Denny Z. H. Levett

The role of nitrogen oxides in human adaptation to hypoxia.

Lowland residents adapt to the reduced oxygen availability at high altitude through a process known as acclimatisation, but the molecular changes underpinning these functional alterations are not well understood. Using an integrated biochemical/whole-body physiology approach we here show that plasma biomarkers of NO production (nitrite, nitrate) and activity (cGMP) are elevated on acclimatisation to high altitude while S-nitrosothiols are initially consumed, suggesting multiple nitrogen oxides contribute to improve hypoxia tolerance by enhancing NO availability. Unexpectedly, oxygen cost of exercise and mechanical efficiency remain unchanged with ascent while microvascular blood flow correlates inversely with nitrite. Our results suggest that NO is an integral part of the human physiological response to hypoxia. These findings may be of relevance not only to healthy subjects exposed to high altitude but also to patients in whom oxygen availability is limited through disease affecting the heart, lung or vasculature, and to the field of developmental biology.

Effects of Prolonged Exposure to Hypobaric Hypoxia on Oxidative Stress, Inflammation and Gluco-Insular Regulation: The Not-So-Sweet Price for Good Regulation

Objectives The mechanisms by which low oxygen availability are associated with the development of insulin resistance remain obscure. We thus investigated the relationship between such gluco-insular derangements in response to sustained (hypobaric) hypoxemia, and changes in biomarkers of oxidative stress, inflammation and counter-regulatory hormone responses. Methods After baseline testing in London (75 m), 24 subjects ascended from Kathmandu (1,300 m) to Everest Base Camp (EBC;5,300 m) over 13 days. Of these, 14 ascended higher, with 8 reaching the summit (8,848 m). Assessments were conducted at baseline, during ascent to EBC, and 1, 6 and 8 week(s) thereafter. Changes in body weight and indices of gluco-insular control were measured (glucose, insulin, C-Peptide, homeostasis model assessment of insulin resistance [HOMA-IR]) along with biomarkers of oxidative stress (4-hydroxy-2-nonenal-HNE), inflammation (Interleukin-6 [IL-6]) and counter-regulatory hormones (glucagon, adrenalin, noradrenalin). In addition, peripheral oxygen saturation (SpO2) and venous blood lactate concentrations were determined. Results SpO2 fell significantly from 98.0% at sea level to 82.0% on arrival at 5,300 m. Whilst glucose levels remained stable, insulin and C-Peptide concentrations increased by >200% during the last 2 weeks. Increases in fasting insulin, HOMA-IR and glucagon correlated with increases in markers of oxidative stress (4-HNE) and inflammation (IL-6). Lactate levels progressively increased during ascent and remained significantly elevated until week 8. Subjects lost on average 7.3 kg in body weight. Conclusions Sustained hypoxemia is associated with insulin resistance, whose magnitude correlates with the degree of oxidative stress and inflammation. The role of 4-HNE and IL-6 as key players in modifying the association between sustained hypoxia and insulin resistance merits further investigation.

The Young Everest Study: effects of hypoxia at high altitude on cardiorespiratory function and general well-being in healthy children

Objectives: To assess the effect of altitude and acclimatisation on cardiorespiratory function and well-being in healthy children. Methods: A daily symptom diary, serial measurements of spirometry, end-tidal carbon dioxide (etCO2) and daytime and overnight pulse oximetry (SpO2), were undertaken at sea level and altitudes up to 3500 m in healthy children during a trekking holiday. SpO2 at altitude was compared with that in flight and during acute hypoxic challenge (breathing 15% oxygen) at sea level. Results: Measurements were obtained in nine children aged 6–13 years (median 8). SpO2 decreased significantly during the hypoxic challenge (difference −5%, 95% CI −6 to −3%, p<0.01) but remained above 90% in all children. There was a significant fall in daytime and overnight SpO2 (95% CI −11.9 to −7.5% and −12 to −8, respectively) and etCO2 (−8.5 to −4.5 mm Hg) as the children ascended to 3500 m. There was a significant increase in SpO2 (95% CI 1.1 to 4.9%) and a further drop in etCO2 (−5.9 to −0.8 mm Hg) after a week at altitude, etCO2 being negatively correlated with SpO2. There was no correlation between SpO2 during hypoxic challenge, in flight or at altitude. Lung function remained within 7% of baseline in all but two children, in whom reductions of up to 23% in FVC and 16% FEV1 were observed at altitude. The children generally remained well, but the Lake Louise scoring system was unreliable in this age group. Conclusions: A wide range of physiological responses to altitude are evident in healthy children. This study should inform future larger studies in children to improve understanding of responses to hypoxia in health and disease.

