Rational Drug Selection in Neuroanaesthesia:
the Effect Site and Context Sensitive Decrement Times
Chris Thompson, Royal Prince Alfred Hospital, Sydney, Australia Nov 2000.V2
These web pages are loosely based on a paper that I presented at the inaugural ANZCA Neurosurgical Anaesthesia Special Interest Group Meeting, held on Lindeman Island, Queensland, Australia in October 1998.
My goals were to review the effect site concept, show some graphical simulations of onset, offset and drug interactions for several common anaesthetic agents and narcotics, and to show how these can help use choose the most appropriate anaesthetic agent (or combination of agents) for a given situation. I hoped to provide a detailed understanding of the context sensitive decrement time concept, and to provide standardised graphs comparing the offset of a wide range of anaesthetic agents (intravenous and inhaled) and narcotics.
Converting my slides to web pages has not been particularly satisfactory, since they were not originally designed to 'stand alone'. You can just read my original abstract, or just read on, clicking on slides of interest as required. The Frames Version is much better, provided that you have a big (XGA) screen, since the text is on the left and the slide on the right.
Slide show contents:
I start with some introductory text slides, including the title slide, a list of the topics covered by this presentation, an example of some 'traditional' pharmacokinetic parameters and the clinical situations in which they are most useful and some representative values for fentanyl and alfentanil.
Some graphs and diagrams illustrating the 'new' (effect site oriented) pharmacology follow, indicating changes in effect-site concentration after a bolus dose of remifentanil or alfentanil (which are fairly similar), dose - effect relationships, the 'effect site' concept, the need to integrate effect site concentrations with a dose-response curve to calculate onset and offset of effect (as opposed to simply measuring drug concentrations); finally a text slide listing the 'new' pharmacologic concepts of effect site kinetics, context sensitive elminination times, etc.
Application of effect site data to onset times follows. I have three slides from Ebling's marvellous 1990 paper, graphically illustrating bolus Alfentanyl and Fentanyl kinetics. These 3-D diagrams compare 5 minute, 25minute and 90 minute blood and effect site concentrations, as well as the onset and offset of effect, after boluses of alfentanil and fentanyl. It is easy to see how 'traditional' pharmacology (blood levels) has difficulty explaining the slower onset and offset of Fentanyl, whereas a combination of effect site kinetics and dose-effect response curves shows their 'real-world' kinetics extremely accurately. Unfortunately other opioids like morhpine, diamorphine and pethidine (demerol) have not yet been modelled in the same way!
The Context Sensitive Decrement Time concept is explained next. This diagram shows how measurement of decrement times is different after bolus or infusion, and how the 50% and 80% decrement times are calculated, while the next graph shows the more common form of a context sensitive decrement time diagram, illustrating 50% and 80% decrement times after alfentanyl and remifentanil indusions of different duration.
The next 8 grpahs are context sensitive decrement time digrams for a range of agents. The axes (0 - 10 hour infusion durations on the x axis, 0 - 5 hour decrement times on the y axis) and colours of the decrement time lines are nearly identical. Data on the intravenous agents is from Charles Minto (personal communication). I generated offset data for the volatile agents by using Jim Philips GasMan program. They are, in order of longer offset: remifentanil, nitrous oxide, sevoflurane, isoflurane, propofol, alfentanil, methohexitone, thiopentone and fentanyl. I also have combinations comparing alfentanil, fentanyl and remifentanil and comparing sevoflurane, isoflurane, propofol and thiopentone.
The last part of this paper looks at optimising emergence times by combining optimal doses of a narcotic with an anaesthetic, and is based on the 1997 paper by Vuyk in Anaesthesiology. It is now well known that co-administration of narcotics reduces anaesthetic requirements, and vice versa. Vuyk's work integrates context sensitive decrement time data for two agents given simultaneously and relates this to the combined effect using an interaction model. A three-dimensional graph can be created from each combination of druges and for different durations of anaesthesia. The parabolic black line indicates the point of emergence from anaesthesia. I have provided graphs for propofol / fentanyl, propofol / alfentanil and propofol / remifentanil. The lowest point of the parabolic black line indicates the optimal dosage ratio for the agents and Vuyk describes an infusion rate scheme which optimises emergence. The infusion rates are sufficient for control of surgical incision; it is likely that with nitrous oxide, and during maintenance phase of neurosurgery, they can be reduced considerably.
