The Wilderness Medical Society convened an expert panel to develop a set of evidence-based guidelines for the prevention and treatment of frostbite. We present a review of pertinent pathophysiology. We then discuss primary and secondary prevention measures and therapeutic management. Recommendations are made regarding each treatment and its role in management. These recommendations are graded on the basis of the quality of supporting evidence and balance between the benefits and risks or burdens for each modality according to methodology stipulated by the American College of Chest Physicians. This is an updated version of the guidelines published in 2019.

To provide guidance to clinicians about best practices, the Wilderness Medical Society (WMS) convened an expert panel to develop evidence-based guidelines for prevention, diagnosis, and treatment of acute mountain sickness, high altitude cerebral edema, and high altitude pulmonary edema. Recommendations are graded based on the quality of supporting evidence and the balance between the benefits and risks/burdens according to criteria put forth by the American College of Chest Physicians. The guidelines also provide suggested approaches for managing each form of acute altitude illness that incorporate these recommendations as well as recommendations on how to approach high altitude travel following COVID-19 infection. This is an updated version of the original WMS Consensus Guidelines for the Prevention and Treatment of Acute Altitude Illness published in Wilderness & Environmental Medicine in 2010 and the subsequently updated WMS Practice Guidelines for the Prevention and Treatment of Acute Altitude Illness published in 2014 and 2019.

