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General anesthesia, at a minimum, provides amnesia and unresponsiveness. Although anesthetics have many modulatory effects on neuronal ionophore protein complexes, it is not clear that the resulting electrophysiologic changes are the sole mechanisms of clinical anesthetic action. Cells respond to environmental changes in several ways, including alterations in DNA transcription leading to changes in the cell's proteins. We sought to expose the changes in global genomic expression, seeking potential targets involved in the processes of anesthetic-induced amnesia, and persistent long-term side effects of general anesthesia, including nausea and postoperative cognitive decline. Using Affymetrix GeneChips, we surveyed changes in expression across the entire expressed genome of Sprague-Dawley rat (n = 10 baseline, n = 6 isoflurane) basolateral amygdala 6 h after exposure to 15 min of 2% (1.4 MAC) isoflurane. Isoflurane administration was associated with altered expression in 269 unique genes possessing functional annotation. Affected genes were related to DNA transcription, protein synthesis, metabolism, signaling cascades, cytoskeletal structural proteins, and neural-specific proteins, among others. Even brief exposure to isoflurane leads to widespread changes in the genetic control in the amygdala 6 h after exposure. Gene expression is a dynamic process that may explain some long-term effects of anesthesia and that has the potential to modulate some of those effects using specific molecular therapeutics.

Devices which monitor some aspect of anesthetic drug effects have evolved in the past few years into imperfect, but very useful, clinical tools. With appropriate respect for their limitations these monitors can be used to reduce anesthetic drug utilization and turnover time. The intriguing hypothesis that such monitors will reduce the risk of intraoperative awareness is currently under test.

Background Evoked, recurrent electromyographic activity (F waves) reflect alpha-motor neuron excitability. Based on observations that other inhaled anesthetics do so, we hypothesized that nitrous oxide, alone or in combination with isoflurane, would depress F-wave activity and correlate with depression of movement response to tail clamp or electric stimulation. Methods In study 1, the authors examined the effect of nitrous oxide in combination with isoflurane in 13 normocapnic Sprague-Dawley rats anesthetized with 1.0% isoflurane (0.7 minimum alveolar concentration) in oxygen. The tibial nerve was stimulated at the popliteal fossa, and evoked electromyographic activity [M (direct neuromuscular junctional response) and F waves] were recorded from ipsilateral foot muscles. The effect of the addition of 30% or 70% nitrous oxide was measured. F-wave amplitude/M-wave amplitude ratio (F/M) was determined from each stimulus-electromyographic response pair. F/M vs. movement response to 60-s tail clamp was assessed after each recording session. F-wave amplitude/M-wave amplitude ratio at adjacent doses that permitted and prevented movement were compared. In study 2, the authors examined the effect of (hyperbaric) nitrous oxide as the sole anesthetic agent on F waves. In 11 rats anesthetized with isoflurane, stimulation and recording electrodes were placed as described above, with additional electrodes for stimulation placed in the tail. Rats were placed in a pressure chamber pressurized with nitrous oxide/oxygen to 3.4 atm. Thirty m were allowed for isoflurane washout. Electromyographic activity was evoked and recorded at 1.0, 1.6, 2.2 and 2.7 atm N2O (random order). Movement in response to 60 s of 15 V, 50-Hz tail stimulation was evaluated after each recording session. Results Nitrous oxide with or without isoflurane produced a dose-dependent decrease in F/M. By interpolation of this data, the authors found that 2 atm N2O alone, or 44% N2O added to 1.0% isoflurane at 1.0 atm, produced 1.0 minimum alveolar concentration anesthesia. At the deepest level of isoflurane/ nitrous oxide that permitted movement, mean F/M was 20.6 +/- 17.5%; at the lowest concentration that blocked movement, rats had a mean F/M of 13.7 +/- 13.9% (P = 0.01). At the minimal hyperbaric nitrous oxide blocking movement, rats had a mean F/M of 3.7 +/- 2.9%, whereas the F/M at the highest nitrous oxide dose that permitted movement was 4.4 +/- 2.7% (P < 0.04). Conclusions Because nitrous oxide depressed F-wave but not M-wave activity, the data suggest a central (spinal) rather than neuromuscular junctional site of action of this agent. The direct correlation between nitrous oxide dose, F-wave amplitude depression, and surgical immobility suggests the possibility of using F-wave activity to predict the likelihood of anesthetic-induced immobility. However, the mechanism of action of nitrous oxide may differ from that of the potent inhaled agents.

