Design and conduct of 'Xtreme Alps' : a double-blind, randomised controlled study of the effects of dietary nitrate supplementation on acclimatisation to high altitude

The study of healthy human volunteers ascending to high altitude provides a robust model of the complex physiological interplay that emulates human adaptation to hypoxaemia in clinical conditions. Nitric oxide (NO) metabolism may play an important role in both adaptation to high altitude and response to hypoxaemia during critical illness at sea level. Circulating nitrate and nitrite concentrations can be augmented by dietary supplementation and this is associated with improved exercise performance and mitochondrial efficiency. We hypothesised that the administration of a dietary substance (beetroot juice) rich in nitrate would improve oxygen efficiency during exercise at high altitude by enhancing tissue microcirculatory blood flow and oxygenation. Furthermore, nitrate supplementation would lead to measurable increases in NO bioactivity throughout the body. This methodological manuscript describes the design and conduct of the ‘Xtreme Alps’ expedition, a double-blind randomised controlled trial investigating the effects of dietary nitrate supplementation on acclimatisation to hypobaric hypoxia at high altitude in healthy human volunteers. The primary outcome measure was the change in oxygen efficiency during exercise at high altitude between participants allocated to receive nitrate supplementation and those receiving a placebo. A number of secondary measures were recorded, including exercise capacity, peripheral and microcirculatory blood flow and tissue oxygenation. Results from this study will further elucidate the role of NO in adaption to hypoxaemia and guide clinical trials in critically ill patients. Improved understanding of hypoxaemia in critical illness may provide new therapeutic avenues for interventions that will improve survival in critically ill patients

Clinical review: Evidence-based perioperative medicine?

The present article outlines the basic principles of Evidence Based Medicine (EBM) and how they should guide clinical practice. The evidence supporting a selection of perioperative interventions is assessed against objective criteria. Many of the perioperative interventions that have been widely adopted into clinical practice are supported by very limited evidence. Conversely a high level of evidence supports other interventions that have not been so widely adopted. This may be due to concerns about limitations in the design and conduct of some of the clinical trials

Understanding gastrointestinal perfusion in critical care: so near, and yet so far

An association between abnormal gastrointestinal perfusion and critical illness has been suggested for a number of years. Much of the data to support this idea comes from studies using gastric tonometry. Although an attractive technology, the interpretation of tonometry data is complex. Furthermore, current understanding of the physiology of gastrointestinal perfusion in health and disease is incomplete. This review considers critically the striking clinical data and basic physiological investigations that support a key role for gastrointestinal hypoperfusion in initiating and/or perpetuating critical disease

Hydrology of paraglacial catchments in a changing climate: impacts on biodiversity hotspots

Groundwater (GW) -fed streams are a common feature of paraglacial floodplains and are regarded as ‘biodiversity hotspots’, due to their role as valuable aquatic habitats. The hydrological dynamics which support GW-fed streams remain poorly understood. There is a need to improve understanding given paraglacial environments are extremely sensitive to the impacts of climate change. To address this significant knowledge gap site specific research was conducted on GW-fed streams within Denali National Park & Preserve, Alaska, during 2013 and 2014. Hydrometric, hydrochemical, hydrogeomorphic, and geophysical techniques were utilised to improve understanding of the hydrological dynamics and hydrogeomorphic controls that influence GW-fed stream occurrence. Paleochannels across paraglacial floodplains were identified as important preferential flow pathways (PFPs); and a first-order control upon GW-fed streams. In addition hillslope-runoff was established as an important hydrological flux to GW-fed streams. Colluvial deposits (e.g. talus cones) were highlighted as valuable hydrological stores on valleys-sides that made a direct contribution to streamflow. This research has raised concerns about the long-term stability of GW-fed streams in paraglacial environments due to changes in hydrogeomorphic controls (PFPs). It has also raised more immediate concerns about the short- to medium-term implications of shifting hydrologic regimes (e.g. declining winter snowpack) for GW-fed streams

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, hyper-baria, 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

High altitude respiratory physiology and patho- physiology

At high altitude, reduced atmospheric pressure causes the partial pressure of oxygen to decrease – creating an environment of hypobaric hypoxia which presents a unique set of challenges for the respiratory system. Pulmonary physiological responses such as the hypoxic ventilatory drive are essential for successful acclimatisation, whilst others such as hypoxic pulmonary vasoconstriction may be implicated in the development of altitude illnesses. Pulmonary conditions are some of the most common (e.g. high altitude cough) and also the most serious illnesses seen at altitude (e.g high altitude pulmonary oedema, HAPE). Minimising the chance of developing HAPE through planning an appropriate ascent profile should be strongly encouraged as HAPE can rapidly be fatal if left untreated. Whilst pharmacological agents such as nifedipine can help with the management of HAPE, rapid descent remains the single-most important treatment option once symptomatic. Given the increasing popularity of travelling to altitude, an awareness of how hypobaric hypoxia affects chronic respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD) is also becoming increasingly important for respiratory physician

