Benno Rehberg

Electroencephalogram approximate entropy correctly classifies the occurrence of burst suppression pattern as increasing anesthetic drug effect.

BackgroundApproximate entropy, a measure of signal complexity and regularity, quantifies electroencephalogram changes during anesthesia. With increasing doses of anesthetics, burst–suppression patterns occur. Because of the high-frequency bursts, spectrally based parameters such as median electroencephalogram frequency and spectral edge frequency 95 do not decrease, incorrectly suggesting lightening of anesthesia. The authors investigated whether the approximate entropy algorithm correctly classifies the occurrence of burst suppression as deepening of anesthesia. MethodsEleven female patients scheduled for elective major surgery were studied. After propofol induction, anesthesia was maintained with isoflurane only. Before surgery, the end-tidal isoflurane concentration was varied between 0.6 and 1.3 minimum alveolar concentration. The raw electroencephalogram was continuously recorded and sampled at 128 Hz. Approximate entropy, electroencephalogram median frequency, spectral edge frequency 95, burst–suppression ratio, and burst–compensated spectral edge frequency 95 were calculated offline from 8-s epochs. The relation between burst–suppression ratio and approximate entropy, electroencephalogram median frequency, spectral edge frequency 95, and burst–compensated spectral edge frequency 95 was analyzed using Pearson correlation coefficient. ResultsHigher isoflurane concentrations were associated with higher burst–suppression ratios. Electroencephalogram median frequency (r = 0.34) and spectral edge frequency 95 (r = 0.29) increased, approximate entropy (r = −0.94) and burst–compensated spectral edge frequency 95 (r = −0.88) decreased with increasing burst–suppression ratio. ConclusionElectroencephalogram approximate entropy, but not electroencephalogram median frequency or spectral edge frequency 95 without burst compensation, correctly classifies the occurrence of burst–suppression pattern as increasing anesthetic drug effect.

Central Nervous System Sodium Channels Are Significantly Suppressed at Clinical Concentrations of Volatile Anesthetics

Background Although voltage-dependent sodium channels have been proposed as possible molecular sites of anesthetic action, they generally are considered too insensitive to be likely molecular targets. However, most previous molecular studies have used peripheral sodium channels as models. To examine the interactions of volatile anesthetics with mammalian central nervous system voltage-gated sodium channels, rat brain IIA sodium channels were expressed in a stably transfected Chinese hamster ovary cell line, and their modification by volatile anesthetics was examined. Methods Sodium currents were measured using whole cell patch clamp recordings. Test solutions were equilibrated with the test anesthetics and perfused externally on the cells. Anesthetic concentrations in the perfusion solution were determined by gas chromatography. Results All anesthetics significantly suppressed sodium currents at clinical concentrations. This suppression occurred through at least two mechanisms: (1) a potential-independent suppression of resting or open sodium channels, and (2) a hyperpolarizing shift in the voltage-dependence of channel inactivation resulting in a potential-dependent suppression of sodium currents. The voltage-dependent interaction results in IC50 values for anesthetic suppression of sodium channels that are close to clinical concentrations at potentials near the resting membrane potential. Conclusions Contrary to the hypothesis that sodium channels are insensitive to general anesthetics, the results presented here indicate that current through central nervous system sodium channels examined at physiologic membrane potentials is significantly blocked by clinical concentrations of volatile anesthetics. This anesthetic interaction with sodium channels is voltage-dependent, consistent with a state-dependent modulated receptor model in which anesthetics more strongly affect the inactive state of the channel than the resting state.

Suppression of Central Nervous System Sodium Channels by Propofol

BACKGROUND Previous studies have provided evidence that clinical levels of propofol alter the functions of voltage-dependent sodium channels, thereby inhibiting synaptic release of glutamate. However, most of these experiments were conducted in the presence of sodium-channel activators, which alter channel inactivation. This study electrophysiologically characterized the interactions of propofol with unmodified sodium channels. METHODS Sodium currents were measured using whole-cell patch-clamp recordings of rat brain IIa sodium channels expressed in a stably transfected Chinese hamster ovary cell line. Standard electrophysiologic protocols were used to record sodium currents in the presence or absence of externally applied propofol. RESULTS Propofol, at concentrations achieved clinically in the brain, significantly altered sodium channel currents by two mechanisms: a voltage-independent block of peak currents and a concentration-dependent shift in steady-state inactivation to hyperpolarized potentials, leading to a voltage dependence of current suppression. The two effects combined to give an apparent concentration yielding a half-maximal inhibitory effect of 10 microM near the threshold potential of action potential firing (about -60 mV). Propofol inhibition was also use-dependent, causing a further block of sodium currents at these anesthetic concentrations. CONCLUSIONS In these experiments with pharmacologically unaltered sodium channels, propofol inhibition of currents occurred at concentrations about eight-fold above clinical plasma levels and thus at brain concentrations reached during clinical anesthesia. Therefore, the results indicate a possible role for sodium-channel suppression in propofol anesthesia.

