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1.
High-altitude exposures and intestinal barrier dysfunction.
McKenna, ZJ, Gorini Pereira, F, Gillum, TL, Amorim, FT, Deyhle, MR, Mermier, CM
American journal of physiology. Regulatory, integrative and comparative physiology. 2022;(3):R192-R203
Abstract
Gastrointestinal complaints are often reported during ascents to high altitude (>2,500 m), though their etiology is not known. One potential explanation is injury to the intestinal barrier which has been implicated in the pathophysiology of several diseases. High-altitude exposures can reduce splanchnic perfusion and blood oxygen levels causing hypoxic and oxidative stress. These stressors might injure the intestinal barrier leading to consequences such as bacterial translocation and local/systemic inflammatory responses. The purpose of this mini-review is to 1) discuss the impact of high-altitude exposures on intestinal barrier dysfunction and 2) present medications and dietary supplements which may have relevant impacts on the intestinal barrier during high-altitude exposures. There is a small but growing body of evidence which shows that acute exposures to high altitudes can damage the intestinal barrier. Initial data also suggest that prolonged hypoxic exposures can compromise the intestinal barrier through alterations in immunological function, microbiota, or mucosal layers. Exertion may worsen high-altitude-related intestinal injury via additional reductions in splanchnic circulation and greater hypoxemia. Collectively these responses can result in increased intestinal permeability and bacterial translocation causing local and systemic inflammation. More research is needed to determine the impact of various medications and dietary supplements on the intestinal barrier during high-altitude exposures.
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2.
Iron and Sphingolipids as Common Players of (Mal)Adaptation to Hypoxia in Pulmonary Diseases.
Ottolenghi, S, Zulueta, A, Caretti, A
International journal of molecular sciences. 2020;(1)
Abstract
Hypoxia, or lack of oxygen, can occur in both physiological (high altitude) and pathological conditions (respiratory diseases). In this narrative review, we introduce high altitude pulmonary edema (HAPE), acute respiratory distress syndrome (ARDS), Chronic Obstructive Pulmonary Disease (COPD), and Cystic Fibrosis (CF) as examples of maladaptation to hypoxia, and highlight some of the potential mechanisms influencing the prognosis of the affected patients. Among the specific pathways modulated in response to hypoxia, iron metabolism has been widely explored in recent years. Recent evidence emphasizes hepcidin as highly involved in the compensatory response to hypoxia in healthy subjects. A less investigated field in the adaptation to hypoxia is the sphingolipid (SPL) metabolism, especially through Ceramide and sphingosine 1 phosphate. Both individually and in concert, iron and SPL are active players of the (mal)adaptation to physiological hypoxia, which can result in the pathological HAPE. Our aim is to identify some pathways and/or markers involved in the physiological adaptation to low atmospheric pressures (high altitudes) that could be involved in pathological adaptation to hypoxia as it occurs in pulmonary inflammatory diseases. Hepcidin, Cer, S1P, and their interplay in hypoxia are raising growing interest both as prognostic factors and therapeutical targets.
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3.
Interventions for preventing high altitude illness: Part 2. Less commonly-used drugs.
