Logan J. Voss

The howling cortex: seizures and general anesthetic drugs.

The true incidence of seizures caused by general anesthetic drugs is unknown. Abnormal movements are common during induction of anesthesia, but they may not be indicative of true seizures. Conversely, epileptiform electrocortical activity is commonly induced by enflurane, etomidate, sevoflurane and, to a lesser extent, propofol, but it rarely progresses to generalized tonic-clonic seizures. Even “nonconvulsant” anesthetic drugs occasionally cause seizures in subjects with preexisting epilepsy. These seizures most commonly occur during induction or emergence from anesthesia, when the anesthetic drug concentration is relatively low. There is no unifying neural mechanism of anesthetic drug-related seizurogenesis. However, there is a growing body of experimental work suggesting that seizures are not caused simply by “too much excitation,” but rather by excitation applied to a mass of neurons which are primed to react to the excitation by going into an oscillatory seizure state. Increased &ggr;-amino-butyric acid (GABA)ergic inhibition can sensitize the cortex so that only a small amount of excitation is required to cause seizures. This has been postulated to occur 1) at the network level by increasing the propensity for reverberation (e.g., by prolongation of the “inhibitory lag”), or 2) via different effects on subpopulations of interneurons (“inhibiting-the-inhibitors”) or 3) at the synaptic level by changing the chloride reversal potential (“excitatory GABA”). On the basis of applied neuropharmacology, prevention of anesthetic-drug related seizures would include 1) avoiding sevoflurane and etomidate, 2) considering prophylaxis with adjunctive benzodiazepines (&agr;-subunit GABAA agonists), or drugs that impair calcium entry into neurons, and 3) using electroencephalogram monitoring to detect early signs of cortical instability and epileptiform activity. Seizures may falsely elevate electroencephalogram indices of depth of anesthesia.

Practical use of the raw electroencephalogram waveform during general anesthesia: the art and science.

Quantitative electroencephalogram (qEEG) monitors are often used to estimate depth of anesthesia and intraoperative recall during general anesthesia. As with any monitor, the processed numerical output is often misleading and has to be interpreted within a clinical context. For the safe clinical use of these monitors, a clear mental picture of the expected raw electroencephalogram (EEG) patterns, as well as a knowledge of the common EEG artifacts, is absolutely necessary. This has provided the motivation to write this tutorial. We describe, and give examples of, the typical EEG features of adequate general anesthesia, effects of noxious stimulation, and adjunctive drugs. Artifacts are commonly encountered and may be classified as arising from outside the head, from the head but outside the brain (commonly frontal electromyogram), or from within the brain (atypical or pathologic). We include real examples of clinical problem-solving processes. In particular, it is important to realize that an artifactually high qEEG index is relatively common and may result in dangerous anesthetic drug overdose. The anesthesiologist must be certain that the qEEG number is consistent with the apparent state of the patient, the doses of various anesthetic drugs, and the degree of surgical stimulation, and that the qEEG number is consistent with the appearance of the raw EEG signal. Any discrepancy must be a stimulus for the immediate critical examination of the patient’s state using all the available information rather than reactive therapy to “treat” a number.

Multiscale permutation entropy analysis of EEG recordings during sevoflurane anesthesia

Electroencephalogram (EEG) monitoring of the effect of anesthetic drugs on the central nervous system has long been used in anesthesia research. Several methods based on nonlinear dynamics, such as permutation entropy (PE), have been proposed to analyze EEG series during anesthesia. However, these measures are still single-scale based and may not completely describe the dynamical characteristics of complex EEG series. In this paper, a novel measure combining multiscale PE information, called CMSPE (composite multi-scale permutation entropy), was proposed for quantifying the anesthetic drug effect on EEG recordings during sevoflurane anesthesia. Three sets of simulated EEG series during awake, light and deep anesthesia were used to select the parameters for the multiscale PE analysis: embedding dimension m, lag tau and scales to be integrated into the CMSPE index. Then, the CMSPE index and raw single-scale PE index were applied to EEG recordings from 18 patients who received sevoflurane anesthesia. Pharmacokinetic/pharmacodynamic (PKPD) modeling was used to relate the measured EEG indices and the anesthetic drug concentration. Prediction probability (P(k)) statistics and correlation analysis with the response entropy (RE) index, derived from the spectral entropy (M-entropy module; GE Healthcare, Helsinki, Finland), were investigated to evaluate the effectiveness of the new proposed measure. It was found that raw single-scale PE was blind to subtle transitions between light and deep anesthesia, while the CMSPE index tracked these changes accurately. Around the time of loss of consciousness, CMSPE responded significantly more rapidly than the raw PE, with the absolute slopes of linearly fitted response versus time plots of 0.12 (0.09-0.15) and 0.10 (0.06-0.13), respectively. The prediction probability P(k) of 0.86 (0.85-0.88) and 0.85 (0.80-0.86) for CMSPE and raw PE indicated that the CMSPE index correlated well with the underlying anesthetic effect. The correlation coefficient for the comparison between the CMSPE index and RE index of 0.84 (0.80-0.88) was significantly higher than the raw PE index of 0.75 (0.66-0.84). The results show that the CMSPE outperforms the raw single-scale PE in reflecting the sevoflurane drug effect on the central nervous system.

