Environ Med 1983; 54: 1063-1073. Stamper DA, Sterner RT, Kinsman RA: Symptomatology
December
1987
The American
Journal
of Medicine
subscales for the measurement of acute mountain sickness. Percept Mot Skills 1971; 33: 735-742. Wohns RNW, Colpitts M, Clement T, et al: Phenytoin and acute mountain sickness on Mount Everest. Am J Med 1986; 80: 32-36. Norusis MJ: SPSS/PC+TM for the IBM PC/XT/AT. Chicago: SPSS, 1986. Dixon WJ: BMDP statistical software. Berkley: University of California Press, 1985. Haynes RC, Muran F: Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of adrenocortical steroid biosynthesis. In: Gilman AG, Goodman LS, Rail TW, Muran F, eds. Goodman and Gilman’s the pharmacological basis of therapeutics 7th ed. New York: Macmillan, 1985; 1470-1471. Severinghaus JW, Chiodi H, Eger El, et al: Cerebral blood flow in man at high altitude. Circ Res 1966; 19: 274-282. Hackett PH, Rennie D: Acute mountain sickness. Semin Res Med 1983; 5: 132-140. Carson R, Evans W: Symptomatology, pathophysiology and treatment of acute mountain sickness. Fed Proc 1969; 28: 1085-1091. Maher JT, Cymerman A, Reeves JT, et al: Acute mountain sickness: increased severity in eucapnic hypoxia. Avait Space Environ Med 1975; 46: 826-829. Reeves JT, Moore LG, McCullough RE, et al: Headache at high altitude is not related to internal carotid arterial blood vefocity. J Appl Physiol 1985; 59: 909-915. Lassen NA: The brain: cerebral blood flow. In: Sutton JR, Jones NL, Houston CS, eds. Hypoxia: man at altitude. New York: Thieme-Stratton, 1982. Gutin PH: Corticosteroid therapy in patients with cerebral tumors: benefits, mechanisms, problems, practicalities. Semin Oncol 1975; 2: 49-56. Sutton JR, Houston CS, Mansell AL, et al: Effect of acetazolamide on hypoxemia during sleep at high altitude. N Engl J Med 1979; 301: 1329-1331. Havener WH: Secretory inhibitors. In: Ocular Pharmacology, 4th ed. St. Louis: CV Mosby, 1978; 475-496. Shlim DR: Treatment of Acute Mountain Sickness (letter). N Engl J Med 1985; 313: 891-892.
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