Report of the 11th Annual Meeting of ISAP (International Society of Anaesthetic Pharmacology???formerly SIVA)

The International Society of Anaesthetic Pharmacology (ISAP) held its 11th Annual Meeting on October 11, 2002, in Orlando, FL. The main theme this year was “Perioperative pharmacology in the age of genomics, computers, and designer drugs.” This meeting focused on improving the ways we deliver drugs and hence on improving clinical outcomes. Among the changes to the meeting were two innovations: the introduction of two plenary papers and the presentation of a number of selected posters chosen as candidates for the Elmer Zsigmond Prize (Dr. Zsigmond is a founding member of Society for Intravenous Anesthesia, and its predecessor, Society for Neurolept Anesthesia). The posters were subject to review and comment by a moderator and discussion by the audience. President John Sear opened the meeting. In welcoming the participants, Dr. Sear remarked that the anesthesiologist has a major input into perioperative pharmacology, yet we cannot always predict the results of our endeavors. This may relate to the method of drug administration, to genetic or phenotypic influences on a drug’s pharmacokinetics or pharmacodynamics. Further, we may not be able to accurately measure variables that define a given end point within the spectrum of anesthesia and analgesia. The first session, moderated by the president-elect (Professor Tony Gin, Hong Kong), considered what is new in pharmacokinetics and pharmacodynamics. All anesthesiologists give IV fluids to either maintain or correct deficits in the intravascular fluid volume. But what influences our choice of fluids, and how can we avoid the consequences of inappropriate therapy? In his presentation on “Application of kinetic principles to IV fluid therapy,” Don Prough (Galveston, TX) described the principles of fluid administration in terms of two models: the static physiological model and the mathematical or kinetic model. One of the problems in modeling fluid kinetics is knowing what to measure. For IV fluids, we cannot measure plasma drug concentrations and infer volumes of distribution and clearance, but rather we need to look at the influence of fluids on the concentrations of other marker substances. A suitable marker to measure the kinetics of infused fluids and their effects on extracellular total body water or intravascular volumes should have a short period of equilibration. Unfortunately, frequently used tracers such as indocyanine green or radiolabeled albumin do not meet these requirements. Svensson and Hahn from Stockholm have studied the utility of three endogenous markers: blood water concentration, serum albumin, and hemoglobin. The latter is ideal for the purposes of kinetic analysis because it is only distributed throughout the intravascular volume and provides reliable estimates of distribution and elimination rate constants. However, clearance and distribution occurs not only through the usual first order kinetic principles, but are also controlled by factors such as the neuroendocrine influences of antidiuretic hormone, atrial natriuretic peptide, and aldosterone (to name but a few). Dr. Prough then described studies examining the effects of anesthesia (both regional and general), catecholamines, and acute and chronic hemorrhage on these fluid volumes. Data from these studies suggest that all of these produce important changes in distribution volumes and clearances of IV fluids, whereas, interestingly, sepsis and hypoproteinemia seem to cause only minimal effects on peak plasma volume expansion. However, Dr. Prough suggested that these studies should be viewed with some caution because the tracer methodology they used requires approximately 40 min of sampling, and this may lead to inaccuracies if the fluid load is rapidly redistributing. Isolated hypoproteinemia (to <50% baseline protein concentration) also failed to influence plasma volume kinetics in response to fluid infusion. At the present time, the exact mechanism seems unclear. The second speaker in the opening session (Thomas Schnider, St Gallen, Switzerland) described the uses of kinetic-dynamic simulation software as training tools for educating anesthesiologists about drug handling and effects. One advantage of simulation is that it can go further with data from a specific group of individuals, allowing the user to assess and better understand the effects of changes in kinetic variables, such as clearance and volumes of distribution on overall drug handling. In turn, this allows a better understanding of those factors that may alter the efficacy and duration of drug effect. Available simulation software falls into four main groups: software designed specifically for target-controlled infusions (e.g., STANPUMP, STELPUMP, and RUGLOOP); pharmacokinetic data fitting programs (e.g., NONMEM and WIN-NONLIN); teaching programs for IV anesthesia techniques (e.g., TIVA Trainer and IVA SIM); and commercial software packages for inputting data into spreadsheets. Each has its specific advantages and uses, but for all of them, it is important that the user understands the limitations not only of the software packages, but also of the underlying kinetic and dynamic models. The final speaker in the first session was Michel Struys (Gent, Belgium) who discussed auditory evoked potentials (AEP) as a measure of anesthetic depth. We are still looking for a reliable and sensitive monitor of anesthetic depth. This should provide information that would allow the clinician to titrate drugs more accurately according to the patient’s requirement. It should also predict when anesthesia in the paralyzed patient might be inadequate (either too light or too deep). Three types of evoked potentials can be measured: somatosensory, visual, and AEP. AEP have become established as a valid tool for examining the effects of hypnotics on brain activity. Medium latency AEP (MLAEP), looking at potentials lying between 10 and 100 ms after an auditory stimulus, correlate well with drug-induced hypnotic effects and with their associated plasma, blood, or predicted effect site concentrations. However, there is little correlation between the MLAEP and changing concentrations of opioids. Two useful numerical variables within the MLAEP are the