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Kinetics of Anesthetic Onset Measured with a Direct Index of Neural Activity
Abstract
Previous modeling of the kinetics of uptake and elimination of anesthetic drugs from the site of action has used measures derived from the electroencephalogram. Such measures lag the current brain activity because of the time needed to acquire a signal sample and derive the measure. With a direct measure of anesthetic activity, we could model brain uptake more exactly.
In volunteers, using a double-blind single-session design, we made repeated measurements using a well-known psychomotor test, the 2 target tapping test, during the washin and washout of 30% nitrous oxide. We also assessed maximal drug effect with a test of cognitive function, the digit symbol substitution test. Concentration at the site of action was modeled from end-tidal measurements, using a simple exponential washin and washout function, with half-times between 0.5 and 3 minutes. Comparisons were made within subjects, using 0 and 5% nitrous oxide.
We studied 20 subjects. Nitrous oxide, at 30%, consistently reduced performance of the digit symbol substitution test. Tapping frequency was also reduced, but the effect was less consistent, and only 9 of 20 subjects showed a significant individual reduction in tapping frequency. In these subjects, the relationship between the modeled brain concentration and drug effect was better with a half-time set at 2 minutes, compared with 1.5 or 3 minutes.
Given in subanesthetic concentrations, nitrous oxide has rapid onset and offset, consistent with a half-time of 2 minutes. This value is less than the values expected from studies during anesthesia using processed electroencephalogram, but consistent with measures of blood flow to active cerebral tissue in conscious subjects. Studies of performance in conscious subjects may aid further studies of anesthetic kinetics.
... Using subanaesthetic doses, we described the dose-effect relationships for different subjective and objective features effects of nitrous oxide, sevoflurane, and alcohol, 8 and used a similar measure to assess the kinetics of nitrous oxide effects with repeated measures of a psychomotor test. 9 These tests can be done promptly, and should allow better assessment of kinetics than the processed EEG which incorporates delays. 5 10 11 Our findings were consistent with previous kinetic data for nitrous oxide. ...
... In a similar study of conscious volunteers using a motor test, 9 we found a greater half-time, of the order of 2 min, equivalent to a rate constant of about 0.34 min 21 . This could be because a substantial component of that test consists of limb movement, mediated by different structures that could have less blood flow. ...
/st> Using conscious subjects, measurement of the effects of low concentrations of anaesthetic agents can allow the dynamics of onset and offset of the agent to be measured and kinetic values estimated. However, the tests have to be rapid and preferably assess cerebral function.
/st> We used a short version of the digit symbol substitution test (DSST) that allowed frequent measurement of the impairment caused by nitrous oxide. We compared 10 min of onset and offset of breathing 5% and 30% nitrous oxide in 30% oxygen, compared with 30% oxygen only. End-tidal nitrous oxide concentrations were used to predict the concentration in a central compartment, according to a range of T(1/2) values chosen to be consistent with possible cerebral blood flow values.
/st> We studied 19 volunteers and estimated a mean response. Only 30% nitrous oxide decreased the DSST. When DSST scores were related to the values in the predicted central compartment, the best dose-effect relationship was found when the T(1/2) was 37 s, consistent with a regional blood flow of about 120 ml 100 g(-1) min(-1).
/st> The onset of nitrous oxide effect on DSST is rapid, consistent with the perfusion of metabolically active cerebral cortical tissues. The rate of onset is greater than previous measures based on a motor test which involved the function of subcortical structures in the central nervous system.
In recent years, the glutamate theory of alcoholism has emerged as a major theory in the addiction research field and N-methyl-d-aspartate (NMDA) receptors have been shown to play a major role in alcohol craving and relapse. The NMDA receptors are considered as the primary side of action of the anesthetic gases xenon (Xe) and nitrous oxide (N2 O). Despite the rapid on/off kinetics of these gases on the NMDA receptor, a brief gas exposure can induce an analgesic or antireward effect lasting several days. The aim of this study was to examine the effect of both Xe and N2 O on alcohol-seeking and relapse-like drinking behavior (measured as the alcohol deprivation effect) in Wistar rats.
We used 2 standard procedures-the alcohol deprivation model with repeated deprivation phases and the cue-induced reinstatement model of alcohol seeking-to study the effect of 2 brief gas exposures of either Xe, N2 O, or control gas on relapse-like drinking and alcohol-seeking behavior.
Here, we show that exposure to Xe during the last 24 hours of abstinence produced a trend toward reduced ethanol intake during the first alcohol re-exposure days. In addition, Xe gas exposure significantly decreased the cue-induced reinstatement of alcohol-seeking behavior. N2 O had no effect on either behavior.
Xe reduces alcohol-seeking behavior in rats and may therefore also interfere with craving in human alcoholics.
With the growing use of pharmacokinetic (PK)-driven drug delivery and/or drug advisory displays, identifying the PK model that best characterizes propofol plasma concentration (Cp) across a variety of dosing conditions would be useful. We tested the accuracy of 3 compartmental models and 1 physiologically based recirculatory PK model for propofol to predict the time course of propofol Cp using concentration-time data originated from studies that used different infusion schemes.