Gonzalez Garay, A, Molano Franco, D, Nieto Estrada, VH, Martí-Carvajal, AJ, Arevalo-Rodriguez, I
The Cochrane database of systematic reviews. 2018;(3):CD012983
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Abstract
BACKGROUND High altitude illness (HAI) is a term used to describe a group of mainly cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (˜ 8200 feet). Acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude ascent. In this second review, in a series of three about preventive strategies for HAI, we assessed the effectiveness of five of the less commonly used classes of pharmacological interventions. OBJECTIVES To assess the clinical effectiveness and adverse events of five of the less commonly used pharmacological interventions for preventing acute HAI in participants who are at risk of developing high altitude illness in any setting. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) in May 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text search terms. We scanned the reference lists and citations of included trials and any relevant systematic reviews that we identified for further references to additional trials. SELECTION CRITERIA We included randomized controlled trials conducted in any setting where one of five classes of drugs was employed to prevent acute HAI: selective 5-hydroxytryptamine(1) receptor agonists; N-methyl-D-aspartate (NMDA) antagonist; endothelin-1 antagonist; anticonvulsant drugs; and spironolactone. We included trials involving participants who are at risk of developing high altitude illness (AMS or HACE, or HAPE, or both). We included participants with and without a history of high altitude illness. We applied no age or gender restrictions. We included trials where the relevant medication was administered before the beginning of ascent. We excluded trials using these drugs during ascent or after ascent. DATA COLLECTION AND ANALYSIS We used the standard methodological procedures employed by Cochrane. MAIN RESULTS We included eight studies (334 participants, 9 references) in this review. Twelve studies are ongoing and will be considered in future versions of this review as appropriate. We have been unable to obtain full-text versions of a further 12 studies and have designated them as 'awaiting classification'. Four studies were at a low risk of bias for randomization; two at a low risk of bias for allocation concealment. Four studies were at a low risk of bias for blinding of participants and personnel. We considered three studies at a low risk of bias for blinding of outcome assessors. We considered most studies at a high risk of selective reporting bias.We report results for the following four main comparisons.Sumatriptan versus placebo (1 parallel study; 102 participants)Data on sumatriptan showed a reduction of the risk of AMS when compared with a placebo (risk ratio (RR) = 0.43, CI 95% 0.21 to 0.84; 1 study, 102 participants; low quality of evidence). The one included study did not report events of HAPE, HACE or adverse events related to administrations of sumatriptan.Magnesium citrate versus placebo (1 parallel study; 70 participants)The estimated RR for AMS, comparing magnesium citrate tablets versus placebo, was 1.09 (95% CI 0.55 to 2.13; 1 study; 70 participants; low quality of evidence). In addition, the estimated RR for loose stools was 3.25 (95% CI 1.17 to 8.99; 1 study; 70 participants; low quality of evidence). The one included study did not report events of HAPE or HACE.Spironolactone versus placebo (2 parallel studies; 205 participants)Pooled estimation of RR for AMS was not performed due to considerable heterogeneity between the included studies (I² = 72%). RR from individual studies was 0.40 (95% CI 0.12 to 1.31) and 1.44 (95% CI 0.79 to 2.01; very low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated.Acetazolamide versus spironolactone (1 parallel study; 232 participants)Data on acetazolamide compared with spironolactone showed a reduction of the risk of AMS with the administration of acetazolamide (RR = 0.36, 95% CI 0.18 to 0.70; 232 participants; low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated. AUTHORS' CONCLUSIONS This Cochrane Review is the second in a series of three providing relevant information to clinicians and other interested parties on how to prevent high altitude illness. The assessment of five of the less commonly used classes of drugs suggests that there is a scarcity of evidence related to these interventions. Clinical benefits and harms related to potential interventions such as sumatriptan are still unclear. Overall, the evidence is limited due to the low number of studies identified (for most of the comparison only one study was identified); limitations in the quality of the evidence (moderate to low); and the number of studies pending classification (24 studies awaiting classification or ongoing). We lack the large and methodologically sound studies required to establish or refute the efficacy and safety of most of the pharmacological agents evaluated in this review.
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4.
Interventions for treating acute high altitude illness.