amplitude and latency of the Pb and Na waves, both of which show dose (and in turn concentration) dependence. One of the problems with the conventional measurement of MLAEP is the need for visual inspection of the output signal, which can introduce large inter-individual observer errors in the measurement of these two variables. This has now been overcome by the development of a quantitative approach using waveform analysis and the derivation of appropriate indices. Calculation of an index normally requires a high quality signal and a long sampling period with a large number of sweeps (often 512 or 1024) to obtain an acceptable signal-to-noise ratio. This approach is not ideally suited for the monitoring of depth of anesthesia where a rapid response to a changing surgical stimulus is required. The classical method used to obtain a high signal-to-noise ratio is the “moving time average” technique, but this may be associated with an output delay of up to 40 s. However, Jensen et al. (Med Eng Phys 1998;20:722–8) have described an autoregressive model with an exogenous input adaptive method (ARX), which allows an AEP signal to be generated with a response delay of only 6 s. A new variable, the A-line ARX Index (AAI) is calculated from this fast-extracted MLAEP wave. This forms the basis of a new commercial monitor developed by Alaris (the Alaris AEP monitor; formerly the A-line monitor). In a comparison of the AAI, bispectral index (BIS), and hemodynamic variables and the predicted effect site concentration of propofol (Cep), Dr. Struys observed that AAI, BIS, and predicted Cep were all significant indicators of the level of sedation and loss or recovery of consciousness. In contrast, hemodynamic changes correlated poorly with the hypnotic/anesthetic state of the patient. During recovery, the AAI returned to baseline sooner than the BIS and can therefore be considered a better monitor for predicting recovery of consciousness. The second session, moderated by Adrian Gelb (London, Ontario, Canada), was devoted to “Genomics and perioperative pharmacology.” The first speaker, Pamela Flood (Columbia University, NY), began by explaining the various strategies that geneticists can use to examine the relationship between a gene and its resulting phenotype. There are two main approaches: knockout studies, where a gene is deleted and the resulting phenotype studied for its functional abilities (forward genetics), and reverse genetics, where the investigator either finds or induces a phenotype and then determines the genetic differences between that organism and the wild-type species. Other approaches within the general ambit of the forward genetics model are the addition of genetic material (to produce transgenic animals), knock-in animals, where a functional but abnormal gene is exchanged with the wild-type gene by homologous recombination, site-specific knockouts, and knockdown experiments. These technologies have found applications in four areas of perioperative anesthesiology: (a) in studying the site of benzodiazepine action, (b) examining the effects of anesthetics on γ-aminobutyric acid-A receptors, (c) where mice lacking the β3 gene are found to be less sensitive to the immobilizing effects of enflurane and halothane, but their loss of righting reflex to these drugs is unaltered, and (d) the effects of anesthetics on nicotinic and glutamate receptors. The application of genetics in anesthesiology was extended further in the first of our plenary lectures by Debra Schwinn (Duke University, NC). She gave a masterful presentation entitled “How will genomics research change perioperative pharmacology?” We are well aware that the response to drugs varies between individuals either because of variation in kinetics, in receptor proteins, or in the postreceptor signaling that leads to a response. Studies of these differences can be focused either on examining the genetics associated with a given phenotypic response or looking at different genes and relating variations in the genetic material with different phenotypes. The former approach uses classical Mendelian genetics, genome-wide scanning for alterations, positional cloning studies, and sib-pair (family) studies. The latter looks for candidate genes and then relates these to given phenotypes using association studies. This is the approach that will most likely be used in large perioperative clinical trials. Variations may range from single nucleotide polymorphisms to polymorphisms caused by single-base insertions or deletions. Using the β2-adrenoceptor as an example, different polymorphisms may result in increased receptor expression, enhanced downregulation (predisposing to increased hypertension), or poor coupling of the drug-receptor complex to the second messenger (predisposing to congestive cardiac failure or asthma). If we are to understand more thoroughly the genetic basis of disease, then there is a clear need for association studies involving large numbers of patients with high accuracy genotyping. These should be complemented by family studies and combined with outcome studies. Based on these types of data, it is not hard to imagine that in the near future use will be made of a preoperative gene chip designed to highlight the most notable genetic variants thought to be important in bleeding, inflammatory, and neurologic responses to perioperative stress. This should allow the perioperative physician to have far more robust information for designing the most appropriate and safest anesthetic plan for a given patient, with the development of designer anesthesia. The second plenary lecture was delivered by Ron Miller (University of California, San Francisco, and Editor-in-Chief of Anesthesia & Analgesia) who considered the relationship between pharmacology research in anesthesiology departments and the growth of the specialty over the past four decades and how this may develop in the future. From the 1960s, Dr. Miller took a number of key advances in anesthesia from within his own department (concept of minimum alveolar anesthetic concentration and pharmacokinetics, measurement of blood gases, effect of vasopressors on uterine blood flow, and pharmacology of drugs on the respiratory system) and put forward the argument that these now form the basis of much of our clinical teaching