Concepts in hypoxia reborn

The human fetus develops in a profoundly hypoxic environment. Thus, the foundations of our physiology are built in the most hypoxic conditions that we are ever likely to experience: the womb. This magnitude of exposure to hypoxia in utero is rarely experienced in adult life, with few exceptions, including severe pathophysiology in critical illness and environmental hypobaric hypoxia at high altitude. Indeed, the lowest recorded levels of arterial oxygen in adult humans are similar to those of a fetus and were recorded just below the highest attainable elevation on the Earth's surface: the summit of Mount Everest. We propose that the hypoxic intrauterine environment exerts a profound effect on human tolerance to hypoxia. Cellular mechanisms that facilitate fetal well-being may be amenable to manipulation in adults to promote survival advantage in severe hypoxemic stress. Many of these mechanisms act to modify the process of oxygen consumption rather than oxygen delivery in order to maintain adequate tissue oxygenation. The successful activation of such processes may provide a new chapter in the clinical management of hypoxemia. Thus, strategies employed to endure the relative hypoxia in utero may provide insights for the management of severe hypoxemia in adult life and ventures to high altitude may yield clues to the means by which to investigate those strategies

Phospholipid composition and kinetics in different endobronchial fractions from healthy volunteers

Tracheal secretions may be of value as a surrogate to assess bronchoalveolar lavage fluid surfactant molecular composition and metabolism in healthy people. Despite minor differences, the phospholipid molecular composition of induced sputum also showed similarities to that of bronchoalveolar lavage fluid. Detailed analysis of newly synthesized individual phosphatidylcholine species provided novel insights into mechanisms of surfactant synthesis and acyl remodelling. Lysophosphatidylcholine methyl-D9 incorporation patterns suggest that these species are secreted together with other surfactant phospholipids and are not generated in the air spaces by hydrolysis of secreted surfactant phosphatidylcholine. Application into patient populations may elucidate potential underlying pathophysiological mechanisms that lead to surfactant alterations in disease state

Perceptions of diagnosis and management of patients with acute respiratory distress syndrome: a survey of United Kingdom intensive care physicians

BackgroundAcute respiratory distress syndrome (ARDS) is a potentially devastating refractory hypoxemic illness with multi-organ involvement. Although several randomised controlled trials into ventilator and fluid management strategies have provided level 1 evidence to guide supportive therapy, there are few, established guidelines on how to manage patients with ARDS. In addition, and despite their continued use, pharmacotherapies for ARDS disease modulation have no proven benefit in improving mortality. Little is known however about the variability in diagnostic and treatment practices across the United Kingdom (UK). The aim of this survey, therefore, was to assess the use of diagnostic criteria and treatment strategies for ARDS in critical care units across the UK.MethodsThe survey questionnaire was developed and internally piloted at University Hospital Southampton NHS Foundation Trust. Following ethical approval from University of Southampton Ethics and Research Committee, a link to an online survey engine (Survey Monkey) was then placed on the Intensive Care Society (UK) website. Fellows of The Intensive Care Society were subsequently personally approached via e-mail to encourage participation. The survey was conducted over a period of 3 months.ResultsThe survey received 191 responses from 125 critical care units, accounting for 11% of all registered intensive care physicians at The Intensive Care Society. The majority of the responses were from physicians managing general intensive care units (82%) and 34% of respondents preferred the American European Consensus Criteria for ARDS. There was a perceived decline in both incidence and mortality in ARDS. Primary ventilation strategies were based on ARDSnet protocols, though frequent deviations from ARDSnet positive end expiratory pressure (PEEP) recommendations (51%) were described. The majority of respondents set permissive blood gas targets (hypoxia (92%), hypercapnia (58%) and pH (90%)). The routine use of pharmacological agents is rare. Neuromuscular blockers and corticosteroids are considered occasionally and on a case-by-case basis. Routine (58%) or late (64%) tracheostomy was preferred to early tracheostomy insertion. Few centres offered routine follow-up or dedicated rehabilitation programmes following hospital discharge.ConclusionsThere is substantial variation in the diagnostic and management strategies employed for patients with ARDS across the UK. National and/or international guidelines may help to improve standardisation in the management of ARDS

Exercise interventions for people undergoing multimodal cancer treatment that includes surgery

This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the effect of exercise interventions for people undergoing multimodal treatment including surgery on physical fitness, safety and feasibility, health-related quality of life and other important health outcomes