Background In vitro studies demonstrate that halothane, but not isoflurane, inhibits bradykinin-induced calcium currents and prostacyclin release in cultured endothelial cells. Because bradykinin is an important endogenous mediator of inflammation, we assessed the effects of halothane, isoflurane, and pentobarbital on plasma extravasation, a component of tissue inflammation induced by bradykinin, in rats. Methods We anesthetized 23 rats with halothane (0.8 or 1.3 minimum alveolar concentration [MAC]), isoflurane (1.3 MAC), or pentobarbital (total of 85 mg/kg intraperitoneally). Their tracheas were intubated and their lungs mechanically ventilated. After intravenous administration of Evans blue dye, we perfused normal saline followed by bradykinin or platelet-activating factor, another inflammatory mediator, intraarticularly via needles placed in the knee joint. We collected perfusate and estimated extravasation by measuring dye in the perfusate using spectrophotometry. Results Bradykinin increased plasma extravasation eight- to ninefold above baseline in both pentobarbital- and isoflurane-anesthetized rats. In contrast, bradykinin-induced plasma extravasation at 0.8 MAC and 1.3 MAC of halothane was approximately 40% (P < 0.01) and 15% (P < 0.001), respectively, of that in pentobarbital- and isoflurane-anesthetized rats. Baseline plasma extravasation was lower in rats anesthetized with either concentration of halothane compared with pentobarbital or isoflurane (all P < 0.001). Platelet-activating factor-induced plasma extravasation was similar for all anesthetics. Conclusion Halothane, but not isoflurane or pentobarbital, inhibits both baseline and bradykinin-induced peripheral plasma extravasation, demonstrating that volatile anesthetics differentially modulate this important component of inflammation.

BACKGROUND: The power spectrum of the electroencephalogram (EEG) may be analyzed to provide quantitative measures of EEG activity (e.g., spectral edge, which defines the highest EEG frequency at which significant activity is found). The current study tested the hypothesis that spectral edge and similar measures distinguish different functional depths of anesthesia in humans. METHODS: Three groups were studied. Group 1 consisted of 34 surgical patients (ASA physical status 1 or 2) who received 0.6, 1.0 and 1.4 MAC isoflurane anesthesia. A subgroup (group 2) of group 1 was tested during 1.0 MAC isoflurane anesthesia at surgical incision. Group 3 consisted of 16 volunteers who listened to an audiotape while receiving 0.15, 0.3, and 0.45 MAC isoflurane or 0.3, 0.45, and 0.6 MAC nitrous oxide in oxygen. The audiotape contained information designed to test implicit and explicit memory formation. We tested the ability of six EEG parameters (spectral-edge, 95th percentile power frequency, median power, and zero crossing frequencies and total power in the alpha- [8-13 Hz] and delta- [< 4 Hz] power ranges) to predict movement after surgical incision, purposeful response to command, or memory of information presented during anesthetic administration. RESULTS: Isoflurane decreased EEG activity in group 1 in a dose-related fashion. The 55% of group 2 who made purposeful movements in response to incision did not differ in their EEG from nonresponders (e.g., spectral edge 19.8 +/- 3.1 vs. 19.3 +/- 2.6 Hz, mean +/- SD). In group 3, memory of the information presented did not correlate with values of any EEG parameter. Response to verbal command was associated with lower anesthetic concentrations and with smaller alpha- and delta-band power (298 +/- 66 vs. 401 +/- 80 watts; and 75 +/- 20 vs. 121 +/- 49 watts, mean +/- SD), but there was no difference in values for other parameters. CONCLUSIONS: We conclude that our EEG measures do not predict depth of anesthesia as defined by the response to surgical incision, the response to verbal command or the development of memory.

In essence, the clinical goal of general anesthesia is to produce a state of unresponsiveness and amnesia. These endpoints are commonly achieved with drugs like isoflurane, but the sites and mechanisms by which these specific endpoints are achieved remain unknown. Blocking the somatic motor response to painful stimuli is widely used as an indicator of anesthetic adequacy, and the concentration of anesthetic agent (minimum alveolar concentration [MAC]) required to achieve this unresponsiveness is the benchmark of anesthetic potency. Recent work has demonstrated that precollicular decerebration does not alter MAC in rats, suggesting that the forebrain is not a major site of action of isoflurane in blocking motor responses. The brain stem contains systems that modulate pain processing in the spinal cord. The current study was undertaken to assess the relative roles of the brain stem and spinal cord as sites of anesthetic action in blocking somatic responsiveness.In seven rats, anesthesia was induced and maintained with isoflurane in oxygen. MAC was determined by observing the response to tail clamp and fore- and hind limb toe pinch at three times: after intubation, after cervical laminectomy, and after staged hypothermic spinal cord transection.MAC determined by tail clamp did not change during the protocol (1.28 +/- 0.08% [mean +/- standard deviation] baseline vs. 1.25 +/- 0.18% postlaminectomy vs. 1.03 +/- 0.40% posttransection). In one animal, the MAC value decreased from a prelesion value of 1.2% to 0.25%, accounting for most of the variance in the postlesion mean; the MAC value as determined by withdrawal to rear paw pinch was unchanged from its prelesion value in this animal. The MAC values as determined by toe pinch in all animals remained unchanged after spinal transection of the lesion both rostrally and caudally.Somatic motor responsiveness and its sensitivity to isoflurane appeared to be unaltered despite acute loss of descending cortical and bulbar controls. This observation suggests that the site of anesthetic inhibition of motor response may be in the spinal cord.

