Dexamethasone for prophylaxis and treatment of acute mountain.sickness

Journal of Wilderness Medicine 3, 54-60 (1992) REVIEW Dexamethasone for prophylaxis and treatment of acute mountain.sickness MARK B. RABOLD, MD 28015 80th A ve, Graham, WA 98338, USA Acute mountain sickness (AMS) is a syndrome induced by hypobaric hypoxia in individuals who ascend rapidly to altitudes above 2500 m and may represent an early form of high altitude cerebral edema (HACE). Dexamethasone (DMS) has been advocated for treatment of HACE; several recent studies have sought to investigate its therapeutic role in AMS. Success with DMS in prophylaxis of AMS has been mixed. Five out of seven studies showed statistically significant decreases in the incidence of AMS when compared with placebo. However, all three studies investigating the treatment of AMS with DMS documented significant efficacy. The effective dose for both prophylaxis and treatment is 4 mg orally every 6-8 h at altitudes above 2050 m. In four studies, significant side effects were noted on discontinuation of DMS. The origin of rebound phenomena is uncertain, but may relate to adrenal suppression. DMS appears to be a useful adjunct to descent for the treatment of AMS. Prophylactic use should be limited to unavoidably rapid ascents, such as in rescue situations, and possibly to persons allergic or intolerant to acetazolamide. Key words: acute mountain sickness, acetazolamide, dexamethasone, high altitude cerebral edema Acute mountain sickness (AMS) is a syndrome induced by hypobaric hypoxia in susceptible individuals who ascend rapidly to altitudes greater than 2500 m. The syndrome is characterized by headache, nausea, vomiting, anorexia, lassitude, sleep disturbances, shortness of breath, dry cough, and swelling of hands or face. Symptoms usually appear 3-12 h after ascent. There is wide variability among individuals in onset, severity and resolution. The pathophysiology of the neurological components of AMS is unclear, but most researchers accept the theory of hypobaric hypoxia-induced early cerebral edema [1-4]. The boundary between severe AMS and mild HAPE or HACE is indistinct. AMS is usually benign and self limiting, but may progress to HAPE or high altitude cerebral edema (HACE) in up to 5-10% of cases [5]. In addition, diminished judgment and physical reserves may combine to place the victim in a more compromised situation. Acute mountain sickness is uncomfortable at best, and may progress to a lethal condition at worst. As the popularity of recreation at high altitude increases, the need for safe, reliable, and effective agents to prevent and treat AMS becomes evident. Currently, the best method to avoid AMS is staged ascent over several days [1,5]. Various authors suggest limiting elevation gains to 300 m (1000 ft) per day above 3000 m. A 24 h 'rest day', or halt in ascent, should be taken for every 1000 m gain in elevation [6]. However, this does not guarantee absence of AMS. Additionally, many people are too impatient to abide by this restriction.. To date, the most widely utilized chemoprophylactic agent for AMS is acetazolamide, a carbonic anhydrase inhibitor. Its exact mechanism for preventing the symptoms of 0953-9859/92 1992 Chapman & Hall

Acute mountain sickness 55 AMS has not been identified. One possible explanation is that the diuretic effect hastens renal excretion of bicarbonate, thus producing a metabolic acidosis with respiratory stimulation, particularly during sleep [3,7,8]. Acetazolamide to prevent the symptoms of AMS has been shown effective in several studies [5,10-13]. Though usually more effective than placebo, it is not universally effective [10,13,14]. Its use is somewhat limited by frequent side effects of acral paresthesias, nausea, drowsiness, and diuresis [9,15,16]. In patients with AMS and possible HAPE, it has been suggested in theory that acetazolamide is contraindicated, in that compensatory hyperventilation might not be possible and respiratory failure could result [17]. However, this notion has not generated any studies or case reports. Hackett suggests that acetazolamide limits exercise at altitude. Possible mechanisms include decreased plasma volume, metabolic acidosis, exercise-related dyspnea secondary to increased ventilation, and decreased levels of 2,3 diphosphoglycerate [18]. The limitations of acetazolamide prompted the search for another efficacious pharmacologic agent. If AMS in part represents