Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Adaptations métaboliques du caneton de Barbarie (Cairina moschata) et du Manchot Royal (Aptenodytes patagonicus) en réponse à un stress chronique froid

Because of their huge phenotypic diversity (10,000 species), birds were able to colonize many “extreme” ecological niches. Many studies have been focus on the polar areas (i.e. Arctic and Antarctica) with their typical cold climate. The aim of this work was to explore the onset of thermoregulatory mechanisms in birds. Using an integrative approach, from whole animal (indirect calorimetry) to gene expression (RT-PCR analysis), we investigated metabolic adaptations and avian uncoupling protein implication in non shivering thermogenesis (NST) during chronic cold exposure. In two studies, working on Muscovy ducklings, we have highlighted the “adaptative” aspect of NST and potential implication of avUCP in this mechanism in relation to different ambient temperatures of acclimation and to cold exposure duration.In a third study, we were interested by passage from shore to marine life of King Penguins that represents a key step of their life. This is defined by massive cold stress (cold water) and increase of physical activity (long-time swimming), leading great metabolic adaptations, such as an increase of lipid oxidative capacities which would sustain expensive energetic cost of marine life.De par leur importante diversité phénotypique (10000 espèces), les oiseaux ont colonisé la plupart des niches écologiques, aussi « extrêmes » soient-elles. Les zones polaires (Arctique et Antarctiques) et le climat extrêmement froid qui les aractérise, suscitent l’intérêt de nombreuses études. Ce travail de thèse avait pour but d’explorer les différents mécanismes intervenant dans la mise en place de la thermorégulation chez l’oiseau. Nous nous sommes principalement intéressés, par une approche intégrative, de l’animal entier (méthodes de calorimétrie indirecte) à l’expression génique (techniques de RT-PCR), à caractériser les modifications métaboliques et l’implication d’une protéine découplante (avUCP) dans les mécanismes de thermorégulation, et principalement la thermogenèse sans frisson (NST) en réponse à une exposition chronique au froid.Au cours de deux études menées chez le caneton de Barbarie, nous avons démontré l’aspect « adaptatif » de la NST ainsi que l’implication potentielle de l’UCP aviaire dans ce mécanisme en faisant varier tout d’abord la température d’acclimatation puis la durée d’exposition pour caractériser la mise en place de la NST au cours de la croissance. Lors d’une troisième étude, nous nous sommes intéressés à une étape clé de la vie des manchots royaux (passage en mer) caractérisée par un stress thermique important et une activité physique accrue dus aux longs séjours en eau froide. Ce contexte environnemental et physiologique entraine nécessairement des adaptations métaboliques, comme la mise en place d’un métabolisme lipidique efficace soutenant ainsi les dépenses énergétiques accrues lors des voyages en mer

Metabolic adaptations of Muscovy duckling (Cairina moschata) and King penguin (Aptenodytes patagonicus) to chronic cold exposure

De par leur importante diversité phénotypique (10000 espèces), les oiseaux ont colonisé la plupart des niches écologiques, aussi « extrêmes » soient-elles. Les zones polaires (Arctique et Antarctiques) et le climat extrêmement froid qui les aractérise, suscitent l’intérêt de nombreuses études. Ce travail de thèse avait pour but d’explorer les différents mécanismes intervenant dans la mise en place de la thermorégulation chez l’oiseau. Nous nous sommes principalement intéressés, par une approche intégrative, de l’animal entier (méthodes de calorimétrie indirecte) à l’expression génique (techniques de RT-PCR), à caractériser les modifications métaboliques et l’implication d’une protéine découplante (avUCP) dans les mécanismes de thermorégulation, et principalement la thermogenèse sans frisson (NST) en réponse à une exposition chronique au froid.Au cours de deux études menées chez le caneton de Barbarie, nous avons démontré l’aspect « adaptatif » de la NST ainsi que l’implication potentielle de l’UCP aviaire dans ce mécanisme en faisant varier tout d’abord la température d’acclimatation puis la durée d’exposition pour caractériser la mise en place de la NST au cours de la croissance. Lors d’une troisième étude, nous nous sommes intéressés à une étape clé de la vie des manchots royaux (passage en mer) caractérisée par un stress thermique important et une activité physique accrue dus aux longs séjours en eau froide. Ce contexte environnemental et physiologique entraine nécessairement des adaptations métaboliques, comme la mise en place d’un métabolisme lipidique efficace soutenant ainsi les dépenses énergétiques accrues lors des voyages en mer.Because of their huge phenotypic diversity (10,000 species), birds were able to colonize many “extreme” ecological niches. Many studies have been focus on the polar areas (i.e. Arctic and Antarctica) with their typical cold climate. The aim of this work was to explore the onset of thermoregulatory mechanisms in birds. Using an integrative approach, from whole animal (indirect calorimetry) to gene expression (RT-PCR analysis), we investigated metabolic adaptations and avian uncoupling protein implication in non shivering thermogenesis (NST) during chronic cold exposure. In two studies, working on Muscovy ducklings, we have highlighted the “adaptative” aspect of NST and potential implication of avUCP in this mechanism in relation to different ambient temperatures of acclimation and to cold exposure duration.In a third study, we were interested by passage from shore to marine life of King Penguins that represents a key step of their life. This is defined by massive cold stress (cold water) and increase of physical activity (long-time swimming), leading great metabolic adaptations, such as an increase of lipid oxidative capacities which would sustain expensive energetic cost of marine life

