This thesis describes the day to day interaction between propofol and midazolam as encountered in every day practice. The direct interaction of premedication given to patients before surgery has profound implications. The propofol induction dose can be decreased with respect to the target BIS. Besides the interaction mechanisms of propofol and midazolam, the pharmacological backgrounds of propofol-opioid interactions are given. The future perspectives of PK-PD modeling and the use of additional informative techniques are given in the last chapter.
Chapter 1: This chapter describes the Propofol-Opioid combinations that are widely used in today’s anaesthetic practice. Over the past twenty years the pharmacology of these agents has been described in increasingly greater detail. Together with novel administrating devices and improved anaesthetic depth monitoring, this has created a basis for the optimisation of the administration of propofol-opioid anaesthesia. This article describes the current strategies regarding the application of this type of anaesthesia, focusing on three strategic tools: application of the pharmacokinetic-pharmacodynamic knowledge of propofol and opioids, with particular attention to pharmacodynamic interactions between them; the use of state-of- the-art administration techniques; and the application of bispectral index monitoring. Together, these techniques have improved the level of control, the flexibility and the safety of anaesthetic practice.
Chapter 2: We studied the influence of propofol on the midazolam pharmacokinetics. 8 health male volunteers were studied in a random crossover manner, during which they received either a midazolam bolus infusion in 1 minute followed by an infusion for 59 minutes. During the second session they received the same midazolam infusion and a TCI controlled infusion of propofol. Midazolam plasma levels and whole blood propofol concentrations were measured. In the presence of a mean blood propofol concentration of 1.2 µg/ml, the plasma midazolam concentration increased by 26.9 ± 9.4% compared with midazolam given as single drug. Propofol (Cblood:1.2 µg/ml) reduced midazolam central
volume of distribution from 5.37 to 2.98 L, elimination clearance from 0.39 to 0.31 L/min and rapid distribution clearance from 2.77 to 2.11 L/min. Inclusion of heart rate further improved the pharmacokinetic model of midazolam.
Chapter 3: during our research we encountered three volunteers who were enrolled in our study that were deeply sedated when given the combination of propofol and midazolam. This deep sedation was recorded with online BIS-XP logging and recording of Ramsey scores.
BIS values of 40-60 were recorded, which in daily practice are regarded as surgical depth of anesthesia. Although the volunteers were deeply sedated they were responsive to questions and could answer simple mathematical questions. The effect is partly due to midazolam because of the effect on the EEG. Spindles (low voltage, high frequency EEG) are interpreted as a sign of a high-level anaesthesia, but are merely an effect of midazolam.
Chapter 4: During the reverse study session eight healthy male volunteers were studied on 2 occasions in a random crossover manner. During session A volunteers received propofol 1 mg/kg in 1 min followed by an infusion of 2.5 mg.kg-1.h-1 for 59 min. During session B, in addition to this propofol infusion scheme, a TCI of midazolam (constant Ct: 125 ng/ml) was
given from 15 min before the start until 6 h after termination of the propofol infusion. Arterial blood samples were taken for blood propofol and plasma midazolam concentration analysis until 6 h after termination of the propofol infusion. Nonlinear mixed-effects models examining the influence of midazolam and hemodynamic parameters on propofol pharmacokinetics were constructed using Akaike’s criterion for model selection. In the presence of midazolam (Cblood: 224.8 ± 41.6 ng/ml) the blood propofol concentration increased by 25.1 ± 13.3 %
compared to when propofol was given as single agent. Midazolam (Cblood: 225 ng/ml)
reduced propofol Cl1 from 1.94 to 1.61 L/min, Cl2 from 2.86 to 1.52 L/min and Cl3 from 0.95 to
0.73 L/min. Inclusion of mean arterial pressure (MAP) further improved the propofol pharmacokinetic model.
Chapter 5: we have studied the pharmacokinetic interactions between midazolam and propofol. In this chapter we explore the pharmacodynamic interactions between propofol and midazolam. Our aim was to find the optimal dosing that ensures hemodynamic stability and unconsciousness. The groups that have been studied and the dosing schemes used in the studies are not large enough to reach our goal. We can elude a part of the answers but with respect to a final and definitive answer we will have to study more volunteers with a wider range of dosing schemes. We have found that there is a trend towards synergism between propofol and midazolam for BIS endpoints. During the reconnaissance phase of the PD data and the first calculations a synergistic model was found for propofol and midazolam. The data have been submitted and the reviewers have given us very useful comments. NONMEM interaction with 3D modelling is a useful tool for direct visualization of interaction.
Chapter 6: This review discusses the ways in which anaesthetists can optimize anaesthetic- analgesic drug administration by utilizing pharmacokinetic and pharmacodynamic information. We therefore focus on the dose-response relationship and interactions between intravenous hypnotics and opioids. For intravenous hypnotics and opioids, models that
accurately predict the time course of drug disposition and effect can be applied. Various commercially or experimentally drug effect measurement techniques have been developed and can be implemented to further fine-tune patient individualized drug titration. The development of advisory and closed-loop feedback systems which combine and integrate all sources of pharmacological and effect monitoring, has taken the existing kinetic-based administration technology forwards towards a total coverage of the dose-response relationship.
Future perspectives for intravenous based anesthesia are good. When all developments are considered, there is a thorough basis from which the patient will benefit directly.
The conclusions that can be drawn from this thesis are
Education and study on PK-PD interactions between opioids and Propofol is beneficial for patients, with shorter duration of anesthesia while minimizing side effects.
Pharmacokinetic propofol midazolam interactions prove to be of clinical importance for everyday practice, with regards to induction and maintenance dose.
Pharmacodynamic interactions between propofol and midazolam appear to be synergistic.
Interaction display and effect monitoring during surgery for education and training will be an interactive and useful tool in the operating room.
Future perspectives:
Completion of the pharmacodynamic interaction between propofol and midazolam depends on the implementation of a step up and down model wise approach to the study. At this moment the interaction appears to be synergistic a supplemental study must be considered to draw final conclusions. This thesis has proven that the interaction is worth studying and with a renewed approach will give a more subtle and complete view of this interaction. Introducing the results of the study in display monitoring for surgery with the possibility of introducing premedication, and will be helpful in the OR.