Population pharmacokinetics of amikacin in suspected cases of neonatal sepsis.

AIMS: This study aimed to characterize the population pharmacokinetic parameters of intravenously administered amikacin in newborns and assess the effect of sepsis in amikacin exposure. METHODS: Newborns aged ≥3 days who received at least 1 dose of amikacin during their hospitalization period were eligible for the study. Amikacin was administered intravenously during a 60-min infusion period. Three venous blood samples were taken from each patient during the first 48 h. Population pharmacokinetic parameter estimates were obtained using a population approach with the programme NONMEM. RESULTS: Data from 329 drug assay samples were obtained from 116 newborn patients (postmenstrual age [PMA] 38.3, range 32-42.4 weeks; weight 2.8, range 1.6-3.8 kg). Measured amikacin concentrations ranged from 0.8 to 56.4 mg/L. A 2-compartment model with linear elimination produced a good fit of the data. Estimated parameters for a typical subject (2.8 kg, 38.3 weeks) were clearance (Cl = 0.16 L/h), intercompartmental clearance (Q = 0.15 L/h), volume of distribution of the central compartment (Vc = 0.98 L) and peripheral volume of distribution (Vp = 1.23 L). Total bodyweight, PMA and the presence of sepsis positively influenced Cl. Plasma creatinine concentration and circulatory instability (shock) negatively influenced Cl. CONCLUSION: Our main results confirm previous findings showing that weight, PMA and renal function are relevant factors influencing newborn amikacin pharmacokinetics. In addition, current results showed that pathophysiological states of critically ill neonates, such as sepsis and shock, were associated with opposite effects in amikacin clearance and should be considered in dose adjustments.

Dynamic Stretching Increases the Eccentric Rate of Force Development, but not Jump Height in Female Volleyball Players.

The present study aimed to analyze the effect of static and dynamic stretching exercises on the rate of force development (RFD) during the eccentric braking phase and jump height in a countermovement jump (CMJ) in female volleyball players. Thirty female volleyball players were randomly distributed in a static stretching (n = 10; SG), a dynamic stretching, and (n = 10; DG) a control group (n = 10; CG). A force plate and a 3D analysis system were employed to detect the eccentric braking phase during the CMJ. The RFD was analyzed in RFD (RFDi) intervals and the accumulated RFD (RFDa), and normalized to body mass. The SG experienced a likely small decrease in the RFDa (mean difference -17.4 N/s/kg) and a likely small decrease in the RFDi (mean difference -19.1 N/s/kg). Contrarily, the DG showed a likely small increase in the RFDa (mean difference 31.2 N/s/kg) and a most likely small increase in the RFDi (mean difference 34.8 N/s/kg). The effect of both static and dynamic stretching on jump height was trivial. Practitioners should consider utilizing dynamic stretching exercises instead of static stretching before a competition in female volleyball players. Further research is needed in order to find complementary strategies during the warm-up that could increase jump height.

Incidence and risk factors of preoperative anxiety in Spanish-speaking children living in a Spanish-speaking country.

BACKGROUND: Most research on preoperative anxiety has focused on non-Latino populations. A study performed in the USA found that children from Spanish-speaking Latino families experienced higher anxiety than children from English-speaking families. AIMS: To report the incidence and level of preoperative anxiety in native Spanish-speaking children living in their home country and to assess risk factors associated with higher anxiety levels. METHODS: Data were collected from 204 children aged 2-12 undergoing elective surgery in a Chilean hospital. Patients' demographic data, surgery-related information, and self-reported parental anxiety were collected. Children's anxiety was measured using the Modified Yale Preoperative Anxiety Scale. An anxiety score greater than 30 indicated significant anxiety. The main outcome for analyzing risk factors was children's anxiety level in the operating room. RESULTS: Significant preoperative anxiety was observed in 41.7% (95% CI: 34.8%-48.8%) of patients, with median anxiety score of 26.6 (IQR, 23.4-46.6). A significant positive correlation was observed between self-reported parental anxiety in the preoperative holding room and children's anxiety in the operating room (r = .153, P = .02), with a higher median difference when mothers are present in anesthesia induction (36.8 vs 30.7, respectively; P = .006). Linear regression analysis found previous negative surgical experience to be associated with higher anxiety levels in the operating room (ß = 16.057, P = .014). CONCLUSIONS: Spanish-speaking children undergoing elective surgery in their home country experienced significant rates of preoperative anxiety. Parental anxiety and previous negative surgical experience were risk factors associated with higher anxiety levels.

