Dexamethasone for prophylaxis against acute mountain sickness during rapid ascent to 5334 m

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1 Journal ofwilderness Medicine, 5, (1994) ORIGINAL ARTICLE Dexamethasone for prophylaxis against acute mountain sickness during rapid ascent to 5334 m WILLIAM N. BERNHARD, MDl*, LISA MILLER SCHALICK, RN, MPH!, ALAN GITTELSOHN, PhD2 IDivision ofanesthesiology, Shock Trauma Center, University ofmaryland Medical System, Baltimore, MD , USA, 2CECS, Department ofcommunity Medicine, Dartmouth Medical School, Hanover, NH, USA Twenty-three volunteers participated in a double-blind, randomized trial comparing the steroid dexamethasone 4 mg to placebo every 12 h as prophylaxis against acute mountain sickness (AMS) during a rapid ascent to a shelter on Mt Chaclataya, Bolivia. From sea level, subjects were transported by air and land vehicles to 5334 m within a 72-h period. They were evaluated by cerebral scores derived from the Environmental Symptom Questionnaire and confirmed by AMS-C and AMS-R scores. After 6-8 h at high altitude (day 3), the number of iii persons in the dexamethasone group was less than those iii in the placebo group (X 2 = 7.43, P = 0.01) by chi-square and Fisher's exact tests. After 20 h at high altitude (day 4), the contrast between groups diminished (X 2 = 2.10, p = 0.214). ANOVA and (-test showed that mean cumulative AMS scores of the dexamethasone group were significantly lower (p = 0.01, P = 0.02) than those of the placebo group for both days at high altitude, despite an approximate 82% increase in the mean cumulative score of the dexamethasone group from day 3 to day 4. We conclude that dexamethasone 4 mg every 12 h, though initial1y effective, was not sufficient to sustain prophylaxis from AMS symptoms at 5334 m. Key words: dexamethasone, steroid, high altitude, acute mountain sickness, AMS prophylasix, hypobaric hypoxia Introduction Acute mountain sickness (AMS) represents a constellation of symptoms seen in persons who rapidly ascend to elevations above 3000 m. Characterized by headache, lassitude, insomnia, anorexia, nausea, and vomiting in varying degrees, AMS can compromise a traveler's enjoyment and safety during a visit to high altitude. Although usually benign, AMS can progress to more incapacitating and lethal conditions such as high-altitude cerebral edema (HACE) or high-altitude pulmonary edema (HAPE). The incidence, severity, and duration of AMS symptoms are largely dependent on the rate of ascent, maximum altitude obtained, and, to some degree, individual susceptibility to hypoxia. The occurrence of AMS has been demonstrated to be quite high at altitudes above 4500 m [1,2]. 'To whom correspondence should be addressed Chapman & Hall

2 332 Bernhard, Schalick and Gitteisohn Graduated, staged ascent allowing time for acclimatization is the best preventative measure for AMS. However, such a process is often impractical, as increased numbers of vacationers with time constraints go to high altitudes rapidly to pursue recreational activities. Furthermore, military and rescue missions necessitate rapid ascent [1,3,4]. As modern transportation takes increasing numbers of people to high-altitude environments, it becomes imperative to address the need for a safe and reliable pharmacologic agent for AMS prophylaxis. Traditionally, acetazolamide has been the agent of choice for AMS prophylaxis; however, some of its limitations and undesirable side effects in larger doses have encouraged the exploration for other suitable medications [2,4-12]. In 1984, Johnson et al. [13] were the first to formally report the effectiveness of dexamethasone in preventing the onset of AMS in healthy young males exposed to a rapid simulated ascent to 4570 m. Further studies have shown similar results in simulated and actual ascents with varying dosages of dexamethasone [4,14,15]. Due to reduced side effects experienced by subjects as compared to those who used acetazolamide, Ellsworth et ai. and Zell et ai. acknowledged that further research at very high altitudes with dexamethasone was warranted [4,16]. Hackett was unable to