Three compartmental PK models for propofol, called the "Marsh," the "Schnider," and the "Schüttler" models, and 1 physiologically based recirculatory model called the "Upton" model, were used to simulate the time course of propofol Cp. To test the accuracy of the models, we used published measured plasma concentration data that originated from studies of manual (bolus and short infusion) and computer-controlled (target-controlled infusion [TCI] and long infusion) propofol dosing schemes. Measured/predicted (M/P) propofol Cp plots were constructed for each dataset. Bias and inaccuracy of each model were assessed by median prediction error (MDPE) and median absolute prediction error (MDAPE), respectively.
The M/P propofol Cp in the 4 PK models revealed bias in all 3 compartmental models during the bolus and short infusion regimens. In the long infusion, a worse M/P propofol Cp at higher concentration was seen for the Marsh and the Schüttler models than for the 2 other models. Less biased M/P propofol Cp was found for all models during TCI. In the bolus group, after 1 min, a clear overprediction was seen for all 3 compartmental models for the entire 5 min; however, this initial error resolved after 4 min in the Schnider model. The Upton model did not predict propofol Cp accurately (major overprediction) during the first minute. During the bolus and short infusion, the Marsh model demonstrated worse MDPE and MDAPE compared with the 3 other models. During short infusion, MDAPE for the Schnider and Schüttler models was better than the Upton and the Marsh models. All models showed similar MDPE and MDAPE during TCI simulations. During long infusion, the Marsh and the Schüttler models underestimated the higher plasma concentrations.
When combining the performance during various infusion regimens, it seems that the Schnider model, although still not perfect, is the recommended model to be used for TCI and advisory displays.
Monitoring of anaesthetic depth with EEG-derived indices may detect EEG changes associated with awareness and thereby help to decrease the incidence of intraoperative awareness with postoperative recall. All currently available monitors need varying time periods to calculate a new index when reacting to changes in anaesthetic depth. The exact time delay for calculation of new index values is unknown. In a previous study, we used simulated EEG signals and found considerable time lags for the cerebral state index (Danmeter, Odense, Denmark), the bispectral index (Aspect Medical Systems Inc., Newton, MA, USA), and the Narcotrend index (MonitorTechnik, Bad Bramstedt, Germany). The aim of this study was to investigate whether the time delays observed with simulated EEG signals also applied to real EEG data.
We used perioperatively recorded EEG data from a database corresponding to the awake state, general anaesthesia, and suppression of cortical activity, respectively. After a switch from one state of consciousness to another, the time necessary for all indices to adjust the index value to the underlying input signal was measured.
We found time delays for all indices between 24 (7) and 122 (23) s before the new state was indicated. In accordance with our previous results, these time delays were not constant and depended on the particular starting and target index value. Results were different for decreasing and increasing values.
Our results may show a limitation of the value of electronic EEG indices in prevention of awareness with recall. Furthermore, due to different time delays for ascending and descending values, the results of pharmacodynamic studies may be influenced by this phenomenon.
The time-course of propofol concentrations in the blood and brain following rapid administration of three doses were examined using a sheep preparation and regional pharmacokinetic techniques. These were compared to the time-course of cerebral effects of propofol reported previously. There were marked differences between the time-course of propofol concentrations in arterial blood and the brain, with a close relationship between the time-course of brain concentrations and effects on depth of anaesthesia and CBF. There was evidence that the effect of propofol on cerebral blood flow altered its own rate of elution from the brain. Hysteresis between arterial propofol concentrations and cerebral effects following rapid i.v. administration therefore appears to have a pharmacokinetic basis, and conventional compartmental pharmacokinetic analysis using blood concentrations alone may fail to accurately predict the time-course of both brain propofol concentrations and depth of anaesthesia.
We have studied the effect of nitrous oxide on bispectral index (BIS), calculated from a bipolar encephalogram. Inhalation
of 70% nitrous oxide resulted in loss of consciousness in all healthy volunteers (n = 10) but no change in BIS. Brief inhalation
up to 1.2% sevoflurane also resulted in loss of consciousness in volunteers (n = 5), but with sevoflurane, BIS decreased.
BIS and the haemodynamic effects of adding nitrous oxide were also measured during coronary artery bypass surgery in patients
(n = 10) receiving midazolam and fentanyl infusions. Measurements were made after 0%, 33%, 66% and 0% nitrous oxide, just
before skin incision and after sternotomy. Nitrous oxide caused no change in BIS. BIS may indicate a sufficient hypnotic depth
to prevent awareness during surgery, but our study demonstrated that pharmacological unconsciousness-hypnosis can also be
reached by mechanisms to which BIS is not sensitive. Thus BIS is a sufficient but not a necessary criterion for adequate depth
of anaesthesia or prevention of awareness.