An Open-Label, Dose-Escalation Study to Assess the Safety and Efficacy of IL-22 Agonist F-652 in Patients With Alcohol-associated Hepatitis.

BACKGROUND AND AIMS: Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH. APPROACH AND RESULTS: A phase-2 dose-escalating study was carried out. F-652 (10 µg/kg, 30 µg/kg, or 45 µg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42. CONCLUSIONS: F-652 is safe in doses up to 45 µg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH.

Dexmedetomidine Improves Cardiovascular and Ventilatory Outcomes in Critically Ill Patients: Basic and Clinical Approaches.

Dexmedetomidine (DEX) is a highly selective α2-adrenergic agonist with sedative and analgesic properties, with minimal respiratory effects. It is used as a sedative in the intensive care unit and the operating room. The opioid-sparing effect and the absence of respiratory effects make dexmedetomidine an attractive adjuvant drug for anesthesia in obese patients who are at an increased risk for postoperative respiratory complications. The pharmacodynamic effects on the cardiovascular system are known; however the mechanisms that induce cardioprotection are still under study. Regarding the pharmacokinetics properties, this drug is extensively metabolized in the liver by the uridine diphosphate glucuronosyltransferases. It has a relatively high hepatic extraction ratio, and therefore, its metabolism is dependent on liver blood flow. This review shows, from a basic clinical approach, the evidence supporting the use of dexmedetomidine in different settings, from its use in animal models of ischemia-reperfusion, and cardioprotective signaling pathways. In addition, pharmacokinetics and pharmacodynamics studies in obese subjects and the management of patients subjected to mechanical ventilation are described. Moreover, the clinical efficacy of delirium incidence in patients with indication of non-invasive ventilation is shown. Finally, the available evidence from DEX is described by a group of Chilean pharmacologists and clinicians who have worked for more than 10 years on DEX.

Propofol pharmacokinetic and pharmacodynamic profile and its electroencephalographic interaction with remifentanil in children.

BACKGROUND: Propofol and remifentanil are commonly combined during total intravenous anesthesia. The impact of remifentanil in this relationship is poorly quantified in children. Derivation of an integrated pharmacokinetic and pharmacodynamic propofol model, containing remifentanil pharmacodynamic interaction information, enables propofol effect-site target-controlled infusion in children with a better prediction of its hypnotic effect when both drugs are combined. AIMS: We designed this study to derive an integrated propofol pharmacokinetic-pharmacodynamic model in children and to describe the pharmacodynamic interaction between propofol and remifentanil on the electroencephalographic bispectral index effect. METHODS: Thirty children (mean age: 5.45 years, range 1.3-11.9; mean weight: 23.5 kg, range 8.5-61) scheduled for elective surgery with general anesthesia were studied. After sevoflurane induction, maintenance of anesthesia was based on propofol and remifentanil. Blood samples to measure propofol concentration were collected during anesthesia maintenance and up to 6 hours in the postoperative period. Bispectral index data were continuously recorded throughout the study. A pharmacokinetic-pharmacodynamic model was developed using population modeling. The Greco model was used to examine the pharmacokinetic-pharmacodynamic interaction between propofol and remifentanil for BIS response RESULTS: Propofol pharmacokinetic data from a previous study in 53 children were pooled with current data and simultaneously analyzed. Propofol pharmacokinetics were adequately described by a three-compartment distribution model with first-order elimination. Theory-based allometric relationships based on TBW improved the model fit. The Greco model supported an additive interaction between propofol and remifentanil. Remifentanil showed only a minor effect in BIS response. CONCLUSION: We have developed an integrated propofol pharmacokinetic-pharmacodynamic model that can describe the pharmacodynamic interaction between propofol and remifentanil for BIS response. An additive interaction was supported by our modeling analysis.

