OBJECTIVES: Standard blood flow rates for cardiopulmonary bypass have been assumed to be the same for awake cardiac surgery with thoracic epidural anesthesia as for general anesthesia. However, compared to general anesthesia, awake cardiac surgery with epidural anesthesia may be associated with higher oxygen consumption due to missing effect of general anesthetics. This may result in insufficient oxygen delivery and lactic acidosis when standard blood flow rates were used. The primary aim of our study was to investigate if standard blood flow rates are adequate in awake cardiac surgery. The secondary aim was to evaluate postoperative clinical outcomes of patients undergoing awake cardiac surgery. METHODS: Forty-seven patients undergoing elective on-pump cardiac surgery were assigned to receive either epidural (Group TEA, n=17), combined (Group TEA-GA, n=15) or general (Group GA, n=15) anesthesia. To monitor adequacy of standard blood flow rates, arterial lactate, acid base parameters, central venous and jugular bulb saturation were measured at six time points during in all groups. Blood flow rates were adjusted when needed. Subsequently, early and late postoperative outcome data including hospital and 3-year mortality was recorded and compared among the study groups RESULTS: No lactic acidosis has...

OBJECTIVES: Standard blood flow rates for cardiopulmonary bypass have been assumed to be the same for awake cardiac surgery with thoracic epidural anesthesia as for general anesthesia. However, compared to general anesthesia, awake cardiac surgery with epidural anesthesia may be associated with higher oxygen consumption due to missing effect of general anesthetics. This may result in insufficient oxygen delivery and lactic acidosis when standard blood flow rates were used. The primary aim of our study was to investigate if standard blood flow rates are adequate in awake cardiac surgery. The secondary aim was to evaluate postoperative clinical outcomes of patients undergoing awake cardiac surgery. METHODS: Forty-seven patients undergoing elective on-pump cardiac surgery were assigned to receive either epidural (Group TEA, n=17), combined (Group TEA-GA, n=15) or general (Group GA, n=15) anesthesia. To monitor adequacy of standard blood flow rates, arterial lactate, acid base parameters, central venous and jugular bulb saturation were measured at six time points during in all groups. Blood flow rates were adjusted when needed. Subsequently, early and late postoperative outcome data including hospital and 3-year mortality was recorded and compared among the study groups RESULTS: No lactic acidosis has...

<p>Oxygen (O2) plays a crucial role in the energy metabolism of complex multicellular life on earth. Due to the small and finite energy stores in the body, fine-tuned changes within the body are required to meet metabolic demand during skeletal muscle contractions, such as during exercise and activities of daily living. The skeletal muscle microcirculation is one of the last steps in the O2 transport pathway from the lungs to muscle cells and represents the largest surface area for O2 and substrate exchange. When skeletal muscle O2 uptake increases during contractions to meet metabolic demand, there must be an increase in muscle O2 delivery. To achieve these elevations in O2 delivery, vessel (arteriole) diameter in the microcirculation is increased, known as vasodilation. This process in the skeletal muscle microcirculation is regulated by several factors, such as neurohumoral, mechanical, endothelial, paracrine, and metabolic influences, which are imperative in properly regulating O2 delivery at rest and during muscular contractions. Two vasodilatory pathways of interest in this dissertation are the cyclooxygenase (COX) and nitric oxide (NO) vasodilatory pathways.</p> <p>The primary aim of my dissertation studies was to determine the mechanisms that modulate skeletal muscle oxygenation in health and to define the impact of a potentially effective intervention, whole-body chronic heat therapy (HT), to treat heart failure with preserved ejection fraction (HFpEF). In Chapter 2, we report that acute selective COX-2 inhibition had no effect on resting or exercising skeletal muscle microvascular oxygenation, pulmonary oxygen uptake, or exercise tolerance in healthy young humans. In Chapter 3, we report that NO, via phosphodiesterase type 5 inhibition, regulates myocyte O2 transport at rest and during recovery from muscle contractions in healthy young rats. In Chapter 4, we show that whole-body chronic HT promotes central and peripheral adaptations, which impact positively exercise tolerance in a pre-clinical rat model of HFpEF. Specifically, whole-body chronic HT had beneficial influences on exercise tolerance, skeletal muscle oxygenation from rest to contractions (driven, at least in part, by enhanced NO bioavailability), body composition, and cardiac function. Chapter 5 is a summary of the results and limitations of the projects presented in Chapters 2-4, with a brief discussion of potential future research directions. </p>

Early administration of broad-spectrum antibiotics is the first goal in sepsis treatment. Besides from bacteriostatic/bactericidal effects, some antibiotics may also modify the host´s response to infection. The novel antibiotic tigecycline may exert such properties; however, this property has not been evaluated in large-animal trials. We compared tigecycline with doxycycline and placebo in relation to anti-inflammatory, circulatory and organ dysfunction effects in a sterile pig model of sepsis. Doxycycline, but not tigecycline, reduced the inflammatory response as manifested by tumor necrosis factor alpha levels in plasma. Tigecycline, however, had a stabilizing effect on the circulation not exerted by doxycycline or placebo. To achieve rapid restoration of the circulating blood volume - another major goal in sepsis treatment - fluid bolus administration of is some-times practiced. In addition to crystalloids, albumin-containing solutions are suggested. Yet, some animal-experimental data suggests that rapid bolus administration of albumin reduces albumin’s plasma-expanding effect. We compared a rapid intravenous bolus of radiolabeled albumin with a slow infusion in a sterile pig model of sepsis. Rapid bolus of administration did not reduce plasma levels of albumin following administration and did not increase the amount of albumin that left the circulation. Inadequate oxygen delivery (DO2) by the circulation to the tissues may cause increased plasma lactate, which is the most striking effect of sepsis on the metabolism. However, experimental data and clinical trials refute this link, instead, suggesting other mechanisms, including impaired oxygen extraction, mitochondrial dysfunction and accelerated aerobic glycolysis. We investigated the impact of DO2, oxygen consumption (VO2), hemodynamic parameters and inflammatory response on plasma lactate and organ dysfunction in two experimental sepsis models. In the most severe cases of shock, with DO2, there was an increase in plasma lactate, but without a decrease in VO2, invalidating the assumption that the increase in lactate is due to anaerobic metabolism. To identify critical steps in the sepsis-induced increase in lactate, we inhibited the major energy-producing step in the electron transport chain (ETC). The combination of sepsis and ETC inhibition led to a cellular energy crisis. This finding suggests that early sepsis induces a partial mitochondrial dysfunction.