Comparative Pharmacodynamic Modeling of the Electroencephalography-slowing Effect of Isoflurane, Sevoflurane, and Desflurane

BACKGROUND The most common measure to compare potencies of volatile anesthetics is minimum alveolar concentration (MAC), although this value describes only a single point on a quantal concentration-response curve and most likely reflects more the effects on the spinal cord rather than on the brain. To obtain more complete concentration-response curves for the cerebral effects of isoflurane, sevoflurane, and desflurane, the authors used the spectral edge frequency at the 95th percentile of the power spectrum (SEF95) as a measure of cerebral effect. METHODS Thirty-nine patients were randomized to isoflurane, sevoflurane, or desflurane groups. After induction with propofol, intubation, and a waiting period, end-tidal anesthetic concentrations were randomly varied between 0.6 and 1.3 MAC, and the EEG was recorded continuously. Population pharmacodynamic modeling was performed using the software package NONMEM. RESULTS The population mean EC50 values of the final model for SEF95 suppression were 0.66+/-0.08 (+/- SE of estimate) vol% for isoflurane, 1.18+/-0.10 vol% for sevoflurane, and 3.48+/-0.66 vol% for desflurane. The slopes of the concentration-response curves were not significantly different; the common value was lambda = 0.86+/-0.06. The Ke0 value was significantly higher for desflurane (0.61+/-0.11 min(-1)), whereas separate values for isoflurane and sevoflurane yielded no better fit than the common value of 0.29+/-0.04 min(-1). When concentration data were converted into fractions of the respective MAC values, no significant difference of the C50 values for the three anesthetic agents was found. CONCLUSIONS This study demonstrated that (1) the concentration-response curves for spectral edge frequency slowing have the same slope, and (2) the ratio C50(SEF95)/MAC is the same for all three anesthetic agents. The authors conclude that MAC and MAC multiples, for the three volatile anesthetics studied, are valid representations of the concentration-response curve for anesthetic suppression of SEF95.

Surgical Stimulation Shifts EEG Concentration–Response Relationship of Desflurane

Background Anesthesiologists routinely increase the delivered anesthetic concentration before surgical stimulation in anticipation of increased anesthetic requirement to achieve certain goals (e.g., amnesia, unconsciousness, and immobility). Electroencephalographic monitoring is one method of determining indirectly anesthetic effect on the brain. The present study investigated the effect of surgical stimuli on the concentration–response relation of desflurane-induced electroencephalographic changes. Methods The electroencephalographic activity was recorded from 24 female patients who received only desflurane after a single induction dose of propofol. Twelve patients served as a control group before surgical stimulation. The other 12 patients, all undergoing lower abdominal surgery, were investigated between opening and closure of the peritoneum. Desflurane vaporizer settings were randomly increased and decreased between 0.5 and 1.6 minimum alveolar concentration as long as anesthesia was considered adequate. Spectral edge frequency 95, median power frequency, and Bispectral Index were calculated. Desflurane effect-site concentrations and the concentration–effect curves for spectral edge frequency 95, median power frequency, and Bispectral Index were determined by simultaneous pharmacokinetic and pharmacodynamic modeling. Results Surgical stimulation shifted the desflurane concentration–electroencephalographic effect curves for spectral edge frequency 95, median power frequency, and Bispectral Index toward higher desflurane concentrations. In the unstimulated group, 2.2 ± 0.74 vol% desflurane were necessary to achieve a Bispectral Index of 50, whereas during surgery, 6.8 ± 0.98 vol% (mean ± SE) were required. Conclusions During surgery, higher concentrations of the volatile anesthetic are required to achieve a desired level of cortical electrical activity and, presumably, anesthesia.