early cerebral edema, then it is reasonable to speculate that dexamethasone (DMS) might be effective. Dexamethasone is known to improve cerebral edema of both interstitial and vasogenic origin [19]. Betamethasone was first suggested as treatment for AMS in 1969 for soldiers fighting in the Himalaya [1]. However, the initial study to focus on DMS and AMS was reported in 1984 when Johnson and colleagues utilized a hypobaric chamber [20]. Since then, oral DMS has been evaluated under randomized, doubly blind, and placebo-controlled conditions. The majority of the investigations utilized a standardized Environmental Symptom Questionnaire (ESQ) and/or an Acute Mountain Sickness Score (respiratory and cerebral). Altitudes ranged from 2050 to 4570 m. Study locations included Mt Rainier [16], Mt McKinley (Denali) [29], Monte Rosa [24], Pike's Peak [22], two Colorado ski resorts [28], the Sierra Nevada [26], and three hypobaric chambers [20,21,23]. The first formal study of the prophylactic effect of DMS on AMS was by Johnson in 1984 [20]. Subjects were exposed in a hypobaric chamber to a simulated altitude of 4570 m after 48 h of pretreatment with 4 mg of DMS orally every 6 h, which was maintained throughout the 42 h exposure. Subjects administered DMS had markedly decreased symptoms and incidence (12.5%) of AMS when compared against those dosed with placebo (75%). In addition, treated subjects had significantly smaller retinal artery diameter, consistent with decreased retinal and cerebral blood flow [20]. These results were supported in another chamber study by Rock and colleagues in 1989 [21]. In this study, subjects were exposed to 4570 m after receiving two 4 mg doses of DMS at 12 h intervals prior to ascent. Continued after 'ascent', this dose decreased the incidence and shortened the course of AMS, with incidence at 88% in the placebo group and 25 % in the treated group. However, doses of 1 and 0.25 mg every 12 h were ineffective for prophylaxis [21]. The 12 h dosing schedule appeared less effective than the 6 h schedule of the previous study (8 mg per day vs 16 mg per day, respectively), as measured by symptom scores. It is unclear why there should be a difference between these pharmacologic doses, but this might relate to the dose response curve or time of administration. Other studies have documented the efficacy of 4 mg of DMS every 6 h for AMS prophylaxis. Rock and colleagues demonstrated the effectiveness of this dosage, begun 48 h prior to rapid ascent, at 4300 m on Pike's Peak [22]. The incidence of AMS was 60% in the placebo group versus 31 % in the treated group. On Mt Rainier (4392 m), Ellsworth showed DMS 4 mg every 8 h to be as effective as acetazolamide (250 mg every

56 Rabold 8 h begun 24 h prior to ascent), with fewer side effects [16]. The incidence of AMS in the OMS treated group was 25%, compared to 77% in the placebo group. This study was flawed, as 35% of the OMS treated group had an extra day of acclimatization at 3000 m, which would be expected to decrease the incidence of AMS. The prophylactic effect of acetazolamide and dexamethasone, alone and in combination, was assessed in Nevada backpackers ascending to 3650 m [26]. Medication was begun orally two days prior to ascent and continued during ascent. Acetazolamide 250 mg every 6 h was compared to OMS 4 mg every 6 h and placebo. OMS was not significantly different from placebo in preventing AMS, whereas acetazolamide was efficacious. Acetazolamide and OMS together were more effective than either alone. OMS as a single agent showed a significantly higher percentage of side effects compared to acetazolamide [26]. Montgomery and colleagues demonstrated no significant difference between OMS (4 mg every 6 h orally, begun at time of exposure) and placebo at 2050 m (resort base) [16]. At 2700 m, incidence of AMS was 40% in the placebo group and 7.9% in the OMS treated group. AMS would not be expected to occur at 2050 m; the number of subjects traveling above 2050 m and the maximum or average altitude reached was not measured. Hackett and colleagues demonstrated no prophylactic effect of OMS in soldiers rapidly airlifted from sea level to 4400 m on Mt McKinley (Oenali) [29]. The dose of OMS was 2 mg and given one hour prior to departure; the soldiers engaged in relatively strenuous activity on arrival at altitude [29]. Overexertion under such conditions is thought to contribute to AMS [34]. In summary, despite