In summary, there are good reasons for assuming that anaesthetic-induced synchronization and depression of neuronal activity in the cerebral cortex involve sub-cortical arousal systems. However, as discussed above, we are also faced with data strongly supporting the possibility that direct actions on cortical neurones come into play. How do we evaluate the importance of different potential pathways of drug action? How do we establish a more precise hypothesis that distinguishes between cortical and sub-cortical mechanisms? What type of experiments can be conducted to elucidate the specific contributions made by different local networks? A major problem arises from the fact that distributed local microcircuits are extensively interconnected in intact brains: if can assume that a particular part of the brain, say the neocortex (termed network B in the following) receives excitatory input from a sub-cortical structure (network A), neuronal activity in B may be reduced either because of direct effects on drug targets located in B, or because of a decrease in excitatory drive provided by A. Thus, it is necessary to study drug effects in isolated local networks, which do not receive synaptic input from different brain areas. If it turns out that network B is equally sensitive to drug treatment, regardless of whether synaptic input provided by A is present or not, B is most probably the substrate of drug action. If B is rendered insensitive by removing synaptic input provided by A, the more important effects take place in network A. At this point, the topics addressed above have been considered in order to establish some type of conceptual framework. Such a framework seems to be helpful for recognizing the benefit of brain slice studies and for integrating the results into a general understanding of how anaesthetics work. The research discussed in the following is centred on work dealing with the question of how general anaesthetics alter activity patterns in hippocampal and neocortical brain slices. The focus is on drug actions occurring at the network level.
Anaesthetics which work by different mechanisms may have different patterns of effect. Measurement of these patterns thus may elucidate their mechanisms of action and allow therapeutic choices between the agents.
We compared the effects of ethanol (approximately 80 mg per 100 ml), and different end-tidal concentrations of nitrous oxide (15% and 25%) and sevoflurane (0.3% and 0.5%) in volunteers. We measured speed and accuracy in psychomotor tests, reaction time and memory, touch and pain sensitivity to von Frey filaments, and subjective mood for a range of descriptors.
All treatments caused the same degree of overall abnormal feelings, but sevoflurane caused more obtunding (subjective drowsiness, slow reaction times, and loss of memory function) and nitrous oxide was more analgesic. Ethanol caused a marked feeling of drunkenness, but little drowsiness or analgesia.
In the same volunteer subjects, direct comparison of sub-anaesthetic doses of these agents showed a clear and characteristic pattern of effects. These support the possible mechanisms for these disparate agents and may help choose appropriate agents for specific desired anaesthetic outcomes such as sedation or analgesia.
It is still unknown whether anesthetic state transitions are continuous or binary. Mathematical graph theory is one method by which to assess whether brain networks change gradually or abruptly upon anesthetic induction and emergence.
Twenty healthy males were anesthetized with an induction dose of propofol, with continuous measurement of 21-channel electroencephalogram at baseline, during anesthesia, and during recovery. From these electroencephalographic data a "genuine network" was reconstructed based on the surrogate data method. The effects of topologic structure and connection strength on information transfer through the network were measured independently across different states.
Loss of consciousness was consistently associated with a disruption of network topology. However, recovery of consciousness was associated with complex patterns of altered connection strength after the initial topologic structure had slowly recovered. In one group of subjects, there was a precipitous increase of connection strength that was associated with reduced variability of emergence time. Analysis of regional effects on brain networks demonstrated that the parietal network was significantly disrupted, whereas the frontal network was minimally affected.
By dissociating the effects of network structure and connection strength, both continuous and discrete elements of anesthetic state transitions were identified. The study also supports a critical role of parietal networks as a target of general anesthetics.
The objective of this paper is to assess the suitability of brain function monitors for use in closed-loop anesthesia or sedation delivery. In such systems, monitors used as feedback sensors should preferably be Linear and Time Invariant (LTI) in order to limit sensor-induced uncertainty which can cause degraded performance. In this paper, we evaluate the suitability of the BIS A2000 (Aspect Medical Systems, MA), the M-Entropy Monitor (GE HealthCare), and the NeuroSENSE Monitor (NeuroWave Systems Inc, OH), by verifying whether their dynamic behavior conforms to the LTI hypothesis.
We subjected each monitor to two different composite EEG signals containing step-wise changes in cortical activity. The first signal was used to identify Linear Time-Invariant (LTI) models that mathematically capture the dynamic behavior of each monitor. The identification of the model parameters was carried out using standard Recursive Least Squares (RLS) estimation. The second signal was used to assess the performance of the model, by comparing the output of the monitor to the simulated output predicted by the model.
While a LTI model was successfully derived for each monitor using the first signal, only the model derived for NeuroSENSE was capable to reliably predict the monitor output for the second input signals. This indicates that some algorithmic processes within the BIS A2000 and M-Entropy are non-linear and/or time variant.
While both BIS and M-Entropy monitors have been successfully used in closed-loop systems, we were unable to obtain a unique LTI model that could capture their dynamic behavior during step-wise changes in cortical activity. The uncertainty in their output during rapid changes in cortical activity impose limitations in the ability of the controller to compensate for rapid changes in patients' cortical state, and pose additional difficulties in being able to provide mathematically proof for the stability of the overall closed-loop system. Conversely, the NeuroSENSE dynamic behavior can be fully captured by a linear and time invariant transfer function, which makes it better suited for closed-loop applications.
Conventional compartmental pharmacokinetic models wrongly assume instantaneous drug mixing in the central compartment, resulting in a flawed prediction of drug disposition for the first minutes, and the flaw affects pharmacodynamic modeling. This study examined the influence of the administration rate and other covariates on early phase kinetics and dynamics of propofol by using the enlarged structural pharmacokinetic model.
Fifty patients were randomly assigned to one of five groups to receive 1.2 mg/kg propofol given with the rate of 10 to 160 mg . kg(-1). h(-1). Arterial blood samples were taken frequently, especially during the first minute. The authors compared four basic pharmacokinetic models by using presystemic compartments and the time shift of dosing, LAG time. They also examined a sigmoidal maximum possible drug effect pharmacodynamic model. Patient characteristics and dose rate were obtained to test the model structure.
