Metabolic basis to Sherpa altitude adaptation.

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.

COVID-19: UK frontline intensivists' emerging learning.

The Intensive Care Society held a webinar on 3 April 2020 at which representatives from 11 of the most COVID-19 experienced hospital trusts in England and Wales shared learning around five specific topic areas in an open forum. This paper summarises the emerging learning and practice shared by those frontline clinicians.

Changes in sublingual microcirculatory flow index and vessel density on ascent to altitude.

We hypothesized that ascent to altitude would result in reduced sublingual microcirculatory flow index (MFI) and increased vessel density. Twenty-four subjects were studied using sidestream dark-field imaging, as they ascended to 5300 m; one cohort remained at this altitude (n = 10), while another ascended higher (maximum 8848 m; n = 14). The MFI, vessel density and grid crossings (GX; an alternative density measure) were calculated. Total study length was 71 days; images were recorded at sea level (SL), Namche Bazaar (3500 m), Everest base camp (5300 m), the Western Cwm (6400 m), South Col (7950 m) and departure from Everest base camp (5300 m; 5300 m-b). Peripheral oxygen saturation (SpO2), heart rate and blood pressure were also recorded. Compared with SL, altitude resulted in reduced sublingual MFI in small (<25 microm; P < 0.0001) and medium vessels (26-50 microm; P = 0.006). The greatest reduction in MFI from SL was seen at 5300 m-b; from 2.8 to 2.5 in small vessels and from 2.9 to 2.4 in medium-sized vessels. The density of vessels <25 microm did not change during ascent, but those >25 microm rose from 1.68 (+/- 0.43) mm mm(-2) at SL to 2.27 (+/- 0.57) mm mm(-2) at 5300 m-b (P = 0.005); GX increased at all altitudes (P < 0.001). The reduction in MFI was greater in climbers than in those who remained at 5300 m in small and medium-sized vessels (P = 0.017 and P = 0.002, respectively). At 7950 m, administration of supplemental oxygen resulted in a further reduction of MFI and increase in vessel density. Thus, MFI was reduced whilst GX increased in the sublingual mucosa with prolonged exposure to hypoxia and was exaggerated in those exposed to extreme altitude.

Extracorporeal Membrane Oxygenation as Salvage Therapy in the Peripartum Period: A Case Series.

Despite considerable advances in maternity care, maternal death rates remain unacceptably high. Even with optimal care, unexpected complications can result in catastrophic consequences. Hemorrhage, cardiovascular and coronary conditions, and cardiomyopathy make up the three most common causes of pregnancy-associated deaths, followed by sepsis and thromboembolic disease. Although a number of deaths may be deemed to be potentially avoidable with appropriate education and infrastructure, others such as refractory hypoxia and peripartum cardiomyopathy are not. All possible interventions should be explored, including the use of more novel and aggressive life support technologies, such as extracorporeal membrane oxygenation. We report the successful use of extracorporeal membrane oxygenation in three cases of severe peripartum morbidity. The first case describes spontaneous coronary artery dissection supported with veno-arterial extracorporeal membrane oxygenation for refractory cardiogenic shock after out-of-hospital cardiac arrest. The second is a case of severe pregnancy-related liver disease bridged to emergency liver transplantation with veno-venous extracorporeal membrane oxygenation. Finally, we report the use of extracorporeal cardiopulmonary resuscitation for refractory cardiac arrest in a postpartum patient. Peripartum extracorporeal membrane oxygenation is feasible in carefully selected patients, and should be considered early when conventional therapy is failing, or as a salvage rescue therapy when it has failed.

High-altitude physiology and pathophysiology: implications and relevance for intensive care medicine.

Cellular hypoxia is a fundamental mechanism of injury in the critically ill. The study of human responses to hypoxia occurring as a consequence of hypobaria defines the fields of high-altitude medicine and physiology. A new paradigm suggests that the physiological and pathophysiological responses to extreme environmental challenges (for example, hypobaric hypoxia, hyperbaria, microgravity, cold, heat) may be similar to responses seen in critical illness. The present review explores the idea that human responses to the hypoxia of high altitude may be used as a means of exploring elements of the pathophysiology of critical illness.

Increased gastric-end tidal P(CO2) gap during exercise at high altitude measured by gastric tonometry.

Using automated air gastric tonometry, the hypothesis that gastric perfusion is reduced while exercising at high altitude was explored. This prospective observational study of 5 well acclimatized healthy volunteers was performed during a medical research expedition to Chamlang base camp (5000 m), Hongu valley, Nepal. We used gastric tonometry at rest and during graded submaximal exercise. The end tidal partial pressure of carbon dioxide was subtracted from the gastric mucosal partial pressure of carbon dioxide to calculate the P(CO2) gradient, which is a marker of gastric mucosal perfusion. When compared with rest, there was no increase in the mean P(CO2) gradient at the lower work rate (0.22 vs. 0.18, p 0.10), but an increase was seen between rest and the higher work rate (0.22 vs. 0.77, p = 0.04). We conclude that exercising while at high altitude can lead to a raised P(CO2) gradient when gastric tonometry is performed, indicating reduced perfusion. This may represent reduced gastric mucosal perfusion under these conditions.

