Abstract
Inhaled Steroids for Acute Mountain Sickness Prophylaxis: Is the Lung the Problem?
A recent study from China found that inhaled budesonide (200 ug twice a day), a potent glucocorticoid, was equally effective in preventing acute mountain sickness (AMS) as oral dexamethasone (4 mg twice a day) started one day before passive ascent by automobile to 3900 m and then continued for 3 days (Zheng et al, 2014). Both drugs halved the rate of AMS (60 vs 30%) when compared to placebo. Subjects on either drug had higher arterial oxygen saturation than those on placebo, but only those that took budesonide had less reduction in forced vital capacity. The practical aspect of this study is that inhaled budesonide might be a reasonable alternative for AMS prophylaxis over acetazolamide (which was not examined in this study) and dexamethasone in situations when these oral medications may be contraindicated, but this needs to be confirmed and tested in climbers to higher ascents. Given the differences in dosing (20 fold) and pharmacokinetics that likely lead to insufficient budesonide reaching the brain (Swenson, 2014), this study raises the interesting possibility that hypoxic signaling from hypoxic lungs contributes to AMS and is blunted by pulmonary glucocorticoid receptor stimulation.
Erythropoietin for Acute Mountain Sickness Prophylaxis
In another study of an old drug for a new purpose, Heo et al (2014) tested in an open-label randomized study whether erythropoietin (EPO) given once weekly for 4 weeks could prevent acute mountain sickness (AMS) in a group of 39 trekkers ascending very quickly over 4 days from sea level to the Annapurna base camp (ABC) at 4130 m. The hypothesis advanced by the authors was that an increase in red cell mass would be equivalent to improving O2 carrying capacity by stimulating ventilation with acetazolamide or theophylline. EPO did increase hemoglobin (Hb) concentration and hematocrit by roughly 12% over the controls. The rate of AMS was considerably reduced by EPO (73 vs 30%). There were no reported side effects of EPO including elevated blood pressure, and oxygen saturation values by pulse oximetry were not different between the groups. Interestingly, multiple logistic regression analysis showed that SpO2<87% at ABC, Hb<15 g/dl, and control group assignment were predictive of AMS in the whole group, but only SpO2 and control assignment and not Hb, were predictive in a subset of 13 participants who had severe AMS (Lake Louise score>8), high altitude cerebral edema (HACE) or high altitude pulmonary edema (HAPE) and immediately descended after arrival at ABC. In this subset, 3 had taken EPO, the other 10 had not. The fact that Hb did not predict the most altitude illness development suggests that EPO may have protective effects in the brain and elsewhere beyond any increase in blood oxygen carrying capacity. EPO receptors exist in the brain and vasculature and their activation by EPO induces a number of protective cellular responses to hypoxia. The limitations of this study, beyond the practical issue of using an exceedingly expensive drug and a rate of ascent not recommended by any consensus guidelines, were its lack of a placebo control group and curiously the decision to have all subjects take sildenafil on the last day of ascent.
Birds and Bees at High Altitude
Bar-headed geese (Anser indicus) are renowned as high fliers in their yearly 5000 km migration across the Himalayas from their wintering in India to their breeding grounds on the Tibetan Plateau. This includes anecdotal reports of birds flying over some of the tallest peaks in the range, with a recent documentation of a telemetered bird flying at 7290 m. While several studies have shown remarkable hypoxia tolerance at rest as high as 12,190 m, a previous exercise treadmill study of running bar-headed geese wearing restricting face masks found no evidence of the ability to increase oxygen consumption for the demands of flying. Hawkes et al (2014) in an extraordinary data-rich study studied catheterized bar-headed geese and low-flying migratory barnacle geese with non-invasive respirometry running on a treadmill in a normobaric hypoxic chamber. They found bar-headed geese are capable of O2 uptake, delivery, and consumption sufficient for flight up to 8500 m, without evidence of lactic acidosis or other signs of stress. Barnacle geese were only able maintain flight levels of O2 consumption at altitudes equivalent to 4500 m. In another study of tremendous high altitude performance, Dillon and Dudley (2014) showed that male alpine bumblebees (Bombus impetuosus) captured at 3250 m are capable of sustained flight in hypobaric hypoxia equivalent to 8000 m and can still hover at 9000 m. We await a study of telemetered bumblebees to see if they indeed fly this high in their lives.
High Altitude Residence May Prevent Obesity in Overweight Young People
Animal studies and limited human data suggest that living at high altitude may have weight-reducing hypophagic and hypermetabolic effects. While the animal data are well controlled and make a convincing story, supportive data in humans is largely based on prevalence rates of obesity throughout the world with all the weaknesses of such studies lacking longitudinal data. The question of lower obesity rates with living at high altitude was examined in over 98,000 US military personnel whose postings were above 2 km and below 1 km for a mean duration of 3.2 years. The incident rate of new obesity (body mass index [BMI]>30) developing in the high altitude group (comprising about 10% of the total study population) was about 60% lower than in the lowland group (Voss et al., 2014) after controlling for possible confounding factors of pre-enlistment BMI, age, smoking, race/ethnicity, branch of service, occupation, and time in service. Although it may not be entirely realistic to use ambient hypoxia as a weight reducing or obesity prevention stimulus, these data provide a more convincing case in humans, as in animals, that even mild hypoxia with its biochemical and physiological changes can beneficially alter metabolism. How we harness this knowledge in practical ways remains to be seen, but the consequences could be enormous.
