Loss of Caveolin-1 Accelerates Neurodegeneration and Aging

The aged brain exhibits a loss in gray matter and a decrease in spines and synaptic densities that may represent a sequela for neurodegenerative diseases such as Alzheimer's. Membrane/lipid rafts (MLR), discrete regions of the plasmalemma enriched in cholesterol, glycosphingolipids, and sphingomyelin, are essential for the development and stabilization of synapses. Caveolin-1 (Cav-1), a cholesterol binding protein organizes synaptic signaling components within MLR. It is unknown whether loss of synapses is dependent on an age-related loss of Cav-1 expression and whether this has implications for neurodegenerative diseases such as Alzheimer's disease.We analyzed brains from young (Yg, 3-6 months), middle age (Md, 12 months), aged (Ag, >18 months), and young Cav-1 KO mice and show that localization of PSD-95, NR2A, NR2B, TrkBR, AMPAR, and Cav-1 to MLR is decreased in aged hippocampi. Young Cav-1 KO mice showed signs of premature neuronal aging and degeneration. Hippocampi synaptosomes from Cav-1 KO mice showed reduced PSD-95, NR2A, NR2B, and Cav-1, an inability to be protected against cerebral ischemia-reperfusion injury compared to young WT mice, increased Aβ, P-Tau, and astrogliosis, decreased cerebrovascular volume compared to young WT mice. As with aged hippocampi, Cav-1 KO brains showed significantly reduced synapses. Neuron-targeted re-expression of Cav-1 in Cav-1 KO neurons in vitro decreased Aβ expression.Therefore, Cav-1 represents a novel control point for healthy neuronal aging and loss of Cav-1 represents a non-mutational model for Alzheimer's disease

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Management of Dilutional Coagulopathy during Pediatric Major Surgery

Perioperative dilutional coagulopathy is a major coagulation disorder during adult and pediatric surgery. Although the main underlying mechanisms are comparable, data of the development and management of dilutional coagulopathy in children are scarce. Observational data showed that intraoperative coagulation disorders mainly based on complex disturbances of clot firmness including acquired fibrinogen as well as factor XIII deficiencies, while clotting time and platelet counts remained fairly stable. A fast and reliable monitoring of the entire coagulation process (e.g. thrombelastometry) might be of extreme value for detection and guidance of effective coagulation management. Although the transfusion of fresh frozen plasma was recommended in several guidelines, the use of coagulation factors might offer an alternative and potentially superior approach in managing perioperative coagulation disorders. Further studies are urgently needed to determine the efficacy of modern coagulation management

Impact of catecholamines in cardiac arrest due to acute asphyxia - a study in piglets

BACKGROUND Early intravenous epinephrine administration may help to achieve return of spontaneous circulation in cardiac arrest (CA). However, venous access can be challenging in small children. This study investigates the effect of intravenous and intramuscular epinephrine in treatment of asphyxial CA. METHODS Twenty-eight, 2-5-weeks-old, anesthetized piglets were asphyxiated by ventilation withdrawal. CA was untreated for 8 min, followed by 2 min of basic life support. Following this, epinephrine iv (10 μg•kg(-1) , group IV), epinephrine im (100 μg•kg(-1) , group IM), or normal saline (group NS) were administered. Further doses of epinephrine were given in group IV every 4 min, in group IM after 10 min if required. After twenty-two minutes of CA, iv epinephrine was given to all animals still in CA. Outcome measures were survival and epinephrine plasma concentrations. RESULTS Ten animals regained spontaneous circulation after 2 min of basic life support. Therefore, no drug treatment was administered (drop out). Resuscitation was effective in 2 pigs of group IM (n = 6), in 6 of group NS (n = 8) and in all of group IV (n = 4). Nonsurvivors had higher epinephrine (P < 0.01) and norepinephrine (P < 0.01) plasma concentrations prior to start of resuscitation. Median increase in epinephrine plasma concentration from T0 to T5 was 138, 134, and 29 nm in group IV, IM, and NS, respectively. CONCLUSIONS Intravenous and intramuscular administered epinephrine led to similar increase in plasma concentrations during resuscitation of asphyxial CA without hemodynamic or survival benefit. High endogenous epinephrine and norepinephrine plasma concentrations were negative predictors for survival

Intravenous versus intramuscular epinephrine administration during cardiopulmonary resuscitation - a pilot study in piglets

BACKGROUND: Early epinephrine administration in cardiac arrest seems to be advantageous to achieve return of spontaneous circulation (ROSC). Because intravenous (i.v.) or intraosseous access is not always immediately available, this study compares efficacy of early intramuscular (i.m.) epinephrine administration with early and delayed i.v. epinephrine injection in an animal cardiac arrest model. METHODS: Piglets anesthetized with sevoflurane were intoxicated by an i.v. ropivacaine infusion until circulatory arrest. After 1 min basic life support (chest compression and ventilation), epinephrine i.v. (10 μg·kg(-1), group IV) or epinephrine i.m. (100 μg·kg(-1), group IM) or normal saline (group NS) was applied. Further doses of epinephrine were given in group IV every 4 min and in group IM after 10 min if required. Twenty-one minutes after circulatory arrest, i.v. epinephrine - as necessary - was given to all animals. Thus, group NS represents late epinephrine administration. Outcomes were survival and time to ROSC. RESULTS: Twenty-four pigs aged 19.5 (median, interquartile range 16-22) days, weighing 5.4 (5.0-5.7) kg were investigated. Total amount of ropivacaine administered was 8.9 (8.1-10.1) mg·kg(-1). Cardiac rhythm before starting CPR was pulseless electric activity and asystole in 15 and 9 pigs, respectively. Eight, seven, and four pigs survived in group IV, IM, and NS. Focusing on surviving animals, time to ROSC was 2, 4 and 19.5 min in group IV, IM, and NS. CONCLUSIONS: Early i.m. epinephrine provided similar survival compared with early i.v. epinephrine and was superior to delayed epinephrine administration in resuscitation of ropivacaine-induced cardiac arrest in piglets