Desflurane is a potent inhaled anesthetic associated with a dose-dependent depression of cortical electrical activity. Recently, it has been suggested that the burst suppression pattern seen in dogs given moderately high doses (2.0 MAC) of desflurane may spontaneously subside. This observation suggests the development of acute tolerance to at least some of the anesthetic effects of this drug. No other volatile anesthetic has been found to produce acute tolerance. We attempted to replicate these findings in domestic swine. Five juvenile swine (25-30 kg) were anesthetized with desflurane in oxygen and during normocapnia were exposed to two doses of desflurane sufficient to induce burst suppression (1.5 and 1.7 MAC) for 35 min at each dose, with a period of EEG recovery (0.6 MAC) before, between (in 3 of 5 animals), and after the high doses. Frontoparietal EEG was continuously recorded and the burst suppression ratio continuously calculated. Suppression was more complete at 1.7 MAC than at 1.5 MAC (98.24 +/- 1.75 vs. 90.80 +/- 3.05%, respectively, mean +/- standard deviation). The degree of burst suppression activity did not change over time at either 1.5 (P greater than 0.33) or 1.7 MAC desflurane (P greater than 0.41). There was no EEG evidence of tolerance to desflurane anesthesia in swine.

Desflurane (formerly I-653) is a new inhalaticnal anesthetic with a promising pharmacokinetic profile that includes low solubility in blood and tissue, including fat. Since its lipid solubility is less than that of other volatile agents, it may have lower potency. Low solubility would be expected to increase the rate at which alveolar concentration approaches inspired concentration during induction as well as to increase the rate of elimination of desflurane from blood at emergence. We determined the minimum alveolar concentration (MAC) of desflurane in 44 unpremedicated ASA physical status 1 or 2 patients undergoing elective surgery. We prospectively studied four patient groups distinguished by age and anesthetic regimen: 18-30 versus 31-65 yr and desflurane in 60% N2O/40% O2 versus desflurane in O2. Anesthesia was induced with desflurane or desflurane in 60% N2O/40% O2. MAC was determined by a modification of Dixon's up-and-down method with increments of 0.5% desflurane. The MAC of desflurane in O2 was 7.25 +/- 0.0 (mean +/- SD) in the 18-30-yr age group, and 6.0 +/- 0.29 in the 31-65-yr group; the addition of 60% N2O reduced the MAC to 4.0 +/- 0.29 and 2.83 +/- 0.58, respectively. The median time from discontinuation of desflurane to an appropriate response to commands was 5.25 min. Desflurane appears to be a mild airway irritant but was well tolerated by all patients.

The electroencephalographic (EEG) effects of a new inhaled anesthetic are of interest because of the potential of such agents to produce excitatory (convulsant) activity and because of the potential usefulness of the EEG as an indicator of anesthetic depth and cerebral activity. Accordingly, we examined the EEG in 12 healthy, young male volunteers during desflurane anesthesia. Each subject had a baseline recording and then steady-state exposure to 6, 9, and 12% (0.83, 1.24, and 1.66 MAC) desflurane in O2 alone, and to 3, 6, and 9% desflurane in O2 with 60% N2O. The sequence of doses and the presence of N2O were randomized. We used mechanical ventilation to maintain normocapnia at each dose level. We also tested the effects of hypercapnia secondary to spontaneous ventilation. Additionally, at 1.24 MAC, subjects' lungs were hyperventilated to a PCO2 of 25.8 +/- 0.7 mmHg and exposed to rhythmic, loud clapping to attempt to provoke excitatory phenomena. Finally, after at least 6 h exposure to desflurane, we repeated measurements at 0.83 and 1.66 MAC to assess possible tolerance. Four channels of EEG were monitored visually, and at each dose, a quantitative EEG analysis was performed. Desflurane produced EEG changes comparable to those observed with equipotent levels of isoflurane. No epileptiform activity was seen. Desflurane significantly suppressed EEG activity; prominent burst suppression was seen at 1.24 MAC and higher. Substitution of N2O for 0.42 MAC desflurane reduced the degree of EEG suppression relative to the equipotent administration of desflurane and O2. Quantitative EEG measures for the early doses and for the later, repeated exposures did not differ.

Background Depression of spinal alpha-motor neurons apparently plays a role in the surgical immobility induced by isoflurane. Using the noninvasive technique of F-wave analysis, the authors tested the hypothesis that depressed motor neuron excitability is an effect common to other clinically relevant inhaled anesthetics. Methods The authors measured F-wave amplitude in rats anesthetized with desflurane, enflurane, halothane, or sevoflurane. Each animal received one anesthetic at five equipotent anesthetic concentrations (0.6, 0.8, 1.2, and 1.6 minimum alveolar concentration [MAC] and 0.8 MAC with 65% N2O). F waves were detected as late potentials in electromyographic responses evoked in the intrinsic muscles of the hind paw after monopolar stimulation of the ipsilateral posterior tibial nerve. Results All tested inhaled anesthetics depressed F-wave amplitude but not M-wave (orthodromic, early muscle activation) amplitude, and increased M-F latency in a dose-dependent manner. At 1.0 MAC, the estimated F/M ratio was 70 +/- 13% SD of that at baseline (0.6 MAC). Nitrous oxide added to 0.8 MAC of the potent vapors depressed F/M ratio by 63 +/- 17%. Conclusions All anesthetics tested appeared to depress the excitability of spinal motor neurons. This effect may contribute to surgical immobility, and its magnitude is comparable at equipotent concentrations of agents. The authors hypothesize that this effect is due to hyperpolarization, although, currently, there is insufficient information to discriminate between pre- and postsynaptic mechanisms.

