Differential effects of halothane and isoflurane on lumbar dorsal horn neuronal windup and excitability.

BACKGROUND: Windup of spinal nociceptive neurones may underlie temporal summation of pain, influencing the minimum alveolar concentration (MAC) of anaesthetics required to prevent movement to supramaximal stimuli. We hypothesized that halothane and isoflurane would differentially affect windup of dorsal horn neurones. METHODS: We recorded 18 nociceptive dorsal horn neurones exhibiting windup to 1 Hz electrical hindpaw stimuli in rats. Effects of 0.8 and 1.2 MAC isoflurane and halothane were recorded in the same neurones (counterbalanced, crossover design). Windup was calculated as the total number of C-fibre (100-400 ms latency) plus afterdischarge (400-1000 ms latency) spikes/20 stimuli (area under curve, AUC) or absolute windup (C-fibre plus afterdischarge-20 x initial response). RESULTS: Increasing isoflurane from 0.8 to 1.2 MAC did not affect AUC, but increased absolute windup from 429 (62) to 618 (84) impulses/20 stimuli (P<0.05) and depressed the initial C-fibre response from 14 (3) to 8 (2) impulses (P<0.05). Increasing halothane from 0.8 to 1.2 MAC depressed AUC from 690 (79) to 537 (65) impulses/20 stimuli (P<0.05) and the initial response from 18 (2) to 13 (2) impulses (P<0.05), but absolute windup was not affected. Absolute windup was 117% greater during 1.2 MAC isoflurane compared with 1.2 MAC halothane. CONCLUSIONS: Windup was significantly greater under isoflurane than halothane anaesthesia at 1.2 MAC, whereas the initial C-fibre response was suppressed more by isoflurane. These findings suggest that these two anaesthetics have mechanistically distinct effects on neuronal windup and excitability.

The concentration of isoflurane required to suppress learning depends on the type of learning.

BACKGROUND: Recent reports suggest that one type of learning, fear conditioning to context, requires more neural processing than a related type, fear conditioning to tone. To determine whether these types of learning were differentially affected by anesthesia, the authors applied isoflurane during the training phases of fear conditioning paradigms for freezing to context and freezing to tone. METHODS: The authors trained seven groups of eight rats to fear tone by administering a tone (conditioned stimulus) while breathing various concentrations of isoflurane from 0.00 to 0.75 minimum alveolar concentration (MAC; one concentration per group) separated by 0.12-MAC steps. On the succeeding day, and in the absence of isoflurane, the authors presented the tone (without shock) in a different context (different cage shape and odor) and measured the time each rat froze (became immobile). Six other groups of eight rats were trained to fear context by applying the shock in the absence of a tone but in the presence of environmental cues such as cage shape, texture, and odor. Fear to context was determined the succeeding day by returning the rat to the training cage (without shock) and measuring duration of freezing. Control groups (16 per group) received 0.75 MAC isoflurane but no foot shocks. Group scores were compared using analysis of variance, and the ED50 values for quantal responses of individual rats were calculated using logistic regression. RESULTS: Conditioning to context occurred at 0.00 and 0.13 MAC (P < 0.05 compared with unshocked control) but not 0.25 MAC; the ED50 was 0.25 +/- 0.03 MAC (mean +/- SEM). In contrast, conditioning to tone occurred at 0.48 MAC (P < 0.05) but not 0.62 MAC; the ED50 was 0.47 +/- 0.02 MAC (P < 0.01 for the difference between ED50 values). CONCLUSIONS: Suppression of fear conditioning to tone required approximately twice the isoflurane concentration that suppressed fear conditioning to context. Thus, the concentration of anesthetic required to suppress learning may depend on the neural substrates of learning. Our results suggest that isoflurane concentrations greater than 0.5 MAC may be needed to suppress both forms of fear conditioning.

Inhaled anesthetics have hyperalgesic effects at 0.1 minimum alveolar anesthetic concentration.

