Reduced Acetazolamide Dosing in Countering Altitude Illness: A Comparison of 62.5 vs 125 mg (the RADICAL Trial).

INTRODUCTION: North American guidelines propose 125 mg acetazolamide twice daily as the recommended prophylactic dose to prevent acute mountain sickness (AMS). To our knowledge, a dose lower than 125 mg twice daily has not been studied. METHODS: We conducted a prospective, double-blind, randomized, noninferiority trial of trekkers to Everest Base Camp in Nepal. Participants received the reduced dose of 62.5 mg twice daily or the standard dose of 125 mg twice daily. Primary outcome was incidence of AMS, and secondary outcomes were severity of AMS and side effects in each group. RESULTS: Seventy-three participants had sufficient data to be included in the analysis. Overall incidence of AMS was 21 of 38 (55.3%) in reduced-dose and 21 of 35 (60.0%) in standard-dose recipients. The daily incidence rate of AMS was 6.7% (95% CI 2.5-10.9) for each individual in the reduced-dose group and 8.9% (95% CI 4.5-13.3) in the standard-dose group. Overall severity of participants' Lake Louise Score was 1.014 in the reduced-dose group and 0.966 in the standard-dose group (95% CI 0.885-1.144). Side effects were similar between the groups. CONCLUSIONS: The reduced dose of acetazolamide at 62.5 mg twice daily was noninferior to the currently recommended dose of 125 mg twice daily for the prevention of AMS. Low incidence of AMS in the study population may have limited the ability to differentiate the treatment effects. Further research with more participants with greater rates of AMS would further elucidate this reduced dosage for preventing altitude illness.

A Preliminary Genome-Wide Association Study of Acute Mountain Sickness Susceptibility in a Group of Nepalese Pilgrims Ascending to 4380 m.

There is significant interindividual variation in acute mountain sickness (AMS) susceptibility in humans. To identify genes related to AMS susceptibility, we used a genome-wide association study (GWAS) to simultaneously test associations between genetic variants dispersed throughout the genome and the presence and severity of AMS. DNA samples were collected from subjects who ascended rapidly to Gosainkunda, Nepal (4380 m), as part of the 2005, 2010, and 2012 Janai Purnima festivals. The Lake Louise Score was used to measure AMS severity. The primary analysis was based on 99 male subjects (43 with AMS; 56 without AMS). Genotyping for the GWAS was performed using Infinium Human Core Exome Bead Chips (542,556 single-nucleotide polymorphisms were assayed), and validation genotyping was performed with pyrosequencing in two additional cohorts (n = 101 for each). In total, 270,389 single nucleotide polymorphisms (SNPs) passed quality control, and 4 SNPs (one intronic, three nonsynonymous) in the FAM149A gene were associated with AMS severity after correcting for multiple hypothesis testing (p = 1.8E-7); however, in the validation cohorts, FAM149A was not associated with the presence or severity of AMS. No other genes were associated with AMS susceptibility at the genome-wide level. Due to the large influence of environmental factors (i.e., ascent rate and altitude attained) and the difficulties associated with the AMS phenotype (i.e., low repeatability, nonspecific symptoms, potentially independent ailments), we suggest that future studies addressing the variation in the acute human hypoxia response should focus on objective responses to acute hypoxia instead of AMS.

Physiology and applied sciences in Nepal: 1st annual conference.

With the increasing number of medical schools in Nepal, there is an expected increase in the number of Nepalese physiologists. The first medical school was established in the 1970s. We report here about the first annual conference of Nepalese physiologists on 27-28 September 2013 organized by the Department of Clinical Physiology of the Nepalese Army Institute of Health Sciences (NAIHS) and Kathmandu University School of Medical Sciences (KUMS). Nepalese physiologists are trying to form their own physiological society. In this regard, NAIHS and KUMS have played an important role to bring physiologists from different parts of Nepal involved in teaching, learning, and research activities in medical schools. There were a number of foreign invitees (India, Israel, Italy, Japan, and Sweden). There were plenary presentations on the topics that are relevant in Nepal, e.g., high-altitude physiology and wilderness medicine. The final session of the conference was an open session meeting of Nepalese physiologists. There was an open interaction about establishing Nepalese Physiological Society. After much deliberation, there was an agreement to register the society in Kathmandu with the current ad hoc committee which will elect the first executive body of the society.

A prospective epidemiological study of acute mountain sickness in Nepalese pilgrims ascending to high altitude (4380 m).

BACKGROUND: Each year, thousands of pilgrims travel to the Janai Purnima festival in Gosainkunda, Nepal (4380 m), ascending rapidly and often without the aid of pharmaceutical prophylaxis. METHODS: During the 2012 Janai Purnima festival, 538 subjects were recruited in Dhunche (1950 m) before ascending to Gosainkunda. Through interviews, subjects provided demographic information, ratings of AMS symptoms (Lake Louise Scores; LLS), ascent profiles, and strategies for prophylaxis. RESULTS: In the 491 subjects (91% follow-up rate) who were assessed upon arrival at Gosainkunda, the incidence of AMS was 34.0%. AMS was more common in females than in males (RR = 1.57; 95% CI = 1.23, 2.00), and the AMS incidence was greater in subjects >35 years compared to subjects ≤35 years (RR = 1.63; 95% CI = 1.36, 1.95). There was a greater incidence of AMS in subjects who chose to use garlic as a prophylactic compared to those who did not (RR = 1.69; 95% CI = 1.26, 2.28). Although the LLS of brothers had a moderate correlation (intraclass correlation = 0.40, p = 0.023), sibling AMS status was a weak predictor of AMS. CONCLUSIONS: The incidence of AMS upon reaching 4380 m was 34% in a large population of Nepalese pilgrims. Sex, age, and ascent rate were significant factors in the development of AMS, and traditional Nepalese remedies were ineffective in the prevention of AMS.

A randomized trial of temazepam versus acetazolamide in high altitude sleep disturbance.

This study is the first comparative trial of sleep medications at high altitude. We performed a randomized, double-blind trial of temazepam and acetazolamide at an altitude of 3540 meters. 34 healthy trekkers with self-reports of high-altitude sleep disturbance were randomized to temazepam 7.5 mg or acetazolamide 125 mg taken at bedtime for one night. The primary outcome was sleep quality on a 100 mm visual analog scale. Additional measurements were obtained with actigraphy; pulse oximetry; and questionnaire evaluation of sleep, daytime drowsiness, daytime sleepiness, and acute mountain sickness. Sixteen subjects were randomized to temazepam and 18 to acetazolamide. Sleep quality on the 100 mm visual analog scale was higher for temazepam (59.6, SD 20.1) than acetazolamide (46.2, SD 20.2; p=0.048). Temazepam also demonstrated higher subjective sleep quality on the Groningen Sleep Quality Scale (3.5 vs. 6.8, p=0.009) and sleep depth visual analog scale (60.3 vs. 41.4, p=0.028). The acetazolamide group reported significantly more awakenings to urinate (1.8 vs. 0.5, p=0.007). No difference was found with regards to mean nocturnal oxygen saturation (84.1 vs. 84.4, p=0.57), proportion of the night spent in periodic breathing, relative desaturations, sleep onset latency, awakenings, wake after sleep onset, sleep efficiency, Stanford Sleepiness Scale scores, daytime drowsiness, or change in self-reported Lake Louise Acute Mountain Sickness scores. We conclude that, at current recommended dosing, treatment of high-altitude sleep disturbance with temazepam is associated with increased subjective sleep quality compared to acetazolamide.