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

Hospital-level evaluation of the effect of a national quality improvement programme: time-series analysis of registry data.

BACKGROUND AND OBJECTIVES: A clinical trial in 93 National Health Service hospitals evaluated a quality improvement programme for emergency abdominal surgery, designed to improve mortality by improving the patient care pathway. Large variation was observed in implementation approaches, and the main trial result showed no mortality reduction. Our objective therefore was to evaluate whether trial participation led to care pathway implementation and to study the relationship between care pathway implementation and use of six recommended implementation strategies. METHODS: We performed a hospital-level time-series analysis using data from the Enhanced Peri-Operative Care for High-risk patients trial. Care pathway implementation was defined as achievement of >80% median reliability in 10 measured care processes. Mean monthly process performance was plotted on run charts. Process improvement was defined as an observed run chart signal, using probability-based 'shift' and 'runs' rules. A new median performance level was calculated after an observed signal. RESULTS: Of 93 participating hospitals, 80 provided sufficient data for analysis, generating 800 process measure charts from 20 305 patient admissions over 27 months. No hospital reliably implemented all 10 processes. Overall, only 279 of the 800 processes were improved (3 (2-5) per hospital) and 14/80 hospitals improved more than six processes. Mortality risk documented (57/80 (71%)), lactate measurement (42/80 (53%)) and cardiac output guided fluid therapy (32/80 (40%)) were most frequently improved. Consultant-led decision making (14/80 (18%)), consultant review before surgery (17/80 (21%)) and time to surgery (14/80 (18%)) were least frequently improved. In hospitals using ≥5 implementation strategies, 9/30 (30%) hospitals improved ≥6 care processes compared with 0/11 hospitals using ≤2 implementation strategies. CONCLUSION: Only a small number of hospitals improved more than half of the measured care processes, more often when at least five of six implementation strategies were used. In a longer term project, this understanding may have allowed us to adapt the intervention to be effective in more hospitals

The effect of high-altitude on human skeletal muscle energetics: 31P-MRS results from the caudwell xtreme everest expedition

Many disease states are associated with regional or systemic hypoxia. The study of healthy individuals exposed to high-altitude hypoxia offers a way to explore hypoxic adaptation without the confounding effects of disease and therapeutic interventions. Using 31P magnetic resonance spectroscopy and imaging, we investigated skeletal muscle energetics and morphology after exposure to hypobaric hypoxia in seven altitude-naïve subjects (trekkers) and seven experienced climbers. The trekkers ascended to 5300 m while the climbers ascended above 7950 m. Before the study, climbers had better mitochondrial function (evidenced by shorter phosphocreatine recovery halftime) than trekkers: 16±1 vs. 22±2 s (mean ± SE, p<0.01). Climbers had higher resting [Pi] than trekkers before the expedition and resting [Pi] was raised across both groups on their return (PRE: 2.6±0.2 vs. POST: 3.0±0.2 mM, p<0.05). There was significant muscle atrophy post-CXE (PRE: 4.7±0.2 vs. POST: 4.5±0.2 cm2, p<0.05), yet exercising metabolites were unchanged. These results suggest that, in response to high altitude hypoxia, skeletal muscle function is maintained in humans, despite significant atrophy

Cerebral artery dilatation maintains cerebral oxygenation at extreme altitude and in acute hypoxia : an ultrasound and MRI study

Transcranial Doppler is a widely used noninvasive technique for assessing cerebral artery blood flow. All previous high altitude studies assessing cerebral blood flow (CBF) in the field that have used Doppler to measure arterial blood velocity have assumed vessel diameter to not alter. Here, we report two studies that demonstrate this is not the case. First, we report the highest recorded study of CBF (7,950 m on Everest) and demonstrate that above 5,300 m, middle cerebral artery (MCA) diameter increases (n=24 at 5,300 m, 14 at 6,400 m, and 5 at 7,950 m). Mean MCA diameter at sea level was 5.30 mm, at 5,300 m was 5.23 mm, at 6,400 m was 6.66 mm, and at 7,950 m was 9.34 mm (P<0.001 for change between 5,300 and 7,950 m). The dilatation at 7,950 m reversed with oxygen. Second, we confirm this dilatation by demonstrating the same effect (and correlating it with ultrasound) during hypoxia (FiO2=12% for 3 hours) in a 3-T magnetic resonance imaging study at sea level (n=7). From these results, we conclude that it cannot be assumed that cerebral artery diameter is constant, especially during alterations of inspired oxygen partial pressure, and that transcranial 2D ultrasound is a technique that can be used at the bedside or in the remote setting to assess MCA caliber

Compassionate use of Pulmonary Vasodilators in Acute Severe Hypoxic Respiratory Failure due to COVID-19

Background: there have been over 200 million cases and 4.4 million deaths from COVID-19 worldwide. Despite the lack of robust evidence one potential treatment for COVID-19 associated severe hypoxaemia is inhaled pulmonary vasodilator (IPVD) therapy, using either nitric oxide (iNO) or prostaglandins. We describe the implementation of, and outcomes from, a protocol using IPVDs in a cohort of patients with severe COVID-19 associated respiratory failure receiving maximal conventional support. Methods: prospectively collected data from adult patients with SARS-CoV-2 admitted to the intensive care unit (ICU) at a large teaching hospital were analysed for the period 14 th March 2020 - 11 th February 2021. An IPVD was considered if the PaO 2/FiO 2 (PF) ratio was less than 13.3kPa despite maximal conventional therapy. Nitric oxide was commenced at 20ppm and titrated to response. If oxygenation improved Iloprost nebulisers were commenced and iNO weaned. The primary outcome was percentage changes in PF ratio and Alveolar-arterial (A-a) gradient. Results: fifty-nine patients received IPVD therapy during the study period. The median PF ratio before IPVD therapy was commenced was 11.33kPa (9.93-12.91). Patients receiving an IPVD had a lower PF ratio (14.37 vs. 16.37kPa, p = 0.002) and higher APACHE-II score (17 vs. 13, p = 0.028) at ICU admission. At 72 hours after initiating an IPVD the median improvement in PF ratio was 33.9% (-4.3-84.1). At 72 hours changes in PF ratio (70.8 vs. −4.1%, p &lt; 0.001) and reduction in A-a gradient (44.7 vs. 14.8%, p &lt; 0.001) differed significantly between survivors (n = 33) and non-survivors (n = 26). Conclusions: the response to IPVDs in patients with COVID-19 associated acute hypoxic respiratory failure differed significantly between survivors and non-survivors. Both iNO and prostaglandins may offer therapeutic options for patients with severe refractory hypoxaemia due to COVID-19. The use of inhaled prostaglandins, and iNO where feasible, should be studied in adequately powered prospective randomised trials.</p