Monitoring of Immobility to Noxious Stimulation during Sevoflurane Anesthesia Using the Spinal H-reflex

BackgroundThe spinal H-reflex has been shown to correlate with surgical immobility, i.e., the absence of motor responses to noxious stimulation, during isoflurane anesthesia. Here, the authors established individual concentration–response functions for H-reflex amplitude and tested the predictive power of the H-reflex for movement responses during sevoflurane anesthesia in comparison to electroencephalographic parameters. In addition, they investigated the effect of noxious stimulation on the H-reflex itself. MethodsThe authors studied 12 female patients during sevoflurane anesthesia before surgery. The sevoflurane concentration was increased, a laryngeal mask was inserted, and then the sevoflurane concentration was decreased until H-reflex amplitude (recorded over the soleus muscle) recovered. Thereafter, the end-tidal sevoflurane concentration was kept at a constant value close to the minimum alveolar concentration for suppression of movement responses after tetanic stimulation (MACtetanus), determined by the Dixon up–down method. Pharmacodynamic modeling of H-reflex amplitude and of the Bispectral Index was performed, and predictive values for motor responses to noxious electrical stimulation (50 Hz, 60 mA tetanus, volar forearm) were compared using the prediction probability. ResultsConcentration-dependent depression of H-reflex amplitude by sevoflurane was well modeled (median r2 = 0.97) by a sigmoid function with a median EC50 of 1.5 vol% and a median slope parameter of 3.7, much steeper than the slope for the Bispectral Index. MACtetanus calculated by logistic regression was 1.6 vol%. H-reflex amplitude predicted motor responses to noxious stimulation with a prediction probability of 0.76, whereas the prediction probability for Bispectral Index and spectral edge frequency (SEF95) were not different from chance alone. Noxious stimulation was followed by a substantial increase of H-reflex amplitude for several minutes, whereas the Bispectral Index and SEF95 exhibited no significant changes. ConclusionsSuppression of movement to noxious stimulation and suppression of H-reflex amplitude by sevoflurane follow similar concentration–response functions. Although this does not imply a causal relation, it explains the high predictive value of H-reflex amplitude for motor responses to noxious stimuli, even in a narrow concentration range around the MACtetanus.

Propofol and Sevoflurane in Subanesthetic Concentrations Act Preferentially on the Spinal Cord: Evidence from Multimodal Electrophysiological Assessment

Background Animal experiments in recent years have shown that attenuation of motor responses by general anesthetics is mediated at least partly by spinal mechanisms. Less is known about the relative potency of anesthetic drugs in suppressing cortical and spinal electrophysiological responses in vivo in humans, particularly those, but not only those, connected with motor responses. Therefore, we studied the effects of sevoflurane and propofol in humans using multimodal electrophysiological assessment. Methods We studied nine healthy volunteers in two sessions during steady state sedation with 0.5, 1.0, and 1.5 &mgr;g/l (targeted plasma concentration) propofol or 0.2 and 0.4 vol% (end-tidal) sevoflurane. Following a 15-min equilibration period, motor responses to transcranial magnetic stimulation and peripheral (H-reflex, F-wave) stimulation were recorded, while electroencephalography and auditory evoked responses were recorded in parallel. Results At concentrations corresponding to two thirds of C50 awake, motor responses to transcranial magnetic stimulation were reduced by approximately 50%, H-reflex amplitude was reduced by 22%, F-wave amplitude was reduced by 40%, and F-wave persistence was reduced by 25%. No significant differences between sevoflurane and propofol were found. At this concentration, the Bispectral Index was reduced by 7%, and the middle-latency auditory evoked responses were attenuated only mildly (Nb latency increased by 11%, amplitude PaNb did not change). In contrast, the postauricular reflex was suppressed by 77%. Conclusions The large effect of both anesthetics on all spinal motor responses, compared with the small effect on electroencephalography and middle-latency auditory evoked responses, assuming that they represent cortical modulation, may suggest that the suppression of motor responses to transcranial magnetic stimulation is largely due to submesencephalic effects.

