Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Systematic reviews win in the absence of guidelines
- Martin Goldman (21 August 2000)
-
AMS prophylaxis review.
- Simon Mitchell (24 August 2000)
-
Prophylaxis of acute mountain sickness - a few cautions
- Ken Zafren (17 September 2000)
-
Acetazolamide dose and acute mountain sickness
- John B West (20 September 2000)
-
Recommendation not justified
- Peter Bärtsch (25 September 2000)
-
Flawed analysis
- Peter Hackett (29 September 2000)
-
Diamox in the mountains of Nepal
- Buddha Basnyat (13 October 2000)
-
Authors’ reply
- Lionel Dumont, Chahé Mardirosoff, Martin R Tramèr (1 November 2000)
|
|
|||
|
Martin Goldman, Medical Consultant Nomad Travellers' Clinic, London N8 0PX
Send response to journal:
|
Much has been written about the use of acetazolamide in the prevention of AMS. There has been substantial inconsistency, and the guidance to date has produced hit and miss prescribing. This review now gives evidence based guidance to prescribers. It contrasts with the recent evidence based review of malaria prophylaxis (Ashley Croft, BMJ, 15th July) which presented data which conflicted with the current UK guidelines on prevention of malaria. A key message is that whilst concensus guidelines are highly useful, they may be superceded by evidence based guidelines. |
|||
|
|
|||
|
Simon Mitchell, GP Principal West Midlands
Send response to journal:
|
The recent article by Dumont et al provides advice that is both easy to understand and more importantly impart to patients. As foreign travel becomes increasingly common, simple advice for the traveller becomes harder to get hold of whilst becoming of even greater importance. I hope that similar articles will continue to be printed. |
|||
|
|
|||
|
Ken Zafren, Associate Medical Director (North America) Himalayan Rescue Association Anchorage, Alaska USA
Send response to journal:
|
While the idea of a meta-analysis of prophylaxis for acute mountain sickness is a good one, the current study must be viewed with caution. One must be cautious not to draw overly specific conclusions from the data. The average study size was only 15 and the heterogeneity was great. It is hard to make a dosage recommendation for acetazolamide based on a subset of these small studies, most of which did not address the optimal dosage. Since most studies did not address a single dose regimen, I find the conclusion rather hard to understand: that 500 mg of acetazolamide is not helpful while 750 mg works. What would be the proposed physiological basis for the difference, if there is one? The greatest danger in this study, however, is the lack of recognition that dexamethasone and acetazolamide work by very different mechanisms. Acetazolamide speeds acclimatization while dexamethasone masks symptoms. Use of dexamethasone for prophylaxis is potentially dangerous because it is unwise to ascend further while one is taking dexamethasone. Use of acetazolamide is safer because one can continue ascent while taking it if symptoms are relieved. Ken Zafren, MD, FACEP Associate Medical Director (North America) Himalayan Rescue Association Staff Physician Alaska Native Medical Center and Providence Alaska Medical Center, Anchorage, Alaska USA Clinical Assistant Professor of Surgery, Division of Emergency Medicine Stanford University Medical Center, Stanford, California USA |
|||
|
|
|||
|
John B West, Professor of Medicine and Physiology University of California San Diego
Send response to journal:
|
This article is potentially very misleading. Although the text of the paper contains all sorts of caveats, the summary box at the top of page 271 states "Acute mountain sickness is a disease frequently experienced at high altitude" and below that "Contrary to widespread belief, acetazolamide 500 mg does not work." This is simply not true as a generalization. The authors reached their astonishing conclusion by excluding many studies based on doubtful criteria as discussed by Hackett ( http://www.medicineplanet.com/article/article.phtml?tcat=5&aid=629). Those of us who have worked extensively at high altitude know that acetazolamide 250 mg is very often sufficient to prevent acute mountain sickness, and even 125 mg is valuable in improving sleep. The article as it stands can do a considerable disservice to the many thousands of people who go to high altitude. |