demonstrate that 2 mg every 6 h of dexamethasone was an effective prophylaxis against AMS in soldiers rapidly airlifted to 4400 m; however, he considered that the strenuous exercise engaged in by the soldiers on arrival to altitude contributed to the onset of AMS [17]. Our study was designed to extend previous observations relative to two factors: to confirm whether the lowest dose of dexamethasone (4 mg every 12 h) reported by Rock et al. [14] to prevent AMS during a simulated ascent (4570 m) would also be effective in an actual ascent, and to assess that dosage at a higher altitude (5334 m). In particular, a lower dose would be advantageous in decreasing the intensity of side effects as well as minimizing the risk of a rebound effect on withdrawal of the drug [15-17]. Methods Subjects Twenty-three healthy volunteers, aged 22 to 62 years, on no medications were recruited for the study. Consisting mainly of lowlanders interested in high-altitude research, the group included no subject who had been to high altitude 4 weeks prior to the study. Approximately 40% of the subject group had had experience with mild to moderate AMS at altitudes less than 4000 m, though no volunteer had suffered from severe AMS, highaltitude cerebral edema, or high-altitude pulmonary edema. Fifteen men and 8 women were randomized into two designated drug groups with significant difference between the mean ages (Dexamethasone Group 43 ± 3.9: Placebo Group 32 ± 1.6, p = 0.02). Each subject had been examined for overall health status and interviewed about the medical history. All subjects were in good health with no prior history of any chronic medical conditions including peptic ulcer disease, psychiatric illness, or sensitivity to dexamethasone. One young subject was a diabetic controlled by insulin. Subjects were instructed not to self-prescribe any medications during the study. The study and consent form was approved by the Institutional Review Board of the University of Maryland at Baltimore, Maryland. All subjects signed the informed consent after a briefing on the protocol and prior to entry into the study.

3 Dexamethasone forams during rapid ascent 333 The ascent All volunteers arrived at Miami (sea level) for baseline testing. After testing was completed at the baseline site, the group boarded a 7-h night flight late that evening, arriving the following morning (day 1) in La Paz, Bolivia (3689 m). The group stayed at this altitude for 48 h and then traveled for 2 h by land vehicles on day 3 to the shelter on Mt Chaclataya, located at 5334 m. Subjects were free to pursue sedentary or mild exercise activities when they were not undergoing testing. Most of the subjects rested in the shelter during the 20 h at altitude; others periodically walked around the shelter area. No subject was observed doing strenuous activity. The group stayed at this altitude for a 24-h period (day 4) and then descended to Lake Titicaca at 3818 m. The randomized trial The study was conducted as a randomized double-blind, placebo-controlled trial. Subjects were randomly assigned to receive identical capsules of either dexamethasone 4 mg or placebo every 12 h by mouth for 4 days. The first dose was administered 6 h prior to flight departure. Subsequent doses were administered in the morning with breakfast and during evening meals 12 h later. All subjects continued to take the capsules during the ascent and for the 24-h period at high altitude until the testing was completed. At that time, the randomization code was broken and those subjects assigned to dexamethasone were conservatively weaned over the next 3 days. Assessment ofacute mountain sickness AMS symptoms were assessed by completion of the Environmental Symptom Questionnaire (ESQ) designed by the US Army Research Institute of Environmental Medicine (Natick, MA) to quantitate the severity of symptoms (6-point Likert scale) associated with exposure to high-altitude environments. Though the questionnaire was self-administered daily, only data from the following times was analyzed: sea level, 7-8 h after arrival at intermediate altitude (day 1, La Paz), 6-7 h