Perioperative Cannabinoids Significantly Reduce Postoperative Opioid Requirements in Patients Undergoing Coronary Artery Bypass Graft Surgery.

Background Opioids, commonly used to control pain associated with surgery, are known to prolong the duration of mechanical ventilation and length of hospital stay. A wide range of adjunctive strategies are currently utilized to reduce postoperative pain, such as local and regional nerve blocks, nerve cryoablation, and adjunctive medications. We hypothesized that dronabinol (a synthetic cannabinoid) in conjunction with standard opioid pain management will reduce opioid requirements to manage postoperative pain.

Physiological and microvascular responses to hemoglobin concentration-targeted hemolytic anemia in rats.

Hemolytic anemia (HA) is reduced blood oxygen-carrying capacity resulting from the depletion of red blood cells. Treatment for severe cases involves transfusion to improve oxygen delivery (Do), which carries risk. In humans, a total hemoglobin (tHb) concentration of 8 g/dL is severe, and <7 g/dL indicates transfusion.

Prehospital whole blood resuscitation prevents coagulopathy and improves acid-base status at hospital arrival in a nonhuman primate hemorrhagic shock model.

Background: Hemorrhage remains the primary cause of preventable death in civilian and military trauma. The Committee on Tactical Combat Casualty Care recommends prehospital (PH) resuscitation with whole blood (WB). However, 6% hetastarch in lactated electrolyte (HEX) and crystalloids are more commonly available and used for PH resuscitation in military and civilian environments, respectively.

Chronic Adrenergic Signaling Causes Abnormal RNA Expression of Proliferative Genes in Fetal Sheep Islets.

Intrauterine growth restriction (IUGR) increases the risk of developing diabetes in later life, which indicates developmental programming of islets. IUGR fetuses with placental insufficiency develop hypoxemia, elevating epinephrine and norepinephrine (NE) concentrations throughout late gestation. To isolate the programming effects of chronically elevated catecholamines, NE was continuously infused into normally grown sheep fetuses for 7 days.

Whole blood mitigates the acute coagulopathy of trauma and avoids the coagulopathy of crystalloid resuscitation.

Introduction: The contributions of type and timing of fluid resuscitation to coagulopathy in trauma remain controversial. As part of a multifunctional resuscitation fluid research effort, we sought to further characterize the coagulation responses to resuscitation, specifically as compared to whole blood. We hypothesized that early whole blood administration mitigates the acute coagulopathy of trauma by avoiding the coagulopathy of CR resuscitation.

Nonhuman Primate (Rhesus Macaque) Models of Severe Pressure-Targeted Hemorrhagic and Polytraumatic Hemorrhagic Shock.

Background: We endeavored to develop clinically translatable nonhuman primate (NHP) models of severe polytraumatic hemorrhagic shock.

Methods: NHPs were randomized into five severe pressure-targeted hemorrhagic shock (PTHS) ± additional injuries scenarios: 30-min PTHS (PTHS-30), 60-min PTHS (PTHS-60), PTHS-60 + soft tissue injury (PTHS-60+ST), PTHS-60+ST + femur fracture (PTHS-60+ST+FF), and decompensated PTHS+ST+FF (PTHS-D). Physiologic parameters were recorded and blood samples collected at five time points with animal observation through T = 24 h.

Whole blood and Hextend: Bookends of modern tactical combat casualty care field resuscitation and starting point for multifunctional resuscitation fluid development.

Background: Hemorrhage is the leading cause of preventable death in traumatically injured civilian and military populations. Prehospital resuscitation largely relies on crystalloid and colloid intravascular expansion, as whole blood and component blood therapy are logistically arduous. In this experiment, we evaluated the bookends of Tactical Combat Casualty Care Guidelines recommendations of prehospital resuscitation with Hextend and whole blood in a controlled hemorrhagic shock model within non-human primates, as means of a multifunctional resuscitative fluid development.

Tissue injury suppresses fibrinolysis after hemorrhagic shock in nonhuman primates (rhesus macaque).

Background: Hypoperfusion is associated with hyperfibrinolysis and early death from exsanguination, whereas tissue trauma is associated with hypofibrinolysis and delayed death from organ failure. We sought to elucidate the effects of injury patterns on fibrinolysis phenotypes using a nonhuman primate (NHP) model.