UNLABELLED: We investigated the hyperalgesic (antianalgesic) effect of the inhaled anesthetics isoflurane, halothane, nitrous oxide, and diethyl ether, or the nonimmobilizer 1, 2-dichlorohexafluorocyclobutane at subanesthetic partial pressures (or, for the nonimmobilizer, subanesthetic partial pressures predicted from lipid solubility) in rats. Hyperalgesia was assessed as a decrease in the time to withdrawal of a rat hind paw exposed to heat. All four anesthetics, including nitrous oxide and diethyl ether, produced hyperalgesia at low partial pressures, with a maximal effect at 0.1 minimum alveolar anesthetic concentration (MAC) required to prevent response to movement in 50% of animals, and analgesia (an increased time to withdrawal of the hind paw) at 0. 4 to 0.8 MAC. The nonimmobilizer had neither analgesic nor hyperalgesia effects. We propose that inhaled anesthetics with a higher MAC-Awake (the MAC-fraction that suppresses appropriate responsiveness to command), such as nitrous oxide and diethyl ether, can be used as analgesics because patients are conscious at higher anesthetic partial pressures, including those which have analgesic effects, whereas anesthetics with a lower MAC-Awake do not produce analgesic effects at concentrations that permit consciousness. IMPLICATIONS: The inhaled anesthetics isoflurane, halothane, nitrous oxide, and diethyl ether produce antianalgesia at subanesthetic concentrations, with a maximal effect at approximately one-tenth the concentration required for anesthesia. This effect may enhance perception of pain when such small concentrations are reached during recovery from anesthesia.

Inhaled nonimmobilizers do not alter the middle latency auditory-evoked response of rats.

UNLABELLED: General anesthetics cause surgical immobility and oblivion (unconsciousness and amnesia). A class of compounds known as "nonimmobilizers" were predicted to be anesthetic, based on their physiochemical properties, but found to cause only amnesia. In humans, cerebrocortical electrical activity after auditory stimulation is depressed by concentrations of anesthetics which impair auditory recall. We sought to use these evoked responses to characterize the effects of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) and conventional inhaled anesthetics on early sensory processing in rats. Unrestrained rats with chronically implanted epidural silver screw electrodes were put into a chamber. On separate days, the same population of rats were exposed to isoflurane, desflurane, nitrous oxide, or 2N, each at several subminimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus concentrations. After equilibration at each concentration, auditory-evoked responses were obtained. The behavioral state (activity and righting reflex) and electroencephalogram were also examined. 2N did not significantly change the middle latency auditory-evoked response, whereas the anesthetics all slowed conduction and depressed amplitude in a dose-dependent fashion. 2N neither depressed the righting reflex, nor induced epileptiform activity. IMPLICATIONS: Although the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) suppresses learning, we find that 2N does not depress middle latency auditory-evoked responses. This suggests that 2N may suppress learning by depressing transmission through rostral subcortical structures, such as the amygdala, rather than by acting on the brainstem or neocortical structures.

Forty-hertz midlatency auditory evoked potential activity predicts wakeful response during desflurane and propofol anesthesia in volunteers.