Eficacia analgésica y complicaciones a corto plazo de catéteres peridurales lumbares y torácicos en pacientes pediátricos: una evaluación retrospectiva / Analgesic efficacy and short-term complications of lumbar peridural catheters and thoracic in pediatric patients: a retrospective evaluation

Introducción: la analgesia peridural postoperatoria en niños es efectiva con catéteres insertados al nivel del sitio quirúrgico. Objetivo:comparar la eficacia y las complicaciones de catéteres insertados a nivel lumbar y torácico para analgesia postoperatoria. Método:revisamos la base de datos del Servicio de dolor agudo. Extrajimos información de pacientes de 0-18 años, con analgesia peridural postoperatoria. Los pacientes fueron divididos en grupo lumbar y torácico y, en cada grupo, por edades. Recopilamos información de: variables demográficas, tipo de cirugía, nivel de inserción del catéter peridural, solución de anestésico local administrada, analgésicos sistémicos, coadyuvantes peridurales, dolor postoperatorio y complicaciones. Dividimos las complicaciones según gravedad. Resultados: se analizaron 221 pacientes, 123 con catéter lumbar y 98 con catéter torácico. Catéteres peridurales lumbares y torácicos fueron principalmente insertados en niños de 1-3 años y mayores de 4 años respectivamente. Se utilizó bupivacaína 0,1-0,125 por ciento. Las cirugías fueron urológicas, intraabdominales, ortopédicas, torácicas y cardiovasculares. Los niños con catéteres torácicos tuvieron más dolor (mediana (rango): 3 (0-6) vs. 2 (0-4)) y necesitaron sus catéteres por más días (promedio (DE): 2,96 (1,06) vs. 2,53 (1,09) que aquellos con catéter lumbar. Los requerimientos analgésicos fueron similares en ambos grupos. Hubo 60 complicaciones (27,1 por ciento), principalmente menores (92 por ciento), sin diferencias entre los grupos lumbar y torácica (30 por ciento vs 23 por ciento) ni entre las diferentes edades. Conclusión: los catéteres peridurales insertados en relación al sitio quirúrgico, a nivel lumbar o torácico, proporcionarían analgesia postoperatoria clínicamente aceptable y comparable, con similar incidencia de complicaciones.(AU)

Introduction: postoperative epidural analgesia in children is effective with catheters inserted at the level of the surgical site. Objective: compare the efficacy and complications of epidural catheters inserted at the lumbar and thoracic level for postoperative analgesia in this population. Methods: we review the Acute Pain Service Database. We extracted information of patient from 0 to 18 years with postoperative epidural analgesia. Patients were divided into lumbar and thoracic groups and, in each group, by age. Collected data included: demographic, type of surgery, details of epidural catheters insertion, the local anesthetic administered, systemic analgesics and epidural adjuvant used, postoperative pain and complications. We divide complications according severity. Results: 221 patients were analyzed, 123 with lumbar and 98 with thoracic epidurals catheters. Lumbar and thoracic epidural catheters were mainly placed in patients 1-3 years and older than four years respectively. Bupivacaine 0.1-0.125 percent was the analgesic solution used. Performed surgeries were urological, intraabdominal, orthopedic, thoracic and cardiovascular. Children with thoracic catheters had more pain (median (IQR): 3 (0-6) vs. 2 (0-4)) and needed their catheters more days (mean (SD): 2.96 (1.06) vs. 2.53 (1.09)) than children with lumbar catheters.Analgesic requirements were similar between both groups. There were 60 complications (27.1 percent), mainly minors (92 percent), with no differences between lumbar and thoracic groups (30 percent vs. 23 percent respectively), and among age categories. Conclusion: the epidural catheters inserted about the surgical site, at the lumbar or the thoracic level would provide clinically acceptable and comparable postoperative analgesia with a similar rate of complications.(AU)

Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism.