High Altitude Medicine & BiologyVol. 21, No. 2 Letters to the EditorFree AccessLetter to the Editor: COVID-19 Lung Injury Is Different From High Altitude Pulmonary EdemaHermann Brugger, Buddha Basnyat, John Ellerton, Urs Hefti, Giacomo Strapazzon, and Ken ZafrenHermann BruggerAddress correspondence to: Hermann Brugger, MD, Via Ipazia 2, 39100 Bolzano, Italy E-mail Address: [email protected]Institute of Mountain Emergency Medicine, EURAC Research, Bolzano, Italy.International Society of Mountain Medicine (President), Switzerland.Medical University of Innsbruck, Innsbruck, Austria.International Commission for Alpine Rescue Medical Commission (ICAR MedCom), Zurich, Switzerland.Search for more papers by this author, Buddha BasnyatOxford University Clinical Research Unit—Nepal, Himalayan Rescue Association, and Travel and Mountain Medicine Center, Kathmandu, Nepal.International Society of Mountain Medicine (Past President), Switzerland.Search for more papers by this author, John EllertonInternational Commission for Alpine Rescue Medical Commission (ICAR MedCom) (President), Zurich, Switzerland.Search for more papers by this author, Urs HeftiSwiss Sportclinic, Bern, Switzerland.Medical Commission International Climbing and Mountaineering Federation (UIAA) (President), Bern, Switzerland.Search for more papers by this author, Giacomo StrapazzonInstitute of Mountain Emergency Medicine, EURAC Research, Bolzano, Italy.Medical University of Innsbruck, Innsbruck, Austria.International Commission for Alpine Rescue Medical Commission (ICAR MedCom), Zurich, Switzerland.International Society of Mountain Medicine, Switzerland.Search for more papers by this author, and Ken ZafrenInternational Commission for Alpine Rescue Medical Commission (ICAR MedCom), Zurich, Switzerland.Department of Emergency Medicine, Alaska Native Medical Center, Anchorage, USA.Department of Emergency Medicine, Stanford University Medical Center, Stanford, USA.Search for more papers by this authorPublished Online:17 Jun 2020https://doi.org/10.1089/ham.2020.0061AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookXLinked InRedditEmail Dear Editor,We read with interest the recent article by Luks et al. (2020). Recently, emergency physicians (Solaimanzadeh, 2020; Sidell, 2020) have suggested that there are pathophysiological similarities between coronavirus disease 2019 (COVID-19) pneumonia and high altitude pulmonary edema (HAPE). They have suggested that drugs known to be effective in patients suffering from acute mountain sickness or HAPE, such as acetazolamide, nifedipine, and phosphodiesterase inhibitors, might be useful in the treatment of COVID-19. In this journal, a group of high altitude researchers has debunked this myth and expressed concerns that this misconception may adversely affect the management of COVID-19 patients (Luks et al., 2020). We members of the International Society of Mountain Medicine (ISMM), International Commission for Alpine Rescue Medical Commission (ICAR MedCom), and Medical Commission of the International Climbing and Mountaineering Federation (UIAA) support these concerns and echo their warning.In contrast to HAPE (Swenson and Bärtsch, 2012), the pathophysiology of COVID-19 is still unclear (Mason, 2020). Both can present with severe hypoxemia. There are other similarities between COVID-19 lung injury and HAPE, but the differences far outweigh the similarities (Table 1).Table 1. Differences Between High Altitude Pulmonary Edema (HAPE) and Coronavirus Disease 2019 (COVID-19)HAPECOVID-19Hypoxia causativeHypoxemia secondary to respiratory failureNo infectious agentTransmitted viral diseaseHypoxia-induced pulmonary hypertensionPulmonary hypertension due to multiple causesInflammatory factors secondaryPrimary alveolar-interstitial inflammationReversible with supplemental oxygenNot reversible with oxygen aloneAffects only the lungAffects lung, kidney, heart, and nervous systemNo multi-organ system failureDeaths from multi-organ system failureRarely pre-existing conditions worsen outcomeCommon pre-existing conditions worsen outcomeGenetic susceptibilityPossible genetic susceptibilityAge independentIncreased mortality with increased ageHypobaric hypoxia is the sole cause of HAPE. There is abnormal hypoxic pulmonary vasoconstriction with high pulmonary artery and capillary pressure in response to alveolar hypoxia (Maggiorini et al., 2001). Hypoxia is not the cause of COVID-19.HAPE is not associated with any infectious agent. Alveolar epithelial inflammation is either absent (Swenson et al., 2002) or a secondary benign response to hypoxia and pulmonary hypertension, triggered by pro-inflammatory cytokines (Kubo et al., 1998). In COVID-19, respiratory failure is primarily caused by alveolar inflammation and destruction of cells.In HAPE patients, the excessive rise in pulmonary artery pressure is a direct response to hypobaric hypoxia in susceptible individuals that precedes endothelial dysfunction and pulmonary edema. In COVID-19 patients, the increase in pulmonary arterial pressure is not severe (Fried et al., 2020), multifactorial, and is associated with interstitial edema, hypoxemia, and intravascular thrombosis (Tang et al., 2020).Although HAPE is a life-threatening condition, it can be reversed effectively by descent to lower altitude, administration of supplemental oxygen, or placing the patient in a hyperbaric chamber. Critical care in an intensive care unit (ICU) is almost never necessary (Litch, 1999). Patients with COVID-19 lung injury typically present with a benign upper respiratory infection that progresses to severe acute respiratory distress syndrome (ARDS; Gattinoni et al., 2020). Patients with ARDS due to COVID-19 require ventilator support for several days to weeks and may suffer from permanent residual lung fibrosis.HAPE is limited to the lungs and does not primarily involve other organs. COVID-19 can affect all tissues that have angiotensin converting enzyme 2 (ACE-2) receptors, which are utilized as entering receptors by severe acute respiratory syndrome coronavirus 2. Tissues with ACE-2 receptors include the lungs, kidneys, heart, and possibly the central nervous system. The outcome of patients with COVID-19 disease is dependent not only on lung function, but also on the involvement of the kidneys and the heart. In many patients, multi-organ system failure is the cause of death.Pre-existing diseases usually do not worsen the outcome of HAPE. Individuals can be genetically susceptible to high altitude illnesses, but there are only a few pre-existing conditions that worsen outcome, primarily pulmonary hypertension (Stream et al., 2009).COVID-19 is associated with a higher mortality in patients with pre-existing diseases, including cardiovascular (hypertension, heart failure), pulmonary (chronic obstructive pulmonary disease), or metabolic (diabetes mellitus) conditions.HAPE mainly depends on the rate of decrease of the partial pressure of oxygen, that is, the rate of ascent to high altitude. Age is not an independent risk factor for HAPE. COVID-19 affects individuals of all ages, but patients older than 65 years of age are at higher risk of severe ARDS, with high mortality.For these reasons, we strongly caution against managing COVID-19 lung injury with treatments that are used for HAPE. COVID-19 lung injury and HAPE are fundamentally different in pathogenesis, pathophysiology, prognosis, and treatment.Author Disclosure StatementNone of the authors have any conflicts of interest or financial interests to report regarding the material presented in this manuscript.Funding InformationNo funding was received.ReferencesFried JA, Ramasubbu K, Bhatt R, Topkara VK, Clerkin KJ, Horn E, Rabbani L, Brodie D, Jain SS, Kirtane A, Masoumi A, Takeda K, Kumaraiah D, Burkhoff D, Leon M, Schwartz A, Uriel N, and Sayer G. (2020). The variety of cardiovascular presentations of COVID-19. Circulation [Epub ahead of print]; DOI: 10.1161/CIRCULATIONAHA.120.047164. Crossref, Google ScholarGattinoni L, Chiumello D, Caironi P, Busana M, Romitti F, Brazzi L, and Camporota L. (2020). COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Med [Epub ahead of print]; DOI: 10.1007/s00134-020-06033-2. Crossref, Google ScholarKubo K, Hanaoka M, Hayano T, Miyahara T, Hachiya T, Hayasaka M, Koizumi T, Fujimoto K, Kobayashi T, and Honda T. (1998). Inflammatory cytokines in BAL fluid and pulmonary hemodynamics in high-altitude pulmonary edema. Respir Physiol 111:301–310. Crossref, Medline, Google ScholarLitch JA. (1999). Endotracheal intubation and mechanical ventilation following respiratory arrest from high altitude pulmonary edema. West J Med 170:174–176. Medline, Google ScholarLuks AM, Freer L, Grissom CK, McIntosh SE, Schoene RB, Swenson ER, and Hackett PH. (2020). COVID-19 lung injury is not high altitude pulmonary edema. High Alt Med Biol 21:192–193. Link, Google ScholarMaggiorini M, Mélot C, Pierre S, Pfeiffer F, Greve I, Sartori C, Lepori M, Hauser M, Scherrer U, and Naeije R. (2001). High-altitude pulmonary edema is initially caused by an increase in capillary pressure. Circulation 103:2078–2083. Crossref, Medline, Google ScholarMason RJ. (2020). Pathogenesis of COVID-19 from a cell biology perspective. Eur Resp J [Epub ahead of print]; DOI: 10.1183/13993003.00607-2020. Crossref, Medline, Google ScholarSidell CK. (2020). ER and critical care doctor from NYC. Available at: https://www.youtube.com/watch?v=sKExxcD26_I (accessed April 13, 2020). Google ScholarSolaimanzadeh I. (2020). Acetazolamide, nifedipine and phosphodiesterase inhibitors: rationale for their utilization as adjunctive countermeasures in the treatment of coronavirus disease 2019 (COVID-19). Cureus 12:e7343. Medline, Google ScholarStream JO, Luks AM, and Grissom CK. (2009). Lung disease at high altitude. Expert Rev Respir Med 3:635–650. Crossref, Medline, Google ScholarSwenson ER and Bärtsch P. (2012). High-altitude pulmonary edema. Compr Physiol 2:2753–2773. Crossref, Medline, Google ScholarSwenson ER, Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbäurl H, and Bärtsch P. (2002). Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor. JAMA 287:2228–2235. Crossref, Medline, Google ScholarTang N, Bai H, Chen X, Gong J, Li D, and Sun Z. (2020). Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost [Epub ahead of print]; DOI: 10.1111/jth.14817. Crossref, Google ScholarFiguresReferencesRelatedDetailsCited byCOVID-19-related diffuse posthypoxic leukoencephalopathy and microbleeds masquerades as acute necrotizing encephalopathy30 December 2020 | International Journal of Neuroscience, Vol. 132, No. 11COVID-19 lung injury and high altitude pulmonary edemaMedical Journal of Dr. D.Y. Patil Vidyapeeth, Vol. 15, No. 1High-altitude illnesses: Old stories and new insights into the pathophysiology, treatment and preventionSports Medicine and Health Science, Vol. 3, No. 2Comments on potential re-purposing of medicines against high-altitude illnesses towards SARS-CoV2: possibilities and pitfalls20 January 2021 | Journal of Proteins and Proteomics, Vol. 12, No. 1The Fundamentals of Respiratory Physiology to Manage the COVID-19 Pandemic: An Overview18 February 2021 | Frontiers in Physiology, Vol. 11Altitude and COVID‐19: Friend or foe? A narrative review19 December 2020 | Physiological Reports, Vol. 8, No. 24Effect of Coronavirus Disease 2019 in Pulmonary Circulation. The Particular Scenario of Precapillary Pulmonary Hypertension31 July 2020 | Diagnostics, Vol. 10, No. 8 Volume 21Issue 2Jun 2020 InformationCopyright 2020, Mary Ann Liebert, Inc., publishersTo cite this article:Hermann Brugger, Buddha Basnyat, John Ellerton, Urs Hefti, Giacomo Strapazzon, and Ken Zafren.Letter to the Editor: COVID-19 Lung Injury Is Different From High Altitude Pulmonary Edema.High Altitude Medicine & Biology.Jun 2020.204-205.http://doi.org/10.1089/ham.2020.0061Published in Volume: 21 Issue 2: June 17, 2020Online Ahead of Print:April 30, 2020 TopicsAcute respiratory distress syndromeCOVID-19High altitude pulmonary edemaRespiratory system diseases PDF download