BACKGROUND: Suppression of response to command commonly indicates unconsciousness and generally occurs at anesthetic concentrations that suppress or eliminate memory formation. The authors sought midlatency auditory evoked potential indices that successfully differentiated wakeful responsiveness and unconsciousness. METHODS: The authors correlated midlatency auditory evoked potential indices with anesthetic concentrations permitting and suppressing response in 22 volunteers anesthetized twice (5 days apart), with desflurane or propofol. They applied stepwise increases of 0.5 vol% end-tidal desflurane or 0.5 microg/ml target plasma concentration of propofol to achieve sedation levels just bracketing wakeful response. Midlatency auditory evoked potentials were recorded, and wakeful response was tested by asking volunteers to squeeze the investigator's hand. The authors measured latencies and amplitudes from raw waveforms and calculated indices from the frequency spectrum and the joint time-frequency spectrogram. They used prediction probability (PK) to rate midlatency auditory evoked potential indices and concentrations of end-tidal desflurane and arterial propofol for prediction of responsiveness. A PK value of 1.00 means perfect prediction and a PK of 0.50 means a correct prediction 50% of the time (e.g., by chance). RESULTS: The approximately 40-Hz power of the frequency spectrum predicted wakefulness better than all latency or amplitude indices, although not all differences were statistically significant. The PK values for approximately 40-Hz power were 0.96 during both desflurane and propofol anesthesia, whereas the PK values for the best-performing latency and amplitude index, latency of the Nb wave, were 0.86 and 0.88 during desflurane and propofol (P = 0.10 for -40-Hz power compared with Nb latency), and for the next highest, latency of the Pb wave, were 0.82 and 0.84 (P < 0.05). The performance of the best combination of amplitude and latency variables was nearly equal to that of approximately 40-Hz power. The approximately 40-Hz power did not provide a significantly better prediction than anesthetic concentration; the PK values for concentrations of desflurane and propofol were 0.91 and 0.94. Changes of 40-Hz power values of 20% (during desflurane) and 16% (during propofol) were associated with a change in probability of nonresponsiveness from 50% to 95%. CONCLUSIONS: The approximately 40-Hz power index and the best combination of amplitude and latency variables perform as well as predictors of response to command during desflurane and propofol anesthesia as the steady-state concentrations of these anesthetic agents. Because clinical conditions may limit measurement of steady-state anesthetic concentrations, or comparable estimates of cerebral concentration, the approximately 40-Hz power could offer advantages for predicting wakeful responsiveness.

Craniofacial electromyogram activation response: another indicator of anesthetic depth.

OBJECTIVE: After finding that craniofacial EMG preceding a stimulus was a poor predictor of movement response to that stimulus, we evaluated an alternative relation between EMG and movement: the difference in anesthetic depth between the endpoint of EMG responsiveness to a stimulus and endpoint of movement responsiveness to that stimulus. We expressed this relation as the increment of isoflurane between the two endpoints. METHODS: We measured EMG over the frontalis muscle, over the corrugator muscle, and between the Fp2 and the mastoid process as patients emerged from general anesthesia during suture closing of the surgical incision. Anesthesia was decreased by controlled washout of isoflurane while maintaining 70% N2O, and brain isoflurane concentrations ((C)isoBrain) were calculated. We studied a control group of 10 patients who received only surgical stimulation, and 30 experimental patients who intermittently received test stimuli in addition to the surgical stimulation. Patients were observed for movement responses and EMG records were evaluated for EMG activation responses. We defined an EMG activation response to be a rapid voltage increase of at least 1.0 microV RMS above baseline, with a duration of at least 30 s, in at least one of the three EMG channels. Patient responses to stimuli were classified as either an EMG activation response without a move response (EMG+), a move response without an EMG activation response (MV+), both an EMG activation response and a move response (EMG+MV+), or no response. We defined the EMG+ endpoint to be the threshold between EMG+ response and nonresponse to a stimulus, and estimated (C)isoBrain at this endpoint. We similarly defined the move endpoint and estimated the move endpoint (C)isoBrain. We then calculated the increment of (C)isoBrain at the EMG+ endpoint relative to the move endpoint. MAIN RESULTS: For the 30 experimental patients, the initial response to a test stimulus was an EMG+ in 14 patients (47%), an EMG+MV+ in 12 patients (40%), and a MV+ in 1 patient (3%); no response occurred by the time surgery was completed in 3 patients (10%). No response occurred in 7 of the control patients (70%). Of the 14 patients with an initial EMG+ response to a test stimulus, 9 patients later had a move response. For these 9 patients, the increment of (C)isoBrain between the EMG+ endpoint and move endpoint was 0.11 +/- 0.04 vol%, (mean +/- SD). CONCLUSIONS: Our results suggest that, given the circumstances of our study, an EMG activation response by a nonmoving patient indicates that the patient is at an anesthetic level close to that at which movement could occur. However, because the first EMG activation response may occur simultaneously with movement, the EMG activation response cannot be relied upon to always herald a move response before it occurs. Our results also suggest that EMG responsiveness to a test stimulus may be used to estimate the anesthetic depth of an individual patient.

A measure of association for assessing prediction accuracy that is a generalization of non-parametric ROC area.