Background 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). Methods To identify the neural structures that subtend this somatomotor response, we anesthetized 14 rats with isoflurane in oxygen and performed bilateral parietal-temporal craniotomles. 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. Results 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). Conclusions 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.

BACKGROUND: Sufentanil has been reported to increase cerebral blood flow in comparison with fentanyl. However, because of the use of animal models, supraclinical doses and/or background anesthetic agents, the clinical applicability of these studies remains difficult to assess. Therefore, transcranial Doppler ultrasonography was used to determine the cerebral hemodynamic effects of equianesthetic doses of fentanyl and sufentanil on middle cerebral artery (MCA) blood flow velocity in patients without intracranial pathologic conditions. METHODS: Twenty-four unpremedicated American Society of Anesthesiologists physical status 1 and 2 patients undergoing elective nonintracranial neurosurgery were assigned randomly to receive equipotent blinded infusions of either sufentanil (15 micrograms/min) or fentanyl (150 micrograms/min) for anesthetic induction during spontaneous ventilation of 100% oxygen. Normocapnia, as measured by infrared capnography, was maintained by manually assisting ventilation, as necessary. The cerebral opioid effect was quantified using the spectral edge frequency parameter. The infusion was continued until either 1) spectral edge frequency decreased below 10 Hz or 2) 150 micrograms of sufentanil or 1,500 micrograms of fentanyl was infused, whichever occurred first. On average, the patients received 1.7 +/- 0.55 micrograms/kg or 16 +/- 4 micrograms/kg of sufentanil or fentanyl, respectively. The right MCA mean, peak systolic, and peak diastolic velocities and pulsatility index were measured continuously by transcranial Doppler ultrasonography. RESULTS: The mean arterial pressure decreased slightly in both groups, but only in the fentanyl group were the changes significant. The MCA velocity increased by approximately 25% in both groups. However, the relative changes in MCA velocity were not different between groups. The pulsatility indexes were unchanged in both groups. CONCLUSIONS: These data suggest that, at clinically relevant doses in the absence of other drugs, cerebral blood flow velocity is increased by both fentanyl and sufentanil. Furthermore, there appears to be no significant differences in the cerebral hemodynamic profiles of the two drugs, as assessed by transcranial Doppler ultrasonography.

A meaningful use of the electroencephalogram (EEG) for monitoring depth of anesthesia has proven elusive. Although changes in the EEG with changing anesthetic dose or concentration have been noted for 60 yr, it has been difficult to demonstrate reliable, quantitative correlation between the EEG and other physiologic measures of anesthetic depth. We attempted to correlate several quantitative EEG measurements in rats, including average amplitude, spectral edge frequency, and burst suppression ratio, with the movement response to supramaximal noxious stimulation. We anesthetized 21 Sprague-Dawley rats with isoflurane 1.5% and allowed them to breathe spontaneously. After equilibration, EEG was recorded for off-line analysis; then a noxious stimulation was delivered with a tail clamp and the somatic response noted. Isoflurane concentration was adjusted up and down, and the EEG and movement response to tail clamp were assessed at each level until the minimum alveolar concentration was determined in each rat. We found no EEG dose response to increasing inspired concentrations of isoflurane, except for an increasing degree of burst suppression. We found no difference in any parameter between rats that responded and those that did not respond to stimuli at a given concentration of isoflurane. Finally, we found that the presence of burst suppression did not predict lack of response.

Percutaneous loss of inhaled anesthetics is small relative to their uptake. The minor nature of this loss results in part from the substantial barrier to diffusion posed by the skin. Pleural and peritoneal surfaces pose less effective barriers because diffusion distances are smaller than in the skin. Accordingly, we measured visceral loss to air of desflurane, isoflurane, and halothane from pleural and peritoneal surfaces in five juvenile swine. Pleural and peritoneal losses per percent end-tidal anesthetic correlated directly with the solubility of the anesthetic in blood or tissues. The total pleural losses for the first 30 min of anesthetic administration were desflurane, 1.22 +/- 0.22 mL (mean +/- standard deviation for the 30-min period); isoflurane, 2.34 +/- 0.52 mL; and halothane, 4.69 +/- 0.98 mL; respective peritoneal losses were 0.64 +/- 0.12 mL, 1.23 +/- 0.25 mL, and 2.69 +/- 0.57 mL. Pleural loss per unit time did not change with increasing duration of anesthesia, whereas peritoneal loss increased for all anesthetics. These visceral losses are greater than total percutaneous losses in humans given these anesthetics for the same period of time, but the loss of anesthetic by either route is too small to affect measurements of anesthetic kinetics or recovery.