|||
|
|
|||
|
Peter Bärtsch, Professor of Sports Medicine Division of Sports Medicine, University Hospital, Hospitalstr. 3, D-69115 Heidelberg
Send response to journal:
|
Sir, Dumont et al. report a meta-analysis on controlled studies investigating diamox for prevention of acute mountain sickness (AMS) (1). This paper nicely demonstrates the importance of the ascent rate for studies addressing the prevention of AMS. The authors need dichotomous data (presence or absence of AMS) for their analyis. Therefore they exclude many studies that report AMS scores only. One of their major conclusions is that, contary to the widespread belief, acetazolamide 500mg does not work and they suggest that recommendations on the optimal dose should be adapted. We would like to point out that such a statement is not supported by the presented analysis nor by many papers excluded from this analysis. Figure 3a of the paper by Dumont by al. shows that the relative risk is dependent on the rate of ascent. This means that the effect of different doses can only be compared at the same ascent rate. The authors show 4 data points from 3 studies (2, 3, 4) using 500mg acetazolamide. The ascent rates of these studies are near or below 500m/day (20m/hour). On the contrary, the ascent rates of 4 of the 5 field studies using 750mg acetazolamide are above 2400m/day (100m/hour). A detailed analysis of the 3 studies (2, 3, 4) on acetazolamide 500mg/day shows that these data do not support the conclusions of the authors. One study (3) has a slow ascent rate of 275m/day (16m/hour) and reports data on sleep recordings in 12 individuals. Furthermore, this study does not address the prevention of AMS by acetazolamide. The paper by Hackett et al. (2) reports data from 2 large groups of 60 subjects each. One group ascended 223m/day (9m/hour) and the number needed to treat (NNT) is 20. The other group ascended 549m/day (23m/hour) and shows an NNT value of 4. The study of Hackett et al. indicates that at a slow ascent rate it is not worth taking acetazolamide while, with a faster ascent rate, 500mg of acetazolamide daily prevents AMS as well as the 5 studies using 750mg daily (figure 3b). There remains the study of Zell and Goodman (4) reporting data of 7 subjects on acetazolamide and 8 subjects on placebo during 4 days at altitudes between 3650m and 4150m. AMS was assessed by 2 scores derived from the Environmental Symptom Questionnaire (5): AMS-C for cerebral symptoms and AMS-R for respiratory symptoms. Zell and Goodman report an overall incidence for AMS assessed by the AMS-C score of 38% for placebo and of 16% for acetazolamide (NNT = 4.5). The corresponding values using the AMS-R score are 63% vs. 31% (NNT = 3.0). Our table shows the percentage of subjects with AMS on placebo or acetazolamide and the NNT values for each score and each day taking the data from figure 1 of the paper of Zell and Goodman:
Day 1 (3650m) Day 2 (3650m) Day 3 (4050m) Day 4 (3650m)
Cerebral Symptoms
(AMS-C):
Placebo, % (n)
50 (4) 37.5 (3) 37.5 (3) 25 (2)
Acetazolamide,
% (n) 28.6 (2) 0 (0) 14.3 (1) 28.6 (2)
NNT 4.7 2.7 4.3 -
Respiratory Symptoms
(AMS-R):
Placebo, % (n)
75 (6) 62.5 (5) 50 (4) 62.5 (5)
Acetazolamide,
% (n) 71.4 (5) 28.6 (2) 14.3 (1) 28.6 (2)
NNT 27.8 3.0 2.8 3.0
On the first 3 days, when AMS is most likely to occur, NNT is always below
5 except for day 1 when NNT is 27.8 for AMS assessed by the AMS-R score.
Interestingly, Dumont et al. consider only this single value for
classifying the study of Zell et al. It should also be noted, that the AMS
-C score was evaluated against other scoring systems for AMS (6). It is
well established and widely used. All this is not the case for the AMS-R
score. In our opinion, the study of Zell and Goodman should be given an
NNT value of 4.5 indicating comparable effectiveness with studies using
750mg acetazolamide daily. It is questionable, however, whether such
calculations should be performed at all considering the small number of
subjects.