The Membrane Lipid Cholesterol Modulates Anesthetic Actions on a Human Brain Ion Channel

Background Molecular theories of general anesthesia often are divided into two categories: (l) Anesthetics may bind specifically to proteins, such as ionic channels, and alter their function directly, and (2) anesthetics may alter the functions of integral membrane proteins indirectly through modification of the physical properties of the membrane. Recent studies have provided evidence that anesthetics can bind to proteins and modify their function directly, bringing into question the role of the membrane in anesthetic interactions. To reexamine the role of membrane lipids in anesthetic interactions, an experimental approach was used in which the membrane lipid composition could be systematically altered and the impact on anesthetic interactions with potential targets examined. Methods Sodium channels from human brain cortex were incorporated into planar lipid bilayers with increasing cholesterol content. The anesthetic suppression of these channels by pentobarbital was quantitatively examined by single channel measurements under voltage‐clamp conditions. Results Changes in cholesterol content had no effect on measured channel properties in the absence of anesthetic. In the presence of pentobarbital, however, cholesterol inhibited anesthetic suppression of channel ionic currents, with 1.9% (weight/weight, corresponding to 3.5 mol%) cholesterol decreasing anesthetic suppression of sodium channels by half. Conclusions These results support a critical role for the lipid membrane in some anesthetic actions and further indicate that differences in lipid composition must be considered in the interpretation of results when comparing the anesthetic potencies of potential targets in model systems.

Effects of Sevoflurane and Propofol on the Nociceptive Withdrawal Reflex and on the H Reflex

Background:The predominant target of anesthetics to suppress movement responses to noxious stimuli is located in the spinal cord. Although volatile anesthetics appear to produce immobility by actions on the ventral rather than the dorsal horn, the site of action of propofol remains unclear. Methods:In a crossover design, the authors compared in 13 volunteers the effects of sevoflurane and propofol on the amplitudes of the H reflex, which is mediated exclusively in the ventral horn and a withdrawal reflex (RIII Reflex), which integrates dorsal and ventral horn function. The concentrations were adjusted according to a Dixon up-and-down approach, depending on movement responses to tetanic stimulation. Results:Sevoflurane and propofol concentrations ranged from 1.2 to 1.6 Vol% and 3 to 6 mg/l, respectively. Sevoflurane reduced the H reflex amplitude significantly to 66 ± 17% (mean ± SD) of its control values. Propofol did not significantly reduce the H reflex. The reductions under the two drugs differed significantly. The RIII reflex amplitude was significantly reduced to 19 ± 10% and 27 ± 12% (mean ± SD) of the control values by sevoflurane and propofol, respectively. The reductions did not differ between the drugs. Conclusions:Probably because of the polysynaptic relay, the attenuation of the withdrawal reflex exceeds the attenuation of the H reflex. Sevoflurane produces a larger inhibitory effect on the H reflex than propofol, which confirms that the ventral horn is a more important target for volatile anesthetics, whereas effects of propofol on this site of action are rather limited. Our findings indirectly suggest for propofol a relatively stronger effect within the dorsal horn.

Analysis of Memory Formation during General Anesthesia (Propofol/Remifentanil) for Elective Surgery Using the Process-dissociation Procedure

Background:There have been reports of memory formation during general anesthesia. The process-dissociation procedure has been used to determine if these are controlled (explicit/conscious) or automatic (implict/unconscious) memories. This study used the process-dissociation procedure with the original measurement model and one which corrected for guessing to determine if more accurate results were obtained in this setting. Methods:A total of 160 patients scheduled for elective surgery were enrolled. Memory for words presented during propofol and remifentanil general anesthesia was tested postoperatively by using a word-stem completion task in a process-dissociation procedure. To assign possible memory effects to different levels of anesthetic depth, the authors measured depth of anesthesia using the BIS® XP monitor (Aspect Medical Systems, Norwood, MA). Results:Word-stem completion performance showed no evidence of memory for intraoperatively presented words. Nevertheless, an evaluation of these data using the original measurement model for process-dissociation data suggested an evidence of controlled (C = 0.05; 95% confidence interval [CI] 0.02–0.08) and automatic (A = 0.11; 95% CI 0.09–0.12) memory processes (P < 0.01). However, when the data were evaluated with an extended measurement model taking base rates into account adequately, no evidence for controlled (C = 0.00; 95% CI –0.04 to 0.04) or automatic (A = 0.00; 95% CI –0.02 to 0.02) memory processes was obtained. The authors report and discuss parallel findings for published data sets that were generated by using the process-dissociation procedure. Conclusion:Patients had no memories for auditory information presented during propofol/remifentanil anesthesia after midazolam premedication. The use of the process-dissociation procedure with the original measurement model erroneously detected memories, whereas the extended model, corrected for guessing, correctly revealed no memory.