Our final pharmacokinetic model includes two conventional compartments enlarged with a LAG time and six presystemic compartments and includes following covariates: dose rate for transit rate constant, age for LAG time, and weight for central distribution volume. However, the equilibration rate constant between central and effect compartments was not influenced by infusion rate.
This study found that a combined pharmacokinetic-dynamic model consisting of a two-compartmental model with a LAG time and presystemic compartments and a sigmoidal maximum possible drug effect model accurately described the early phase pharmacology of propofol during infusion rate between 10 and 160 mg . kg(-1). h(-1). The infusion rate has an influence on kinetics, but not dynamics. Age was a covariate for LAG time.
Evaluating the effects of sub-immobilizing anesthetic doses on movement will identify target neural circuits for investigation as sites of action for anesthetic-induced immobility.
Eleven pithed Northern Leopard frogs received 0, 0.4, 0.8, and 1.2 times the 50% effective dose for production of immobility (ED(50)) of desflurane and a further 7 received 0 and 0.4 ED(50) desflurane in random order. An electric stimulus applied to the forelimb elicited a hindlimb wiping reflex that was captured on video for later analysis. Isometric tension developed in the hindlimb during the 30 s stimulus application was measured.
Compared to 0 ED(50), 0.4 ED(50) desflurane significantly increased latency to wipe 0.8 (0.1, 4.0) to 17.3 (0.4, 30.0) s (median [min max]), distance traveled by the hindfoot 0.42 (0.09, 1.82) to 0.89 (0.16, 4.82) m, and proximity of the hindfoot to stimulus 1 (0, 5) to 7 (1, 40) mm. It did not alter hindlimb maximum velocity or isometric tension but significantly reduced total hindlimb force 7.3 (1.7, 23.6) to 3.2 (1.4, 13.8) N. s proportionate to a reduced number of movements from 12 (3, 28) to 8 (2, 14). From 0.4 to 0.8 ED(50,) motor depressant effects of desflurane became apparent with significant reductions in maximum tension from 2.0 (0.6, 5.5) to 0.8 (0.1, 1.6) N and total force from 3.2 (1.4, 13.8) to 0.9 (0.0, 2.5) N.s.
Proprioceptive function is more sensitive to anesthetic-induced depression than motor function in frogs. This suggests that the most anesthetic-sensitive component of the spinal neural circuitry underlying movement generation in response to noxious stimulus is prior to the level of the motoneuron.
Previous investigations indicate that the spinal cord, perhaps with a minor cerebral contribution, mediates the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation. The implications of these investigations may be limited by the trauma associated with their experimental methods (e.g., cardiopulmonary bypass or transection of the spinal cord). The present study avoided such trauma.
Thirty goats received emulsified isoflurane via either the initial section of the aorta (arterial group; preferential isoflurane delivery to the spinal cord) or an ear vein (venous group; equal delivery of isoflurane to the cord and brain). The authors determined the minimum partial pressure of isoflurane (the isoflurane partial pressure in the blood required to produce immobility in 50% of the goats exposed to a noxious stimulus).
For the venous group, the minimum partial pressure in carotid versus femoral arterial blood (9.56 +/- 1.86 mmHg vs. 9.68 +/- 1.90 mmHg) did not differ. For the arterial group, the minimum partial pressure in carotid arterial blood was half that in femoral arterial blood (5.35 +/- 1.45 mmHg vs. 10.97 +/- 3.04 mmHg, P < 0.05). As these data show, the minimum partial pressure in femoral arterial blood did not differ for the arterial group versus the venous group.
In this novel and minimally traumatic model, the anesthetic partial pressure delivered to the spinal cord governed the suppression of movement in response to noxious stimulation. The results indicate that the spinal cord is the primary mediator of immobility and that the brain plays little or no role.
A number of commonly used anesthetics, including nitrous oxide (N2O), are poorly detected by current electroencephalography (EEG)-based measures of anesthetic depth such as the bispectral index. Based on a previously elaborated theory of electrocortical rhythmogenesis we developed a physiologically inspired method of EEG analysis that was hypothesized to be more sensitive in detecting and characterizing N2O effect than the bispectral index, through its combined EEG estimates of cortical input and cortical state. By evaluating sevoflurane-induced loss of consciousness in the presence of low brain concentrations of N2O in 38 elective surgical patients, N2O was associated with a statistically significant reduction in the input the frontal cortex received from other cortical and subcortical areas. In contrast the bispectral index responded only to low, but not to high, concentrations of N2O.
Approximate entropy (AE) has been proposed as a measure of anesthetic drug effect in electroencephalographic data. Recently, a new method called permutation entropy (PE) based on symbolic dynamics was also proposed to measure the complexity in an electroencephalographic series. In this study, the AE and PE were applied to electroencephalographic recordings for revealing the effect of sevoflurane on brain activity. The dose-response relation of PE during sevoflurane anesthesia was compared with that of AE.
Nineteen patients' electroencephalographic data were collected during the induction of general anesthesia with sevoflurane. PE and AE were applied to the electroencephalographic recordings, and the performance of both measures was assessed by pharmacokinetic-pharmacodynamic modeling and prediction probability. To ensure an accurate complexity measure of electroencephalographic recordings, a wavelet-based preprocessor was built in advance.
