Morphine pharmacokinetic-pharmacodynamic modeling administered by patient controlled analgesia (PCA) pump in the postoperative period of myocardial revascularization surgery / Modelagem farmacocinética-farmacodinâmica da morfina administrada através de bomba controlada pelo paciente no pós-operatório de revascularização do miocárdio

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

Introduction: Morphine administration using patient controlled analgesia (PCA) for treatment of post surgical and traumatic pain has been a current practice in many hospitals. However, large or repeated doses of this opioid are associated to dose dependent adverse events, including, respiratory depression. Considering patients submitted to thoracic surgery, in addition to the postoperatory analgesia, two other relevant parameters must be considered: regional anesthesia (intrathecal) in the intra-operatory period, which should contribute to the respiratory function improvement and decrease in the extubation time; and the cardiopulmonary bypass (OPCAB), that potentially alters the drugskinetics. Objectives: To investigate the influence of intrathecal morphine administration and cardiopulmonary bypass (OPCAB) in the morphine PCA drug requirements, area under the curve of morphine plasma concentration versus time and pain scores in the postoperative period, and to choose a pharmacokinetic-pharmacodynamic model to correlate these variables. In addition, an analytical method was developed to quantify morphine in plasma. Methods: 59 patients submitted to elective coronary artery bypass grafting (CABG) with (CPB) and without cardiopulmonary bypass (OPCAB), with and without intrathecal morphine in the intra-operative period were distributed by the combination of the above mentioned interventions. In the postoperative period, all the patients were given an IV bolus of 1mg of morphine, and then PCA device was installed in the intensive care unit by a venous catheter after the orotracheal extubation. Morphine PCA was delivered on demand (boluses of 1 mg), lock-out of 5 min until 36 hours of the postoperative period. A serial of blood samples were collected from venous catheter of patients at the postoperative period (3,6,12,18,24,36 hrs) and morphine plasma concentrations were determined by Liquid Chromatography-Mass Spectrometry ((LC-MS/MS ESI+)) after the purification of plasma samples. Pain scores were monitored during the same period by a visual analogue scale, VAS or 1-2-3 pain scale. PK-PD modeling was investigated by applying the GraphPad Prism 5.0. Results: Drug dose requirements and analgesia were significant different in patients of groups investigated. EMAX model and the hysteresis curve were proposed by PK-PD modeling to correlate drug requirements and AUC 0-36 or VAS. Conclusions: LC-MS/MS (ESI+) method was adequate for drug measurements in plasma. Morphine dose requirements and analgesia were different by comparison of groups. Lower doses of morphine by PCA were required for the groups that have received intrathecal morphine intraoperatively. It was demonstrated a non linear correlation between parameters by EMAX model when drug requirements and AUC0-36 were plotted, and the hysteresis curve was obtained when analgesia dose requirements was plotted against pain score.

ASSUNTO(S)

morfina acp intensidade da dor pós-operatória modelo pk-pd postoperative pain pk-pd modeling fármaco lc-ms/ms (esi+) Área sob a curva morphine pca lc-ms/ms (esi+) pharmaco area under the curve

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