There is a need for a measure of prediction accuracy that generalizes non-parametric receiver operating characteristic (ROC) area to polytomous ordinal patient state. We describe such a measure, prediction probability PK derived from Kim's measure of association. We show that the value of PK equals the value of non-parametric ROC area for dichotomous patient state and is a meaningful generalization of non-parametric ROC area for polytomous state.

EEG Predicts movement response to surgical stimuli during general anesthesia with combinations of isoflurane, 70% N2O, and fentanyl.

OBJECTIVE: Our objective was to evaluate the performance of the EEG as an indicator of anesthetic depth by measuring EEG prediction of movement response to surgical stimuli. METHODS: While using 5 different combinations of isoflurane, 70% N2O, and fentanyl, we measured the EEG of 246 patients during pelvic laparoscopy and observed their movement responses to opening stimuli (defined as skin incision, CO2 needle insertion, or trocar insertion) and also to closing stimuli (defined as sutures during incision closure). The EEG was expressed as F95, the frequency in hertz below which resides 95% of the power in the EEG frequency spectrum. The relations between F95 and movement response were expressed as logistic regression curves. F95-response logistic regression curves, which are analogous to dose-response curves, were calculated for each of the 2 stimuli administered during each of the 5 anesthetic techniques. The prediction of patient responsiveness by F95 was tested using beta (beta), a measure of the slope of an F95-response logistic curve. The presence of shifts among the F95-response logistic curves was tested using the differences in F95 values between curves. Hypothesis tests used a level of significance of P = 0.05. MAIN RESULTS: The slopes of the F95-response logistic regression curves showed a statistically significant ability to predict movement response to stimuli for 9 of the 10 combinations of stimuli and anesthetic techniques. We did not calculate an F95-response logistic curve for the tenth combination because it contained burst suppression, which our EEG analysis method was not designed to process. The F95-response logistic curves were shifted relative to each other, and the shifts were affected by the type of stimulus and the combination of anesthetic agents. Referenced to opening curves, the mean shift of the closing curves was +4.2 +/- 0.3 Hz (mean +/- SD). With increasing doses of fentanyl, the use of 70% N2O, or both, the curves shifted to higher values of F95; the range in shifts was 0.2 to 8.1 Hz. The slope beta values of the F95-response logistic curves and the shifts among the curves were similar to the beta values and shifts that might be expected from changes in anesthetic agent doses. CONCLUSIONS: The EEG, expressed as F95, predicted movement response to surgical stimuli during combinations of isoflurane, 70% N2O, and fentanyl. The F95-response curves shifted upward on the frequency scale for the less intense stimuli and for anesthetic techniques using 70% N2O, fentanyl, or both. F95 prediction of movement response appeared to be related to anesthetic agent doses. Our F95-response curves may provide helpful guidelines for using F95 to titrate the administration of anesthetic agents and for assessing the depth of general anesthesia.

Measuring the performance of anesthetic depth indicators.

BACKGROUND: An appropriate measure of performance is needed to identify anesthetic depth indicators that are promising for use in clinical monitoring. To avoid misleading results, the measure must take into account both desired indicator performance and the nature of available performance data. Ideally, anesthetic depth indicator value should correlate perfectly with anesthetic depth along a lighter-deeper anesthesia continuum. Experimentally, however, a candidate anesthetic depth indicator is judged against a "gold standard" indicator that provides only quantal observations of anesthetic depth. The standard anesthetic depth indicator is the patient's response to a specified stimulus. The resulting observed anesthetic depth scale may consist only of patient "response" versus "no response," or it may have multiple levels. The measurement scales for both the candidate anesthetic depth indicator and observed anesthetic depth are no more than ordinal; that is, only the relative rankings of values on these scales are meaningful. METHODS: Criteria were established for a measure of anesthetic depth indicator performance and the performance measure that best met these criteria was found. RESULTS: The performance measure recommended by the authors is prediction probability PK, a rescaled variant of Kim's dy.x measure of association. This performance measure shows the correlation between anesthetic depth indicator value and observed anesthetic depth, taking into account both desired performance and the limitations of the data. Prediction probability has a value of 1 when the indicator predicts observed anesthetic depth perfectly, and a value of 0.5 when the indicator predicts no better than a 50:50 chance. Prediction probability avoids the shortcomings of other measures. For example, as a nonparametric measure, PK is independent of scale units and does not require knowledge of underlying distributions or efforts to linearize or to otherwise transform scales. Furthermore, PK can be computed for any degree of coarseness or fineness of the scales for anesthetic depth indicator value and observed anesthetic depth; thus, PK fully uses the available data without imposing additional arbitrary constraints, such as the dichotomization of either scale. And finally, PK can be used to perform both grouped- and paired-data statistical comparisons of anesthetic depth indicator performance. Data for comparing depth indicators, however, must be gathered via the same response-to-stimulus test procedure and over the same distribution of anesthetic depths. CONCLUSIONS: Prediction probability PK is an appropriate measure for evaluating and comparing the performance of anesthetic depth indicators.