Both PE and AE could distinguish between the awake and anesthetized states and were highly correlated to each other (r = 0.8, P = 0.004). The pharmacokinetic-pharmacodynamic model adequately described the dose-response relation between PE and AE and sevoflurane effect site concentration. The coefficient R between PE and effect site concentration was 0.89 +/- 0.07 for all patients, compared with 0.60 +/- 0.14 for AE. Prediction probabilities of 0.86 +/- 0.04 and 0.79 +/- 0.09 for PE and AE showed that PE has a stronger ability to differentiate between the awake and anesthetic states.
The results show that PE can estimate the sevoflurane drug effect more effectively than AE. This method could be applied to design a new electroencephalographic monitoring system to estimate sevoflurane anesthetic drug effect.
The concentrations of nitrous oxide and halothane which are found in the unscavenged operating theatre environment are of the order of 600 and 10 p.p.m. respectively (Smith, 1976). These concentrations are equivalent to approximately 0.05 and 0.1% of the MAC value for each agent respectively. The balance of experimental evidence presented in this review would indicate that much higher concentrations than these (of the order perhaps of 5-10% of MAC) are required to produce detrimental effects on those aspects of performance which have been subjected so far to investigation. It is concluded, therefore, that pollution of the operating theatre with anaesthetic agents is not likely to affect the performance of staff. There are, however, two important caveats to this statement: When using unscavenged anaesthetic circuits, particularly of the Magill type, anaesthetists may be exposed to very high concentrations of anaesthetic agents in comparison with other staff in the theatre (Smith, 1976) and conceivably may suffer impairment of performance. Chronic exposure to trace concentrations of anaesthetic agents may have effects which are not seen during acute exposure in volunteers (conversely, if there were an effect with acute exposure, tolerance might occur with chronic exposure). In addition, one cannot exclude the possibility of interactions between low, subthreshold concentrations of anaesthetics and other factors to produce a definite impairment in performance.
Using audiovisual reaction times, no effects were found in 12 subjects exposed to 1, 2, 4, or 8% nitrous oxide. In subsequent studies on 30 subjects, a positive effect on performance was found at a concentration of between 8 and 12% nitrous oxide. In addition, there was no difference in mean reaction time in 12 subjects exposed to air or 8% nitrous oxide. It is concluded that the threshold concentration of nitrous oxide for an effect on psychomotor performance as assessed by choice reaction times probably lies between 8 and 12%.
SUMMARY A cross-over trial was performed in 12 volunteers to compare the relative potency of 25% nitrous oxide and 0.4% isoflurane
when breathed for a period of 20 min. Oxygen was used as a control. The effects were observed for 35 min after drug administration.
Choice reaction time, ability to tap two areas on a board and ability to perform mathematical problems were significantly
impaired when inhaling nitrous oxide, the maximum effect being obtained within 5 min. With isoflurane, the effects were significantly
greater than with nitrous oxide. The effect obtained after 15 min inhalation was greater than that at 5 min. Tests returned
promptly to the base line after the discontinuation of the test agent. Subjective assessments were made using a series of
eight visual analogue scales. Results of the scales represented by physical and mental sedation indicated that 0.4% isoflurane
was more potent than 25% nitrous oxide. Significant effects were detected up to 15 min after the inhalation of the agent was
stopped. Subanaesthetic concentrations of isoflurane warrant further study in patients undergoing dental treatment in which
a rapid recovery from sedation is important.
The minimum alveolar concentration of anesthetic (MAC) necessary to prevent movement in response to a painful stimulus was relatively constant in dogs anesthetized with halothane. MAC varied over a two-fold range with the intensity of the stimulus, but appeared to reach an upper limit beyond which a further increase in intensity did not increase MAC. For the same stimulus MAC was constant from dog to dog. MAC was unaffected by duration of anesthesia, unaltered by hypocarbia or hypercarbia, by phenylephrine-in-duced hypertension or by mild hypoxia (Pao2 30 to 60 mm. of mercury). Hemorrhagic hypotension or marked acute metabolic acidosis reduced MAC by 10 to 20 per cent. Severe hypoxia (Pao2 less than 30 mm. of mercury) reduced MAC by 25 to 50 per cent.
A normal population of mice was separated into two groups with reproducibly high (greater than 1.63 atm) or reproducibly low (less than 1.29 atm) nitrous oxide requirements. Males (n = 4) and females (n = 5) with the reproducibly high anesthetic requirements were mated, as were males (n = 4) and females (n = 3) with the reproducibly low anesthetic requirements. The first-generation offspring from parents with the high anesthetic requirements had a higher nitrous oxide ED50 (concentration of nitrous oxide required to abolish the righting reflex in half of the animals) than did offspring from parents with the low anesthetic requirements. Mice with the lowest and the highest anesthetic requirements in the first generation were bred to give the second generation. By repeating this process of breeding, nitrous oxide ED50 testing, and selection of mice with the highest and lowest anesthetic requirements through five generations, the authors were able to breed two groups of mice separated by approximately 0.5 atm in nitrous oxide requirements. This alteration in anesthetic requirement could not be explained by an altered synaptic membrane lipid composition, since no significant difference in synaptic membrane phospholipid, fatty acid, or cholesterol compositions could be detected in the two groups of mice with high and low anesthetic requirements.
