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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.
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Sepse Neonatal , Sepse , Humanos , Recém-Nascido , Amicacina/farmacocinética , Antibacterianos , Sepse Neonatal/tratamento farmacológico , Sepse/tratamento farmacológico , Taxa de Depuração MetabólicaRESUMO
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.
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Ansiedade , Pais , Ansiedade/epidemiologia , Criança , Hispânico ou Latino , Humanos , Incidência , Fatores de RiscoRESUMO
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.
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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.
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Eletroencefalografia/efeitos dos fármacos , Propofol/farmacologia , Propofol/farmacocinética , Remifentanil/farmacologia , Analgésicos Opioides/farmacologia , Anestésicos Intravenosos/sangue , Anestésicos Intravenosos/farmacocinética , Anestésicos Intravenosos/farmacologia , Criança , Pré-Escolar , Interações Medicamentosas , Feminino , Humanos , Lactente , Masculino , Propofol/sangueRESUMO
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)
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Humanos , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Eficácia , Anestesia Epidural , Dor Pós-Operatória , Complicações Pós-Operatórias , Criança , Catéteres , Manejo da DorRESUMO
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.
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Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Cardiotônicos/farmacologia , Dexmedetomidina/farmacologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Cardiotônicos/uso terapêutico , Células Cultivadas , Técnicas de Cocultura , Dexmedetomidina/uso terapêutico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
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.
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Animais , Ratos , Traumatismo por Reperfusão/prevenção & controle , Óxido Nítrico Sintase/efeitos dos fármacos , Precondicionamento Isquêmico Miocárdico/métodos , Dexmedetomidina/administração & dosagem , Agonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Cardiotônicos/administração & dosagem , Western Blotting , Ratos Sprague-Dawley , Modelos Animais de Doenças , Reação em Cadeia da Polimerase em Tempo RealAssuntos
Humanos , Adolescente , Adulto , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Dexmedetomidina/farmacocinética , Hipnóticos e Sedativos/farmacocinética , Obesidade/metabolismo , Estudos Transversais , Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Taxa de Depuração MetabólicaRESUMO
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.