The alpha2-adrenergic receptor agonist Dexmedetomidine (Dex) is a sedative medication used by anesthesiologists. Dex protects the heart against ischemia-reperfusion (IR) and can also act as a preconditioning mimetic. The mechanisms involved in Dex-dependent cardiac preconditioning, and whether this action occurs directly or indirectly on cardiomyocytes, still remain unclear. The endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway and endothelial cells are known to play key roles in cardioprotection against IR injury. Therefore, the aims of this work were to evaluate whether the eNOS/NO pathway mediates the pharmacological cardiac effect of Dex, and whether endothelial cells are required in this cardioprotective action. Isolated adult rat hearts were treated with Dex (10nM) for 25min and the dimerization of eNOS and production of NO were measured. Hearts were then subjected to global IR (30/120min) and the role of the eNOS/NO pathway was evaluated. Dex promoted the activation of eNOS and production of NO. Dex reduced the infarct size and improved the left ventricle function recovery, but this effect was reversed when Dex was co-administered with inhibitors of the eNOS/NO/PKG pathway. In addition, Dex was unable to reduce cell death in isolated adult rat cardiomyocytes subjected to simulated IR. Cardiomyocyte death was attenuated by co-culturing them with endothelial cells pre-treated with Dex. In summary, our results show that Dex triggers cardiac protection by activating the eNOS/NO signaling pathway. This pharmacological effect of Dex requires its interaction with the endothelium.

Dexmedetomidina genera óxido nítrico mediante un mecanismo independiente de la óxido nítrico sintasa inducible / Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism

El infarto del miocardio es una de las principales causas de muerte a nivel mundial y se produce a consecuencia de procesos de isquemia-reperfusión (IR). El daño miocárdico generado por IR puede ser atenuado a través del pre-condicionamiento isquémico (PI) temprano, mediado por la vía RISK o PI tardío, que se asocia a una respuesta genómica en la que se activan proteínas como óxido nítrico sintasa inducible (iNOS). Las vías de señalización que median el PI también pueden ser activadas farmacológicamente. Dexmedetomi-dina (Dex) es un agonista alfa2-adrenérgico, que se ha descrito como un potente agente cardioprotector frente a IR. Recientemente, nuestro grupo describió que Dex requiere el endotelio y la activación de la vía óxido nítrico sintasa endotelial (eNOS)-óxido nítrico (NO) para pre-condicionar el miocardio. Sin embargo, no existen estudios que muestren la posible participación de iNOS en la protección conferida por Dex. La presente adenda tiene por objetivo evaluar si Dex activa iNOS en el corazón y en cardiomiocitos. Para esto, corazones de rata adulta fueron estimulados con Dex 10 nM y se observó que el fármaco aumentó la producción de NO medida por cuantificación de nitritos, mas no estimuló la activación de iNOS medida por Western blot. Además, Dex tampoco indujo el aumento de mRNA de iNOS en cardiomiocitos adultos. Por lo tanto, Dex genera NO independiente a iNOS durante su efecto pre-condicionante agudo. Sin embargo, se requieren más estudios que clarifiquen su papel en una posible protección a largo plazo frente a IR generada por Dex.

Myocardial infarction is one of the leading causes of death worldwide and is generated as a consequence of ischemia-reperfusion (IR). Myocardial damage inflicted by IR can be attenuate by early ische-mic pre-conditioning (IP), which is mediated by the RISK pathway or late IP, which is associated to a genomic response involving the activation of proteins such as inducible nitric oxide synthase (iNOS). The signaling pathways mediating IP can also be pharmacologically activated. Dexmedetomidine (Dex) is an alpha2-adrenergic receptor agonist, which has been described as a strong cardio protective agent against IR. Recently, our group reported that Dex requires the endothelium and the activation of the endothelial nitric oxide synthase (eNOS)-ni-tric oxide (NO) pathway to precondition the myocardium. However, there are no studies showing the involvement of iNOS in the protection elicited by Dex. The aim of this Addendum is to evaluate if Dex activates iNOS in the heart and cardiomyocytes. To test this, adult rat hearts were stimulated with Dex 10 nM and we observed that NO production measured by quantification of nitrites was increased, but Dex did not activate iNOS measured by Western blot. Moreover, Dex did not induce an increase in the mRNA levels of iNOS in adult cardiomyocytes. Therefore, Dex generates NO independent of iNOS during its early pre-conditioning effect. Nevertheless, more studies are required to clarify its role in a possible long term protection against IR generated by Dex.