In this five-period randomised double-blind crossover study, 12 healthy volunteers inhaled mixtures of nitrous oxide at concentrations of 0% (placebo); 5%, 10%; 20% and 40% in oxygen. Each concentration was inhaled for about 1 h, each period being on a separate day. The effects of nitrous oxide were measured using a comprehensive battery of performance tests including measures of attention, psychomotor function, memory and cognition. Mood was assessed with visual analogue scales. All tests except critical flicker fusion showed substantial effects at the highest does (40%). No measure showed evidence of change at the lowest concentration (5%). Several measures showed significant impairment at 10%, viz: digit-symbol substitution, choice reaction time (latency and total), tapping, and continuous attention. Subjects felt dizzy and muzzy on nitrous oxide, but no significant effect was seen on the Alert-Drowsy VAS. The dose-response profiles of the various tests showed substantial differences. Thus tapping was virtually linear, while choice reaction motor time and body sway showed steeply accelerating impairment with increasing dose. These results indicate that comparisons of profiles of drug-induced change must take into account the variable effects of dose before interpretations in terms of specific drug effects can be made.
Previous studies suggest that anesthetics produce immobility by an action on the spinal cord. We postulated that immobility results from a depression of alpha-motor neuron excitability in vivo, and that this depression would be reflected in a depression of recurrent, (F)-wave activity.
The lungs of 15 normocapnic, normothermic, normotensive rats were mechanically ventilated with 0.5, 0.8, 1.2, and 1.6 MAC isoflurane, in random sequence, with at least 30 min of equilibration at each step. In addition, at 1.2 MAC, inspired carbon dioxide was altered to create hypercapnia and hypocapnia. The sizes of the orthodromic (M) wave and F wave were measured in ten sequential trials as the activity in the intrinsic muscles of the ipsilateral foot evoked by stimulation of the tibial nerve.
M-wave amplitude did not change. F-wave amplitude did not decrease between 0.5 and 0.8 MAC but decreased 50% between 0.8 and 1.2 MAC (P < 0.001) and 60% between 1.2 and 1.6 MAC (P < 0.05). Hypocapnia (17 mmHg) increased F-wave amplitude by 15%, and hypercapnia (73 mmHg) reduced it by 60% compared with normocapnia at 1.2 MAC (31 mmHg) (P < 0.0001).
Anesthetics may cause and moderate hypercapnia may contribute to surgical immobility by depressing excitability of alpha-motor neurons. Monitoring F waves may indicate the adequacy of this aspect of anesthesia and may detect states in which spontaneous or nocifensive movements might occur.
The ability of general anesthetics to suppress somatomotor responses to surgical incision and other noxious stimuli is of particular clinical relevance. When the blockade is due to inhaled agents, this effect can be quantified as the minimum alveolar concentration (MAC), i.e., that concentration that blocks movement evoked by a noxious stimulus (ED50).
To identify the neural structures that subtend this somatomotor response, we anesthetized 14 rats with isoflurane in oxygen and performed bilateral parietal-temporal craniotomies. In each rat, MAC was repeatedly tested using tail-clamping and Dixon's up-down concentration technique. After determination of baseline MAC, seven rats underwent aspiration decerebration, after which MAC was repeatedly measured.
In the control group (N = 7), MAC (mean +/- SD) remained constant at 1.30 +/- 0.25% for more than 6 h. In the seven rats that underwent aspiration decerebration, baseline MAC was 1.26 +/- 0.14%. These seven rats with histologically validated precollicular decerebration demonstrated no change in MAC relative to control rats, as much as 11 h after decerebration (P = 0.14).
These findings suggest that the anesthetic-induced unresponsiveness to noxious stimuli measured by MAC testing does not depend on cortical or forebrain structures in the rat.
Nitrous oxide (N2O) is a commonly used sedative for painful diagnostic procedures and dental work. The authors sought to characterize the effects of N2O on quantitative electroencephalographic (EEG) variables including the bispectral index (BIS), a quantitative parameter developed to correlate with the level of sedation induced by a variety of agents.
Healthy young adult volunteers (n = 13) were given a randomized sequence of N2O/O2 combinations via face mask. Five concentrations of N2O (10, 20, 30, 40, and 50% atm) were administered for 15 min (20 min for the first step). EEG was recorded from bilateral frontal poles continuously. At the end of each exposure, level of sedation was assessed using primarily the Observer Assessment of Alertness/Sedation (OAA/S) scale.
One subject withdrew from the study because of emesis at 50% N2O. N2O (50%) increased theta, beta, 40-50 Hz, and 70-110 Hz band powers. BIS and spectral edge frequency during 50% N2O/O2 did not differ significantly from baseline values. Abrupt decreases from higher to lower concentrations frequently evoked a profound, transient slowing of activity. No significant change in OAA/S was detected during the study.
Although the spectral content of the EEG changed during N2O administration, reflecting some pharmacologic effect, the subjects remained cooperative and responsive throughout, and therefore N2O can only be considered a weak sedative at the tested concentrations. Despite changes in the lower and higher frequency ranges of EEG activity, the BIS did not change, which is consistent with its design objective as a specific measure of hypnosis.