Changes in muscle proteomics in the course of the Caudwell Research Expedition to Mt. Everest.

This study employed differential proteomic and immunoassay techniques to elucidate the biochemical mechanisms utilized by human muscle (vastus lateralis) in response to high altitude hypoxia exposure. Two groups of subjects, participating in a medical research expedition (A, n = 5, 19d at 5300 m altitude; B, n = 6, 66d up to 8848 m) underwent a ≈ 30% drop of muscular creatine kinase and of glycolytic enzymes abundance. Protein abundance of most enzymes of the tricarboxylic acid cycle and oxidative phosphorylation was reduced both in A and, particularly, in B. Restriction of α‐ketoglutarate toward succinyl‐CoA resulted in increased prolyl hydroxylase 2 and glutamine synthetase. Both A and B were characterized by a reduction of elongation factor 2alpha, controlling protein translation, and by an increase of heat shock cognate 71 kDa protein involved in chaperone‐mediated autophagy. Increased protein levels of catalase and biliverdin reductase occurred in A alongside a decrement of voltage‐dependent anion channels 1 and 2 and of myosin‐binding protein C, suggesting damage to the sarcomeric structures. This study suggests that during acclimatization to hypobaric hypoxia the muscle behaves as a producer of substrates activating a metabolic reprogramming able to support anaplerotically the tricarboxylic acid cycle, to control protein translation, to prevent energy expenditure and to activate chaperone‐mediated autophagy.

The Young Everest Study: preliminary report of changes in sleep and cerebral blood flow velocity during slow ascent to altitude in unacclimatised children

Background Cerebral blood flow velocity (CBFV) and sleep physiology in healthy children exposed to hypoxia and hypocarbia are under-researched. Aim To investigate associations between sleep variables, daytime end-tidal carbon dioxide (EtCO2) and CBFV in children during high-altitude ascent. Methods Vital signs, overnight cardiorespiratory sleep studies and transcranial Doppler were undertaken in nine children (aged 6–13 years) at low altitude (130 m), and then at moderate (1300 m) and high (3500 m) altitude during a 5-day ascent. Results Daytime (130 m: 98%; 3500 m: 90%, p=0.004) and mean (130 m: 97%, 1300 m: 94%, 3500: 87%, p=0.0005) and minimum (130 m: 92%, 1300 m: 84%, 3500 m: 79%, p=0.0005) overnight pulse oximetry oxyhaemoglobin saturation decreased, and the number of central apnoeas increased at altitude (130 m: 0.2/h, 1300 m: 1.2/h, 3500 m: 3.5/h, p=0.2), correlating inversely with EtCO2 (R2 130 m: 0.78; 3500 m: 0.45). Periodic breathing occurred for median (IQR) 0.0 (0; 0.3)% (130 m) and 0.2 (0; 1.2)% (3500 m) of total sleep time. At 3500 m compared with 130 m, there were increases in middle (MCA) (mean (SD) left 29.2 (42.3)%, p=0.053; right 9.9 (12)%, p=0.037) and anterior cerebral (ACA) (left 65.2 (69)%, p=0.024; right 109 (179)%; p=0.025) but not posterior or basilar CBFV. The right MCA CBFV increase at 3500 m was predicted by baseline CBFV and change in daytime SpO2 and EtCO2 at 3500 m (R2 0.92); these associations were not seen on the left. Conclusions This preliminary report suggests that sleep physiology is disturbed in children even with slow ascent to altitude. The regional variations in CBFV and their association with hypoxia and hypocapnia require further investigation.