We examined the metabolism of desflurane in 13 healthy volunteers given 7.35 +/- 0.81 MAC-hours (mean +/- SD) of desflurane and 26 surgical patients given 3.08 +/- 1.84 MAC-hours (mean +/- SD). Markers of desflurane metabolism included fluoride ion measured via an ion-specific electrode, nonvolatile organic fluoride measured after sodium fusion of urine samples, and trifluoroacetic acid determined by a gas chromatographic-mass spectrometric method. In both volunteer and patient groups, postanesthesia serum fluoride ion concentrations did not differ from background fluoride ion concentrations. Similarly, postanesthesia urinary excretion of fluoride ion and organic fluoride in volunteers was comparable to preanesthesia excretion rates. However, small but significant levels of trifluoroacetic acid were found in both serum and urine from volunteers after exposure to desflurane. A peak serum concentration of 0.38 +/- 0.17 mumol/L of trifluoroacetic acid and a peak urinary excretion rate of 0.169 +/- 0.107 mumol/h were detected in volunteers at 24 h after desflurane exposure. Although these increases in trifluoroacetic acid after exposure to desflurane were statistically significant, they are approximately 10-fold less than levels seen after exposure to isoflurane. Thus, desflurane strongly resists biodegradation, but a small amount is metabolized in humans.

We studied the ventilatory effects of desflurane (formerly I-653) with and without N2O in healthy male volunteers. After insertion of venous and arterial (radial and pulmonary) catheters, baseline measurements of tidal volume (VT), respiratory rate (RR), ventilatory response to CO2, and arterial and mixed venous blood gases were made. Subjects were randomly assigned to receive either desflurane with O2 (n = 6) or with O2 and 60% N2O (n = 6). Anesthesia was induced by inhalation of desflurane followed by tracheal intubation without muscle relaxants. In each volunteer, at end-tidal concentrations totaling 0.83, 1.24, and 1.66 MAC, we repeated measurements of VT, RR, response to CO2, and arterial and mixed venous blood gases. As depth of anesthesia increased, VT significantly (P less than 0.05) decreased from 363 +/- 22 ml awake to 76 +/- 22 ml at 1.66 MAC without N2O and from 473 +/- 70 ml awake to 128 +/- 6 ml at 1.66 MAC with N2O (mean +/- SE). Similarly, RR increased from 15 +/- 0.5 breaths per min awake to 32 +/- 2 breaths per min at 1.66 MAC without N2O and from 14 +/- 0.5 breaths per min awake to 40 +/- 3 breaths per min at 1.66 MAC with N2O. Desflurane without N2O depressed the ventilatory response to CO2 to 45 +/- 9, 31 +/- 5, and 11 +/- 4% of the awake values at 0.83, 1.24, and 1.66 MAC, respectively. With N2O, values were 52 +/- 14, 23 +/- 5, and 26 +/- 9% of the awake value at 0.83, 1.24, and 1.66 MAC, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the cardiovascular actions of drugs commonly combined with inhalation anesthetics, we administered one drug from each of several classes of adjuvants to seven swine already anesthetized with equipotent concentrations (1.2 MAC) of desflurane, formerly I-653, a new inhaled anesthetic, or isoflurane. Succinylcholine (1 and 2 mg/kg), atracurium (0.6 mg/kg), and atropine (5 micrograms/kg) plus edrophonium (5 mg/kg) had no cardiovascular effects. Fentanyl was given in amounts that decreased MAC for the inhaled anesthetics by 25%-35%. A dose of 50 micrograms/kg IV had no cardiovascular effects during either anesthetic, whereas 100 micrograms/kg IV modestly increased systemic vascular resistance without changing other variables. Naloxone (100 micrograms/kg IV) during infusion of fentanyl decreased systemic vascular resistance and increased cardiac output during both desflurane and isoflurane anesthesia, increased heart rate during only isoflurane anesthesia, and did not affect mean arterial blood pressure during either anesthetic. Thiopental (2.5 and 5.0 mg/kg IV) decreased mean aortic blood pressure, cardiac output, stroke volume, and systemic vascular resistance during both anesthetics without altering heart rate or left- or right-sided cardiac filling pressures. The addition of 60% nitrous oxide caused no cardiovascular changes during desflurane anesthesia, but increased systemic vascular resistance and decreased cardiac output and stroke volume during isoflurane without altering heart rate or cardiac preload. We conclude that the usual clinical doses of adjuvants commonly administered during anesthesia have no untoward cardiovascular actions during 1.2 MAC desflurane or isoflurane anesthesia in swine.

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.

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 (P0.001) and 60% between 1.2 and 1.6 MAC (P0.05). 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) (P0.0001).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.