conflicting reports, OMS may be an effective prophylactic agent when a 4 mg dose is initiated beginning 6 h prior to ascent or at initial exposure to altitudes above 2700 m. (Table 1.) Three studies focusing on treatment of AMS with OMS recorded significant efficacy. In a chamber study subjects were decompressed to 3700 m and those afflicted with AMS Table 1. Dexamethasone prophylaxis summary Altitude Length ofpre treatment/ treatmentpost ascent IncidentAMS (DMS/placebo) Dose Rebound phenomenon Montgomery28 Ellsworth 16 Hackett 18 Rock 21 Rock 22 ZelF6 Johnson 20 2050m 2700m 4392m 4400m 4300m 4050m None/Yes None/Yes 24hrs/Yes 1 h/yes 12 hrs/yes 12 hrs/yes 12 hrs/yes 48 hrs/yes 48 hrs/yes 48 hrs/yes 7.9%/40% 25%/77% 25%/88% 31%/60% 12.5%/75% 4mg 8h- 1 2mg 6h- 1 0.25mg 12h- 1 1mg 12h- 1 4mg 12h- 1 ONQ ONQ 91% 38% 71% = no significant difference = not mentioned ONQ = observed, but not quantitated

Acute mountain sickness 57 were treated with OMS (4 mg every 6 h) [23]. All subjects (n) had significantly improved ESQ scores after an average 5 doses of OMS, when compared with placebo. Average score for the OMS group was 63% versus 23% for placebo. No rebound phenomenon or untoward side effects were described, beyond mild hyperglycemia (132 mg dl- 1, average). Similar results were achieved with the same maintenance dose at 4559 m on Monte Rosa in the Swiss Alps [24]. Symptomatic subjects were treated initially with OMS 8 mg, followed by 4 mg every 6 h. After 12 h, all subjects reported significant improvement; 47% reported complete resolution. In the second phase of Hackett's study, the entire placebo group (8/8) and most of the OMS pretreatment group (5/7) were symptomatic from AMS after 5 h [29]. Persons with moderate to severe symptoms (11115) were treated with OMS 4 mg every 6 h, orally or intramuscularly. All subjects were markedly improved after two doses. Average improvement in symptom scores was 77%. In a single case report, an AMS victim at 5200 m whose symptoms were refractory to acetazolamide had total resolution of symptoms after several 4 mg doses of OMS, enabling him to continue a climb to the summit [27]. Thus OMS in a minimal dose of 4 mg every 6 h appears to be efficacious in the treatment of AMS. (Table 2.) OMS appears to generate side effects attributed to rebound AMS and to 'steroid withdrawal'. In four of the reviewed studies, significant side effects were noted on discontinuation of OMS [22,26,28,29]. In Zell's paper, 87.5% (7/8) of subjects taking OMS alone reported fatigue, depression, and insomnia after cessation of 6 days of therapy [26]. The symptoms were of such severity that the 71% (5/7) of subjects reporting depression stated that they would never again take the drug. In an anecdotal self-report, a physician related symptoms 'consistent with steroid withdrawal' after abruptly discontinuing OMS after two days of treatment for AMS [22]. In the Hackett study on Denali, 91% (10/11) of subjects suffered rebound AMS symptoms 48 h after OMS was stopped. In addition, one subject reported depression 24 h after discontinuing OMS [29]. In the study by Rock and colleagues, after discontinuing OMS, the treated group's mean ESQ score was worse than that of the placebo group [22]. Montgomery and colleagues noted rebound symptoms, but did not quantify these [28]. No other studies have mentioned presence or absence of this phenomenon. Other side effects may include mild hyperglycemia (132 mg dl- I average), measured in one study [23]. The etiology for rebound phenomena is unclear. It is reasonable to suggest suppression of the hypothalamic-pituitary-adrenal axis as a contributing factor. Although clinical adrenal suppression at this level of steroid administration is thought to require seven to ten days to occur, exogenous low-dose OMS administered every 6-12 hover 48 h significantly decrease serum cortisol level. This normalizes within 48 h after cessation of OMS, as demonstrated by an ACfH stimulation test [21,23]. Another possible mechan- Table 2. Dexamethasone treatment summary Altitude DMS/placebo % Dose/6h- 1 Rebound improvement phenomenon Levine 23 3700m 63%/23% 4mg not measured Ferrazinj24 4559m 76%/ 8% 4mg not measured Hackett 29 4400m 77%/no placebo 4mg 91%