Background: Genetic testing for pedigree accuracy is critical for managing genetic diversity in North American (NA) yak (Bos grunniens), a population expanded mostly from imported zoological park specimens. DNA testing also enhances species conservation by identifying recent B. taurus F1 hybrid ancestors (within three generations). Biallelic single nucleotide polymorphisms (SNPs) can accomplish either task, but increases the marker count and costs necessary to achieve both. Our aim was to identify novel, multifunctional, triallelic yak SNPs (tySNPs), with each having two alleles for yak parentage testing, and a third allele for identifying recent cattle introgression. Methods: Genome sequences were aligned to the cattle UMD3.1 assembly and SNPs were screened for 1) heterozygosity in a NA and a Chinese yak, 2) a third allele at high frequency in cattle, and 3) flanking sequences conserved in both species. Subsequently, tySNPs were filtered for unique alignment to the haplotype-resolved F1 yak assembly. Allele frequencies were estimated in a subset of 87 tySNPs by genotyping 170 NA yak. Results: We identified 610 autosomal tySNPs, distributed in 441 clusters with 5 Mb average genome spacing. The average NA yak minor allele frequency was high (0.296), while average introgressed cattle alleles were low (0.004). In simulations with tySNPs, 28 were sufficient for globally-unique animal identification (PI=5.81x10-12), 87 were able to exclude 19 random bulls from parentage at the 99% level without using the dam’s genotype (PE=5.3x10-4), and 87 were able to detect F1 hybridization events after three generations of yak backcrosses (1/16th B. taurus germplasm). Conclusions: Identifying animals, determining parentage and detecting recent hybridization events was efficient with as few as 87 tySNPs. A similar triallelic approach could be used with other bottlenecked Bos species that hybridize with cattle, such as NA plains bison (B. bison).

BACKGROUND:The development of trio binning as an approach for assembling diploid genomes has enabled the creation of fully haplotype-resolved reference genomes. Unlike other methods of assembly for diploid genomes, this approach is enhanced, rather than hindered, by the heterozygosity of the individual sequenced. To maximize heterozygosity and simultaneously assemble reference genomes for 2 species, we applied trio binning to an interspecies F1 hybrid of yak (Bos grunniens) and cattle (Bos taurus), 2 species that diverged nearly 5 million years ago. The genomes of both of these species are composed of acrocentric autosomes.RESULTS:We produced the most continuous haplotype-resolved assemblies for a diploid animal yet reported. Both the maternal (yak) and paternal (cattle) assemblies have the largest 2 chromosomes in single haplotigs, and more than one-third of the autosomes similarly lack gaps. The maximum length haplotig produced was 153 Mb without any scaffolding or gap-filling steps and represents the longest haplotig reported for any species. The assemblies are also more complete and accurate than those reported for most other vertebrates, with 97% of mammalian universal single-copy orthologs present.CONCLUSIONS:The high heterozygosity inherent to interspecies crosses maximizes the effectiveness of the trio binning method. The interspecies trio binning approach we describe is likely to provide the highest-quality assemblies for any pair of species that can interbreed to produce hybrid offspring that develop to sufficient cell numbers for DNA extraction.