We examined the potential toxicity of desflurane in 13 young 25.0 +/- 2.3 (mean +/- SD) yr-old men, given 7.35 +/- 0.81 MAC-hours of desflurane anesthesia. Hepatic and renal function tests, serum electrolytes, and standard urine and hematologic tests were performed before, during, and after anesthesia. No toxicity was found. There were no changes in tests of hepatocellular integrity (plasma alanine transferase activity), synthetic function (serum albumin, prothrombin time, partial thromboplastin time), or renal function (serum creatinine concentration, blood urea nitrogen concentration). Decreases in red blood cell count, hematocrit, and blood hemoglobin concentration during and immediately after anesthesia were attributed to blood sampling and infusion of intravenous electrolyte solution. These values returned by 4 days after anesthesia to values not different from those before anesthesia. Increased white blood cell counts and blood glucose concentrations noted during anesthesia with other inhaled anesthetics were also seen in these volunteers. Desflurane appears to have no greater toxicity than currently used inhaled anesthetics and, because of its lesser metabolism, may have lesser or not toxicity.

We investigated the cardiovascular actions of desflurane (formerly I-653) during spontaneous ventilation. We gave 0.8-0.9, 1.2-1.3, and 1.6-1.7 MAC desflurane in oxygen (n = 6) and in 60% nitrous oxide, balance oxygen (n = 6) to unmedicated healthy male volunteers. Both anesthetic regimens decreased ventilation, increased partial pressure of arterial carbon dioxide, and produced similar cardiovascular changes. In comparison with values obtained when the volunteers were conscious, desflurane anesthesia with spontaneous ventilation decreased systemic vascular resistance and mean arterial blood pressure. Cardiac index, heart rate, stroke volume index, and central venous blood pressure increased. Left ventricular ejection fraction increased at 0.83 MAC desflurane in oxygen, and otherwise did not differ from the conscious value. The velocity of ventricular circumferential fiber shortening, estimated by echocardiography, increased with desflurane in oxygen but did not change with desflurane in nitrous oxide. Oxygen consumption increased during desflurane and oxygen anesthesia, but not when nitrous oxide plus oxygen was the background gas. Desflurane increased oxygen transport, the ratio of oxygen transport to oxygen consumption, mixed venous partial pressure of oxygen, and oxyhemoglobin saturation. The cardiovascular changes with desflurane during spontaneous ventilation differ from those during controlled ventilation. With both background gases, spontaneous ventilation, in comparison with controlled ventilation, increased cardiac index, stroke volume, central venous pressure, left ventricular ejection fraction, velocity of circumferential fiber shortening, oxygen transport, and the ratio of oxygen transport to oxygen consumption but did not change mean arterial blood pressure except at 1.66 MAC desflurane in oxygen (when it was higher with spontaneous than with controlled ventilation).

The cardiovascular actions of three concentrations of desflurane (formerly I-653), a new inhalation anesthetic, were examined in 12 unmedicated normocapnic, normothermic male volunteers. We compared the effects of 0.83, 1.24, and 1.66 MAC desflurane with measurements obtained while the same men were conscious. Desflurane caused a dose-dependent increase in right-heart filling pressure and a decrease in systemic vascular resistance and mean systemic arterial blood pressure. As measured by echocardiography, left ventricular end-diastolic area did not change except for a small increase at 1.66 MAC desflurane, and systolic wall stress was less at all concentrations of desflurane than during the conscious state. Desflurane did not change cardiac index or left ventricular ejection fraction. Heart rate did not change at 0.83 MAC, but progressively increased with deeper desflurane anesthesia. Stroke volume index was less at all concentrations of desflurane than while the men were conscious, but desflurane did not alter the velocity of ventricular circumferential fiber shortening. Mixed venous blood PO2 and oxyhemoglobin saturation were higher during all concentrations of desflurane anesthesia than during the conscious state. No volunteer developed a metabolic acidosis. We conclude that desflurane with controlled ventilation and constant PaCO2 causes cardiovascular depression, as indicated by the increased cardiac filling pressure and decreased stroke volume index and by no change in the velocity of circumferential fiber shortening in the presence of decreased systolic wall stress. However, cardiac output is well maintained, and heart rate does not increase at light levels of anesthesia. The cardiovascular actions of 0.83 and 1.66 MAC desflurane were also reexamined in 6 of the 12 men during the seventh hour of anesthesia. Prolonged desflurane anesthesia resulted in lesser cardiovascular depression than was evidenced during the first 90 min. The measures of cardiac filling (central venous pressure and left ventricular end-diastolic cross-sectional area) did not differ between the early and late periods of anesthesia. Systemic vascular resistance decreased further during the late period, but systolic wall stress did not differ between the two time periods. During the seventh hour of desflurane anesthesia, heart rate and cardiac index were higher at both anesthetic concentrations than during the first 90 min of anesthesia. Left ventricular ejection fraction and velocity of fiber shortening did not change with duration of desflurane anesthesia. Oxygen consumption, oxygen transport, the ratio of the two, mixed venous PO2, and mixed venous oxyhemoglobin saturation (SO2) increased late in the anesthetic in comparison with the first 90 min.