L’objectif général de ce travail était d’évaluer l’effet du diabète de Type 1 et de l’hyperglycémie chronique (reflétée par un niveau élevé d’HbA1c), chez des patients indemnes de complications micro et macrovasculaires, sur la disponibilité en oxygène (O2) au niveau musculaire et cortical et ses répercussions sur l’aptitude physique aérobie. Dans un premier temps, nous nous sommes attardés à étudier l’effet du diabète et des niveaux élevés d’HbA1c sur les différentes étapes de la cascade d’oxygène (à savoir la diffusion alvéolo-capillaire, le transport artériel et la libération de l’O2 au niveau musculaire) ainsi que sur l’oxygénation musculaire estimée par la Spectroscopie dans le proche Infra-Rouge (NIRS) durant un exercice incrémental et voir les répercussions possibles sur la consommation maximale d’oxygène (&#12310;V &#775;O&#12311;_2max). Nous avons montré que les patients DT1 présentent une capacité de diffusion alvéolo-capillaire ainsi qu’une capacité de transport artériel d’O2 comparable aux sujets sains. En revanche, les patients ayant un niveau élevé d’HbA1c présentent une altération de &#12310;V &#775;O&#12311;_2max ainsi qu’une réduction du volume sanguin musculaire (reflétée par une baisse de l’hémoglobine totale) et une nette baisse de la déoxyhémoglobine (HHb) au niveau du muscle actif aux intensités proches de l’exercice maximal. Ce dernier résultat pourrait s’expliquer par l’affinité plus importante de HbA1c pour l’O2 et/ou une altération de la redistribution de débit sanguin entre les vaisseaux nutritifs et non nutritifs. L’altération du volume sanguin au niveau musculaire chez les patients présentant un mauvais contrôle glycémique peut prévenir les cliniciens du dysfonctionnement de la microcirculation survenant avant même qu’une microangiopathie se manifeste à l’état clinique (Étude 1). Dans un second temps, nous nous sommes intéressés à la fonction cérébrale. Notre objectif étant d’évaluer l’hémodynamique cérébrale durant un exercice incrémental maximal. Nous avons trouvé une altération de l’hémodynamique cérébrale (baisse de l’hémoglobine totale) aux intensités proches de l’exercice maximal chez les patients DT1 qui présentent un mauvais contrôle glycémique (Étude 2). Ces deux travaux nous montrent bien que les sujets diabétiques de type 1 indemnes des complications micro et/ou marcovasculaires présentent une faible aptitude physique aérobie qui peut s’expliquer à la fois par une altération de l’oxygénation musculaire et cérébrale. Ces études mettent également en évidence l’intérêt d’associer la NIRS avec un exercice maximal. Ce dernier place les tissus en situation de besoin maximal en O2 ce qui permet de mettre en exergue des altérations fonctionnelles de la microcirculation avant même l’apparition de complications microvasculaires détectables par les tests cliniques habituels. / This study sought to investigate whether type 1 diabetes and high levels of glycated hemoglobin (HbA1c) influence oxygen supply including alveolar capillary diffusion, oxygen delivery and release, to active muscle and prefrontal cortex during maximal exercise. We first studied the effect of high level of HbA1c on oxyhemoglobin dissociation at the active muscle measured by Near Infra-Red Spectroscopy (NIRS) during maximal exercise. We found that alveolar capillary diffusion and arterial oxygen content was comparable between patients with type 1 diabetes and healthy subjects. However, patients with inadequate glycemic control but without any clinically detectable vascular complications displayed an impaired aerobic capacity as well as a reduction in blood volume and a dramatic impairment in deoxyhemoglobin (HHb) increase in active skeletal muscle during intense exercise. The latter supports the hypotheses of an increase in O2 affinity induced by hemoglobin glycation and/or of a disturbed balance between nutritive and nonnutritive muscle blood flow. Furthermore, reduced exercise muscle blood volume in poorly controlled patients may warn clinicians of microvascular dysfunction occurring even before overt microangiopathy (Study 1). Secondly, we aimed at investigating prefrontal cortex hemodynamic during an incremental maximal exercise in patients with uncomplicated type 1 diabetes, taking into account chronic glycemic control. We observed that levels and changes in regional cerebral blood volume – as reflected by change in total hemoglobin – were lower at high intensities of exercise in patients with inadequate glycemic control (Study 2).In summary, the physiological stimulus of maximal exercise coupled with NIRS measurement highlighted subclinical disorders of both cerebral hemodynamic and muscle oxygenation in poorly-controlled patients with type 1 diabetes albeit free from any clinical microangiopathy.