Studies reporting symptom scores rather than presence or absence of AMS show that 500mg of acetazolamide daily significantly reduces symptoms of AMS. A meta-analysis (7) of all controlled trials until 1993 lists 5 studies (involving a total of 122 subjects) that found a significant decrease of AMS scores while in 2 studies (32 subjects) the decrease was not statistically significant. We conclude that the recommendation of 500mg acetazolamide daily for prevention of AMS during rapid ascent is supported by scientific evidence to which, in our opinion, the analysis of Dumont contributes. Whether 500mg or 750mg or another daily dose are more effective can only be determined with studies of equal ascent rates. Peter Bärtsch and Michael Schneider
Reference List 1. Dumont L, Mardirosoff C, Tramèr MR. Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review. BMJ 2000;321:267-272. 2. Hackett PH, Rennie D, Levine HD. The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 1976;II(Nov. 27):1149-1154. 3. Nicholson AN, Smith PA, Stone BM, Bradwell AR, Coote JH. Altitude insomnia: Studies during an expedition to the Himalayas. Sleep 1988;11:354 -361. 4. Zell SC, Goodman PH. Acetazolamide and dexamethasone in the prevention of acute mountain sickness. West J Med 1988;148:541-545. 5. Sampson JB, Cymerman A, Burse RL, Maher JT, Rock PB. Procedures for the measurement of acute mountain sickness. Aviat Space Environ Med 1983;54:1063-1073. 6. Ried LD, Carter, KA, Ellsworth A. Acetazolamide or dexamethasone for prevention of acute mountain sickness: A meta-anaylsis. J Wilderness Med 1994; %: 34-48. 7. Maggiorini M, Müller A, Hofstetter D, Bärtsch P, Oelz O. Assessment of acute mountain sickness by different score protocols in the Swiss Alps. Aviat Space Environ Med |
|||
|
|
|||
|
Peter Hackett
Send response to journal:
|
Dear Editor: The recent article by Dumont and colleagues [1] reaches a false and potentially harmful conclusion. The article purports to show that only the highest doses of acetazolamide actually are effective, and that "contrary to widespread belief, acetazolamide 500mg does not work." This assertion must be challenged. The Dumont analysis is flawed for the following reasons: 1) The authors were far too restrictive (or perhaps biased) in their selection criteria; they excluded too many studies, using only nine out of more than 25 available controlled research studies. They used only four trials of acetazolamide at 500mg/day, and excluded six other important controlled trials. As a result, only 143 individuals were represented in the acetazolamide 500mg/day studies, and 120 of these were from one study.[2] In that one study, the rate of ascent in one of the two trials was so slow that acetazolamide did not make a significant difference in AMS scores, as would be expected. In the other trial, with a faster rate of ascent, acetazolamide was very effective. In contrast, a very similar analysis of the literature in 1994 used 10 trials of acetazolamide 500mg/day (with 306 individuals) and concluded that it was effective.[3] If Dumont, et al., had used more of the available studies, they would have concluded that acetazolamide 500mg/day is indeed effective. 2) Rate of ascent was quite different. Their conclusion that "500mg of acetazolamide does not work" is not based on comparing the 750mg per day dose to 500mg per day, as it initially seems. Instead, they evaluated studies that used the 750mg dose of acetazolamide (250mg three times per day), during a particularly rapid rate of ascent, and compared them to 500mg/day groups with much slower rate of ascent. Without testing the 500mg dose during an abrupt ascent similar to the group taking the 750mg dose, the comparison is not valid. 3) Dumont, et al., chose a very strict endpoint for the studies that they reviewed; the dichotomous presence or absence of AMS. The authors did not take into account a symptom score. In fact, many persons have bothersome symptoms, like a headache, but do not meet the definition of AMS. Acetazolamide will help these individuals. Supporting this, Dumont did note that acetazolamide was effective for prevention of headache, insomnia, nausea and dizziness in various other studies. 