Succinate oxidation rescues mitochondrial ATP synthesis at high temperature in Drosophila melanogaster

Decreased NADH‐induced and increased reduced FADH 2 ‐induced respiration rates at high temperatures are associated with thermal tolerance in Drosophila . Here, we determined whether this change was associated with adjustments of adenosine triphosphate (ATP) production rate and coupling efficiency (ATP/O) in Drosophila melanogaster . We show that decreased pyruvate + malate oxidation at 35°C is associated with a collapse of ATP synthesis and a drop in ATP/O ratio. However, adding succinate triggered a full compensation of both oxygen consumption and ATP synthesis rates at this high temperature. Addition of glycerol‐3‐phosphate (G3P) led to a huge increase in respiration with no further advantage in terms of ATP production. We conclude that succinate is the only alternative substrate able to compensate both oxygen consumption and ATP production rates during oxidative phosphorylation at high temperature, which has important implications for thermal adaptation

Data from: Novel energy-saving strategies to multiple stressors in birds: the ultradian regulation of body temperature

This study aimed to examine thermoregulatory responses in birds facing two commonly experienced stressors, cold and fasting. Logging devices allowing long-term and precise access to internal body temperature were placed within the gizzards of ducklings acclimated to cold (CA) (5°C) or thermoneutrality (TN) (25°C). The animals were then examined under three equal 4-day periods: ad libitum feeding, fasting and re-feeding. Through the analysis of daily as well as short-term, or ultradian, variations of body temperature, we showed that while ducklings at TN show only a modest decline in daily thermoregulatory parameters when fasted, they exhibit reduced surface temperatures from key sites of vascular heat exchange during fasting. The CA birds, on the other hand, significantly reduced their short-term variations of body temperature while increasing long-term variability when fasting. This phenomenon would allow the CA birds to reduce the energetic cost of body temperature maintenance under fasting. By analysing ultradian regulation of body temperature, we describe a means by which an endotherm appears to lower thermoregulatory costs in response to the combined stressors of cold and fasting

Proline as a fuel for insect flight: enhancing carbohydrate oxidation in hymenopterans

International audienceBees are thought to be strict users of carbohydrates as metabolic fuel for flight. Many insects, however, have the ability to oxidize the amino acid proline at a high rate, which is a unique feature of this group of animals. The presence of proline in the haemolymph of bees and in the nectar of plants led to the hypothesis that plants may produce proline as a metabolic reward for pollina- tors. We investigated flight muscle metabolism of hymenopteran species using high-resolution respirometry performed on permeabilized muscle fibres. The muscle fibres of the honeybee, Apis mellifera, do not have a detectable capacity to oxidize proline, as those from the migratory locust, Locusta migratoria, used here as an outgroup representative. The closely related bumblebee, Bombus impatiens, can oxidize proline alone and more than doubles its respiratory capacity when proline is combined with carbohydrate-derived substrates. A distant wasp species, Vespula vulgaris, exhibits the same metabolic pheno- type as the bumblebee, suggesting that proline oxidation is common in hymenopterans. Using a combination of mitochondrial substrates and inhibi- tors, we further show that in B. impatiens, proline oxidation provides reducing equivalents and electrons directly to the electron transport system. Together, these findings demonstrate that some bee and wasp species can greatly enhance the oxidation of carbohydrates using proline as fuel for flight