Dexmedetomidine pharmacokinetics in the obese.

PURPOSE: This study aims to characterize the influence of body weight and composition on the pharmacokinetics of dexmedetomidine. METHODS: Twenty obese patients and 20 non-obese patients scheduled for elective laparoscopic surgery were given dexmedetomidine infusion schemes. Venous blood samples were taken during and after dexmedetomidine administration. Population pharmacokinetic modeling was undertaken to investigate fat free mass (FFM) and normal fat mass (NFM) as size descriptors of volumes and clearances using non-linear mixed effects modeling. NFM partitions total body weight into FFM and fat mass calculated from total body weight (TBW) minus FFM. The relative influence of fat mass compared to FFM is described by the fraction of fat mass that makes fat equivalent to FFM (Ffat). RESULTS: Theory-based allometric scaling using FFM best described weight and body composition differences in clearances and volumes A negative effect of fat mass of with an exponential parameter of -0.00541/kg (95 % CI -0.0118 to -0.00246) was estimated for clearance which indicates increased fat mass is associated with impairment of clearance. CONCLUSIONS: The use of theory-based allometry with predictions of fat free mass has been able to separate the influences of weight and body composition and indicates that size-normalized clearance of dexmedetomidine is impaired in patients who are obese.

Propofol concentration to induce general anesthesia in children aged 3-11 years with the Kataria effect-site model.

BACKGROUND: The propofol pharmacokinetic model derived by Kataria et al. was recently modified to perform effect-site target-controlled infusion (TCI). Effect-site concentration (Ce) targets to induce general anesthesia with this model in children have not been described. The aim of this study was to identify propofol Ce targets associated with success rates of 50% (Ce50) and 95% (Ce95) among children 3-11 years of age. METHODS: Forty-two children were assigned to one of seven groups of six patients each according to propofol target Ce. After fentanyl administration propofol TCI was started with an assigned Ce target. A successful response was defined as loss of eyelash reflex and bispectral index < 50, 45 s after reaching the assigned Ce. Logistic regression analysis was performed to calculate propofol Ce50 and Ce95. RESULTS: Twenty-eight children had a successful response with the assigned propofol Ce. In these patients, a significant decrease in mean arterial blood pressure (79-59, P < 0.0001) and in heart rate (95-83, P < 0.0001) was observed. Propofol Ce and age showed a statistically significant effect in the logistic regression model. The overall calculated propofol Ce50 and Ce95 were 3.8 µg·ml(-1) (95% CI: 3.1-4.4 µg·ml(-1) ) and 6.1 µg·ml(-1) (95% CI: 4.6-7.6 µg·ml(-1) ), respectively. CONCLUSION: Our results identified useful propofol targets to be used with the Kataria effect-site model to induce anesthesia in children between 3 and 11 years. The recommended targets should be reduced progressively with increasing age most probably due to PK model misspecifications.

Dexmedetomidine-ketamine combination and caudal block for superficial lower abdominal and genital surgery in children.

BACKGROUND: The use of dexmedetomidine-ketamine combination to perform different diagnostic and surgical pediatric procedures has increased. The optimal ketamine dose to combine with dexmedetomidine has not been determined. The goal of this study was to determine the ED50 and ED95 of ketamine, which in combination with, dexmedetomidine (1 µg · kg(-1)) provides an adequate anesthetic effect to perform a caudal block and then the ensuing superficial lower abdominal or genital surgery. MATERIAL AND METHODS: Twenty-five patients, aged 1-8 years, scheduled for superficial lower abdominal or genital surgery, were studied. All patients received an intravenous dose of dexmedetomidine 1 µg · kg(-1) and a random dose of ketamine from 1 mg · kg(-1) to 2 mg · kg(-1). After ketamine administration, a caudal block was performed and then surgery was initiated. Hemodynamics, respiratory variables, sedation level, and postoperative complications were recorded. The ED50 and ED95 of ketamine were calculated using logistic regression analysis. RESULTS: The ED50 and ED95 of ketamine to perform a caudal block were 1.53 (1.29-1.76) mg · kg(-1) and 2.25 (1.63-2.88) mg · kg(-1), respectively. The ED50 and ED95 of ketamine to perform a caudal block and to complete the entire procedure were 1.76 (1.57-1.95) mg · kg(-1), and 2.21 (1.77-2.64) mg · kg(-1), respectively. Three patients presented mild, self-limited, intraoperative bradycardia. CONCLUSIONS: These results suggest that adding ketamine 2 mg · kg(-1) to dexmedetomidine 1 µg · kg(-1) should produce an effective anesthetic level to perform a caudal block and the ensuing superficial lower abdominal or genital surgery in children.

