Misha Perouansky

Myocardial infarction after vascular surgery: the role of prolonged stress-induced, ST depression-type ischemia.

OBJECTIVES The goal of this study was to investigate the nature of the association between silent ischemia and postoperative myocardial infarction (PMI). BACKGROUND Silent ischemia predicts cardiac morbidity and mortality in both ambulatory and postoperative patients. Whether silent stress-induced ischemia is merely a marker of extensive coronary artery disease or has a closer association with infarction has not been determined. METHODS In 185 consecutive patients undergoing vascular surgery, we correlated ischemia duration, as detected on a continuous 12-lead ST-trend monitoring during the period 48 h to 72 h after surgery, with cardiac troponin-I (cTn-I) measured in the first three postoperative days and with postoperative cardiac outcome. Postoperative myocardial infarction was defined as cTn-I >3.1 ng/ml accompanied by either typical symptoms or new ischemic electrocardiogram (ECG) findings. RESULTS During 11,132 patient-hours of monitoring, 38 patients (20.5%) had 66 transient ischemic events, all but one denoted by ST-segment depression. Twelve patients (6.5%) sustained PMI; one of those patients died. All infarctions were non-Q-wave and were detected by a rise in cTn-I during or immediately after prolonged, ST depression-type ischemia. The average duration ofischemia in patients with PMI was 226+/-164 min (range: 29 to 625), compared with 38+/-26 min (p = 0.0000) in 26 patients with ischemia but not infarction. Peak cTn-I strongly correlated with the longest, as well as cumulative, ischemia duration (r = 0.83 and r = 0.78, respectively). Ischemic ECG changes were completely reversible in all but one patient who had persistent new T wave inversion. All ischemic events culminating in PMI were preceded by an increase in heart rate (delta heart rate = 32+/-15 beats/min), and most (67%) of them began at the end of surgery and emergence from anesthesia. CONCLUSIONS Prolonged, ST depression-type ischemia progresses to MI and is strongly associated with the majority of cardiac complications after vascular surgery.

Effects of halothane on glutamate receptor-mediated excitatory postsynaptic currents. A patch-clamp study in adult mouse hippocampal slices.

Background The effects of halothane on excitatory synaptic transmission in the central nervous system of mammals have been studied in vivo and in vitro in several investigations with partially contradicting results. Direct measurements of the effects of halothane on isolated glutamate receptor-mediated (glutamatergic) excitatory postsynaptic currents (EPSCs), however, have not been reported to date.

Presynaptic and postsynaptic actions of halothane at glutamatergic synapses in the mouse hippocampus

Whole‐cell patch‐clamp recordings in adult mouse hippocampal slices were used to test the mechanism by which the volatile anesthetic halothane inhibits glutamate receptor‐mediated synaptic transmission. Non‐N‐methyl‐D‐aspartate (nonNMDA) and NMDA receptor‐mediated currents in CA1 pyramidal cells were pharmacologically isolated by bath application of D,L‐2‐amino‐5‐phosphonovaleric acid (APV; 100 μM) or 6‐cyano‐7‐nitro‐quinoxaline‐2,3‐dione (CNQX; 5 μM), respectively. Halothane blocked both nonNMDA and NMDA receptor‐mediated excitatory postsynaptic currents (EPSCs) to a similar extent (IC50 values of 0.66 and 0.57 mM, respectively). Partial blockade of the EPSCs by lowering the extracellular concentration of calcium ([Ca2+]o), but not by application of CNQX (1 μM), was accompanied by an increase in paired‐pulse facilitation (PPF). Halothane‐induced blockade of the EPSCs also was associated with an increase in PPF. The effects of halothane on α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) and NMDA receptor‐mediated currents induced by agonist iontophoresis, were compared. AMPA‐induced currents were blocked with an IC50 of 1.7 mM. NMDA‐induced currents were significantly less sensitive to halothane (IC50 of 5.9 mM). The effect of halothane on iontophoretic AMPA dose‐response curves was tested. Halothane suppressed the maximal response to AMPA without affecting its EC50, suggesting a noncompetitive mechanism of inhibition. All effects of halothane were reversible upon termination of the exposure to the drug. These data suggest that halothane blocks central glutamatergic synaptic transmission by presynaptically inhibiting glutamate release and postsynaptically blocking the AMPA subtype of glutamate receptors.

Neurotoxicity of general anesthetics: cause for concern?