Clinicians and scientists have suggested therapies for coronavirus disease-19 (COVID-19) that are known to be effective for other medical conditions. A recent publication suggests that pathophysiological mechanisms underlying acute mountain sickness (a syndrome of nonspecific neurological symptoms typically experienced by nonacclimatized individuals at altitudes >2500 m) may overlap with the mechanisms causing COVID-19. In this short review, we briefly evaluate this mistaken analogy and demonstrate that this concept is not supported by scientific evidence.

To provide guidance to clinicians, the Wilderness Medical Society convened an expert panel to develop evidence-based guidelines for the out-of-hospital evaluation and treatment of victims of accidental hypothermia. The guidelines present the main diagnostic and therapeutic modalities and provide recommendations for the management of hypothermic patients. The panel graded the recommendations based on the quality of supporting evidence and a balance between benefits and risks/burdens according to the criteria published by the American College of Chest Physicians. The guidelines also provide suggested general approaches to the evaluation and treatment of accidental hypothermia that incorporate specific recommendations. This is the 2019 update of the Wilderness Medical Society Practice Guidelines for the Out-of-Hospital Evaluation and Treatment of Accidental Hypothermia: 2014 Update.

MR imaging of high-altitude cerebral edema shows reversible WM edema, especially in the corpus callosum and subcortical WM. Recent studies have revealed hemosiderin deposition in WM long after high-altitude cerebral edema has resolved, providing a high-altitude cerebral edema "footprint." We wished to determine whether these microbleeds are present acutely and also describe the evolution of all MR imaging findings. In 8 patients with severe high-altitude cerebral edema, we obtained 26 studies: 18 with 3T and 8 with 1.5T scanners, during the acute stage, recovery, and follow-up in 7 patients and acutely in 1 patient. Imaging confirmed reversible cytotoxic and vasogenic WM edema that unexpectedly worsened the first week during clinical improvement before resolving. The 3T SWI, but not 1.5T imaging, showed extensive microbleeds extending beyond areas of edema seen acutely, which persisted and with time coalesced. These findings support cytotoxic and vasogenic edema leading to capillary failure/leakage in the pathophysiology of high-altitude cerebral edema and provide imaging correlation to the clinical course.

Background Assemblies of diploid genomes are generally unphased, pseudo-haploid representations that do not correctly reconstruct the two parental haplotypes present in the individual sequenced. Instead, the assembly alternates between parental haplotypes and may contain duplications in regions where the parental haplotypes are sufficiently different. Trio binning is an approach to genome assembly that uses short reads from both parents to classify long reads from the offspring according to maternal or paternal haplotype origin, and is thus helped rather than impeded by heterozygosity. Using this approach, it is possible to derive two assemblies from an individual, accurately representing both parental contributions in their entirety with higher continuity and accuracy than is possible with other methods.Results We used trio binning to assemble reference genomes for two species from a single individual using an interspecies cross of yak ( Bos grunniens ) and cattle ( Bos taurus ). The high heterozygosity inherent to interspecies hybrids allowed us to confidently assign >99% of long reads from the F1 offspring to parental bins using unique k-mers from parental short reads. Both the maternal (yak) and paternal (cattle) assemblies contain over one third of the acrocentric chromosomes, including the two largest chromosomes, in single haplotigs.Conclusions These haplotigs are the first vertebrate chromosome arms to be assembled gap-free and fully phased, and the first time assemblies for two species have been created from a single individual. Both assemblies are the most continuous currently available for non-model vertebrates.* Mb : megabases kb : kilobases MYA : millions of years ago MHC : major histocompatibility complex SMRT : single molecule real time

Andrew M. Luks, MD; Paul S. Auerbach, MD, MS; Luanne Freer, MD; Colin K. Grissom, MD; Linda E. Keyes, MD; Scott E. McIntosh, MD, MPH; George W. Rodway, PhD, APRN; Robert B. Schoene, MD; Ken Zafren, MD; Peter H. Hackett, MD Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA; Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA; Yellowstone National Park, WY; Midway Atoll National Wildlife Refuge, Honolulu, HI; Everest ER, Himalayan Rescue Association, Kathmandu, Nepal; Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Salt Lake City, UT; Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT; Department of Emergency Medicine, University of Colorado, Denver, CO; Boulder Community Health, Boulder, CO; Division of Emergency Medicine, University of Utah, Salt Lake City, UT; University of California, Davis School of Nursing, Sacramento, CA; Division of Pulmonary and Critical Care Medicine, Sound Physicians, St. Mary’s Medical Center, San Francisco, CA; Himalayan Rescue Association, Kathmandu, Nepal; Altitude Research Center, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO

The Wilderness Medical Society convened an expert panel in 2011 to develop a set of evidence-based guidelines for the recognition, prevention, and treatment of heat illness. We present a review of the classifications, pathophysiology, and evidence-based guidelines for planning and preventive measures, as well as best practice recommendations for both field- and hospital-based therapeutic management of heat illness. These recommendations are graded based on the quality of supporting evidence and balance the benefits and risks or burdens for each modality. This is an updated version of the original Wilderness Medical Society Practice Guidelines for the Treatment and Prevention of Heat-Related Illness published in 2013.