4) The experimental design used in most of these studies does not take into account how most people use acetazolamide. The authors limited their review to studies over 13,120 feet (4,000m). The vast majority of acetazolamide use is not for abrupt ascents to over 13,000 feet, but rather for use at ski resort altitudes of 7,500 to 10,000 feet (2,500 to 3,000m), and for abrupt ascents to locations like La Paz, Bolivia and Lhasa, Tibet, both 12,300 feet (3,750m). While rigorous trials comparing acetazolamide dosages are lacking at any altitude, a rather huge clinical experience cannot be ignored: Climbers, trekkers, and tourists find the lower dose of acetazolamide very useful, and with fewer side effects. Acetazolamide almost always causes tingling in the fingers and toes, and increased urination, but at lower doses, these potentially bothersome side effects are minimized. In fact, the clinical impression that acetazolamide works at the lower dose of 250mg twice a day has been so strong over the years that many clinicians (myself included) lowered the dose to 125mg twice a day, with no apparent decrease in effectiveness. The Dumont analysis does confirm the need for rigorous trials of the 250 mg/day dose. Climbers, hikers and travelers to high altitude destinations will be able to prove to themselves whether acetazolamide works for them, and in what dosage it is effective. Medicineplanet and many authoritative sources continue to recommend using acetazolamide at a dose of 125mg to 250mg twice a day for prevention of AMS, and 250mg twice to three times a day for treatment of already established AMS. References 1. Dumont, L., C. Mardirosoff, and M. Tramer, Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review. BMJ, 2000. 321: p. 267-272. 2. Hackett, P.H., I.D. Rennie, and H.D. Levine, The incidence, importance, and prophylaxis of acute mountain sickness. Lancet, 1976. 2: p. 1149-1154. 3. Reid, L., K. Carter, and A. Ellsworth, Acetazolamide or dexamethasone for prevention of acute mountain sickness: a meta-analysis. J Wild Med, 1994. 5(1): p. 34-48. Sincerely, Peter Hackett, M.D.
|
|||
|
|
|||
|
Buddha Basnyat, Medical Director, Nepal International Clinic and the Himalaya Rescue Association
Send response to journal:
|
Clinical field studies of high altitude sickness are slow in being carried out in developing countries like Nepal where a great portion of the high altitude trekking and climbing is located and where thousands of tourists with their porters trek to every year. For almost a decade now we have used acetazolamide 125 mg twice a day for the prevention of acute mountain sickness(AMS). And,although we have observed its efficacy in hundreds of sojourners ( for example in those flying to Lhasa Tibet, altitude 3605m), we have not been able to carry out any study with this low dosage due to our usual research constraints. We believe however that Dumont and colleagues' recommendation (1) in the BMJ of taking 750 mg of acetazolamide per day for the prevntion of AMS may only succeed in adding to the many causes of severe parasthesia ( " jhum jhum" in Nepali) in the mountains(2) as this symptom is a very common side effect of the drug and seems to be dose dependent. 1 Dumont L, Mardirosoff C, Tramer MR Efficacy and harm of pharmacological prevention of acute mountain sickness: qunatitative systematic review. BMJ 2000; 321: 267-272 2 Basnyat B, Zimmerman M, Sleggs J, Vaidhya H. "Jhum Jhum" is a symptom. Lancet 1999;353:2074. |
|||
|
|
|||
|
Lionel Dumont Division of Anaesthesiology, Geneva University Hospital, Chahé Mardirosoff, Martin R Tramèr
Send response to journal:
|
We are overwhelmed by the numerous responses to our systematic review on the pharmacological prevention of acute mountain sickness (AMS). The bottom line of the responses suggests that our review was timely, and that we were able to put some light on important issues such as the impact of the rate of ascent on the risk of AMS. Some of the comments, however, were rather based on assumptions than on evidence. For instance, global statements that acetazolamide 250 mg is very often sufficient to prevent AMS, and that even 125 mg may be valuable in improving sleep are not very helpful in this context. «Maté De Coca» has been recommended for centuries by the Incas, and even magnesium 1, pervincamine 2, methylen blue 3, or certain teas 4 may be beneficial to some extent. In absence of valid randomised controlled trials, however, an observation stays observation. We would like to clarify some of the raised issues; this may prevent further confusion. 