Inhalational anesthetics produce dose-dependent effects on electroencephalogram-derived parameters, such as 95% spectral edge frequency (SEF) and bispectral index (BIS). The authors analyzed the relationship between end-tidal sevoflurane and isoflurane concentrations (FET) and BIS and SEF and determined the speed of onset and offset of effect (t1/2k(e0)).
Twenty-four patients with American Society of Anesthesiologists physical status I or II were randomly assigned to receive anesthesia with sevoflurane or isoflurane. Several transitions between 0.5 and 1.5 minimum alveolar concentration were performed. BIS and SEF data were analyzed with a combination of an effect compartment and an inhibitory sigmoid Emax model, characterized by t1/2k(e0), the concentration at which 50% depression of the electroencephalogram parameters occurred (IC50), and shape parameters. Parameter values estimated are mean +/- SD.
The model adequately described the FET-BIS relationship. Values for t1/2k(e0), derived from the BIS data, were 3.5 +/- 2.0 and 3.2 +/- 0.7 min for sevoflurane and isoflurane, respectively (NS). Equivalent values derived from SEF were 3.1 +/- 2.4 min (sevoflurane) and 2.3 +/- 1.2 min (isoflurane; NS). Values of t1/2k(e0) derived from the SEF were smaller than those from BIS (P < 0.05). IC50 values derived from the BIS were 1.14 +/- 0.31% (sevoflurane) and 0.60 +/- 0.11% (isoflurane; P < 0.05).
The speed of onset and offset of anesthetic effect did not differ between isoflurane and sevoflurane; isoflurane was approximately twice as potent as sevoflurane. The greater values of t1/2k(e0) derived from the BIS data compared with those derived from the SEF data may be related to computational and physiologic delays.
Unlabelled:
Two defining effects of inhaled anesthetics (immobility in the face of noxious stimulation, and absence of memory) correlate with the end-tidal concentrations of the anesthetics. Such defining effects are characterized as MAC (the concentration producing immobility in 50% of patients subjected to a noxious stimulus) and MAC-Awake (the concentration suppressing appropriate response to command in 50% of patients; memory is usually lost at MAC-Awake). If the concentrations are monitored and corrected for the effects of age and temperature, the concentrations may be displayed as multiples of MAC for a standard age, usually 40 yr. This article provides an algorithm that might be used to produce such a display, including provision of an estimate of the effect of nitrous oxide.
Implications:
Two defining effects of inhaled anesthetics (immobility in the face of noxious stimulation, and absence of memory) correlate with the end-tidal concentrations of the anesthetics. Thus, these defining effects may be monitored and the results displayed if the concentrations are known and corrected for the effects of age and temperature.
It has been shown that spinal reflexes such as the H-reflex predict motor responses to painful stimuli better than cortical parameters derived from the EEG. The precise concentration-dependence of H-reflex suppression by anaesthetics, however, is not known. Here we investigated this concentration-response relationship and the equilibration between the alveolar and the effect compartment for sevoflurane.
In 26 patients, the H-reflex was recorded at a frequency of 0.1 Hz while anaesthesia was induced and maintained with sevoflurane at increasing and decreasing concentrations. Population pharmacodynamic modelling was performed using the NONMEM software package, yielding population mean parameters as well as indicators of interindividual variability.
Suppression of H-reflex amplitude occurred at lower concentrations (mean EC(50) 1.04 +/- 0.10 vol%, SE of NONMEM estimate) than the effect on either BIS or SEF(95) of the EEG (mean EC(50) 1.55 +/- 0.08 and 1.72 +/- 0.18 vol%, respectively), and exhibited a higher interindividual variability. The concentration-response function for the H-reflex was also steeper (mean ë 2.83 +/- 0.25). In addition, the equilibration between alveolar and effect compartment was slower for the H-reflex (mean k(e0) 0.15 +/- 0.01 min(-1)) than for BIS or SEF(95) (mean k(e0) 0.22 +/- 0.02 and 0.41 +/- 0.05 min(-1)).
The differences in EC(50) and slope of the concentration-response relationships for H-reflex suppression and the EEG parameters point to different underlying mechanisms. In addition, the differences in time constant for equilibration between alveolar and effect compartment confirm the notion that immobility is caused at a different anatomic site than suppression of the EEG.
Two recent studies have examined the pharmacokinetics of sevoflurane in adults. Lu et al.(Pharmacokinetics of sevoflurane uptake into the brain and body, Anaesthesia 2003; 58: 951-6) observed that jugular bulb sevoflurane concentration initially rose unexpectedly rapidly and then approached arterial concentrations unexpectedly slowly, suggesting that a blood-brain diffusion barrier exists. They also observed a large alveolar-arterial sevoflurane gradient, suggesting that an alveolar-arterial diffusion barrier exists. Nakamura et al. (Predicted sevoflurane partial pressure in the brain with an uptake and distribution model: Comparison with the measured value in internal jugular vein blood. Journal of Clinical Monitoring and Computing 1999; 15: 299-305) found no diffusion barriers. We used a computer model to analyse both data sets and show that the observations of Lu et al. can be explained by contamination of jugular samples with extracerebral blood. It is possible that the alveolar-arterial gradients observed by Lu et al. are due to discrepancies in conversions between blood concentrations and gas partial pressures. Our study suggests that there is no blood-brain diffusion barrier for sevoflurane and that the data of Lu et al. must be interpreted with caution.