General anesthetics are highly lipid soluble and can dissolve in every membrane, penetrate into organelles and interact with numerous cellular constituents. Their actions have long been considered rapid and fully reversible, with the pharmacodynamic time course of anesthesia dictated solely by the pharmacokinetic profiles of anesthetic uptake and elimination. But recent laboratory data call for a cautious reassessment of this assumption. In the last decade, it has become apparent that anesthetics can affect gene expression, protein synthesis and processing, and cellular function in poorly understood ways that provide plausible biochemical substrates for durable long-term effects in a number of tissues. While in most patients physiological homeostasis is restored soon following general anesthesia, anesthetics have potentially profound and long-lasting effects that, in animal models, appear particularly consequential in specific developmental periods and pathophysiological contexts. Could a class of drugs employed for many decades without evidence of long-term damage have insidious and heretofore unrecognized neurotoxic effects? Here we critically evaluate available scientific evidence for general anesthetic ‘neurotoxicity’ and the potential clinical implications. Since the scope of this clinical commentary is limited, numerous deserving laboratory investigations could not be mentioned in this focused overview. Our goal as physician-scientists not directly involved in this area of research is to summarize the diverse directions of research in this field, while highlighting the limitations of existing data with respect to clinical practice in order to provide the reader with a rational platform for discussions with colleagues and patients. The barriers that must be overcome to permit clinical translation of the available laboratory research are emphasized, along with the need for further research, as recently highlighted in a consensus statement by a group including authoritative researchers in this field.1 As with any emerging field of research, new evidence continues to accrue such that conclusions are by necessity preliminary and will require frequent reappraisal.

Halothane Blocks Synaptic Excitation of Inhibitory Interneurons

Background Activation of principal hippocampal neurons is controlled by feedforward and feedback inhibition mediated by gamma-aminobutyric acidergic interneurons. The effects of halothane on glutamate receptor-mediated synaptic excitation of inhibitory interneurons have not been reported yet. Methods The effects of halothane on glutamatergic excitatory postsynaptic currents and on spike threshold in visually identified interneurons were studied with tight-seal, whole-cell voltage- and current-clamp recordings in thin slices from adult mouse hippocampus. The excitatory postsynaptic currents were pharmacologically isolated into their N-methyl-D-aspartate and non-N-methyl-D-aspartate receptor-mediated components using selective antagonists. Results Halothane (0.37-2.78 mM) reversibly blocked non-N-methyl-D-aspartate and N-methyl-D-aspartate excitatory postsynaptic currents in hippocampal oriens-alveus interneurons. Half-maximal inhibition was observed at similar concentrations (0.59 mM and 0.50 mM, respectively). Halothane inhibited synaptically generated action potentials at concentrations that did not elevate the spike threshold. Conclusions Halothane blocks glutamate receptor-mediated synaptic activation of inhibitory interneurons in the mouse hippocampus.

Slowing of the hippocampal θ-rhythm correlates with anesthetic-induced amnesia

Background:Temporary, antegrade amnesia is one of the core desirable endpoints of general anesthesia. Multiple lines of evidence support a role for the hippocampal &thgr; rhythm, a synchronized rhythmic oscillation of field potentials at 4–12 Hz, in memory formation. Previous studies have revealed a disruption of the &thgr; rhythm at surgical levels of anesthesia. We hypothesized that &thgr;-rhythm modulation would also occur at subhypnotic but amnestic concentrations. Therefore, we examined the effect of three inhaled agents on properties of the &thgr; rhythm considered critical for the formation of hippocampus-dependent memories. Methods:We studied the effects of halothane and nitrous oxide, two agents known to modulate different molecular targets (GABAergic [&ggr;-aminobutyric acid] vs. non-GABAergic, respectively) and isoflurane (GABAergic and non-GABAergic targets) on fear-conditioned learning and &thgr; oscillations in freely behaving rats. Results:All three anesthetics slowed &thgr; peak frequency in proportion to their inhibition of fear conditioning (by 1, 0.7, and 0.5 Hz for 0.32% isoflurane, 60% N2O, and 0.24% halothane, respectively). Anesthetics inconsistently affected other characteristics of &thgr; oscillations. Conclusions:At subhypnotic amnestic concentrations, &thgr;-oscillation frequency was the parameter most consistently affected by these three anesthetics. These results are consistent with the hypothesis that modulation of the &thgr; rhythm contributes to anesthetic-induced amnesia.

The Quest for a Unified Model of Anesthetic ActionA Century in Claude Bernard's Shadow

An accepted truism among clinicians and researchers attributes the persistence of the quest for a unitary mechanism of anesthetic action to the lasting influence of Hans Meyer and Ernest Overton. This article presents a different view: the experiments that led to the Meyer-Overton rule were the consequence—not the source—of a unitary paradigm that was formulated by Claude Bernard a quarter of a century earlier. Bernard firmly believed that the sensitivity to anesthesia was a fundamental criterion that separated ‘true life’ from ‘mere chemistry.’ Bernards scientific authority in the context of 19th century natural philosophy is responsible for establishing a unified (i.e., unitary mechanism and universality across life forms) paradigm of anesthetic action. Meyer and Overtons work was targeted at systematizing and solidifying existing knowledge within this paradigm, not at discovering novelty, and its publication did not substantially affect contemporary research. Claude Bernards paradigm, by contrast, still influences investigations of mechanisms of anesthetic action.

Differential uptake of volatile agents into brain tissue in vitro. Measurement and application of a diffusion model to determine concentration profiles in brain slices.