1. It seems odd to us, that some people make a fuss about acetazolamide. Our study was not only about this drug. Acetazolamide is an old and cheap drug with a low adverse effect profile. In our analysis, there was evidence that 750 mg was effective in the prevention of AMS, and there was a lack of evidence for 500 mg for the same endpoint. Already 35 years ago, 750 mg has been considered to be a low and well tolerated dose for acetazolamide 5. 2. The increased efficacy with acetazolamide 750 mg is plausible. There is no pharmacology without dose-responsiveness. Few people only would argue that the increase of the dose of a drug by 50% may not lead to increased efficacy. 3. In our analysis, the main efficacy endpoint was complete prevention of AMS. This is different from simply improving symptoms. As we are explaining in length in our paper, we felt obliged to concentrate on this high hurdle of efficacy in order to avoid both observational bias and unnecessary heterogeneity of the data. As with all systematic reviews, the advantage of such rigorous analyses is that readers may go back, get the papers, and redo their own analysis using their own endpoints. For instance, to re-analyse the acetazolamide 500 mg data using a different endpoint (AMS-C data instead of AMS-R data 6, as suggested) would change the pooled NNT for prevention of AMS from 7.1 to 6.6. This difference is unlikely to be of clinical relevance. 4. The suspicion has been raised by a few that our analysis was based on a biased and doubtful selection of studies, and that in a previously published meta-analysis 7 ten trials on acetazolamide 500 mg have been analysed (and not only four, as in ours). We did not include all ten trials for three reasons. First, there are only nine. Second, of these nine, we excluded four since they were not randomised 8-11. Finally, of the remaining five, one reported no dichotomous data on efficacy or harm 12. We could have analysed continuous data and provided weighted mean differences and p values. The clinical relevance of such data, however, is not obvious. What indicates, for instance, an effect size of –0.61 (95%CI, –0.29 to–0.93)7 ? For rational decision making we need to know how well something works, and not only that it works. We could have added a qualitative analysis of the studies which did not report on dichotomous efficacy data. Such analyses, however, are more prone to bias, since they cannot weight the size of an effect (for instance, trial size cannot be taken into account). 5. We agree that the pivotal trial should randomise subjects at similar rates of ascent to different doses of acetazolamide. In the mean time we stay with the conclusion that within a range of rates of ascent of 34 to 170 meters per hour, there is a lack of evidence for acetazolamide 500 mg to prevent AMS. References 1. Dumont L, Mardirosoff C, Soto-Debef G, Tassonyi E. Magnesium and acute mountain sickness. Aviat Space Environ Medicine 1999; 70:625. 2. Adenis L. Expédititon Noel 1974 au kilimandjaro (5885 m). Essais de la pervicamine Forte retard. J Sci Med Lille 1976;94:125-126. 3. Moldenhauer Brooks M. Methylene blue, an antidote to altitude sickness. Aviat Med 1948; 18:198-299. 4. Larrick JW. The methyl xanthine hypothesis: does tea consumption by Tibetan natives blunt the effects of high altitude? Med Hypotheses 1991;34:99-104. 5. Cain SM, Dunn JE. Low dose of acetazolamide to aid accomodation of men to altitude. J Appl Physiol 1966;21:1195-200. 6. Zell SC, Goodman PH. Acetazolamide and dexamethasone in the prevention of acute mountain sickness. West J Med 1988;148:541-5 7. Ried LD, Carter KA, Ellsworth A. Acetazolamide or dexamethasone for prevention of acute mountain sickness: a meta-analysis. J Wilderness Med 1994;5:34-48. 8. Fletcher RF, Wright AD, Jones GT, Bradwell AR. The clinical assessment of acute mountain sickness Q J Med 1985;54:91-100. 9. Gray GW, Bryan AC, Frayser R, Houston CS, Rennie ID. Control of acute mountain sickness. Aerosp Med 1971;42:81-84. 10. McIntosh IB, Prescott RJ. Acetazolamide in prevention of acute mountain sickness. J Int Med Res 1986;14:285-7. 11. White AJ Cognitive impairment of acute mountain sickness and acetazolamide. Aviat Space Environ Med 1984;55:598-603. 12. Bradwell AR, Burnett D, Davies F. Acetazolamide in control of acute mountain sickness. Lancet 1981;1:180-3. |
|||