Prediction of lidocaine tissue concentrations following different dose regimes during cardiac arrest using a physiologically based pharmacokinetic model

• Published in: Resuscitation 2001-09, Vol.50 (3), p.331-340
• Main Authors: Grillo, Joseph A, Venitz, Jürgen, Ornato, Joseph P
• Format: Article
• Language: English
• Subjects: Algorithms; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthetics, Local - pharmacokinetics; Biological and medical sciences; Cardiopulmonary resuscitation; Emergency and intensive cardiocirculatory care. Cardiogenic shock. Coronary intensive care; Farmacocinética; Heart arrest; Heart Arrest - metabolism; Humans; Intensive care medicine; Lidocaine; Lidocaine - pharmacokinetics; Lidocaı́na; Medical sciences; Models, Cardiovascular; Paragem cardı́aca; Pharmacokinetics; Predictive Value of Tests; Reanimação; Reproducibility of Results; Resuscitation; Sensitivity and Specificity; Tissue Distribution
• ISSN: 0300-9572; 1873-1570
• DOI: 10.1016/S0300-9572(01)00355-0

Background: The purpose of our study was to develop a physiologically based pharmacokinetic (PBPK) model describing the behavior of lidocaine in humans by scaling up physiological variables from animal models of cardiac arrest. We attempted to identify the optimal dose regime for lidocaine during cardiac arrest using this model. Methods and results: We designed a flow-dependent PBPK model representing nine body tissues for lidocaine. Physiological organ flow rates, tissue volumes, and plasma-tissue partition parameters for lidocaine in humans were taken from the literature. Data from published animal studies were used to estimate loss of organ blood flow during cardiac arrest and lidocaine tissue partition coefficients. The model assumed a 70 kg cardiac arrest patient. The following five lidocaine dose regimes were simulated: (1) 4 mg/kg IV push (IVP) (2) 1.5 mg/kg IVP then 1.5 mg/kg IVP in 4 min, (3) 3 mg/kg IVP, (4) 2 mg/kg IVP, and (5) 1.5 mg/kg IVP. A simulation of Regimen 2, which is the current American Heart Association (AHA) recommendation, suggests that the concentration of lidocaine is suboptimal at the decision point (3–5 min) to administer another dose. Regimen 4 offers a slightly more rapid progress towards optimal cardiac concentrations and more acceptable brain concentrations compared to regimes 1–3. Conclusion: Simulations from our PBPK model suggest that the current AHA lidocaine dose regime for cardiac arrest may not result in optimal lidocaine concentrations in the heart and brain. Simulations suggest that 2 mg/kg IVP may be the most acceptable lidocaine dose regime during cardiac arrest. Introdução: O objectivo deste estudo foi desenvolver um modelo farmacocinético baseado na fisiologia (PBPK) descrevendo o comportamento da lidocaı́na em humanos a partir de um modelo animal de paragem cardio respiratória (PCR) Procuramos identificar, com este modelo, o melhor regime de administração de lidocaı́na durante a paragem cardı́aca. Método e Resultados: Desenhamos um modelo PBPK para a lidocaı́na, dependente do fluxo, representando 9 tecidos corporais. Os parâmetros de perfusão fisiológica dos órgãos, volumes tecidulares, e coeficientes de partição plasma-tecido para a lidocaı́na em humanos foram retirados da literatura. Foram também utilizados resultados de estudos animais para determinar a perda de volume sanguı́neo durante a PCR e os coeficientes de partição tecidular da lidocaı́na. O modelo assumiu um doente de 70 Kg em PCR. Foram simulados