Prolonged (several days or repeated) exposure to nitrous oxide (N2O) can cause injury or death. To assess whether relatively prolonged anesthesia with N2O in normal patients might similarly cause untoward effects, we investigated whether the addition of N2O to isoflurane anesthesia caused injury to patients having surgical resection of acoustic neuroma lasting approximately 10 h. Twenty-six patients undergoing surgical resection of acoustic neuroma were randomly assigned to a regimen that included or excluded N2O (50%-60%) during isoflurane anesthesia plus intravenous adjuvants. On average, slightly less isoflurane (0.24%) was used during anesthesia with N2O. We measured standard clinical variables (blood pressure, heart rate), oxygen saturation, neurologic status, pain, and the incidence and type of morbid outcomes. Exposure to N2O did not increase the incidence of morbid outcomes (including hepatic injury, infection, or hypoxemia), prolong hospitalization, or increase common postoperative complaints such as nausea, vomiting, coughing, or headache. Patients anesthetized with either regimen were equally satisfied with their anesthetic.

We asked whether the sympathomimetic effect of nitrous oxide (N2O) predisposed patients receiving N2O to arrhythmias in response to epinephrine administration. We also asked whether aging contributed to the development of arrhythmias, with or without N2O. One hundred patients having transsphenoidal hypophysectomy were randomly assigned to receive anesthesia including (n = 49) or excluding (n = 51) N2O. All patients were given an injection of epinephrine 1:200,000, with 0.5% lidocaine to produce hemostasis. Using intermittent 12-lead and continuous lead II electrocardiography, we determined the incidence of premature ventricular contraction, isorhythmic atrioventricular (AV) dissociation, and changes in T-wave morphology. Patients given N2O had a significantly higher incidence of isorhythmic AV dissociation (61.2% vs 41.2%). A trend toward a higher incidence of multiple premature ventricular contractions (16.3% vs 7.8%) was not statistically significant. Both anesthetic groups had a high incidence of postoperative changes in T-wave morphology (46.9% in the N2O group vs 50.9% in the group not given N2O). Aging alone did not affect the incidence of ventricular ectopic beats, isorhythmic AV dissociation, or changes in electrocardiographic morphology, but correlated with the development of ventricular ectopy during N2O anesthesia. We conclude that the use of N2O correlated with a higher incidence of isorhythmic AV dissociation in response to injection of epinephrine with lidocaine.

Desflurane, formerly known as I-653 (CF2H-O-CFH-CF3), is a new inhalation anesthetic derived by fluorine substitution for the alpha-ethyl chlorine of isoflurane (CF2H-O-CClH-CF3). The lower solubility and increased stability of desflurane provided by the C-F bond lessen biotransformation to potentially hepatotoxic metabolites. Repeated administration of desflurane to rats, with or without induced hepatic enzymes, does not result in evidence of hepatic injury. In the recent study we extended the tests for liver cell injury to another species, the pig. Our test included prolonged exposure to desflurane or isoflurane, both in the absence and presence of commonly used adjuvants. We measured plasma alanine aminotransferase activity in eight young female swine anesthetized in random order with desflurane (0.8-1.6 MAC) and isoflurane (0.7-1.4 MAC), for a total dose of about 5.5 MAC-hours of each anesthetic, 3-8 days apart. Plasma alanine aminotransferase activities remained in the normal range, and were not significantly greater over baseline values in samples drawn immediately after, 4 h after, or 3-8 days after (mean +/- SD, 6.1 +/- 2.1) the administration of either anesthetic was discontinued after the first study with either desflurane or isoflurane. Five additional pigs were given a mean total dose of 9.7 MAC-hours of desflurane or isoflurane in conjunction with succinylcholine, N2O, fentanyl, naloxone, atracurium, thiopental, edrophonium, and atropine. No changes in plasma alanine aminotransferase activity were detected in blood samples drawn at termination of the anesthesia, 24 h later, and 4-7 days later (mean +/- SD, 5.8 +/- 1.3).(ABSTRACT TRUNCATED AT 250 WORDS)

I653 is a new inhalation anesthetic having especially desirable recovery characteristics because of its very low blood and tissue solubility. Investigations of its cardiovascular and electroencephalographic effects have revealed actions similar to those of isoflurane. However, these studies did not evaluate the potential of I653 to predispose the heart to epinephrine-induced arrhythmias. In this investigation, we studied eight domestic swine to compare the effects of I653 with those of other anesthetics on the cardiac arrhythmogenic actions of intravenously infused epinephrine. I653, isoflurane, and halothane each were given, on separate days, at 0.7-0.8 and at 1.1-1.2 MAC. The rate of infusion of epinephrine needed to produce premature ventricular contractions (PVCs) when the animals were anesthetized with I653 (6.9 +/- 0.7 and 6.6 +/- 0.9 micrograms.kg-1.min-1 at 0.8 and 1.2 MAC) did not differ from that during isoflurane anesthesia (5.7 +/- 1.1 and 6.0 +/- 1.0 micrograms.kg-1.min-1 at 0.7 and 1.1 MAC), but was greater than that required during halothane anesthesia (1.3 +/- 0.2 and 1.1 +/- 0.3 micrograms.kg-1.min-1 at 0.7 and 1.1 MAC). Similar mean arterial blood pressures and heart rates resulted from like infusions of epinephrine during I653 and isoflurane anesthesia. PVCs occurred at lesser infusion rates of epinephrine and at lower mean arterial blood pressures and heart rates with halothane than with I653 or isoflurane. Anesthetic concentration, over the range studied, did not alter the infusion rate of epinephrine required to produce arrhythmias with any anesthetic. The authors conclude that I-653 and isoflurane have similar properties with respect to epinephrine-induced arrhythmias and increases in heart rate and arterial blood pressure.