Subanesthetic concentrations of desflurane and propofol suppress recall of emotionally charged information.

Whether anesthetized patients register emotionally charged information remains controversial. We tested this possibility using subanesthetic concentrations of propofol or desflurane. Twenty-two volunteers (selected for hypnosis susceptibility) received propofol and desflurane (on separate occasions, and in a random order) at a concentration 1.5-2 times each individual's minimum alveolar anesthetic concentration (MAC)-awake (or equivalent for propofol). We gave vecuronium, intubated the trachea of each volunteer, controlled ventilation, and then presented a neutral (control) drama or a "crisis" drama stating that the oxygen delivery system had failed, assigning crisis and control dramas in a blinded, randomized, and balanced manner. One day later, interviewers blinded to the assigned drama conducted a 2-h structured interview (including hypnosis) to determine whether the contents of the interviews after crisis and control dramas differed. In addition, messages permitting subsequent assessment of learning of matter-of-fact information (Trivial Pursuit-type question task and a behavior task) were presented at the anesthetic concentration just sufficient to prevent response to command in each volunteer. No analyses of the tasks involving matter-of-fact information revealed learning except one which correlated hypnosis susceptibility with behavior task performance. Both propofol and desflurane suppressed memory of the crisis. Consistent with previous findings for isoflurane and nitrous oxide, propofol and desflurane suppressed learning of matter-of-fact information at concentrations just above MAC-awake, except that volunteers' susceptibility to hypnosis correlated with performance of a behavior suggested during anesthesia. Propofol and desflurane suppressed learning of emotionally charged information at anesthetic concentrations 1.5-2 times MAC-awake (less than MAC), a different result from that previously reported for ether.

Concentrations of desflurane and propofol that suppress response to command in humans.

The anesthetic concentration just suppressing appropriate response to command (minimum alveolar anesthetic concentration awake [MAC-awake] for volatile anesthetics or plasma concentration to prevent a response in 50% of patients [Cp50]-awake for intravenous anesthetics) provides three important measures. First, along with pharmacokinetics, the ratio of the awakening concentration to the anesthetizing concentration (MAC-awake/MAC or Cp50-awake/Cp50) determines time to awakening. Second, a correlation between MAC-awake and the anesthetic concentration sufficient to prevent learning suggests MAC-awake provides a surrogate measure of amnestic potency. Third, population values for MAC-awake provide evidence for or against commonality in anesthetic mechanisms. We studied 22 male volunteers twice to determine both MAC-awake for desflurane (2.60% +/- 0.46%) and Cp50-awake for propofol (2.69 +/- 0.56 microgram/mL). Awakening with desflurane occurs at a concentration closer to its anesthetizing concentration (36% of MAC) than propofol (18% of Cp50); that is, 1) desflurane requires less of a decrement in anesthetic concentration at the effect site for arousal; and 2) if MAC-awake (Cp50-awake) values reflect the concentrations providing amnesia, propofol is a more potent amnestic. Of interest, the dose response curves of desflurane and propofol were equivalently steep, a finding consistent with a common mechanism of action. In contrast, sensitivity of each volunteer to desflurane did not correlate with sensitivity to propofol (r2 < 0.01, P = 0.98) arguing against a common mechanism.