Simancas-Racines, D, Arevalo-Rodriguez, I, Osorio, D, Franco, JV, Xu, Y, Hidalgo, R
The Cochrane database of systematic reviews. 2018;(6):CD009567
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Abstract
BACKGROUND Acute high altitude illness is defined as a group of cerebral and pulmonary syndromes that can occur during travel to high altitudes. It is more common above 2500 metres, but can be seen at lower elevations, especially in susceptible people. Acute high altitude illness includes a wide spectrum of syndromes defined under the terms 'acute mountain sickness' (AMS), 'high altitude cerebral oedema' and 'high altitude pulmonary oedema'. There are several interventions available to treat this condition, both pharmacological and non-pharmacological; however, there is a great uncertainty regarding their benefits and harms. OBJECTIVES To assess the clinical effectiveness, and safety of interventions (non-pharmacological and pharmacological), as monotherapy or in any combination, for treating acute high altitude illness. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science, CINAHL, Wanfang database and the World Health Organization International Clinical Trials Registry Platform for ongoing studies on 10 August 2017. We did not apply any language restriction. SELECTION CRITERIA We included randomized controlled trials evaluating the effects of pharmacological and non-pharmacological interventions for individuals suffering from acute high altitude illness: acute mountain sickness, high altitude pulmonary oedema or high altitude cerebral oedema. DATA COLLECTION AND ANALYSIS Two review authors independently assessed the eligibility of study reports, the risk of bias for each and performed the data extraction. We resolved disagreements through discussion with a third author. We assessed the quality of evidence with GRADE. MAIN RESULTS We included 13 studies enrolling a total of 468 participants. We identified two ongoing studies. All studies included adults, and two studies included both teenagers and adults. The 13 studies took place in high altitude areas, mostly in the European Alps. Twelve studies included participants with acute mountain sickness, and one study included participants with high altitude pulmonary oedema. Follow-up was usually less than one day. We downgraded the quality of the evidence in most cases due to risk of bias and imprecision. We report results for the main comparisons as follows.Non-pharmacological interventions (3 studies, 124 participants)All-cause mortality and complete relief of AMS symptoms were not reported in the three included trials. One study in 64 participants found that a simulated descent of 193 millibars versus 20 millibars may reduce the average of symptoms to 2.5 vs 3.1 units after 12 hours of treatment (clinical score ranged from 0 to 11 ‒ worse; reduction of 0.6 points on average with the intervention; low quality of evidence). In addition, no complications were found with use of hyperbaric chambers versus supplementary oxygen (one study; 29 participants; low-quality evidence).Pharmacological interventions (11 trials, 375 participants)All-cause mortality was not reported in the 11 included trials. One trial found a greater proportion of participants with complete relief of AMS symptoms after 12 and 16 hours when dexamethasone was administered in comparison with placebo (47.1% versus 0%, respectively; one study; 35 participants; low quality of evidence). Likewise, when acetazolamide was compared with placebo, the effects on symptom severity was uncertain (standardized mean difference (SMD) -1.15, 95% CI -2.56 to 0.27; 2 studies, 25 participants; low-quality evidence). One trial of dexamethasone in comparison with placebo in 35 participants found a reduction in symptom severity (difference on change in the AMS score: 3.7 units reported by authors; moderate quality of evidence). The effects from two additional trials comparing gabapentin with placebo and magnesium with placebo on symptom severity at the end of treatment were uncertain. For gabapentin versus placebo: mean visual analogue scale (VAS) score of 2.92 versus 4.75, respectively; 24 participants; low quality of evidence. For magnesium versus placebo: mean scores of 9 and 10.3 units, respectively; 25 participants; low quality of evidence). The trials did not find adverse events from either treatment (low quality of evidence). One trial comparing magnesium sulphate versus placebo found that flushing was a frequent event in the magnesium sulphate arm (percentage of flushing: 75% versus 7.7%, respectively; one study; 25 participants; low quality of evidence). AUTHORS' CONCLUSIONS There is limited available evidence to determine the effects of non-pharmacological and pharmacological interventions in treating acute high altitude illness. Low-quality evidence suggests that dexamethasone and acetazolamide might reduce AMS score compared to placebo. However, the clinical benefits and harms related to these potential interventions remain unclear. Overall, the evidence is of limited practical significance in the clinical field. High-quality research in this field is needed, since most trials were poorly conducted and reported.
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5.
Going High with Heart Disease: The Effect of High Altitude Exposure in Older Individuals and Patients with Coronary Artery Disease.