after arrival at high altitude (day 3, Mt Chaclataya), and 20 h at high altitude (day 4, Mt Chaclataya). Blood oxygen saturation and heart rate were recorded by a portable pulse oximeter (Nellcor N-lO, Hayward, CA). The presence of symptoms commonly ascribed to cerebral manifestations of AMS was noted from the ESQ. Of the 68-item inventory, a total of 16 questions was employed which related to the following symptoms: lightheadedness, headache, dizziness, syncope, dimness of vision, lack of coordination, weakness, nausea, loss of appetite, fatigue, hangover, insomnia, loss of concentration, forgetfulness, sleepiness, and malaise. This selection of cerebral-related symptoms ("modified ESQ") was based primarily on the Lake Louise Consensus on the Definition and Quantification of Altitude Illness document presented at the 1991 International Hypoxia Symposium [18] and the work of Sampson and colleagues [19]. The intensity-grading scores (ordinal scale of0 to 5, with 0 representing no symptoms and 5 representing extreme symptoms) for these symptoms were added. The sums for each subject were analyzed at 3689 m (day 1) and 5334 m (days 3 and 4) for comparison of dexamethasone to placebo. An alternative analysis of these data were performed by arbitrarily defining illness as the presence of at least three cerebral symptoms with a minimum ofone symptom having an intensity score of > 2. In addition, a weighted average of cerebral symptoms was calculated from the results of the ESQ labeled AMS-C and a weighted average of respiratory symptoms labeled AMS-R. As suggested by previous

4 334 Bernhard, Schalick and Gittelsohn studies, scores of greater than 0.7 for AMS-C and 0.6 for AMS-R reliably identify subjects with AMS [19]. Statistical analysis Data are represented as means ± SEM except where otherwise stated. Chi-square and Fisher's 2-tailed exact tests were used to assess the difference between occurrences of illness by altitude. Mean cumulative symptom scores were calculated for each drug group using the above-described itinerary. ANOVA and t-test were used for cumulative score differences within altitudes. A p-value of less than 0.05 was considered statistically significant. Statistical calculations were performed with SAS 501 version statistical software package [20]. Results No subject reported AMS illness on the questionaire at baseline (Miami). At 3689 m (day 1 at altitude), AMS symptoms were identified in both groups but there were no significant differences between the two drug groups noted, including frequency of illness (placebo 33%, dexamethasone 27%), mean cumulative AMS scores, (placebo 7.54, dexamethasone 8.54), AMS-C scores, AMS-R scores, oxygen saturation, and heart rates. However, on ascent to the high-altitude testing site, differences between the two groups developed quickly within 2-6 h. Mean cumulative scores with standard errors are shown in Table 1. Using ANOVA and t-tests, cumulative symptom scores at high altitude for days 3 and 4 were significantly lower (p = 0.01) for subjects receiving dexamethasone than those for subjects taking placebo (Table 1). It is noteworthy that after 20 h at altitude, the dexamethasone group's mean cumulative score increased by approximately 82%, whereas the placebo mean score remained relatively stable. However, the difference between the two groups remained significant (p = 0.02). Table 1. Group comparisons Day 3 Day m 5334m Dex Placebo Dexv. Dex Placebo Dexvs. n = 11 n = 12 placebo n = 11 n = 12 placebo Cumulative symptom score 8.5 ± ±6.5 * 15.5 ± ±4.8 AMS-C score 0.3 ± ± ± ±0.4 * AMS-R score 0.3 ± ±0.2 * 0.7 ± ±0.2 * O 2 saturation (%) 76.0 ± ± ± ±2.2 Heart rate 101 ± ± ±7.6 94±4.3 Note: Data expressed as means ± SEM. No significant differences were noted at 3689 m for any variable. Significance of difference determined by 2-sample t-test on SAS. Cumulative symptom score derived from "modified ESQ." AMS-C and AMS-R scores based on work of Sampson et al. [19]. tp :$ 0.05 significance. *p :$ 0.01 significance. * *

