Clinical pharmacology on display.

In this issue of Anesthesia & Analgesia are 3 articles that most subscribers will never read. Not even the abstract will garner their interest. Nevertheless, these articles and related work help form the foundation underlying 2 recently introduced commercial displays, Navigator Applications Suite (GE Healthcare, Helsinki, Finland) and SmartPilot View (Dräger Medical, Lübeck, Germany), intended for everyday use in the operating room. These sophisticated displays show the concentrations and predicted effects of combined anesthetic drugs to facilitate more precise titration and outcome. The accuracy of these displays depends on the accuracy of the models they use. This editorial, and the following two, attempt to explain how complex research in pharmacokinetic/ pharmacodynamic (PK/PD) modeling is being translated to everyday clinical practice. We need to titrate anesthetic drugs because of the individual variability in response, and the rapidly changing level of stimulation in the operating room. We adjust our dose according to the effect that we want to achieve. However, because of our incomplete understanding of the complex anesthetic state and consequent technical limitations, we often have very little direct feedback to precisely guide this titration. It would be helpful if we could “see” the effect of our drugs in real time, as well as forward projections of the current trajectory. For example, cardiovascular drugs are typically easy to titrate because we have monitors that display heart rate and arterial blood pressure in real time. Can we develop a real-time display showing the effects of all our anesthetic drugs? For many years, we have measured the effect of neuromuscular blocking drugs using peripheral nerve stimulators. Although mechanomyography was a research tool, electromyography was available for routine clinical practice more than 20 years ago using the Relaxograph (Datex, Helsinki, Finland). The graphical trend of twitch height depression and train-of-four ratio allowed one to appreciate the time course of drug effect (Fig. 1). There has been a resurgence of interest in neuromuscular monitoring, with integration into anesthesia workstations permitting centralized displays of neuromuscular block. With this ready display of drug effect, anesthesiologists have not generally been interested in knowing the actual plasma concentration of neuromuscular blocking drugs. For the volatile anesthetics, the picture is more complex because they cause more than one desirable effect. Is the drug being titrated to cause hypnosis, suppress somatic responses, or suppress autonomic responses? The effect of volatile anesthetics on the suppression of somatic response has long been characterized by the minimum alveolar concentration (MAC). This value (sometimes uncorrected) is displayed on many anesthetic monitors, permitting anesthesiologists to adjust inhaled anesthetic delivery to obtain a desired fraction or multiple of MAC. MAC is an effective dose (ED)50 on the quantal response/no response curve, meaning that it is the concentration at which 50% of subjects do not move. Who wants to give a concentration at which half the patients move? Who knows at what concentration or multiple of MAC nearly all patients (say 95%) would not move? Instead of displaying the volatile concentration as a fraction or multiple of MAC, it is possible to display the volatile concentration as its effect on the quantile dose-response curve. For example, 2.07% sevoflurane is 1.21 MAC, but this is also the ED95 for no movement (Fig. 2). Similarly, if our effect of interest was hypnosis, the concentration could be displayed as an EDx where x% of the population would be expected to not respond to verbal command. This may be more useful than a fraction of MAC (or multiple of MAC-awake). In contrast to the neuromuscular blocking drugs, some knowledge of the volatile agent concentration seems important, but at least we can readily measure it. The population values of MAC and MAC-awake were derived from patients that may be very different from any particular patient. Is it possible to have a measure of anesthetic drug effect in the patient currently undergoing anesthesia, similar to that for neuromuscular block? Individual monitoring of motor spinal reflexes is possible, but rarely used. There is much more interest in monitoring hypnosis using derived measures of the electroencephalogram (EEG) such as the Bispectral Index (BIS) and entropy. Although the raw EEG reflects the current state of the patient, the derived indices are also based on models from previous studies. The BIS is supposed to reflect the hypnotic component of anesthesia and help guide drug dosage From the Department of Anaesthesia and Intensive Care, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.