Dreaming and Electroencephalographic Changes during Anesthesia Maintained with Propofol or Desflurane

Background:Dream recall is reportedly more common after propofol than after volatile anesthesia, but this may be due to delayed emergence or more amnesia after longer-acting volatiles. The electroencephalographic signs of dreaming during anesthesia and the differences between propofol and desflurane also are unknown. The authors therefore compared dream recall after propofol- or desflurane-maintained anesthesia and analyzed electroencephalographic patterns in dreamers and nondreamers and in propofol and desflurane patients for similarities to rapid eye movement and non–rapid eye movement sleep. Methods:Three hundred patients presenting for noncardiac surgery were randomized to receive propofol- or desflurane-maintained anesthesia. The raw electroencephalogram was recorded from induction until patients were interviewed about dreaming when they became first oriented postoperatively. Using spectral and ordinal methods, the authors quantified the amount of sleep spindle-like activity and high-frequency power in the electroencephalogram. Results:The incidence of dream recall was similar for propofol (27%) and desflurane (28%) patients. Times to interview were similar (median 20 [range 4–114] vs. 17 [7–86] min; P = 0.1029), but bispectral index values at interview were lower (85 [69–98] vs. 92 [40–98]; P < 0.0001) in propofol than in desflurane patients. During surgery, the raw electroencephalogram of propofol patients showed more and faster spindle activity than in desflurane patients (P < 0.001). The raw electroencephalogram of dreamers showed fewer spindles and more high-frequency power than in nondreamers in the 5 min before interview (P < 0.05). Conclusions:Anesthetic-related dreaming seems to occur just before awakening and is associated with a rapid eye movement-like electroencephalographic pattern.

Pharmacokinetic-pharmacodynamic modeling the hypnotic effect of sevoflurane using the spectral entropy of the electroencephalogram

Spectral entropy is a new electroencephalogram (EEG)-derived parameter that may be used to model the pharmacokinetic-pharmacodynamic (PKPD) effects of general anesthetics. In the present study we sought to derive a PKPD model of the relationship between sevoflurane concentration and spectral entropy of the EEG. We collected spectral entropy data during increasing and decreasing sevoflurane anesthesia from 20 patients. The first cycle consisted of induction and lightening phases with no supplemental medications. An effect-site compartment and inhibitory Emax model described the relation between sevoflurane concentration and spectral entropy. PKPD parameters were derived from the full cycle and separately from the increasing and decreasing stages. The second anesthetic cycle consisted of a redeepening phase only and included airway manipulation and routinely administered adjunctives. PKPD data obtained from the first cycle were used to predict second cycle entropy changes. There was a consistent relationship between effect-site sevoflurane concentration and spectral entropy (median absolute weighted residual = 11.6%). For complete first-cycle response entropy (mean ± sd): T1/2 Keo = 2.4 ± 1.5 min, &ggr; = 5.9 ± 2.3, EC50 = 1.7 ± 0.3. We found significant differences between &ggr; values when the sevoflurane concentration was increasing (61.1 ± 55.2) compared with the decreasing part of the cycle (5.7 ± 2.8). Above an effect-site concentration of 3%, spectral entropy of the EEG is unresponsive to further increases in sevoflurane concentration. The effect-compartment inhibitory Emax model accurately describes the relation between sevoflurane concentration and spectral entropy of the EEG. Spectral entropy decreases with increasing sevoflurane concentrations up to 3%. The steepness of the dose-response curve varies between phases of increasing and decreasing anesthetic concentrations.