Defective insulin signaling and mitochondrial dynamics in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a common consequence of longstanding type 2 diabetes mellitus (T2DM) and encompasses structural, morphological, functional, and metabolic abnormalities in the heart. Myocardial energy metabolism depends on mitochondria, which must generate sufficient ATP to meet the high energy demands of the myocardium. Dysfunctional mitochondria are involved in the pathophysiology of diabetic heart disease. A large body of evidence implicates myocardial insulin resistance in the pathogenesis of DCM. Recent studies show that insulin signaling influences myocardial energy metabolism by impacting cardiomyocyte mitochondrial dynamics and function under physiological conditions. However, comprehensive understanding of molecular mechanisms linking insulin signaling and changes in the architecture of the mitochondrial network in diabetic cardiomyopathy is lacking. This review summarizes our current understanding of how defective insulin signaling impacts cardiac function in diabetic cardiomyopathy and discusses the potential role of mitochondrial dynamics.

Performance of propofol target-controlled infusion models in the obese: pharmacokinetic and pharmacodynamic analysis.

BACKGROUND: Obesity is associated with important physiologic changes that can potentially affect the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anesthetic drugs. We designed this study to assess the predictive performance of 5 currently available propofol PK models in morbidly obese patients and to characterize the Bispectral Index (BIS) response in this population. METHODS: Twenty obese patients (body mass index >35 kg/m), aged 20 to 60 years, scheduled for laparoscopic bariatric surgery, were studied. Anesthesia was administered using propofol by target-controlled infusion and remifentanil by manually controlled infusion. BIS data and propofol infusion schemes were recorded. Arterial blood samples to measure propofol were collected during induction, maintenance, and the first 2 postoperative hours. Median performance errors (MDPEs) and median absolute performance errors (MDAPEs) were calculated to measure model performance. A PKPD model was developed using NONMEM to characterize the propofol concentration-BIS dynamic relationship in the presence of remifentanil. RESULTS: We studied 20 obese adults (mean weight: 106 kg, range: 85-141 kg; mean age: 33.7 years, range: 21-53 years; mean body mass index: 41.4 kg/m, range: 35-52 kg/m). We obtained 294 arterial samples and analyzed 1431 measured BIS values. When total body weight (TBW) was used as input of patient weight, the Eleveld allometric model showed the best (P < 0.0001) performance with MDPE = 18.2% and MDAPE = 27.5%. The 5 tested PK models, however, showed a tendency to underestimate propofol concentrations. The use of an adjusted body weight with the Schnider and Marsh models improved the performance of both models achieving the lowest predictive errors (MDPE = <10% and MDAPE = <25%; all P < 0.0001). A 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (ke0) adequately described the propofol concentration-BIS data. A lag time parameter of 0.44 minutes (SE = 0.04 minutes) to account for the delay in BIS response improved the fit. A simulated effect-site target of 3.2 µg/mL (SE = 0.17 µg/mL) was estimated to obtain BIS of 50, in the presence of remifentanil, for a typical patient in our study. CONCLUSIONS: The Eleveld allometric PK model proved to be superior to all other tested models using TBW. All models, however, showed a trend to underestimate propofol concentrations. The use of adjusted body weight instead of TBW with the traditional Schnider and Marsh models markedly improved their performance achieving the lowest predictive errors of all tested models. Our results suggest no relevant effect of obesity on both the time profile of BIS response and the propofol concentration-BIS relationship.

Influence of glucose metabolism on vascular smooth muscle cell proliferation.