5 Dexamethasone for AMS during rapid ascent 335 Dexamethasone appeared to have had a significant effect of reducing the number of persons becoming ill at high altitude compared with placebo (Table 2). A subject was considered ill if he/she had at least three cerebral symptoms from the "modified ESQ" with a minimum score of ;::: 2. No significant difference in the number of ill subjects was noted at intermediate altitude (3689 m). On day 3, at 5334 m, 2 of 11 (18%) subjects taking dexamethasone had AMS symptoms. In contrast, 9 of 12 (75%) subjects on placebo were ill. This difference was significant by chi-square (X 2 = 7.43) and Fisher's 2-tailed exact tests (p = 0.1). On day 4, 20 h later, the dexamethasone/placebo contrast was no longer significant (X 2 = 2.10, P = 0.2) in that the number of ill subjects on dexamethasone increased to 4 (45%) and the number of ill subjects on placebo remained at 9 (75%). Weighted averaged scores (AMS-C and AMS-R) were calculated for each group and yielded results similar to the mean cumulative group scores derived from the modified ESQ (Table 1). Subjects with AMS-C scores greater than 0.7 and AMS-R scores greater than 0.6 were considered ill [19]. Differences between mean AMS-C scores of the two groups were significant at high altitude for day 3 (p < 0.01) and day 4 (p = 0.01) by ANOYA and T-test. AMS-R scores also showed significant differences between the two drug groups on day 3 (p = 0.04) and day 4 (p = 0.01). In our analysis regarding the number of ill subjects based on the AMS-C and AMS-R scores, the difference between occurrence of illness in the dexamethasone and placebo groups were significant for AMS-C (X 2 = 5.49, p = 0.03) and AMS-R (X 2 = 5.86, p = 0.03) at high altitude on day 3. However, on day 4 the contrast between the two groups was reduced and was nonsignificant for both AMS-C and AMS-R scoring (Table 3). There was no significant differences in mean oxygen saturation between groups at high altitude for both days. The dexamethasone group had overall higher heart rates (101 ± 4.5) after 6-8 h at high altitude compared to the placebo group (86 ± 4.3). This difference was significant (p = 0.03). On day 4, this difference essentially disappeared. Subjects were closely monitored for complications resulting from altitude exposure and dexamethasone. Some subjects were given analgesics for severe headaches once a testing session was completed. Most subjects found that the analgesics were minimally effective in reducing the intensity of the headache. After the study was completed, we noted that the majority (90%) of the subjects requesting analgesics had been on placebo. One subject on Table 2. Comparison of illness for drug groups Locale Drug No. of No. of Sick Chi-square Fisher's exact p persons sick (%) (2-tail) La Paz-day 1 Placebo m dexamethasone High-day 3 Placebo * 5334m dexamethasone High-day 4 Placebo m dexamethasone Note: Personson dexamethasone had significantly less illness at 5334 m than persons on placebo on day 3. By day 4, illness in the dexamethasone group increased and the dexamethasone/placebo contrast was no longer significant. *p < 0.05 significance. Illness defined as the presence of at least three cerebral symptoms with a minimum of one symptom having an intensity score of 2: 2 from "modified ESQ."

6 336 Bernhard, Schalick and Gittelsohn Table 3. Comparison of illness for drug groups using AMS-C and AMS-R scores Locale Drug No. of No. of Sick Chi-square Fisher's exact p persons sick (%) (2-tail) AMS-C Day m Placebo P = 0.03* Dexamethasone Day m Placebo P = 0.37 Dexamethasone AMS-R Day m Placebo P = 0.03* Dexamethasone Day Placebo p = 0.64 Dexamethasone Note: Illness defined as AMS-C score > 0.07 and AMS-R score > 0.06 (Sampson et al. [19]). Based on AMS-C and AMS-R scores, the dex group has significantly less illness at 5334 m than persons on placebo on day 3. By day 4, illness in the dex group increased and the dex/placebo contrast was no longer significant. 