Acetazolamide Blunts Hypoxic Pulmonary Vasoconstriction but not by Carbonic Anhydrase Inhibition
Previous work in rabbits, rats, dogs, and humans has shown that acetazolamide in doses used for acute mountain sickness (AMS) prophylaxis reduces or abolishes hypoxic pulmonary vasoconstriction (HPV) and so might prevent high altitude pulmonary edema as do other pulmonary vasodilators, such nifedipine or tadalafil. Experiments in live dogs and in isolated rat pulmonary artery smooth muscle cells demonstrate that other even more potent carbonic anhydrase (CA) inhibitors than acetazolamide, yet different in their structure beyond the critical unsubstituted sulfonamide (-SH2-NH2) moiety, do not reduce HPV or the intracellular calcium signaling necessary to initiate vasoconstriction. Pickerodt and coworkers (2014) studied conscious spontaneously breathing beagle dogs and showed intravenous, oral and inhaled acetazolamide all lowered HPV. They hypothesized that inhalation dosing might avoid the systemic effects of CA inhibition, diuresis and systemic metabolic acidosis, but this was not realized, although lower doses were not studied. In a second set of experiments, two analogs of acetazolamide methylated either on the thiadiazole ring to still retain CA inhibiting activity (methazolamide) or at the critical sulfonamide moiety necessary for tight binding to CA (n-methyl acetazolamide) were both able to reduce HPV although not as fully as acetazolamide. N-methyl acetazolamide, in contrast to methazolamide and acetazolamide caused no evidence of CA inhibition as assessed by changes in urine output or acid-base status and might be a useful analog for high altitude pulmonary edema prevention without the side effects of CA inhibition.
Genome Wide Expression Analysis Study in High Altitude Pulmonary Edema Susceptibility
A genetic basis for high altitude pulmonary edema (HAPE) has long been sought. Numerous gene polymorphisms in a candidate gene approach have been identified in HAPE-susceptible individuals, many of which have obvious relevance for pulmonary vascular regulation at high altitude and for the particularly strong HPV that is necessary but not wholly sufficient to cause HAPE. However, not all identified candidate genes have been replicated across studies and population groups. Furthermore, other contributors to HAPE susceptibility beyond HPV may exist in the activation of inflammatory responses and alveolar epithelial fluid reabsorption. Sharma et al (2014) in a first global expression profiling effort studied 17 male sea level residents of Indian origin who developed HAPE within 3 days after arrival at 3250 m and compared them to 14 age, sex, and duration-matched men who did not have HAPE after ascent. They performed their analysis of whole blood mRNA taken when the subjects with HAPE were ill and in the control subjects after an equivalent time at altitude. They found concurrent modulation of numerous pathways involving genes controlling vascular homeostasis, intermediary metabolism, inflammatory signaling and hypoxia sensing and response. In a brief commentary of this nature, it is not possible to enumerate the several hundred genes they identified as being up or down-regulated. The information will be useful in better understanding the complex pathophysiology of HAPE and offer possible targets for intervention. However, as the authors discuss, there are limitations in that primary and secondary events cannot be identified, the more relevant tissues such as endothelial cells, lung epithelium, alveolar macrophages to name a few were not studied, and gene differences were not analyzed. A next step will be to perform an unbiased genome wide association study (GWAS), but this will require a much larger number of subjects, something that may be facilitated by a recently initiated HAPE registry under the auspices of the International Society of Mountain Medicine.
Positive End-Expiratory Pressure Improves Oxygenation in Healthy Subjects at High Altitude
Past studies have shown that various means of applying positive end-expiratory (PEEP) improves gas exchange in those with acute mountain sickness (AMS) or high altitude pulmonary edema (HAPE). Postulated mechanisms have included increased ventilation accompanying application of an obtrusive mask or in response to pressurization of the thorax, recruitment of atelectatic lung regions or interstitial fluid redistribution or reabsorption. In a comprehensive study, Nespoulet et al (2014) studied 16 normal middle-aged healthy subjects at sea level and 9 well acclimatizing subjects 2 days after arrival to 4350 m. In the sea level study, subjects breathed 12% oxygen over the time of the study. Both groups were studied during spontaneous breathing, with 0, 5 and 10 cm H2O PEEP, and with pursed lip breathing (a technique that may duplicate applied PEEP). To control for the slight change in breathing pattern and ventilation that may occur with PEEP, the subjects also breathed freely at a pattern and rate equal to that they assumed with 10 cm H2O PEEP. At both locations, application of 10 cm H2O PEEP improved arterial oxygenation by almost 6–7% within only several minutes and quadriceps muscle oxygenation measured by near infrared spectroscopy. Pursed lip breathing was not effective. Changes in ventilation with each intervention were slight and not-statistically significant. The improvement at sea level could not be reasonably attributed to early interstitial edema given that the hypoxia was of such short duration in resting subjects. The best explanation would be a PEEP-induced improvement in VA/Q matching for which direct measurement of VA/Q heterogeneity by the multiple inert gas elimination technique would be necessary. The clinical implication of these findings and shown by others in earlier work is that PEEP, if tolerable for extended use, could be used to prevent AMS and/or HAPE.