Levine, BD
High altitude medicine & biology. 2015;(2):89-96
Abstract
Levine, Benjamin D. Going high with heart disease: The effect of high altitude exposure in older individuals and patients with coronary artery disease. High Alt Med Biol 16:89-96, 2015.--Ischemic heart disease is the largest cause of death in older men and women in the western world (Lozano et al., 2012 ; Roth et al., 2015). Atherosclerosis progresses with age, and thus age is the dominant risk factor for coronary heart disease in any algorithm used to assess risk for cardiovascular events. Subclinical atherosclerosis also increases with age, providing the substrate for precipitation of acute coronary syndromes. Thus the risk of high altitude exposure in older individuals is linked closely with both subclinical and manifest coronary heart disease (CHD). There are several considerations associated with taking patients with CHD to high altitude: a) The reduced oxygen availability may cause or exacerbate symptoms; b) The hypoxia and other associated environmental conditions (exercise, dehydration, change in diet, thermal stress, emotional stress from personal danger or conflict) may precipitate acute coronary events; c) If an event occurs and the patient is far from advanced medical care, then the outcome of an acute coronary event may be poor; and d) Sudden death may occur. Physicians caring for older patients who want to sojourn to high altitude should keep in mind the following four key points: 1). Altitude may exacerbate ischemic heart disease because of both reduced O2 delivery and paradoxical vasoconstriction; 2). Adverse events, including acute coronary syndromes and sudden cardiac death, are most common in older unfit men, within the first few days of altitude exposure; 3). Ensuring optimal fitness, allowing for sufficient acclimatization (at least 5 days), and optimizing medical therapy (especially statins and aspirin) are prudent recommendations that may reduce the risk of adverse events; 4). A graded exercise test at sea level is probably sufficient for most clinical decision making and will allow for assessment of exercise capacity, and provocable ischemia. Given these considerations, most older individuals with CHD should be able to tolerate exposure to high altitude safely, and with minimal increased risk.
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6.
High-altitude retinopathy--case report.
Wilczyński, M, Kucharczyk, M, Filatow, S
Klinika oczna. 2014;(3):180-3
Abstract
High-altitude retinopathy is one of altitude-related illnesses. Its signs include high-altitude retinal hemorrhages, dilated vessels and peripapillary hyperemia. Increased intracranial pressure seems to be the main cause of all high-altitude diseases including high-altitude retinopathy, cerebral oedema and high-altitude pulmonary oedema. We present the case of high-altitude retinopathy in a 35-year-old woman who reported decreased vision in her right eye, scotomas and high-altitude retinopathy after ascending to more than 7000 meters above sea level. The associated optical coherence tomography findings, fundus photography and literature review are presented. High-altitude retinopathy is an important multifactorial condition of unknown mechanism and etiology, which significantly impacts human vision. Climbing high mountains can cause retinopathy in otherwise healthy people and may lead to permanent sequelae such as retinal nerve fiber layer and optic nerve defects. These symptoms, however, may resolve without causing any permanent damage to the retina. Conservative treatment may help to relieve them. With increasing popularity of mountaineering, ophthalmologists should be prepared to diagnose and treat high-altitude retinopathy.
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7.
[Travelling to high altitudes: do not increase fluid intake].
Meinders, AJ, Bosch, FH, Meinders, AE
Nederlands tijdschrift voor geneeskunde. 2011;(18):A3526
Abstract
A negative water and sodium balance develops during the first hours to days after reaching a high altitude. The fluid and sodium balance does not alter in cases of altitude sickness, or may even become positive. This is attributed to a decreased diuresis and natriuresis in those who develop altitude sickness, while their fluid intake is no different to that of people who do not suffer from altitude sickness. This is a consequence of stimulation of the renin-angiotensin-aldosterone system (RAAS) and an increased secretion of antidiuretic hormone (ADH) combined with a higher than normal sympathetic activity. Therefore there is no argument for an increased fluid intake for the prevention of altitude illness. In theory this might even be harmful.
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8.