Roach, Robert C., Peter H. Hackett, Oswald Oelz, Peter Bärtsch, Andrew M. Luks, Martin J. MacInnis, J. Kenneth Baillie, and The Lake Louise AMS Score Consensus Committee. The 2018 Lake Louise Acute Mountain Sickness Score. High Alt Med Biol 19:1-4, 2018.- The Lake Louise Acute Mountain Sickness (AMS) scoring system has been a useful research tool since first published in 1991. Recent studies have shown that disturbed sleep at altitude, one of the five symptoms scored for AMS, is more likely due to altitude hypoxia per se, and is not closely related to AMS. To address this issue, and also to evaluate the Lake Louise AMS score in light of decades of experience, experts in high altitude research undertook to revise the score. We here present an international consensus statement resulting from online discussions and meetings at the International Society of Mountain Medicine World Congress in Bolzano, Italy, in May 2014 and at the International Hypoxia Symposium in Lake Louise, Canada, in February 2015. The consensus group has revised the score to eliminate disturbed sleep as a questionnaire item, and has updated instructions for use of the score.

High altitude illness encompasses a spectrum of clinical entities to include: acute mountain sickness, high altitude cerebral edema, and high altitude pulmonary edema. These illnesses occur as a result of a hypobaric hypoxic environment. Although a mild case of acute mountain sickness may be self-limited, high altitude cerebral edema and high altitude pulmonary edema represent critical emergencies that require timely intervention. This article reviews recent advances in the prevention and treatment of high altitude illness, including new pharmacologic strategies for prophylaxis and revised treatment guidelines.