Excitatory effects of gap junction blockers on cerebral cortex seizure-like activity in rats and mice

Purpose:  The role of gap junctions in seizures is an area of intense research. Many groups have reported anticonvulsant effects of gap junction blockade, strengthening the case for a role for gap junctions in ictogenesis. The cerebral cortex is underrepresented in this body of research. We have investigated the effect of gap junction blockade on seizure‐like activity in rat and mouse cerebral cortex slices.

Cerebral cortical effects of desflurane in sheep: comparison with isoflurane, sevoflurane and enflurane.

Background:  Different volatile anesthetic agents have differing propensities for inducing seizures. A measure of the predilection to develop seizures is the presence of interictal spike discharges (spikes) on the electrocorticogram (ECoG). In this study, we investigated the propensity of desflurane to induce cortical spikes and made a direct objective comparison with enflurane, isoflurane, and sevoflurane. The ECoG effects of desflurane have not been previously reported.

Connexin36 knockout mice display increased sensitivity to pentylenetetrazol-induced seizure-like behaviors

OBJECTIVE Large-scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions. To explore roles for connexin36 (Cx36) gap junctions in seizures, we examined the seizure threshold of connexin36 knockout (Cx36KO) mice using a pentylenetetrazol (PTZ) model. METHODS Mice (2-3months old) with Cx36 wildtype (WT) or Cx36KO genotype were treated with vehicle or 10-40mg/kg of the convulsant PTZ by intraperitoneal injection. Seizure and seizure-like behaviors were scored by examination of video collected for 20min. Quantitative real-time PCR (QPCR) was performed to measure potential compensatory neuronal connexin (Cx30.2, Cx37, Cx43 and Cx45), pannexin (PANX1 and PANX2) and gamma-aminobutyric acid type A (GABA(A)) receptor α1 subunit gene expression. RESULTS Cx36KO animals exhibited considerably more severe seizures; 40mg/kg of PTZ caused severe generalized (≥grade III) seizures in 78% of KO, but just 5% of WT mice. A lower dose of PTZ (20mg/kg) induced grade II seizure-like behaviors in 40% KO vs. 0% of WT animals. There was no significant difference in either connexin, pannexin or GABA(A) α1 gene expression between WT and KO animals. CONCLUSION Increased sensitivity of Cx36KO animals to PTZ-induced seizure suggests that Cx36 gap junctional communication functions as a physiological anti-convulsant mechanism, and identifies the Cx36 gap junction as a potential therapeutic target in epilepsy.

Effects of Volatile Anesthetic Agents on Cerebral Cortical Synchronization in Sheep

Background:The exact neurophysiological mechanisms of anesthetic-induced unconsciousness are not yet fully elucidated. The cortical information integration theory hypothesizes that loss of consciousness during general anesthesia is associated with breakdown of long-distance cortical connectivity across multiple brain regions. However, what is the effect of anesthetics on neural activities at a smaller spatial scale? Methods:The authors analyzed a set of previously published eight-channel electrocorticogram data, obtained from a 14-mm-long linear array of electrodes in eight adult merino sheep during general anesthesia induced by sevoflurane, desflurane, isoflurane, and enflurane. The S-estimator was applied to the bi-channel coherence matrix to construct an overall index called the SI, which is the entropy of the eigenvalues of the cortical coherence for each pair of channels within the multichannel electrocorticographic dataset. Results:The SI values increased ~30–50% from the waking to the burst-suppression states, and returned to baseline during recovery. The anesthetic-induced increase in synchrony was most marked in the &agr; (8–13 Hz) and &bgr; (13–30 Hz) frequency bands (P < 0.05). Using prediction probability (PK) analysis, we found a significant correlation between the increase in spatial synchrony (as estimated by the SI at various frequency bands) and anesthetic-induced cortical depression (as estimated by the approximate entropy). Conclusions:The results suggest that it is feasible to use the SI to measure cortical synchrony, and over a local spatial scale of 2–14 mm, synchrony increased during general anesthesia.

Measuring the effects of sevoflurane on electroencephalogram using sample entropy.

Monitoring the effect of anesthetic drugs on the neural system is a major ongoing challenge for anesthetists. During the past few years, several electroencephalogram (EEG)‐based methods such as the response entropy (RE) as implemented in the Datex‐Ohmeda M‐Entropy Module have been proposed. In this paper, sample entropy is used to quantify the predictability of EEG series, which could provide an index to show the effect of sevoflurane anesthesia. The dose–response relation of sample entropy is compared with that of RE.