58 Rabold ism for rebound would be simply a recurrence of AMS symptoms without the protective effect of OMS. The mechanism of action of OMS is not known. It may produce euphoria and counteract the lassitude associated with AMS [23]. OMS is a potent antiemetic which has been used to counter nausea during cancer chemotherapy [23,30]. If OMS improves cerebral edema from interstitial and vasogenic origins, it may diminish early HACE [19]. In a rat glioma study, both OMS and non-steroidal anti-inflammatory agents effectively decreased cerebral edema [31]. However, Meehan found naproxen alone ineffective for prevention ofams [32]. Perhaps the mechanism is beyond anti-inflammatory and membrane stabilizing actions. Johnson and colleagues demonstrated decreased retinal artery diameter in OMS-treated subjects. If retinal artery flow reflects cerebral circulation, OMS may have reduced cerebral blood flow, which would reduce edema formation by decreasing filtration through the microcirculation [20,33]. Another possibility is that OMS simply facilitates acclimatization. However, considering the rebound phenomenon, this is unlikely. If OMS does not facilitate acclimatization, but rather, blocks symptoms, then important warning signs of AMS might be missed. This would be akin to an injection of anesthetic into an injured limb to dull the senses and allow continued activity. Thus far, there is no evidence to support this hypothesis. Rather, it seems more likely that OMS offers true physiologic improvement. Two studies demonstrated significant improvement in hemoglobin saturation (3.7-6.5% increase) and AMS scores in persons treated with OMS [24,29]. In a hypobaric chamber rat study, OMS prevented hypoxia-induced increase in transvascular protein loss and lung water when compared with placebo [25]. Perhaps OMS also stabilizes alveolar membranes and improves the hypoxia associated with AMS. Summary Oexamethasone appears to be an effective prophylactic and therapeutic agent for the cerebral component of AMS. Effective dosage is 4 mg minimum every 6-8 h orally. Prophylactic use should begin 24 to 48 h prior to ascent, be continued during ascent, and tapered during descent. However, OMS should be used cautiously in prophylaxis, as it could require extended administration. OMS is not universally effective in this capacity, and may be associated with prominent side effects. Prophylactic use should be limited to persons allergic or intolerant to acetazolamide who must ascend rapidly for rescue situations. OMS is an important adjunct to descent for persons severely ill with AMS. It should not be substituted for descent unless weather, avalanche danger, or another factor prevents ascension. Persons stricken ill who improve with treatment should be discouraged from ascending further, unless they have been weaned from OMS and remain asymptomatic. References 1. Singh, I., Khanna, P.K., Srivastava, M.e., Madan, L., Sujoy, R. and Subramanyam, C.S.V. Acute mountain sickness. N Engl J Med 1969; 280, 175-84.

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60 Rabold transvascular protein escape in rats. Modulation by glucocorticoids. 1 Clin Invest 1988; 82, 1840-7. 26. Zell, S.c. and Goodman, P.H. Acetazolamide and dexamethasone in the prevention of acute mountain sickness. West Med1 1988; 148, 541-4. 27. Ferreira, P. and Grundy, P. Dexamethasone in the treatment of acute mountain sickness. N Engl1 Med 1985; 312, 1390. 28. Montgomery, AB., Luce, J.M., Michael, P. and Mills, J. Effects of dexamethasone on the incidence of acute mountain sickness at two intermediate altitudes. lama 1989; 261, 734-6. 29. Hackett, P.H., Roach, RC., Wood, RA, Fouteh, RG., Meehan, RT., Rennie, D. and Mills, H.J. Dexamethasone for prevention and treatment of acute mountain sickness. A viation Space Environ Med 1988; 59, 950-4. 30. Cassileth, P.A, Lusk, KJ., Torri, S., DiNubile, N. and Gerson, S.L. Antiemetic efficacy of dexamethasone therapy in patients receiving cancer chemotherapy. Arch Intern Med 1983; 143, 1347-9. 31. Reichman, H.R, Farrell, c.l. and Del Maestro, RF. Effects of steroids and non-steroidal antiinflammatory agents on vascular permeability in a rat glioma model. 1 Neurosurg 1986; 65, 233-7. 32. Meehan, RT., Cymerman, A, Rock, P., Fulco, C.S., Hoffman, J., Abernathy, c., Needleman, S. and Maher, J.T. The effect of naproxen on acute mountain sickness and vascular responses to hypoxia. Am 1 Med Sci 1986; 292, 15-20. 33. Lassen, N.A and Harper, AM. High-altitude cerebral edema. Lancet 1975; 2, 1154. 34. Auerbach, P.S. and Geehr, E.C., eds. Managementof Wilderness and Environmental Emergencies. 2nd ed. St. Louis: c.y. Mosby Co., 1989.