HIGHLIGHTED TOPIC | HypoxiaHypoxiaTranslation in progress: HypoxiaRobert C. Roach, Peter D. Wagner, and Peter H. HackettRobert C. RoachUniversity of Colorado Altitude Research Center, Department of Emergency Medicine, Anschutz Medical Campus, Aurora, Colorado; , Peter D. WagnerDepartment of Medicine, University of California, San Diego, La Jolla, California; and , and Peter H. HackettUniversity of Colorado Altitude Research Center, Department of Emergency Medicine, Anschutz Medical Campus, Aurora, Colorado; Institute for Altitude Medicine, Telluride, ColoradoPublished Online:01 Apr 2014https://doi.org/10.1152/japplphysiol.00145.2014This is the final version - click for previous versionMoreSectionsPDF (43 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat recent discoveries of molecular oxygen sensors in the hypoxia-inducible factor (HIF) system (1, 9–11) have brought together systems physiology and genomics in an exciting, wide-ranging exploration of how humans and other organisms sense and respond to hypoxia. Reflecting this growing and widespread interest in hypoxia, PubMed “hypoxia” citations have doubled in the last decade, to over 50,000 published articles. Since 2000, this is the third Highlighted Topic in the Journal of Applied Physiology with an emphasis on hypoxia (13, 14), indicative of the rapid, continuing evolution of the topic. The reviews that appear in this current Highlighted Topic originated from the 18th International Hypoxia Symposium that took place in Lake Louise, Canada in February 2013. The biannual International Hypoxia Symposia (IHS) bring together scientists and clinicians to focus on the integrative and translational biology of hypoxia, and because of the profound and protean biological impacts of hypoxia, the topics covered are diverse. The unique emphasis on integration of basic science with clinical medicine that distinguishes the IHS is reflected in the following six mini-reviews from leaders in this vigorous field. Taken together, they provide an overview of current stimulating topics in the biology of hypoxia and offer enticing clues for future research.The first review by Chapman et al. (2) addresses a key question for sports physiologists, trainers, and athletes: if one trains at high altitude to improve low-altitude athletic performance, when is the ideal time to compete after return to low altitude? Altitude training is now nearly universal for competitive “aerobic” athletes, but the data to answer this fundamental question are limited. The Journal of Applied Physiology has a long history of interest in this general topic (4, 7), and this newest review objectively explores the physiological parameters involved in picking the optimal time for peak performance on return from high-altitude training. The authors conclude that the time-dependent processes of neocytolysis, ventilatory deacclimatization, and altered biomechanical factors with return to low altitude all need to be considered in relation to the exact athletic event. This fresh look at the question will help establish a better scientific basis for recommendations and also encourage more research on this important and practical issue.In the second review, Immink et al. (5) examine the role of balance between PaCO2 and PaO2 in syncope, with implications for the overall control of the cerebrovascular circulation. They point out that despite a transient drop in cerebral blood flow with hypocapnia, it is insufficient to cause loss of consciousness, even with postural stress. However, when combined with decreased cardiac output, syncope may result. Whether hypoxemia, cardiovascular disease, or problems with cerebral blood flow/control may increase the likelihood of syncope with hyperventilation is an unanswered important issue. Joyner and Casey (6) present an intriguing synthesis of their work on the tight coupling of oxygen demand and supply during exercise and the redundancy of mechanisms serving to maintain oxygen delivery in hypoxia or hypoperfusion. This review is highlighted because of its implications for clinical medicine as well as elegant physiology. Dempsey et al. (3) in the fourth piece in the series review the mechanisms of cardiorespiratory acclimatization and deacclimatization to hypoxia and then discuss the pros and cons of such adjustments in terms of arterial oxygenation, the work of breathing, sympathoexcitation, systemic blood pressure, and exercise performance. They provocatively caution that the same deleterious cardiovascular impacts of intermittent hypoxia, such as those seen in patients with sleep apnea, may also apply to athletes upon return to low altitude from high-altitude training. This could also apply to persons with more transient intermittent altitude exposure, and their speculation will hopefully lead to appropriate investigation. The final two reviews in the series focus on two important roles of HIF. Shimoda and Laurie (12) discuss the importance of the HIF system in pulmonary vascular responses to hypoxia and the potential for pharmacologic modification of those responses. Targeting downstream HIF products offers an opportunity for treating pulmonary hypertension and also other HIF-related maladies. In the final paper in the series, Petousi and Robbins (8) review the exciting recent genomic work showing natural selection acting on oxygen-sensitive genes in Tibetans. Importantly, they point out that integrative systems physiology must be combined with genomics to further our understanding of human evolution in response to high-altitude hypoxia.These reviews by Shimoda and Laurie and Petousi and Robbins we think highlight an important need and an opportunity for readers of the Journal of Applied Physiology in the area of hypoxia research.Many of us are confronted daily with new findings from genomics or another arm of the omics revolution, absent any integration or translation to systems physiology. But rarely do we see a careful integration of genomics and physiology as suggested above for the role of hypoxia in pulmonary hypertension or in the global physiological responses to hypoxia of high-altitude natives. This approach can be extended to almost any area of hypoxia research, from altitude training, the control of the pulmonary or cerebral or skeletal muscle circulation, to how high-altitude natives outperform all others at high altitude. In summary, major future advances in hypoxia research will come from physiologists and clinicians working together with genomic scientists to understand the integrated systems physiology of human responses to hypoxia. This paradigm will continue to be the purpose of the International Hypoxia Symposia and of Highlighted Topics such as this.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).AUTHOR CONTRIBUTIONSAuthor contributions: R.C.R. and P.H.H. drafted manuscript; R.C.R., P.D.W., and P.H.H. edited and revised manuscript; R.C.R., P.D.W., and P.H.H. approved final version of manuscript.REFERENCES1. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 279: 38458–38465, 2004.Crossref | PubMed | ISI | Google Scholar2. Chapman RF, Laymon Stickford AS, Lundby C, Levine BD. Timing of return from altitude training for optimal sea level performance. J Appl Physiol; doi:10.1152/japplphysiol.00663.2013.Link | ISI | Google Scholar3. Dempsey JA, Powell FL, Bisgard GE, Blain GM, Poulin MJ, Smith CA. Role of chemoreception in cardiorespiratory acclimatization to, and deacclimatization from, hypoxia. J Appl Physiol; doi:10.1152/japplphysiol.01126.2013.Link | ISI | Google Scholar4. Faulkner JA, Daniels JT, Balke B. Effects of training at moderate altitude on physical performance capacity. J Appl Physiol 23: 85–89, 1967.Link | ISI | Google Scholar5. Immink RV, Pott FC, Secher NH, Van Lieshout JJ. Hyperventilation, cerebral perfusion, and syncope. J Appl Physiol; 10.1152/japplphysiol.00637.2013.Link | ISI | Google Scholar6. Joyner MJ, Casey DP. Muscle blood flow, hypoxia, and hypoperfusion. J Appl Physiol; doi:10.1152/japplphysiol.00620.2013.Link | ISI | Google Scholar7. Levine BD, Stray-Gundersen J. “Living high-training low”: effect of moderate-altitude acclimatization with low-altitude training on performance. J Appl Physiol 83: 102–112, 1997.Link | ISI | Google Scholar8. Petousi N, Robbins PA. Human adaptation to the hypoxia of high altitude: The Tibetan paradigm from the pregenomic to the postgenomic era. J Appl Physiol; doi:10.1152/japplphysiol.00605.2013.Link | ISI | Google Scholar9. Ratcliffe PJ. Oxygen sensing and hypoxia signalling pathways in animals: the implications of physiology for cancer. J Physiol 591: 2027–2042, 2013.Crossref | PubMed | ISI | Google Scholar10. Semenza GL. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology 19: 176–182, 2004.Link | ISI | Google Scholar11. Semenza GL. Oxygen sensing, homeostasis, disease. N Engl J Med 365: 537–547, 2011.Crossref | PubMed | ISI | Google Scholar12. Shimoda LA, Laurie SS. HIF and pulmonary vascular responses to hypoxia. J Appl Physiol; doi:10.1152/japplphysiol.00643.2013.Link | ISI | Google Scholar13. Sieck GC. Highlighted Topic: Hypoxia influence on gene expression. J Appl Physiol 88: 1153–1154, 2000.Link | ISI | Google Scholar14. Sieck GC. Highlighted Topic: Pulmonary circulation and hypoxia. J Appl Physiol 98: 1–2, 2005.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: R. C. Roach, Altitude Research Center, Dept. of Emergency Medicine, Univ. of Colorado, Aurora, CO 80045 (e-mail: Robert.[email protected]edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByTranslation in Progress: Hypoxia 2017Robert C. Roach, Peter D. Wagner, Philip N. Ainslie, and Peter H. Hackett26 October 2017 | Journal of Applied Physiology, Vol. 123, No. 4Translation in progress: Hypoxia 2015Robert C. Roach, Peter D. Wagner, Bengt Kayser, and Peter H. Hackett15 November 2015 | Journal of Applied Physiology, Vol. 119, No. 10 More from this issue > Volume 116Issue 7April 2014Pages 835-836 Copyright & PermissionsCopyright © 2014 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00145.2014PubMed24557798History Published online 1 April 2014 Published in print 1 April 2014 Metrics