Stroke at High Altitude Diagnosed in the Field Using Portable Ultrasound

A tool that can differentiate ischemic stroke from other neurological conditions (eg, hemorrhagic stroke, high-altitude cerebral edema) in the field could enable more rapid thrombolysis when appropriate. The resources (eg, an MRI or CT scanner) to investigate stroke at high altitude may be limited, and hence a portable tool would be of benefit. Such a tool may also be of benefit in emergency departments when CT scanning is not available. We report a case of a 49-year-old man who, while climbing at 5900 m, suffered a left middle cerebral infarct. The clinical diagnosis was supported using 2D Power Doppler. The patient received aspirin and continuous transcranial Doppler was used for its potential therapeutic effects for 12 hours. The patient was then evacuated to a hospital in Kathmandu over the next 48 hours. This case report suggests that portable ultrasound could be used in the prehospital arena to enable early diagnosis of thrombotic stroke.

Metabolic basis to Sherpa altitude adaptation

Significance A relative fall in tissue oxygen levels (hypoxia) is a common feature of many human diseases, including heart failure, lung diseases, anemia, and many cancers, and can compromise normal cellular function. Hypoxia also occurs in healthy humans at high altitude due to low barometric pressures. Human populations resident at high altitude in the Himalayas have evolved mechanisms that allow them to survive and perform, including adaptations that preserve oxygen delivery to the tissues. Here, we studied one such population, the Sherpas, and found metabolic adaptations, underpinned by genetic differences, that allow their tissues to use oxygen more efficiently, thereby conserving muscle energy levels at high altitude, and possibly contributing to the superior performance of elite climbing Sherpas at extreme altitudes. The Himalayan Sherpas, a human population of Tibetan descent, are highly adapted to life in the hypobaric hypoxia of high altitude. Mechanisms involving enhanced tissue oxygen delivery in comparison to Lowlander populations have been postulated to play a role in such adaptation. Whether differences in tissue oxygen utilization (i.e., metabolic adaptation) underpin this adaptation is not known, however. We sought to address this issue, applying parallel molecular, biochemical, physiological, and genetic approaches to the study of Sherpas and native Lowlanders, studied before and during exposure to hypobaric hypoxia on a gradual ascent to Mount Everest Base Camp (5,300 m). Compared with Lowlanders, Sherpas demonstrated a lower capacity for fatty acid oxidation in skeletal muscle biopsies, along with enhanced efficiency of oxygen utilization, improved muscle energetics, and protection against oxidative stress. This adaptation appeared to be related, in part, to a putatively advantageous allele for the peroxisome proliferator-activated receptor A (PPARA) gene, which was enriched in the Sherpas compared with the Lowlanders. Our findings suggest that metabolic adaptations underpin human evolution to life at high altitude, and could have an impact upon our understanding of human diseases in which hypoxia is a feature.

Re-designing the pathway to surgery: better care and added value

The case for radical pathway re-design before surgery is in part driven by healthcare system pressures which are in turn the result of continuously rising demand in the face of tightly constrained resources. Such circumstances tend to drive revolutionary, rather than incremental, change. The current approach to preoperative assessment, that typically occurs in the weeks leading up to surgery, but is all too often only a few days before surgery, results in a lost opportunity for perioperative physicians to improve patient care. Re-engineering this process based on a patient-focused, pathway-driven vision of perioperative medicine offers a means of exploiting this opportunity. This review explores drivers for change, the opportunity offered by pathway re-design, and suggests a variety of strategies to add value in the preoperative pathway, each of which is facilitated by early engagement between perioperative physician and patient: collaborative decision-making, collaborative behavioural change, targeted comorbidity management as well as expectation management and psychological preparation for surgery including surgery schools.