Sleep Disturbance Does not Correlate with Other Symptoms of Lake Louise Score
Hall and colleagues (Hall et al., 2014) assessed acute mountain sickness (AMS) by Lake Louise scores (LLS) and by visual analog scales (VAS) for each item of the Lake Louise questionnaire simultaneously in 103 subjects (921 questionnaires) at 3600 or 5200 m in Bolivia and in 189 mountaineers at 4730 m on Kilimanjaro. Analysis of the pooled data confirms that there is a strong correlation between LLS and VAS, that sildenafil 150 mg daily, or an antioxidants cocktail prior to and during ascent have no effect on AMS. The most important finding is that headache, nausea, dizzinessn and fatigue all correlate with each other whereas sleep is an outlier and correlates only with fatigue. This study contributes to the actual discussion about eliminating sleep disturbance from the LLS. Speculations of the authors regarding different underlying pathophysiology of various symptoms of AMS are based on a cluster analysis that may have been affected by confounding effects of repeated measures in acclimatizing subjects, of drug intake, and of including data from active and passive ascents.
Moderate Intensity Exercise Does Not Exacerbate Acute Mountain Sickness
Twelve subjects performed 3 bouts of 80 min exercise on a bicycle ergometer at 45% of maximal power during an 11 hour exposure to normobaric hypoxia (FIO2 0.12) and normoxia. They were also exposed for 11 hours to normobaric hypoxia with an FIO2 adjusted to match the SpO2 recorded during the exposure with exercise in hypoxia (Rupp et al., 2013). Acute mountain sickness (AMS) scores and prevalence of AMS were not significantly different between the hypoxic exposures with and without exercise. A minor exacerbation of AMS by exercise cannot be excluded because of the low statistical power and a small trend to higher AMS scores and prevalence with exercise. This study confirms the results of recent publications which showed no effect of moderate exercise on AMS in normobaric hypoxia (Mairer et al., 2013; Schommer et al., 2012).
Acclimatization to 5260 m and Its Retention after 2 or 3 Weeks
This article of the Altitude Omics group describes the effects of acclimatization over 16 days at 5260 m on hemoglobin, arterial blood gases, acute mountain sickness (AMS), cognitive function, and physical exercise capacity (Subudhi et al., 2014). Re-induction to 5260 m after sojourning 14 days at 1525 m showed retention of arterial oxygenation and exercise performance and complete protection from AMS whereas hemoglobin and cognitive performance were not retained. After 21 days at 1525 m there was still a partial protection from AMS while all other parameters were not any more significantly different from values obtained on the initial acute exposure. It will be interesting to see how the pending data form the OMICS analysis can help to explain the underlying mechanisms of acclimatization and its retention.
Acclimatization to 5260 m Attenuates Exercise-Induced Supraspinal Fatigue
Supraspinal fatigue was assessed by pre- and post-exercise twitch response to femoral nerve stimulation and transcranial stimulation in 7 recreationally active subjects in normoxia, acute normobaric hypoxia (FIO2=0.105) and after staying 14 days at 5260 m (Goodall et al., 2014). Improvement of the hypoxia-induced decline in post-exercise supraspinal fatigue with acclimatization to hypoxia was associated with an increased excitability of the brain to muscle pathway and with increased cerebral oxygen delivery as assessed by prefrontal near infrared spectroscopy and transcranial Doppler.
Isolated Long-Term Supine Immobilization And Prolonged Moderate Hypoxia Have No Effect on Blood Coagulation
Markers of blood coagulation were not changed compared to base line in 24 healthy, non-smoking adult women during a 60 days lasting −6° head-down bed rest nor in 25 healthy men during a stay in the CONCORDIA station in Antarctica at an altitude of 3233 m (Venemans-Jellema et al., 2014). This study extends the finding of no clinically relevant activation of blood coagulation with acute exposure to moderate hypoxia to a prolonged exposure over many months and it demonstrates that prolonged supine head down immobilization is not thrombogenic by itself. Extrapolation from the latter finding to the “immobilization” in a sitting position in the economy class of an airplane, as the authors do, seems questionable.
Hypoxic Training Has no Ergogenic Effects at Low Altitude in Moderately Trained Subjects
Robach and colleagues (Robach et al., 2014) performed a double blind randomized trial investigating the effects of six weeks of endurance training 3–4 times/week either in normoxia (n=8) or in normobaric hypoxia (FIO2=0.15) (n=9) on mitochondrial function and exercise performance in moderately trained athletes. Training in hypoxia increased total hemoglobin mass significantly but it did not alter skeletal muscle respiratory capacity or V
Greater Decrement of Cycling Performance in Hypobaric vs Normobaric Hypoxia
Twelve healthy and fit men (average V