Ontogeny of non-shivering thermogenesis in Muscovy ducklings (Cairina moschata)

International audienceIn precocial birds, developing the capacity for early regulatory thermogenesis appears as a fundamental prerequi- site for survival and growth in cold environments. However, the exact nature of these processes has not been thoroughly investigated. Several bird species, such as Muscovy ducks (Cairina moschata), develop muscular non- shivering thermogenesis when chronically exposed to cold. The aim of this study was to investigate the age- dependent development of non-shivering thermogenesis in ducklings reared either at thermoneutrality (25 °C) or in the cold (4 °C). Non-shivering thermogenesis was assessed weekly by simultaneously measuring whole body metabolic heat production and electromyographic activity during shivering at different temperatures ranging from 29 °C to 0 °C. We found that ducklings reared at thermoneutrality displayed a capacity for non-shivering thermogenesis during the ␣rst month of post-hatching life. This thermogenic mechanism increased further in ducklings chronically exposed to a cold environment, but it decreased over time when birds were kept in a thermoneutral environment

Absence of mitochondrial responses in muscles of zebrafish exposed to several heat waves

International audienceHeat waves are extreme thermal events whose frequency and intensity will increase with global warming. As metabolic responses to temperature are time-dependent, we explored the effects of an exposure to several heat waves on the mitochondrial metabolism of zebrafish Danio rerio. For this purpose, zebrafish were acclimated at 26 ◦C or 31 ◦C for 4 weeks and some fish acclimated at 26 ◦C underwent 2 types of heat waves: 2 periods of 5 days at 31 ◦C or 10 days at 31 ◦C. After this acclimation period, mitochondrial respiration of red muscle fibres was measured at 26 ◦C and 31 ◦C for each fish, with the phosphorylation (OXPHOS) and basal (LEAK) respi- rations obtained with activation of complex I, complex II or complexes I and II. The respiratory control ratio (RCR) and the mitochondrial aerobic scope (CAS) were also calculated at both temperatures after the activation of complexes I and II. Under our conditions, heat waves did not result in variations in any mitochondrial pa- rameters, suggesting a high tolerance of zebrafish to environmental temperature fluctuations. However, an acute in vitro warming led to an increase in the LEAK respiration together with a higher temperature effect on complex II than complex I, inducing a decrease of mitochondrial efficiency to produce energy at high temperatures. Increased interindividual variability for some parameters at 26 ◦C or 31 ◦C also suggests that each individual has its own ability to cope with temperature fluctuations

Low oxygen levels can help to prevent the detrimental effect of acute warming on mitochondrial efficiency in fish

Aerobic metabolism of aquatic ectotherms is highly sensitive to fluctuating climates. Many mitochondrial traits exhibit phenotypic plasticity in response to acute variations in temperature and oxygen availability. These responses are critical for understanding the effects of environmental variations on aquatic ectotherms' performance. Using the European seabass, Dicentrarchus labrax, we determined the effects of acute warming and deoxygenation in vitro on mitochondrial respiratory capacities and mitochondrial efficiency to produce ATP (ATP/O ratio). We show that acute warming reduced ATP/O ratio but deoxygenation marginally raised ATP/O ratio, leading to a compensatory effect of low oxygen availability on mitochondrial ATP/O ratio at high temperature. The acute effect of warming and deoxygenation on mitochondrial efficiency might be related to the leak of protons across the mitochondrial inner membrane, as the mitochondrial respiration required to counteract the proton leak increased with warming and decreased with deoxygenation. Our study underlines the importance of integrating the combined effects of temperature and oxygen availability on mitochondrial metabolism. Predictions on decline in performance of aquatic ectotherms owing to climate change may not be accurate, since these predictions typically look at respiratory capacity and ignore efficiency of ATP production