Endocrine aspects of high altitude acclimatization and acute mountain sickness.
Woods, DR, Stacey, M, Hill, N, de Alwis, N
Journal of the Royal Army Medical Corps. 2011;(1):33-7
Abstract
The acute acclimatization to high altitude is underpinned by a diuresis (and to a lesser extent a natriuresis) that facilitates a reduction in plasma volume. This allows a haemoconcentration to occur that increases the oxygen carrying capacity of a given volume of blood, a vital effect in the presence of a reduced partial pressure of oxygen. This critical acclimatization process is orchestrated by the endocrine system. This review will present the key evidence regarding the changes in several important hormones that affect this process.
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9.
Ginkgo biloba for prevention of acute mountain sickness: does it work?
van Patot, MC, Keyes, LE, Leadbetter, G, Hackett, PH
High altitude medicine & biology. 2009;(1):33-43
Abstract
Tissot van Patot, Martha, Linda E. Keyes, Guy Leadbetter III, and Peter H. Hackett. Ginkgo biloba for the prevention of acute mountain sickness: does it work? High Alt. Med. Biol. 10:00-00, 2009.-We review the current literature regarding the prophylactic use of Ginkgo biloba extract (GBE) in acute mountain sickness (AMS). We compare studies with regard to GBE dose, composition, study design, altitude reached, ascent rate, exercise, and risk of AMS. We then review what is known about the active components of GBE and their biological effects and apply this knowledge to interpret the results of AMS prevention trials. Overall, the literature suggests that due to the complexity of GBE the standardization of the product is inadequate, which likely explains the disparate clinical results. The variability in commercially available GBE products makes it impossible to determine whether GBE is truly effective for preventing or ameliorating AMS. However, investigating the roles of specific active components of GBE in the prevention of AMS could yield rewards both clinically and in our understanding of the pathophysiology of AMS.
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10.
Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review.
Dumont, L, Mardirosoff, C, Tramèr, MR
BMJ (Clinical research ed.). 2000;(7256):267-72
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Abstract
OBJECTIVE To quantify efficacy and harm of pharmacological prevention of acute mountain sickness. DATA SOURCES Systematic search (Medline, Embase, Cochrane Library, internet, bibliographies, authors) in any language, up to October 1999. STUDY SELECTION Randomised placebo controlled trials. DATA EXTRACTION Dichotomous data on efficacy and harm from 33 trials (523 subjects received 13 different interventions, 519 a placebo). DATA SYNTHESIS At above 4000 m the mean incidence of acute mountain sickness with placebo was 67% (range 25% to 100%); incidence depended on the rate of ascent, but not on the altitude or the mode of ascent. Across all ascent rates, dexamethasone 8-16 mg prevented acute mountain sickness (relative risk 2.50 (95% confidence interval 1.71 to 3.66); number needed to treat (NNT) 2.8 (2.0 to 4.6)), without evidence of dose responsiveness. Acetazolamide 750 mg was also efficacious (2.18 (1.52 to 3.15); NNT 2.9 (2.0 to 5.2)), but 500 mg was not. In two trials, adverse reaction (including depression) occurred after dexamethasone was stopped abruptly (4.45 (1.08 to 18); NNT 3.7 (2.5 to 6.9)). With acetazolamide, paraesthesia (4.02 (1.71 to 9.43); NNT 3.0 (2.0 to 6.0)) and polyuria (4.24 (1.92 to 9.37); NNT 3.6 (2.5 to 6.2)) were reported. Data were sparse on nifedipine, frusemide (furosemide), dihydroxyaluminium-sodium, spironolactone, phenytoin, codeine, phenformin, antidiuretic hormone, and ginkgo biloba. CONCLUSIONS At above 4000 m, with a high ascent rate, fewer than three subjects need to be treated with prophylactic dexamethasone 8-16 mg or acetazolamide 750 mg for one subject not to experience acute mountain sickness who would have done so had they all received a placebo. Acetazolamide 500 mg does not work.