For short procedures emergence after appropriate doses is rapid no matter what you do. However, for long anaesthetics, optimising the ratio of narcotic to propofol can have profound effects on wake up time. Interestingly, even though alfentanil has slower offset than propofol, using the two together results in more rapid emergence than depending on either alone. With remifentanil emergence is more rapid than with the other narcotics, regardless of infusion duration. In fact when remifentanil is used, emergence is essentially entirely due to the offset of propofol, even if the dose of remifentanil is inappropriately high. Conversely, when fentanyl is used with propofol, the offset of fentanil can easily become the limiting factor, particularly if given in excessive doses.
Finally I have some summary slides, emphasising that remifentanil is radically different in offset from any other narcotic, key features of alfentanil, some tips on optimising anaesthetic agent offset and finally a reminder that optimal dosage is associated with optimal recovery and the main references.
This last point cannot be emphasised strongly enough. Not only is it important to choose an appropriate agent and to add an appropriate amount of a suitable narcotic, but one must avoid inadvertent overdose or underdose in sensitive or resistant individuals. Even if the right drugs are given in the right combinations, delayed emergence can be guaranteed if too much is given! Since there is at least a fourfold clinical variation in repsonse to a given infusion rate, even more so after long infusions, and since we all have a strong desire to ensure amnesia during surgery for all our patients, our natural tendency is to overdose most patients to prevent small numbers of patients from experiencing intraoperative awareness.
If we can ensure that our infusions are given in the correct dose for that individual patient, then we will have the best of both worlds, ie rapid emergence and absence of awareness.
Individualising drug administration is the key to sloving this problem, however the use of surrogate indicators of the 'depth of anaeshesia', such as heart rate or blood pressure, are being increasingly recognised as inappropriate and misleading.
Nothing can substitute for good clinical judgement and experience, however the EEG, and probably the BIS or equivalent devices, are highly likely to provide important additional information about 'what is going on inside the head' which cannot be obtained by any other means. I am confident that individualising anaesthetic dose to EEG effect will be extremely helpful in terms of providing predictable and reliable emergence after prolonged intravenous anaesthesia and will soon become a mainstream neurosurgical monitoring modality.
I welcome feedback about this document (e-mail to Chris Thompson), so don't hesitate to contact me if you think it can be improved in some way.
References:
Bailey JM. Context-sensitive half-times and other decrement times of inhaled anesthetics. Anesth Analg 1997;85:691-6
Kapila A, Glass PS, Jacobs JR, et. al. Measured context-sensitive half-times of remifentanil and alfentanil. Anes 1995; 83(5): 968-975
Hughes MA, Glass PS, Jacobs JR. Context sensitive half-time in multicompartment pharmacokinetic modesl for intravenous anesthetic drugs. Anes 1992;76:334-341
Minto CF, Power I. New opiod analgesics: an update. Intl Anes Clin 1997;35(2):49-65
Egan TD. Minto CF. Hermann DJ. Barr J. Muir KT. Shafer SL. Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology. 84(4):821-33, 1996 April.
Ebling WF, Lee EN, Stanski DR. Understanding pharmacokinetics and pharmacodynamics through computer simulation: I. The comparative clinical profiles of fentanyl and alfentanil. Anesthesiology. 72(4):650-8, 1990 April
Vuyk J, Lim T, Engbers FHM, et. al. The pharmacodynamic interaction of propofol and alfentail during lower abdominal surgery in women. Anes 1995;83:8-22
Vuyk J, Engbers FHM, Burm AGL, et. al. Performance of computer-controlled infusion of propofol: An evaluation of five pharmacokinetic parameter sets Anesth Analg 1995;81:1275-1282
Vuyk J. Mertens MJ. Olofsen E. Burm AG. Bovill JG. Propofol anesthesia and rational opioid selection: determination of optimal EC50-EC95 propofol-opioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology. 87(6):1549-62, 1997 Dec.
Vuyk J. Pharmacokinetic and pharmacodynamic interactions between opioids and propofol. J Clin Anes 1997;9:23S-26S