Methods: NHPs were randomized to three injury groups (n = 8/group): 60 minutes severe pressure-targeted controlled hemorrhagic shock (HS); HS + soft tissue injury (HS+); or HS + soft tissue injury + femur fracture (HS++).

Islet adaptations in fetal sheep persist following chronic exposure to high norepinephrine.

Complications in pregnancy elevate fetal norepinephrine (NE) concentrations. Previous studies in NE-infused sheep fetuses revealed that sustained exposure to high NE resulted in lower expression of α-adrenergic receptors in islets and increased insulin secretion responsiveness after acutely terminating the NE infusion. In this study, we determined if the compensatory increase in insulin secretion after chronic elevation of NE is independent of hyperglycemia in sheep fetuses and whether it is persistent in conjunction with islet desensitization to NE.

Inflammatory Profile in Response to Uncontrolled Hemorrhage in a Non-Human Primate (Rhesus Macaque) Model.

Background: Uncontrolled hemorrhage (UH), the leading cause of potentially survivable combat-related death, elicits a deleterious inflammatory response. Our group previously reported an increased secretion of pro-inflammatory cytokines in a novel non-human primate model of UH; however, to better understand the molecular profile of the inflammatory response to UH, we performed a comprehensive evaluation of inflammation at the proteomic and transcriptomic level.

Methods: Anesthetized rhesus macaques (n = 8) underwent UH by 60% left lobe hepatectomy T = 0 min.

Intrauterine growth-restricted sheep fetuses exhibit smaller hindlimb muscle fibers and lower proportions of insulin-sensitive Type I fibers near term.

Intrauterine growth restriction (IUGR) reduces muscle mass and insulin sensitivity in offspring. Insulin sensitivity varies among muscle fiber types, with Type I fibers being most sensitive. Differences in fiber-type ratios are associated with insulin resistance in adults, and thus we hypothesized that near-term IUGR sheep fetuses exhibit reduced size and proportions of Type I fibers.

Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose-Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction.

In pregnancies complicated by placental insufficiency and intrauterine growth restriction (IUGR), fetal glucose and oxygen concentrations are reduced, whereas plasma norepinephrine and epinephrine concentrations are elevated throughout the final third of gestation. Here we study the effects of chronic hypoxemia and hypercatecholaminemia on β-cell function in fetal sheep with placental insufficiency-induced IUGR that is produced by maternal hyperthermia. IUGR and control fetuses underwent a sham (intact) or bilateral adrenal demedullation (AD) surgical procedure at 0.

Rapid assessment of shock in a nonhuman primate model of uncontrolled hemorrhage: Association of traditional and nontraditional vital signs to mortality risk.

Background: Heart rate (HR), systolic blood pressure (SBP) and mean arterial pressure (MAP) are traditionally used to guide patient triage and resuscitation; however, they correlate poorly to shock severity. Therefore, improved acute diagnostic capabilities are needed. Here, we correlated acute alterations in tissue oxygen saturation (StO2) and end-tidal carbon dioxide (ETCO2) to mortality in a rhesus macaque model of uncontrolled hemorrhage.

Control of severe intra-abdominal hemorrhage with an infusible platelet-derived hemostatic agent in a nonhuman primate (rhesus macaque) model.

Background: Hemorrhage remains the leading cause of potentially survivable trauma mortality. Recent reports indicate that injuries sustained in noncompressible anatomic locations (i.e.

Fetal adrenal demedullation lowers circulating norepinephrine and attenuates growth restriction but not reduction of endocrine cell mass in an ovine model of intrauterine growth restriction.

Placental insufficiency is associated with fetal hypoglycemia, hypoxemia, and elevated plasma norepinephrine (NE) that become increasingly pronounced throughout the third trimester and contribute to intrauterine growth restriction (IUGR). This study evaluated the effect of fetal adrenal demedullation (AD) on growth and pancreatic endocrine cell mass. Placental insufficiency-induced IUGR was created by exposing pregnant ewes to elevated ambient temperatures during mid-gestation.

Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep.

Hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGFA) are paracrine hormones that mediate communication between pancreatic islet endothelial cells (ECs) and β-cells. Our objective was to determine the impact of intrauterine growth restriction (IUGR) on pancreatic vascularity and paracrine signaling between the EC and β-cell. Vessel density was less in IUGR pancreata than in controls.

Myoblasts from intrauterine growth-restricted sheep fetuses exhibit intrinsic deficiencies in proliferation that contribute to smaller semitendinosus myofibres.

Intrauterine growth restriction (IUGR) reduces skeletal muscle mass in fetuses and offspring. Our objective was to determine whether myoblast dysfunction due to intrinsic cellular deficiencies or serum factors reduces myofibre hypertrophy in IUGR fetal sheep. At 134 days, IUGR fetuses weighed 67% less (P < 0.

Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep.

Intrauterine growth-restricted (IUGR) fetuses experience prolonged hypoxemia, hypoglycemia, and elevated norepinephrine (NE) concentrations, resulting in hypoinsulinemia and β-cell dysfunction. Previously, we showed that acute adrenergic blockade revealed enhanced insulin secretion responsiveness in the IUGR fetus. To determine whether chronic exposure to NE alone enhances β-cell responsiveness afterward, we continuously infused NE into fetal sheep for 7 days and, after terminating the infusion, evaluated glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-induced insulin secretion (GPAIS).

Reductions in insulin concentrations and β-cell mass precede growth restriction in sheep fetuses with placental insufficiency.

In pregnancy complicated by placental insufficiency (PI) and intrauterine growth restriction (IUGR), the fetus near term has reduced basal and glucose-stimulated insulin concentrations and reduced β-cell mass. To determine whether suppression of insulin concentrations and β-cell mass precedes reductions in fetal weight, which would implicate insulin deficiency as a cause of subsequent IUGR, we measured basal and glucose-stimulated insulin concentrations and pancreatic histology at 0.7 gestation in PI fetuses.

Hypoxaemia-induced catecholamine secretion from adrenal chromaffin cells inhibits glucose-stimulated hyperinsulinaemia in fetal sheep.

Abstract  Hypoxaemia elicits adrenergic suppression of fetal glucose-stimulated hyperinsulinaemia. We postulate that this effect is mediated by catecholamines, exclusively, from fetal adrenal chromaffin cells. To investigate this hypothesis, square-wave hyperglycaemic clamp studies were performed under normoxaemic (26 ± 0.

Chronic pulsatile hyperglycemia reduces insulin secretion and increases accumulation of reactive oxygen species in fetal sheep islets.

Children from diabetic pregnancies have a greater incidence of type 2 diabetes. Our objective was to determine if exposure to mild-moderate hyperglycemia, by modeling managed diabetic pregnancies, affects fetal β-cell function. In sheep fetuses, β-cell responsiveness was examined after 2 weeks of sustained hyperglycemia with 3 pulses/day, mimicking postprandial excursions, and compared to saline-infused controls (n = 10).

Characterization of glucose-insulin responsiveness and impact of fetal number and sex difference on insulin response in the sheep fetus.

GSIS is often measured in the sheep fetus by a square-wave hyperglycemic clamp, but maximal β-cell responsiveness and effects of fetal number and sex difference have not been fully evaluated. We determined the dose-response curve for GSIS in fetal sheep (0.9 of gestation) by increasing plasma glucose from euglycemia in a stepwise fashion.

Roles of insulin signalling and p38 MAPK in the activation by lithium of glucose transport in insulin-resistant rat skeletal muscle.

We have demonstrated previously in insulin-sensitive skeletal muscle that lithium, an alkali metal and non-selective inhibitor of glycogen synthase kinase-3 (GSK-3), activates glucose transport by engaging the stress-activated p38 mitogen-activated protein kinase (p38 MAPK). However, it is presently unknown whether this same mechanism underlies lithium action on the glucose transport system in insulin-resistant skeletal muscle. We therefore assessed the effects of lithium on basal and insulin-stimulated glucose transport, glycogen synthesis, insulin signalling (insulin receptor (IR), Akt, and GSK-3), and p38 MAPK in soleus muscle from female obese Zucker rats.