OBJECTIVE:To evaluate whether women engage in outdoor activities and high altitude travel during pregnancy; the health care advice received regarding high altitude during pregnancy; and the association between high altitude exposure and self-reported pregnancy complications.METHODS:An online survey of women with at least 1 pregnancy distributed on websites and e-mail lists targeting mothers and/or mountain activities. Outcome measures were outdoor activities during pregnancy, high altitude (>2440 m) exposure during pregnancy, and pregnancy and perinatal complications.RESULTS:Hiking, running, and swimming were the most common activities performed during pregnancy. Women traveled to high altitude in over half of the pregnancies (244/459), and most did not receive counseling regarding altitude (355, 77%), although a small proportion (14, 3%) were told not to go above 2440 m. Rates of miscarriage and most other complications were similar between pregnancies with and without travel above 2440 m. Pregnancies with high altitude exposure were more likely to have preterm labor (odds ratio [OR] 2.3; 95% CI 0.97-5.4; P = .05). Babies born to women who went to high altitude during pregnancy were more likely to need oxygen at birth (OR 2.34; 95% CI 1.04-5.26; P < .05) but had similar rates of neonatal intensive care unit admission (P = not significant).CONCLUSIONS:Our results suggest pregnant women who are active in outdoor sports and travel to high altitude have a low rate of complications. Given the limitations of our data, further research is necessary on the risks associated with high altitude travel and physical activity and how these apply to the general population.

Despite advances in outdoor clothing and medical management of frostbite, individuals still experience catastrophic amputations. This is a particular risk for those in austere environments, due to resource limitations and delayed definitive treatment. The emerging best therapies for severe frostbite are thrombolytics and iloprost. However, they must be started within 24 hours after rewarming for recombinant tissue plasminogen activator (rt-PA) and within 48 hours for iloprost. Evacuation of individuals experiencing frostbite from remote environments within 24 to 48 hours is often impossible. To date, use of these agents has been confined to hospitals, thus depriving most individuals in the austere environment of the best treatment. We propose that thrombolytics and iloprost be considered for field treatment to maximize chances for recovery and reduce amputations. Given the small but potentially serious risk of complications, rt-PA should only be used for grade 4 frostbite where amputation is inevitable, and within 24 hours of rewarming. Prostacyclin has less risk and can be used for grades 2 to 4 frostbite within 48 hours of rewarming. Until more field experience is reported with these agents, their use should probably be restricted to experienced physicians. Other modalities, such as local nerve blocks and improving oxygenation at high altitude may also be considered. We submit that it remains possible to improve frostbite outcomes despite delayed evacuation using resource-limited treatment strategies. We present 2 cases of frostbite treated with rt-PA at K2 basecamp to illustrate feasibility and important considerations.

The pathophysiology of acute mountain sickness and high-altitude cerebral edema, the cerebral forms of high-altitude illness, remain uncertain and controversial. Persistently elevated or pathological fluctuations in intracranial pressure are thought to cause symptoms similar to those reported by individuals suffering cerebral forms of high-altitude illness. This review first focuses on the basic physiology of the craniospinal system, including a detailed discussion of the long-term and dynamic regulation of intracranial pressure. Thereafter, we critically examine the available literature, based primarily on invasive pressure monitoring, that suggests intracranial pressure is acutely elevated at altitude due to brain swelling and/or elevated sagittal sinus pressure, but normalizes over time. We hypothesize that fluctuations in intracranial pressure occur around a slightly elevated or normal mean intracranial pressure, in conjunction with oscillations in arterial Po 2 and arterial blood pressure. Then these modest fluctuations in intracranial pressure, in concert with direct vascular stretch due to dilatation and/or increased blood pressure transmission, activate the trigeminal vascular system and cause symptoms of acute mountain sickness. Elevated brain water (vasogenic edema) may be due to breakdown of the blood-brain barrier. However, new information suggests cerebral spinal fluid flux into the brain may be an important factor. Regardless of the source (or mechanisms responsible) for the excess brain water, brain swelling occurs, and a “tight fit” brain would be a major risk factor to produce symptoms; activities that produce large changes in brain volume and cause fluctuations in blood pressure are likely contributing factors.