Background The rate of onset of drug actions in experiments with brain slices in vitro can vary widely. One factor that influences the rate is access to tissue sites of action. To study the effects of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6, also termed 2N in the literature) on physiologic processes under defined tissue concentrations, the authors performed electrophysiologic measurements of the effects of F6 and halothane, measured the uptake of these agents into brain tissue, and performed computational modeling to determine concentration–depth profiles during drug application. Methods Hippocampal brain slices 500 &mgr;m thick were prepared from adult rats. Evoked population responses in the CA1 region were obtained using extracellular recordings and electrical stimulation of the Schaffer collateral pathway. F6 (24 &mgr;m) and halothane (270 &mgr;m) were applied via superfusion for 40 min. Uptake of drug into tissue slices was measured using gas chromatography. Computational modeling was used to obtain estimates of drug diffusion coefficients in brain tissue and to calculate tissue concentration as a function of time and depth during drug application. Results Halothane reduced the amplitude of the evoked population spike and reduced the population excitatory postsynaptic potential slope. F6 had no effect on either measure. Uptake experiments yielded a diffusion coefficient of 0.1 × 10−6 cm2/s for F6 and 0.8 × 10−6 cm2/s for halothane. After 40 min of drug application, the concentration reached at tissue depths from which physiologic signals were obtained, approximately the top 200 &mgr;m of the slice, was estimated to be 58% of the final equilibrium value for F6 and 93% for halothane. Conclusions Diffusion into tissue is substantially slower for F6 than for halothane, and its impact is great enough that this must be considered when designing or interpreting in vitro experiments. However, impaired access does not account for the lack of effect of F6 on electrophysiologic responses in rat hippocampal slices.

Amnestic concentrations of etomidate modulate GABAA,slow synaptic inhibition in hippocampus.

Background:&ggr;-Aminobutyric acid type A (GABAA) receptor-mediated inhibition in the central nervous system exists in two forms: phasic (inhibitory postsynaptic currents, IPSCs) and tonic (nonsynaptic). Phasic inhibition is further subdivided into fast (GABAA,fast) and slow (GABAA,slow) IPSCs. By virtue of its dendritic location and kinetics, GABAA,slow has been proposed to control synaptic plasticity and memory. Etomidate is a nonbarbiturate, intravenous anesthetic that selectively modulates GABAA receptors and produces amnesia at low doses in vivo. This study tested whether correspondingly low concentrations of etomidate in vitro alter GABAA,fast and GABAA,slow phasic inhibition. Methods:Electrophysiological recordings were obtained from hippocampal slices prepared from postnatal day 3–8 mice and maintained in organotypic culture for 10–14 days. Etomidate was applied at concentrations corresponding to one-half to four times the half maximal effective concentration that impairs hippocampus-dependent learning and memory – i.e., 0.125–1.0 &mgr;m. Results:Etomidate 0.25 &mgr;m (the half maximal effective concentration) doubled the time constant of decay of GABAA,slow IPSCs, but it had no detectable effect on GABAA,fast IPSCs. Higher concentrations of etomidate had stronger effects on both types of phasic inhibition: 0.5 and 1 &mgr;m etomidate prolonged the time constant of decay by 310% and 410% for GABAA,slow and by 25% and 78% for GABAA,fast. Concentrations of etomidate up to 1 &mgr;m had no significant effects on the amplitudes of either GABAA,fast or GABAA,slow IPSCs. Conclusions:At concentrations that impair hippocampus-dependent memory, etomidate modulates GABAA,slow more strongly than GABAA,fast IPSCs. Effects of etomidate on GABAA,slow IPSCs may contribute to etomidate-induced amnesia.

Amnesic Concentrations of the Nonimmobilizer 1,2-Dichlorohexafluorocyclobutane (F6, 2N) and Isoflurane Alter Hippocampal Oscillations In Vivo

Background:Drug-induced temporary amnesia is one of the principal goals of general anesthesia. The nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6, also termed 2N) impairs hippocampus-dependent learning at relative, i.e., lipophilicity-corrected, concentrations similar to isoflurane. Hippocampal &thgr; oscillations facilitate mnemonic processes in vivo and synaptic plasticity (a cellular model of memory) in vitro and are thought to represent a circuit level phenomenon that supports memory encoding. Therefore, the authors investigated the effects of F6 and isoflurane on &thgr; oscillations (4–12 Hz). Methods:Thirteen adult rats were implanted with multichannel depth electrodes to measure the microelectroencephalogram and were exposed to a range of concentrations of isoflurane and F6 spanning the concentrations that produce amnesia. Five of these animals also underwent control experiments without drug injection. The authors recorded the behavioral state and hippocampal field potentials. They confirmed the electrode location postmortem by histology. Results:The tested concentrations for isoflurane and F6 ranged from 0.035% to 0.77% and from 0.5% to 3.6%, respectively. Isoflurane increased the fraction of time that the animals remained immobile, consistent with sedation, whereas F6 had the opposite effect. Electroencephalographic power in the &thgr; band was less when the animals were immobile than when they explored their environment. F6 suppressed the power of oscillations in the &thgr; band. Isoflurane slowed &thgr; oscillations without reducing total power in the &thgr; band. Conclusions:Drug-induced changes in &thgr; oscillations may be a common basis for amnesia produced by F6 and isoflurane. The different patterns suggest that these drugs alter network activity by acting on different molecular and/or cellular targets.