'p < 0.05 significance. placebo was given an injection of dexamethasone 4 mg shortly after our testing session at high altitude on day 3. Though she reported some relief from her symptoms of headache and nausea for approximately 2 h, her overall scores remained higher than those of the prophylaxis group. Several subjects elected to enter the Gamow@> hyperbaric bag for 1 h during the night at high altitude. Upon emergence from the bag, subjects reported relief from their symptoms, only to reexperience them approximately 2 h later. All of these subjects had been on placebo. Once the testing after 20 h at high altitude was completed, the entire group descended to Lake Titicaca at 3813 m. No one reported any side effects from the weaning schedule from dexamethasone or symptoms of AMS at the lower altitude. A day or two after the study, a portion of the group went on to climb Mt Illimani (6457 m) and reported no ill effects. This may be due to the group's partial acclimatization from the rapid ascent to 5334 m. Discussion Dexamethasone reduced the symptoms of AMS when subjects were exposed to a rapid ascent to 5334 m. Two approaches to calculating and analyzing symptom scores were used and both revealed a significant difference in mean cumulative scores between the two groups at high altitude despite a substantial rise in the scores of the dexamethasone group on day 4. This was due in part to the increase in number of subjects identified as ill in the dexamethasone group after 20 h at high altitude. In our study, the prophylactic administration of dexamethasone 4 mg every 12 h initially ameliorated the symptoms of AMS in

7 DexamethasoneforAMS during rapid ascent 337 subjects who rapidly ascended to 5334 m. This dampening of symptoms appeared to be temporary despite sedentary activity. The number of ill subjects increased sharply in the dexamethasone group after 20 h at altitude, negating the significance ofthe dexamethasone/ placebo contrast. The relative stability of the mean cumulative scores and the stable number of ill subjects in the placebo group at high altitude may reflect the self-limiting nature of the syndrome, as evidenced in previous studies [17,21]. On day 3 at high altitude, we noted that the mean heart rate found in the dexamethasone group was significantly higher compared to the placebo group. It is possible that this rise in heart rate in the dexamethasone group was due to the significant difference in age between the two groups, with the dexamethasone group older than the placebo group. Hashimoto and colleagues reported that older trekkers (51 ± 11 years) had sustained sinus tachycardia compared to their younger comrades at high altitude (4700 m). Possible associations include differences in cardiovascular fitness, increased vagal tone in the young, and/or increased sensitivity to catecholamine levels in older subjects [22]. The difference noted in our groups essentially disappeared by day 4. Johnson et at. [13] reported effective AMS prophylaxis by dexamethasone 4 mg every 6 h for 42 h at 4570 m. Rock et at. repeated the same dosage and demonstrated that dexamethasone reduced AMS scores over a 6-day period at 4300 m [15]. Later, Rock et ai. [14] reported that a lower dose of 4 mg every 12 h worked effectively for 45 h at 4570 m; however, this same dosage in our study was not sufficient to sustain an effect at 5334 m. Hackett et ai. [17] suggested that dexamethasone 2 mg every 6 h (8 mg per day) prophylactically may be more effective in sedentary persons than in those undergoing strenuous exercise. Our results suggest that a total dosage of8 mg per day (4 mg every 12 h) is insufficient for sedentary subjects at a higher altitude of 5334 m. The severity of illness for the placebo group at 5334 m was comparable to the level of severity reported by Hackett et at. at 4400 m. Perhaps a higher dosage of dexamethasone would provide a sustained period of protection at a very high altitude (5334 m). However, there is presently no evidence to support this suggestion. Moreover, a more frequent time interval than every 12 h at this dose may lead to a more successful outcome. Larger doses and prolonged use of the steroid increases the risk of serious adverse effects. Careful weaning of the drug would lessen this risk. Although others have reported an increase in AMS symptoms on withdrawal of dexamethasone [15-17], we