Sublingual microcirculatory blood flow and vessel density in Sherpas at high altitude.

Anecdotal reports suggest that Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitude, despite exhibiting lower arterial oxygen content than acclimatized lowlanders. This study tested the hypothesis that Sherpas exposed to hypobaric hypoxia on ascent to 5,300 m develop increased microcirculatory blood flow as a means of maintaining tissue oxygen delivery. Incident dark-field imaging was used to obtain images of the sublingual microcirculation from 64 Sherpas and 69 lowlanders. Serial measurements were obtained from participants undertaking an ascent from baseline testing (35 m or 1,300 m) to Everest base camp (5,300 m) and following subsequent descent in Kathmandu (1,300 m). Microcirculatory flow index and heterogeneity index were used to provide indexes of microcirculatory flow, while capillary density was assessed using small vessel density. Sherpas demonstrated significantly greater microcirculatory blood flow at Everest base camp, but not at baseline testing or on return in Kathmandu, than lowlanders. Additionally, blood flow exhibited greater homogeneity at 5,300 and 1,300 m (descent) in Sherpas than lowlanders. Sublingual small vessel density was not different between the two cohorts at baseline testing or at 1,300 m; however, at 5,300 m, capillary density was up to 30% greater in Sherpas. These data suggest that Sherpas can maintain a significantly greater microcirculatory flow per unit time and flow per unit volume of tissue at high altitude than lowlanders. These findings support the notion that peripheral vascular factors at the microcirculatory level may be important in the process of adaptation to hypoxia.NEW & NOTEWORTHY Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitude, yet the physiological mechanisms underlying this tolerance remain unknown. In our prospective study, conducted on healthy volunteers ascending to Everest base camp (5,300 m), we demonstrated that Sherpas have a higher sublingual microcirculatory blood flow and greater capillary density at high altitude than lowlanders. These findings support the notion that the peripheral microcirculation plays a key role in the process of long-term adaptation to hypoxia.

Physiology, pharmacology, and rationale for colloid administration for the maintenance of effective hemodynamic stability in critically ill patients.

The semisynthetic colloid solutions (gelatins, dextrans, and hydroxyethyl starches) are complex drugs. Their principal role in the care of the critically ill is as plasma volume expanders, but they may also affect hemorrheology, hemostasis, and inflammatory processes. The pattern of beneficial and detrimental effects varies between products. Understanding of the physiology of plasma volume expansion, as well as the nature and magnitude of these additional pharmacological qualities, is necessary for rational prescription of these commonly used products. The composition of the solute carrier solution can influence the clinical effects of colloid solutions. A large amount of data from laboratory and small clinical studies is available to inform this choice of colloid in a variety of situations. Significant patient outcome data from large studies has until recently been lacking, and clinicians have continued to prescribe a variety of crystalloids and colloids for the maintenance of effective hemodynamic stability in critically ill patients. The recently published Saline vs Albumin Fluid Evaluation Study demonstrates that albumin has an equivalent effectiveness and safety profile to 0.9% saline as a resuscitation fluid. The choice of clinical endpoints to guide dosage (infused volume) of colloids is probably therefore more important than the choice between individual products.

Reduced coagulation at high altitude identified by thromboelastography.

The impact of hypoxaemia on blood coagulation remains unclear despite use of a variety of measures to address the issue. We report the first use of thromboelastography (TEG) at high altitude to describe the dynamics of clot formation in whole blood samples. Seventeen healthy volunteers ascended to 5,300 m following an identical ascent profile; TEG measurements at 4,250 m and 5,300 m were compared with those from sea level. Peripheral oxygen saturation (SpO2) and haematocrit were also measured. Ascent resulted in a decline in SpO2 from 97.8 (± 1.2) % at sea level to 86.9 (± 3.3) % at 4,250 m and 79.5 (± 5.8) % at 5,300 m (p<0.001); haematocrit rose from 43.7 (± 2.8) % at sea level, to 46.7 (± 3.9) % and 52.6 (± 3.2) % at 4,250 m and 5,300 m, respectively (p<0.01). TEG reaction (R)-time and kinetic (K)-time were both increased at 5,300 m compared to sea level, 8.95 (± 1.37) minutes (min) to 11.69 (± 2.91) min (p=0.016) and 2.40 (± 0.66) min to 4.99 (± 1.67) min (p<0.001), respectively. Additionally the alpha (α)-angle was decreased from 57.7 (± 8.2) to 51.6 (± 6.4) (p<0.001). There was no change in maximum amplitude (MA) on ascent to altitude. These changes are consistent with an overall pattern of slowed coagulation at high altitude.