Differentiation of vascular smooth muscle cells (VSMC) is an essential process of vascular development. VSMC have biosynthetic, proliferative, and contractile roles in the vessel wall. Alterations in the differentiated state of the VSMC play a critical role in the pathogenesis of atherosclerosis and intimal hyperplasia, as well as in a variety of other human diseases, including hypertension, asthma, atherosclerosis and vascular aneurysm. This review provides an overview of the current state of knowledge of molecular mechanisms involved in controlling VSMC proliferation, with particular focus on glucose metabolism and its relationship with mitochondrial bioenergetics. Increased levels of glucose transporter 1 (GLUT1) are observed in VSMC after endothelial injury, suggesting a relationship between glucose uptake and VSMC proliferation. Mitochondrial dysfunction is a common feature in VSMC during atherosclerosis. Alterations in mitochondrial function can be produced by dysregulation of mitofusin-2, a small GTPase associated with mitochondrial fusion. Moreover, exacerbated proliferation was observed in VSMC from pulmonary arteries with hyperpolarized mitochondria and enhanced glycolysis/glucose oxidation ratio. Several lines of evidence highlight the relevance of glucose metabolism in the control of VSMC proliferation, indicating a new area to be explored in the control of vascular pathogenesis.

Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart.

Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an α(2)-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigate whether dexmedetomidine administration activates cardiac survival kinases and induces cardioprotection against regional ischemia/reperfusion injury. In in vivo and ex vivo models, rat hearts were subjected to 30 min of regional ischemia followed by 120 min of reperfusion with dexmedetomidine before ischemia. The α(2)-adrenergic receptor antagonist yohimbine was also given before ischemia, alone or with dexmedetomidine. Erk1/2, Akt and eNOS phosphorylations were determined before ischemia/reperfusion. Cardioprotection after regional ischemia/reperfusion was assessed from infarct size measurement and ventricular function recovery. Localization of α(2)-adrenergic receptors in cardiac tissue was also assessed. Dexmedetomidine preconditioning increased levels of phosphorylated Erk1/2, Akt and eNOS forms before ischemia/reperfusion; being significantly reversed by yohimbine in both models. Dexmedetomidine preconditioning (in vivo model) and peri-insult protection (ex vivo model) significantly reduced myocardial infarction size, improved functional recovery and yohimbine abolished dexmedetomidine-induced cardioprotection in both models. The phosphatidylinositol 3-kinase inhibitor LY-294002 reversed myocardial infarction size reduction induced by dexmedetomidine preconditioning. The three isotypes of α(2)-adrenergic receptors were detected in the whole cardiac tissue whereas only the subtypes 2A and 2C were observed in isolated rat adult cardiomyocytes. These results show that dexmedetomidine preconditioning and dexmedetomidine peri-insult administration produce cardioprotection against regional ischemia/reperfusion injury, which is mediated by the activation of pro-survival kinases after cardiac α(2)-adrenergic receptor stimulation.

Infarto perioperatorio en cirugía no-cardíaca y dexmedetomidina / Perioperative myocardical infaction in non-cardiac surgery and dexmedetomidine

La patología cardiovascular es la primera causa de muerte en Chile y en el mundo. Desde el punto de vista quirúrgico, anestesiólogos y cirujanos enfrentan más frecuentemente pacientes mayores con patología cardiovascular. La incidencia de isquemia miocárdica en pacientes de alto riesgo, sometidos a cirugía no-cardíaca, es cercana al 40 por ciento durante el perioperatorio. La incidencia de infarto miocárdico y muerte en cirugía no-cardíaca, oscila entre 1 y 5 por ciento. Existe una estrecha relación entre los eventos isquémicos perioperatorios y el aumento de la morbimortalidad cardiovascular. Por este motivo, se han desarrollado medidas terapéuticas orientadas a disminuir la incidencia de isquemia perioperatoria y aminorar el daño asociado a ella. La adecuada identificación de pacientes de riesgo, la optimización del tratamiento médico de patologías asociadas y el uso de fármacos cardioprotectores durante el perioperatorio, han mostrado disminuir la incidencia de complicaciones cardíacas. Dexmedetomidina es un agonista beta2-adrenérgico de uso frecuente en anestesia. La evidencia sugiere que posee propiedades cardioprotectoras que podrían beneficiar a pacientes quirúrgicos de alto riesgo cardiovascular. La cardioprotección conferida por dexmedetomidina estaría mediada por la modulación del sistema nervioso autónomo. La disminución de la frecuencia cardíaca y de la presión arterial observada durante su uso, evitarían el desbalance entre aporte y demanda de oxígeno miocárdico y atenuarían el estrés sobre placas ateromatosas inestables. Hasta este momento se desconoce si dexmedetomidina produce precondicionamiento cardíaco y si activa vías transduccionales asociadas a cardioprotección. Frente a la actual realidad epidemiológica en Chile y el mundo, es importante estudiar y definir, cuales son los fármacos de uso frecuente en anestesia con capacidad cardloprotectora y los mecanismos Involucrados en esta protección. Sería Interesante lograr...