Wakeful response to command indicates memory potential during emergence from general anesthesia.

OBJECTIVE: An important aspect of assessing anesthetic depth is determining whether a patient will remember events during surgery. We looked for a clinical sign that would indicate a patient's potential for memory formation during emergence from anesthesia. A clinical sign indicating memory potential could be a useful endpoint for measuring the performance of anesthetic depth monitors and for titrating administration of anesthetic agents. METHODS: We evaluated patients' responses to commands to open the eyes, squeeze the hand four times, and count 20 numbers. These responses were correlated with results on recall, cued recall, and multiple-choice memory tests. MAIN RESULTS: Patients did not have evidence of memory formation until they sustained wakefulness sufficiently long to complete at least four hand squeezes or count four numbers. Of 28 patients, 13 (46%) with this sustained wakeful response had memory. Of 22 patients, 0 (0%) had evidence of memory formation when they demonstrated a brief wakeful response, defined as being responsive to command but unable to complete more than one hand squeeze or count, or an intermediate response, defined as two or three hand squeezes or counts. CONCLUSIONS: We conclude that a brief wakeful response to command indicates that a patient is unlikely to form memories, while a sustained wakeful response indicates that a patient may form memories. Thus, a patient's wakeful response to command could be a useful indicator of potential for memory.

Brief wakeful response to command indicates wakefulness with suppression of memory formation during surgical anesthesia.

OBJECTIVE: In a previous study of patients emerging from anesthesia following surgery, we found that a brief wakeful response to command of an eye opening or single hand squeeze or count was not associated with memory formation, while the response of four hand squeezes or counts was associated with memory. We wanted to determine the anesthetic requirements for obtaining this brief wakeful response endpoint during surgery and to determine if memory occurred at this endpoint during surgical anesthesia. METHODS: Six different combinations of isoflurane, 70% N2O, and fentanyl were administered to 326 patients undergoing pelvic laparoscopy. After insertion of the trocar, anesthesia was reduced while patients were given verbal commands, and they were observed for movement responses to surgery and to command. Patients were classified as either not arousing, arousing with a movement response to surgery, or arousing with a wakeful response to command. For the patients who aroused, we calculated the percentage of arousal responses that were wakeful responses to command. The effect of fentanyl dosage upon the percentage of arousal responses that were wakeful responses to command was determined by using a Mann-Whitney test to compare a group of patients receiving fentanyl 2 micrograms/kg or less, with a group receiving fentanyl 4 micrograms/kg. In a subset of 39 patients, the potential for memory formation was evaluated by presenting a target sound to 29 patients during a period of either no arousal, movement response to surgery, or wakeful response to command; for a control group of 10 patients, no target sound was presented. All 39 patients were tested for memory of the target sound; the results from each group receiving a target sound were compared with the results of the control group, using a Mann-Whitney test. MAIN RESULTS: A total of 68 patients aroused with either a movement response or a wakeful response to command. Wakeful responses occurred with only 1 of 39 patients (3%) receiving fentanyl 2 micrograms/kg or less; but, wakeful responses occurred with 17 of 29 patients (59%) receiving fentanyl 4 micrograms/kg. The difference between the groups was significant at p = 0.01. None of the 68 patients had recall of intraoperative events or unpleasant dreams. None of these patients who were in the multiple-choice memory subset recalled the target sound. There were no statistically significant differences on the multiple-choice memory test between the groups presented with the target sound and the control group. Patient anecdotes suggested that some patients may have had memory of the target sound; but, memory was no more likely in patients with a brief wakeful response to command than in those who responded with a movement to surgical stimulation or those who did not have an arousal response. CONCLUSIONS: A brief wakeful response to a command of opening the eyes or squeezing the hand was not associated with increased memory formation during surgery. A brief wakeful response to command was found during surgery when patients received fentanyl 4 micrograms/kg; but it was rarely found at fentanyl dosages of 2 micrograms/kg or less.