We thank Brown et al for their response1Brown D. Ellerton J. Paal P. Boyd J. Hypothermia evidence, afterdrop, and practical experience.Wilderness Environ Med. 2015; 26: 439-440Google Scholar to our article "Wilderness Medical Society practice guidelines for the out-of-hospital evaluation and treatment of accidental hypothermia."2Zafren K. Giesbrecht G.G. Danzl D.F. et al.Wilderness Medical Society practice guidelines for the out-of-hospital evaluation and treatment of accidental hypothermia: 2014 update.Wilderness Environ Med. 2014; 25: 66-85Abstract Full Text Full Text PDF Scopus (72) Google Scholar We did our best to use the available evidence to provide useful guidelines. Although we agree that some aspects regarding management of accidental hypothermia are controversial, the basics of hypothermia pathophysiology are well established. We disagree with the assessment of Brown et al that the evidence is not sufficiently robust to guide treatment. The basis of our recommendation to delay standing or walking a mildly hypothermic patient for 30 minutes is related to the potential for afterdrop as well as hypotension with clinical deterioration.3Hayward J.S. Eckerson J.D. Kemna D. Thermal and cardiovascular changes during three methods of resuscitation from mild hypothermia.Resuscitation. 1984; 11: 21-33Abstract Full Text PDF PubMed Scopus (103) Google Scholar, 4Giesbrecht G.G. Bristow G.K. The convective afterdrop component during hypothermic exercise decreases with delayed exercise onset.Aviat Space Environ Med. 1998; 69: 17-22PubMed Google Scholar We should have been more explicit that this recommendation does not apply to a mildly hypothermic patient who is already walking, and may not be advisable when rescuers have limited resources to provide shelter and rewarming. We advise practical and sensible application of the guidelines rather than strict adherence. Rescue personnel should do the best they can under the circumstances. Brown et al counted the types of studies in our list of references. We reviewed all the relevant studies we could identify. In the supplemental materials,2Zafren K. Giesbrecht G.G. Danzl D.F. et al.Wilderness Medical Society practice guidelines for the out-of-hospital evaluation and treatment of accidental hypothermia: 2014 update.Wilderness Environ Med. 2014; 25: 66-85Abstract Full Text Full Text PDF Scopus (72) Google Scholar we mentioned that the experimental physiology randomized clinical trials we cited were limited to studying nonhypothermic or mildly hypothermic subjects. The subjects were generally young and healthy. It is probable that afterdrop would be greater and adverse effects more likely in older, less healthy, and more severely hypothermic patients, especially when hypothermia is combined with volume depletion and exhaustion under field conditions. Brown et al suggest that it would be better to wait for stronger evidence to make Grade 1 recommendations. We used the classification system of the American College of Chest Physicians in which recommendations are Grade 1 (strong) or Grade 2 (weak).5Guyatt G. Gutterman D. Baumann M.H. et al.Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force.Chest. 2006; 129: 174-181Crossref PubMed Scopus (972) Google Scholar The strength of evidence is rated separately by a letter. For example, Grade 1A is a strong recommendation based on strong evidence. Providers of medical care often must act with incomplete information, especially in the prehospital setting. We attempted to be conservative in our recommendations to avoid harm to patients. It is appropriate to make strong recommendations based on low-quality evidence when potential benefits clearly seem to outweigh risks. Guidelines that make mainly Grade 2 (weak) recommendations do not provide much guidance to those who use them. We agree with Brown et al that organ failure, particularly ventricular fibrillation causing circulatory arrest, is important. It is the main cause of death due to hypothermia. We also remind our readers that "there is great variation among individuals in response to core temperature, as with any other physiologic parameter." There is good evidence to suggest that afterdrop and peripheral vasodilation are clinically important and should be minimized in moderate and severe hypothermia to decrease morbidity and mortality.3Hayward J.S. Eckerson J.D. Kemna D. Thermal and cardiovascular changes during three methods of resuscitation from mild hypothermia.Resuscitation. 1984; 11: 21-33Abstract Full Text PDF PubMed Scopus (103) Google Scholar, 6Althaus U. Aeberhard P. Schupbach P. Nachbur B.H. Muhlemann W. Management of profound accidental hypothermia with cardiorespiratory arrest.Ann Surg. 1982; 195: 492-495Crossref PubMed Scopus (167) Google Scholar, 7Stoneham M.D. Squires S.J. Prolonged resuscitation in acute deep hypothermia.Anaesthesia. 1992; 47: 784-788Crossref PubMed Scopus (33) Google Scholar, 8Giesbrecht G.G. Hayward J.S. Problems and complications with cold-water rescue.Wilderness Environ Med. 2006; 17: 26-30Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Experimental evidence in humans demonstrates that circulation contributes more to afterdrop than conduction.9Giesbrecht G.G. Bristow G.K. A second postcooling afterdrop: more evidence for a convective mechanism.J Appl Physiol. 1992; 73: 1253-1258PubMed Google Scholar It is not possible to decrease the conductive component of afterdrop, but it is possible to limit the contribution of circulation. We do not state or imply that rewarming causes afterdrop. Any intervention that increases blood flow to cold extremities, including some rewarming methods, increases afterdrop. The studies that Brown et al cite in which hypothermic patients were rewarmed without afterdrop were in-hospital studies. The patients likely had already experienced afterdrop in the prehospital phase. Our recommendations are to avoid movement or warming of extremities initially to limit afterdrop caused by return of cold peripheral blood to the core. Brown et al are correct that rescue collapse occurs in terrestrial rescue. It is usually impractical to measure core temperature before rescue collapse. A patient who has had rescue collapse is assumed to have been moderately or severely hypothermic. For this reason, there is unlikely to be a report of rescue collapse of a mildly hypothermic patient without comorbidities. Like Brown et al, we recommend giving a mildly hypothermic patient additional insulation and calories. For the source of calories, we recommend high carbohydrate liquids and food.2Zafren K. Giesbrecht G.G. Danzl D.F. et al.Wilderness Medical Society practice guidelines for the out-of-hospital evaluation and treatment of accidental hypothermia: 2014 update.Wilderness Environ Med. 2014; 25: 66-85Abstract Full Text Full Text PDF Scopus (72) Google Scholar If adequate resources are not available, the patient might need to walk to safety, with an observation period that is limited to the time it takes to insulate and provide calories, with an increased risk of rescue collapse. We would agree with Brown et al not to limit standing or walking of mildly hypothermic patients if we could determine reliably which patients are only very mildly hypothermic. Owing to extreme variability in responses to hypothermia, this determination cannot be based reliably on clinical evaluation. Field measurement of core temperature is also not sufficiently accurate. If we erred in our recommendations, it was an attempt to err on the side of caution. Hypothermia Evidence, Afterdrop, and Practical ExperienceWilderness & Environmental MedicineVol. 26Issue 3PreviewWe congratulate Zafren et al1 for their recent publication "Wilderness Medical Society practice guidelines for the out-of-hospital evaluation and treatment of accidental hypothermia." In particular, we commend them for identifying clinically important questions and attempting to answer these using an evidence-based approach. We would like to share our opinion that much remains unknown about the optimal management of accidental hypothermia patients and that significant controversies remain. Our intention is to underline that the evidence supporting some of the Wilderness Medical Society (WMS) recommendations may not be as robust as suggested by their evidence grades. Full-Text PDF