Cardiovascular disease is the leading cause of death In Chile and worldwide. Anesthesiologists and surgeons often face more elderly surgical patients with cardiovascular disease. The incidence of myocardial Ischemia in patents at high risk, undergoing non-cardiac surgery is about 40 percent during the perioperative period. The incidence of myocardial Infarction and death in non-cardiac surgery is between 1 and 5 percent. There is a close relationship between perioperative Ischemic events and increased cardiovascular morbidity and mortality Therefore, therapeutic approaches have been developed to reduce the Incidence of perioperative Ischemia and lessen the damage associated with it. The proper Identification of patients at risk, optimizing the medical treatment of associated diseases and the use of cardioprotective drugs during the perioperative period have shown to decrease the Incidence of cardiac complications. The beta2-adrenergic agonist dexmedetomidine is commonly used in anesthesia. The evidence suggests that possesses cardioprotective properties that could benefit surgical patients at high cardiovascular risk. The cardioprotection conferred by dexmedetomidine would be mediated by modulation of the autonomic nervous system. The decrease in heart rate and blood pressure observed during its use could avoid the Imbalance between supply and myocardial oxygen demand and lessen the stress on unstable athermanous plaques. So far it is unknown whether dexmedetomidine produces cardiac preconditioning by activating cardioprotective-signaling pathways. Faced with the current worldwide epidemiologic situation, It would be Important to study the cardioprotective capacity of drugs frequently used in anesthesia and the mechanisms Involved In that protection. It would be interesting to achieve that definition regarding the perioperative use of dexmedetomidine.

Remifentanil requirements during propofol administration to block the somatic response to skin incision in children and adults.

BACKGROUND: During sevoflurane administration, children require a remifentanil infusion rate twofold higher than adults to block responses to skin incision. Similar data concerning remifentanil requirements are unavailable during total IV anesthesia. METHODS: We prospectively determined the infusion rate (IR) of remifentanil necessary to block the somatic response to skin incision in 50% (IR50) of adults (n = 20, aged 20-60 yr) and children (n = 20, aged 3-11 yr) during propofol anesthesia. In each patient undergoing lower abdominal surgery, a remifentanil infusion was initiated, followed by target-controlled infusion of propofol set at a plasma concentration of 6 mug/mL. After tracheal intubation, propofol was reduced to 3 microg/mL until the end of the study. Remifentanil IR was determined according to Dixon's up-and-down method, with the first patient in each group receiving 0.2 microg x kg(-1) x min(-1) followed by the consecutive patient receiving 0.02 microg x kg(-1) x min(-1) modifications according to the response of the previous patient. The remifentanil IR was kept unchanged for at least 20 min before surgery. At the beginning of surgery, only the skin incision was performed, and the somatic response was observed. If there was any gross movement of extremity the response was considered positive. RESULTS: The IR50 (CI(95%)) was 0.08 (0.06-0.12) microg x kg(-1) x min(-1) in adults and 0.15 (0.13-0.17) microg x kg(-1) x min(-1) in children (P < 0.001). CONCLUSION: These results demonstrate that, similar to sevoflurane anesthesia, during total IV anesthesia with propofol, children require a remifentanil IR almost twofold higher than adults to block the somatic response to skin incision.