today. In the present decade, there are few departments in the United States (US) undertaking basic research, and much of this is not clinically orientated. The number of residents proceeding to research fellowships is small, and most National Institute of Health (NIH) grants in anesthesiology are frequently going to nonphysicians. Why is this? In the last 10 or so years, there has been increasing clinical pressures on the clinician with the need to provide services and preserve what we have gained in the operating room (OR), as well as undertaking clinical work to preserve the income of academic departments. As a consequence, research has taken a back seat. Overall, in the US, anesthesiology receives <1% of total NIH funding. Of the 132 academic departments in the US, 45 at present have no NIH funding. Ten departments receive 50% of the funding, with four being major recipients. As a result, scientific publications in anesthesia from the US are decreasing. Dr. Miller emphasized that these few, and fortunate, academic departments must accept a responsibility for the specialty’s future. As a challenge to all anesthesiologists, Dr. Miller suggested that unless the profession sorts out these problems, there is the real possibility that all surgical anesthesias by the year 2030 could be administered by computers with no need for professional supervision! How can we address these problems? The profession needs to start involving clinicians again in research endeavors, advertise our research progress, and encourage the profession and the American Society of Anesthesiologists of the importance of funding research. We also need to have the vision to go into exciting new areas of translational research involving genetics, molecular engineering, neuroscience, and immunology. We need to avoid our total preoccupation with the OR. The development of advanced surgical procedures must go hand-in-hand with the training of super-anesthesiologists who can advance our contribution to the understanding of improved patient care. The over-lunch poster session showed increased popularity, with 22 presentations covering a wide range of pharmacological issues. Four of these were chosen for comment by Dr. Miller and discussion by the audience. The Elmer Zsigmond award for the best poster presentation went to Pierre Fiset (Montreal, Canada) for his poster “Compartmental modeling of an irreversible PET tracer: Quantification of the binding of muscarinic cholinergic receptors during unconsciousness produced by propofol in healthy human volunteers.” Three other posters were awarded certificates of commendation: “Intrathecal ondansetron modulates isoflurane anesthesia and analgesia” (Jason Scott, Columbia University, NY); “Volatile anesthetics bind to synaptic SNARE proteins and the SNARE complex” (Peter Nagele, Washington University, St Louis, MO); and “Role of P-glycoprotein in intestinal absorption and clinical effects of morphine, fentanyl and methadone” (Evan Kharasch, University of Washington, Seattle, WA). The final session, moderated by Pierre Fiset, was devoted to “New areas of perioperative pharmacology.” The first speaker, Evan Kharasch, discussed the role of COX-2 inhibitors in the provision of perioperative analgesia. The COX-1 form of cyclo-oxygenase is constitutive and produces prostaglandins that are responsible for homeostatic functions in the body (e.g., control of gastric and bowel blood flow, mucosal integrity, renal blood flow and the glomerular filtration rate, and platelet aggregation). However, the COX-2 isozyme is inducible and plays a key role in inflammatory cytokine production and pain signal transmission. Recent data from animal studies show that COX-2, but not COX-1, is upregulated in the dorsal spinal column and thalamus in response to nerve injury. The mechanism of this upregulation is not fully defined but is probably caused by the release of inflammatory cytokines such as IL-1β. Selective COX-2 inhibitors have been developed through synthesis of molecules designed to fit the active site of the COX-2 enzyme but not that of the COX-1 enzyme. Drugs presently available are the oral drugs celecoxib and rofecoxib and the more selective valdecoxib (recently approved in the US). In Europe, there is also a parenteral COX-2 inhibitor, parecoxib, a pro-drug that is rapidly hydrolyzed in vivo to valdecoxib. Efficacy studies support use of these drugs after a variety of types of surgery; there is still concern over their side effect profiles, although the most unambiguous data relate to their hematologic effects. Long-term comparisons of COX-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs also show the former to be associated with a decreased incidence of gastric ulceration, but there are less clear differences between the classes in their ability to cause salt and water retention. COX-2 inhibitors should not be used in patients with preexisting renal insufficiency. The final lecture was given by Jerrold Levy (Emory University School of Medicine, Atlanta, GA) on the new anticoagulants. He focused his talk on novel antithrombins and the risk they pose for bleeding in surgical patients. The new drugs can be broadly classified into direct thrombin inhibitors (such as r-hirudin, bivalirudin, and argatroban), AT-III dependent inhibitors such as unfractionated heparin, low molecular weight heparins (LMWH), and warfarin. However, none of these drugs is free of problems. These include difficulties in monitoring the degree of anticoagulation, the lack of an antidote to hirudin and LMWH, and potential antigenicity. Because of the complex interactions among hemostatic factors and platelets in producing thrombus, future therapies may be directed at combinations of novel short-acting thrombin inhibitors with other potential AT-III also seems to be a to further ability to with transgenic the potential to produce However, with all these we will need better of to the of and allow appropriate of Each of the presentations at this meeting the of advances and research into a better understanding of the pharmacology of the perioperative looks forward to further new approaches at future We look forward to welcoming during our meeting year in San Francisco, on the the American Society of

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