did not observe any adverse effects on our subjects during our weaning schedule or on discontinuation of the drug. Conclusions We conclude that dexamethasone 4 mg every 12 h is not effective in sustaining a relatively symptom-free state with a rapid ascent to 5334 m. Continued altitude exposure may intensify AMS symptoms and thus compromise a traveler's judgment and safety. Further research should define the effect of specific dose regimens of dexamethasone at very high altitudes. Acknowledgments The authors gratefully acknowledge Frank Gibney, president of The Explorer's Network, for performing travel logistics and valuable support throughout the expedition, Dr Clark

8 338 Bernhard, Schalick and Gittelsohn Watts for funding support, Organon, Inc. for pharmaceutical supplies, and Nellcor, Inc. for the use ofpulse oximetry units and donation ofsupplies. References 1. Hackett, P.H., Rennie, D. and Levine, H.D. The incidence, importance and prophylaxis of acute mountain sickness. Lancet 1976; 2, Greene, M.K., Kerr, AM., McIntosh, I.B. and Prescott, RJ. Acetazolamide in prevention of acute mountain sickness: a double-blind controlled cross-over study. Br Med] 1981: 283, Singh, I., Khanna, P.K., Srivastava, M.C., Lal, M., Sujoy, B.R and Subramanyam, C.S.V. Acute mountain sickness. N Engl]Med 1969; 280, Ellsworth, AJ., Larson, E.B. and Strickland, D. A randomized trial of dexamethasone and acetazolamide for acute mountain sickness prophylaxis.am]med 1987; 83, Rabold, M.B. Dexamethasone for prophylaxis and treatment of acute mountain sickness. ] Wilderness Med 1992; 3, Forward, S.A, Landowe, M., Follansbee, J.N. and Hansen, J.E. Effect of acetazolamide on mountain sickness. N Engl]Med 1968; 279, Larson, E.B., Roach, RC., Schoene, RB. and Hornbein, T.F. Acute mountain sickness and acetazolamide.]ama 1982; 248, Birmingham Medical Research Expeditionary Society Sickness Study Group. Acetazolamide in control of acute mountain sickness. Lancet 1981; 2, i Evans, W.O., Robinson, S.M., Horstmann, D.H. and Jackson, RE. Amelioration of the symptoms ofams by staging and acetazolamide. Aviat Space Environ Med 1976; 47, Swenson, E.R. and Maren, T.H. Letter to the editor. N Eng]Med 1989; 320, Hackett, P.H., Schoene, R.B., Winslow, RM., Peters, RM. and West, J.B. Acetazolamide and exercise in sojourners to 6300 meters-a preliminary study. Med Sci Sports Exercise 1985; 17, Burki, N.K., Kahn, S.A and Hameed, M.A The effects of acetazolamide on the ventilatory response to high altitude hypoxia. Chest 1992; 101, Johnson, T.S., Rock, P.B., Fulco, C.S., Trad, L.A, Spark, R.F. and Maher, J.T. Prevention of acute mountain sickness by dexamethasone. N Engl]Med 1984; 310, Rock, P.B., Johnson, T.S., Larsen, RF., Fulco, C.S., Trad, L.A and Cymernam, A Dexamethasone as prophylaxis for acute mountain sickness. Effect of dose level. Chest 1989; 95, Rock, P.B., Johnson, T.S., Cymerman, A, Burse, RL., Falk, L.J. and Fulco, C.S. Effect of dexamethasone on symptoms of acute mountain sickness at Pikes Peak, Colorado (4300 m). Aviat Space Environ Med 1987; 58, Zell, S.c. and Goodman, P.H. Acetazolamide and dexamethasone in the prevention of acute mountain sickness. West Med] 1988; 148, Hackett, P.H., Roach, RC., Wood, R.A, Foutch, RG., Meehan, R.T., Rennie, D. and Mills, H.J. Dexamethasone for prevention and treatment of acute mountain sickness. Aviat Space Environ Med 1988; 59, The Lake Louise consensus of the definitions and quantification of altitude illness. In: Sutton, J.R, Coates, G. and Houston, C.S., eds. Hypoxia and Mountain Medicine. Burlington, VT: Queen City Printers, 1992; Sampson, J.B., Cymerman, A, Burse, RL., Maher, J.T. and Rock, P.B. Procedures for the measurement of acute mountain sickness. Aviat Space Environ Med 1983; 54, SAS Institute: SAS 501 Version. Cary, NC: SAS Institute Inc. 21. Evans, W.O., Robinson, S.M., Horstmann, D.H. and Jackson, RE. Amelioration of the symptoms of AMS by staging and acetazolamide. Aviat Space Environ Med 1976; 47, Hashimoto, F" Appenzeller, 0., Abrams, J. and Qualls, C. Ambulatory electrocardiographic monitoring at high altitude.]wilderness Med 1992; 3,