Effect of Lanz Pressure Regulating Valve on Self-sealing Mechanism and Air Leakage Across the Tracheal Tube Cuffs in a Benchtop Model

Background: The aim of the present study was to investigate the effect of the Lanz system on air sealing by self-inflation in high volume-low pressure (HVLP) tube cuffs. Methods: In vitro tracheal air sealing was studied in HVLP tracheal tube cuffs (internal diameter [ID] 8.0 mm) made from polyurethane ([PU] Seal Guard tracheal tube, Covidien, Athlone, Ireland) and from polyvinylchloride ([PVC] HiLo tracheal tube, Covidien) with and without Lanz pressure regulating valve. Tube cuffs were placed in a vertical 22 mm ID artificial trachea and inflated to 5, 10, 15, 20, 25, or 30 cm H(2)O cuff pressures. Pressure control ventilation with peak inspiratory pressures (PIPs) of 20 or 25 cm H(2)O was applied and air leakage was assessed spirometrically as the ratio of expiratory to inspiratory tidal volumes. Nonparametric Mann-Whitney test was applied to compare the air leakage with and without Lanz system for both cuff types at each cuff pressure and PIP (P < .05). Results: The PVC tube cuffs with Lanz system resulted in significant air leakage at both 20 and 25 cm H(2)O PIP as compared to those without the Lanz system, especially at cuff pressures lower than the preset PIP (P < .05). Although PU tube cuffs with Lanz system showed reduced air sealing when compared with cuffs without Lanz, the difference was not statistically significant. Conclusion: Cuff pressure compensation with the Lanz system during cyclic respiratory pressure changes interferes with the self-sealing mechanism in HVLP tube cuffs at cuff pressures lower than PIP level. This results in larger air leak across tube cuffs particularly in tube cuffs made from PVC

Reproducibility of thrombelastometry (ROTEM®): point-of-care versus hospital laboratory performance

Thrombelastometry (ROTEM®) has gained wide acceptance in detecting and tailoring acquired hemostatic changes in adults and children. We investigated in this observational trial whether the reproducibility of this point-of-care testing was influenced by performance at the bedside or in the hospital laboratory. In addition, difference in time of performance between both measurements was compared. Perioperative blood samples obtained during major pediatric surgery were run in duplicate on two different ROTEM® devices located in the OR and in the hospital laboratory. The Bland-Altman test was used to compare differences of both measurements. ROTEM® measurements of 90 blood samples obtained from 24 children showed no overall clinically meaningful differences, whether they were performed bedside or in the hospital laboratory. Minor differences were found for the InTEM clot formation time (CFT) showing a mean bias of 10.79 seconds. Time saving was 11 minutes (8-16 minutes) if ROTEM® measurements were performed bedside (p < 0.001). In conclusion, there were minimal effects on ROTEM® measurements irrespective of whether they were performed in the hospital laboratory or at the bedside by a single trained staff member, while the latter saved valuable time

Electrocardiographic and blood pressure alterations caused by intravenous injection of ropivacaine - a study in piglets

OBJECTIVES: Objective signs to detect inadvertent intravascular injection of local anesthetics are essential in the anesthetized pediatric patient. For early detection of intravenous bupivacaine administration, it was shown that an epinephrine containing test dose reliably provoked T-wave alterations, changes in heart rate (HR) and blood pressure, whereas intravenous injection of plain bupivacaine could not be detected until high doses were applied. This study investigates electrocardiographic and hemodynamic alterations caused by intravenous ropivacaine. METHODS: Twenty-four piglets, anesthetized with sevoflurane, were randomized into two groups: Group R received as test dose plain ropivacaine 0.2% and group RE, ropivacaine 0.2% + epinephrine 5 μg·ml(-1) . Under stable conditions, 0.2 ml kg(-1) of the test solution was intravenously injected. Twenty minutes later, 0.4 ml kg(-1) was applied. A positive effect was defined as HR increase ≥10 bpm, increase in mean arterial pressure (MAP) ≥15 mmHg, T-wave increase ≥25% baseline. In another setting ropivacaine was intravenously infused until cardiac arrest. RESULTS: After injection of 0.2 or 0.4 ml kg(-1) test solution, a positive increase in HR and MAP was found in 0% of group R and in 100% of group RE. An increase in T-wave ≥25% was found in 42% of group R and in 100% of group RE. During intoxication, T-elevation was seen in 83%. CONCLUSIONS: An epinephrine containing test dose ropivacaine reliably provoked T-wave elevations and increases in HR and MAP. A small dose plain ropivacaine caused T-elevations in a remarkable percentage, whereas higher, quite toxic doses provoked T-elevations in most of the pigs