Farmacocinética y farmacodinámica de los antibióticos betalactámicos en pacientes críticos / Pharmacokinetics and pharmacodynamics of beta-lactam antibiotics in critically ill patients

La terapia antibiótica óptima en los pacientes en estado crítico puedecomplicarse por la alteración de la fisiología asociada a esta etapa de laenfermedad. La farmacocinética y la exposición a los antibióticos puedenverse alteradas por la enfermedad crítica subyacente y las intervencionesmédicas que reciben estos pacientes en la unidad de cuidados intensivos.Además, las cepas que suelen encontrarse en la unidad de cuidados intensivossuelen ser menos susceptibles y “resistentes” a los antibióticos máshabituales. De hecho, una dosificación de antibióticos que no tenga encuenta estas diferencias únicas, probablemente fracasará y dará lugar aresultados clínicos deficientes y a la aparición de resistencia a los antibióticosen la unidad de cuidados intensivos. Los objetivos de esta revisión sondescribir la farmacocinética de los antibióticos betalactámicos en pacientescríticos, destacar los objetivos farmacocinéticos/farmacodinámicos paralos pacientes y exponer algunas estrategias importantes que pueden optimizarla dosificación de los antibióticos betalactámicos en pacientes críticosen la unidad de cuidados intensivos.

Optimal antibiotic therapy for critically ill patients can be complicated bythe altered physiology associated with critical illness. Antibiotic pharmacokinetics and exposures can be altered driven by the underlying critical illnessand medical interventions that critically ill patients receive in the intensivecare unit. Furthermore, pathogens that are usually isolated in the intensivecare unit are commonly less susceptible and “resistant” to common antibiotics. Indeed, antibiotic dosing that does not consider these unique differences will likely fail leading to poor clinical outcomes and the emergenceof antibiotic resistance in the intensive care unit. The aims of this narrativereview were to describe the pharmacokinetics of beta-lactam antibiotics incritically ill patients, to highlight pharmacokinetic/pharmacodynamic targetsfor both non-critically ill and critically ill patients, and to discuss importantstrategies that can be undertaken to optimize beta-lactam antibiotic dosingfor critically ill patients in the intensive care unit.

Modelagem farmacocinética-farmacodinâmica do propofol em pacientes submetidos à cirurgia cardíaca com anestesia venosa contínua alvo-controlada / Propofol pharmacokinetic-pharmacodynamic modeling in patients submitted to cardiac surgery with continuos venous target controlled anesthesia

O propofol é um sedativo eficiente, largamente empregado em anestesia e geralmente associado a grande números de analgésicos opióides em cirurgias de grande porte, como a cirurgia cardíaca de revascularização do miocárdio (RM) com ou sem circulação extracorpórea (CEC). Devido às suas características farmacocinéticas é administrado através de infusão alvo controlada (TCI) de forma a manter os níveis plasmáticos ótimos para obtenção de sedação e profundidade de anestesia adequadas durante a intervenção cirurgica. O objetivo do presente estudo foi investigar a famacocinética e farmacodinâmica do propofol administrado através de TCI em pacientes submetidos a RM com e sem CEC. Na administração da medicação hipnótica, fez-se necessária a validação do Diprifusor (AstraZeneca), incluindo a bomba de infusão e o software programado com o modelo famacocinético de 3 compartimentos, que necessita apenas da inclusão de dados individuais do paciente, tais como peso corporal...

Propofol is an effective sedative, largely applied in anesthesia and in general it is associated to opioids for analgesia in major surgeries, like the cardiac surgery to coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (CPB). It is administered by a target controlled infusion system (TCI) to maintain the optimal depth of sedation and anesthesia during the intervention, due to its pharmacokinetic characteristics. The objective of this study was to investigate the influence of CPB in pharmacokinetics and in pharmacodynamics of propofol, applying PK-PD modeling. For drug administration, Diprifusor (AstraZeneca), including pump plus software must enter individual data as body weight from the patient, once pharmacokinetic parameters were included previously. To validate this system of infusion, the prediction error by target controlled infusion must be estimated by comparison between obtained and predict concentration plasma ratio. In the present protocol, 20 patients (10 CONTROL and 10 CPB) were selected based on inclusion criteria for the comparative study. Patients were informed in details about the investigation and before the protocol starts, they signed the informed written consent to participate of the study. Protocol was approved by the local ethical committees of all institutions involved. Rate of infusion and the range of obtained plasma propofol concentrations required to reach 2 µg/mL and to maintain the bispectral index (BIS:40) during cardiac surgery were monitored. Subsequently, at the end of surgery, both rate of infusion and range of obtained plasma propofol concentrations required to reach 1 µg/mL were monitored either. Depth of sedation was assessed with BIS during all period reaching maximum effect in 40 at level of sedation in the operative period. At the end of surgery, the Ramsay score achieved sedation level 6, when the target plasma propofol was adjusted to 1 µg/mL; Additionally, at the end of infusion in the postoperative period, BIS and Ramsay were monitored simultaneously up to 18-20 hours for all patients. Blood samples were collected and propofol plasma levels were monitored during (TCI : 2 µg/mL) and after surgery (TCI: 1 µg/mL). Blood samples also were collected at the end of infusion for pharmacokinetics. Volumes of blood lower than 90 mL were necessary for drug monitoring and pharmacokinetic purposes. Plasma levels were determined by a quite simple, selective, sensitive and robustness analytical method HPLC, using fluorescence detector, C18 column, and binary system at low flow rate. Confidence limits were: 0.1-10 µg/mL (linearity, r2 0.9977), 0.05 µg/mL(LD), 0.1 flg/mL(LQ), 93.9% (absolute recovery), 8.4 and 8.8% (intra and inter day precision), 91.8 and 93.3% (accuracy intra and inter day). Additionally, good stability was shown for the drug and its internal standard (tymol). Plasma levels showed a large fluctuation for the CONTROL compared to CPB in the perioperative period, mainly during the surgical intervention, indicating a higher predicting error for CONTROL group. Pharmacokinetics applying three compartment open model showed significant increases on drug elimination (ClT, ß, γ) for CPB compared to CONTROL, once plasma levels for CPB Group were lower than CONTROL in the period of study.