This study evaluated the relative importance of perfusion and diffusion mechanisms in compartmental models of blood:tissue helium exchange in the brain. Helium has different physiochemical properties from previously studied gases, and is a common diluent gas in underwater diving where decompression schedules are based on theoretical models of inert gas kinetics. Helium kinetics across the cerebrum were determined during and after 15 min of helium inhalation, at separate low and high steady states of cerebral blood flow in seven sheep under isoflurane anaesthesia. Helium concentrations in arterial and sagittal sinus venous blood were determined using gas chromatographic analysis, and sagittal sinus blood flow was monitored continuously. Parameters and model selection criteria of various perfusion-limited or perfusion-diffusion compartmental models of the brain were estimated by simultaneous fitting of the models to the sagittal sinus helium concentrations for both blood flow states. Purely perfusion-limited models fitted the data poorly. Models that allowed a diffusion-limited exchange of helium between a perfusion-limited tissue compartment and an unperfused deep compartment provided better overall fit of the data and credible parameter estimates. Fit to the data was also improved by allowing countercurrent diffusion shunt of helium between arterial and venous blood. These results suggest a role of diffusion in blood:tissue helium equilibration in brain.
The purpose of this study was to clarify the difference between cerebral blood flow (CBF) by perfusion computed tomography (CT) and that by xenon-enhanced CT (Xe-CT) through simultaneous measurement.
Xenon-enhanced CT and perfusion CT were continually performed on 7 normal subjects. Ratios of CBF by perfusion CT (P-CBF) to CBF by Xe-CT (Xe-CBF) were measured for 5 arterial territories; 3 were territories of 3 major arteries (the anterior [ACA], middle [MCA], and posterior [PCA] cerebral arteries), and the other 2 were areas of the thalamus and putamen.
The ratios were 1.30 +/- 0.10, 1.26 +/- 0.15, 1.61 +/- 0.15, 0.801 +/- 0.087, and 0.798 +/- 0.080 for the ACA, MCA, PCA, thalamus, and putamen, respectively. Although a good correlation was observed between P-CBF and Xe-CBF for each territory, the ratios were significantly different (P < 0.0001) between 3 territory groups (group 1: ACA and MCA, group 2: PCA, and group 3: thalamus and putamen).
The difference in the ratio of P-CBF to Xe-CBF between the 3 territory groups was considered to result principally from the features of P-CBF. To evaluate P-CBF properly, its territorial characteristics should be taken into account.
On the basis of electroencephalographic analysis, several parameters have been proposed as a measure of the hypnotic component of anesthesia. All currently available indices have different time lags to react to a change in the level of anesthesia. The aim of this study was to determine the latency of three frequently used indices: the Cerebral State Index (Danmeter, Odense, Denmark), the Bispectral Index (Aspect Medical Systems Inc., Newton, MA), and the Narcotrend Index (MonitorTechnik, Bad Bramstedt, Germany).
Artificially generated signals were used to produce up to 14 constant index values per monitor that indicate "awake state," "general anesthesia," and "deep anesthesia" and smaller steps in between. The authors simulated loss of and return to consciousness by changing between the artificial electroencephalographic signals in a full-step and two stepwise approaches and measured the time necessary to adapt the indices to the particular input signal.
Time delays between 14 and 155 s were found for all indices. These delays were not constant. Results were different for decreasing and increasing values and between the full-step and the stepwise approaches. Calculation time depended on the particular starting and target index value.
The time delays of the tested indices may limit their value in prevention of recall of intraoperative events. Furthermore, different latencies for decreasing and increasing values may indicate a limitation of these monitors for pharmacodynamic studies.
Selective breeding produces animal strains with varying anesthetic sensitivity. It thus seems unlikely that various human ethnicities have identical anesthetic requirements. Therefore, the authors tested the hypothesis that the minimum alveolar concentration of sevoflurane differs significantly as a function of ethnicity.
The authors recruited 90 American Society of Anesthesiologists physical status I and II adult patients belonging to three Jewish ethnic groups: European, Oriental, and Caucasian (from the Caucasus Mountain region). All were scheduled to undergo surgery requiring a skin incision exceeding 3 cm. Without premedication, anesthesia was induced with 6-8% sevoflurane in 100% oxygen, and tracheal intubation was facilitated with succinylcholine. The skin incision was made after a predetermined end-tidal concentration of sevoflurane of 2.0% was maintained for at least 10 min in the first patient in each group. Blinded investigators observed the patient for movement during the subsequent minute. The concentration in the next patient was increased by 0.2% when patients moved, or decreased by the same amount when they did not. Results are presented as means [95% confidence intervals].
Morphometric and demographic characteristics were similar among the groups; however, mean arterial pressure was slightly greater in European Jews. Minimum alveolar concentration for sevoflurane was greatest in Caucasian Jews (2.32% [2.27-2.41%]), less in Oriental Jews (2.14% [2.06-2.22%]), and still less in European Jews (1.9% [1.82-1.99%]) (P < 0.001).
The results suggest that minimum alveolar concentration varies as a function of ethnicity. However, the extent to which confounding characteristics contribute, including lifestyle choices and environmental factors, remains unknown.
Threshold concentration of nitrous oxide affecting psychomotor performance.
- Allison