Qualitatively different responses of ADP levels have previously been observed in the brain during hypercarbia. One investigation has found that cerebral ADP stayed constant during hypercarbia in rats that were anesthetized with halothane, while another observed that ADP decreased during supercarbia in rats that received no supplemental anesthesia. This article reports an in vivo31P nuclear magnetic resonance study to test the hypothesis that halothane anesthesia accounts for the discrepant observations. Isoflurane anesthesia was also studied in a second group of rats to see if a different general anesthetic agent would cause the same effects that halothane causes. The two groups of five rats underwent dual episodes of hypercarbia that were separated by a 45-min recovery period. General anesthesia, either 0.5% halothane or 1.0% isoflurane, was administered during the first episode but not during the second. Hypercarbia during halothane anesthesia caused the measured phosphocreatine (PCr) to decrease by 40%, while the calculated change in ADP was 10%, in agreement with the former investigation. In contrast, hypercarbia during either isoflurane anesthesia or no anesthesia caused a decrease of only 10% in PCr, which meant that the calculated decrease in ADP was 60%, in agreement with the results of the second investigation. We conclude that during hypercarbia, clinical concentrations of halothane, unlike clinical concentrations of isoflurane, interfere with the regulation of ATP metabolism.

I653 is a new volatile anesthetic structurally similar to enflurane and isoflurane. Since enflurane can induce convulsions, whereas isoflurane progressively depresses cortical electrical activity, the authors believed it important to assess the effect of I653 on the EEG (in both the "time" and "frequency" domain). The EEG was assessed visually and quantitatively, and a new EEG parameter was introduced. The burst-suppression ratio (percentage of time the EEG was isoelectric) quantified the extent of burst suppression phenomena. Eight swine were anesthetized with I653 or isoflurane in oxygen and in random sequence, exposed to approximately 0.8, 1.2, or 1.6 MAC with normocapnea and to 1.2 MAC with hypocapnea (PETCO2 of 25 mmHg). Four animals were also anesthetized with 3.2% (1.2 MAC) enflurane in oxygen. Both I653 and isoflurane produced a dose-related depression of cortical electrical activity. At 0.8 and 1.2 MAC of either agent, occasional sharp waves occurred singly, were apparently not related to external (auditory) stimuli, and probably represented normal variation in the EEG. No electrographic or gross motor seizures occurred with either I653 or isoflurane. In contrast, all pigs given enflurane developed seizures during hypocapnea. At equipotent concentrations, I653 and isoflurane had the same effect on EEG parameters. Increasing doses of either I653 or isoflurane caused decreasing amplitude and frequency and increasing suppression. Hypocapnea during either agent slightly increased high-frequency activity, and slightly decreased burst suppression.

1653 (difluoromethyl 1-fluoro 2,2,2-trifluoroethyl ether) is a new inhalation anesthetic with a low blood-gas partition coefficient and no demonstrable toxicity. The authors examined its cardiovascular effects at 0.8, 1.2, and 1.6 MAC in eight chronically instrumented domestic swine mechanically ven

The blood pressure (BP) response to cerebellar retraction during microvascular decompression of the fifth cranial nerve was investigated in 26 ASA physical status 2 or 3 patients with trigeminal neuralgia. One surgeon performed all operations. To determine the effect of three anesthetic techniques on the BP response, patients were randomly assigned to receive halothane, isoflurane, or sufentanil in sufficient doses with 60% nitrous oxide to achieve a precerebellar retraction systolic BP that was 10-20% below the average ward systolic BP (as per standard clinical practice). The resultant doses were halothane 1.65 +/- 0.27 (mean +/- SD) MAC, isoflurane 1.56 +/- 0.17 MAC (P greater than 0.05), and sufentanil 2.7 micrograms/kg (MAC values include 0.6 MAC contribution from 60% nitrous oxide). In all patients BP increased during the cerebellar retractor placement period compared with the preretractor placement period (P less than 0.05). The peak increase in systolic BP in response to cerebellar retraction was 17 +/- 6 mmHg for halothane, 38 +/- 20 mmHg for isoflurane, and 26 +/- 19 mmHg for sufentanil. The difference between halothane and isoflurane was significant (P less than 0.05). Mean and diastolic BP showed similar significant differences. The authors conclude that halothane attenuates the hypertensive response to cerebellar retraction more than isoflurane when administered in approximately 1.6 MAC concentrations (MAC value includes contribution from nitrous oxide).

Fluoride ion concentrations were measured in plasma samples taken from chronically instrumented domestic swine before, immediately after, and 4 hours after exposure to either I-653 or isoflurane. Each anesthetic was administered at concentrations between 0.7 and 1.6 MAC and the total dose of anesthetic given was approximately 5.5 MAC hours for each agent. Plasma fluoride ion concentrations immediately after and 4 hours after exposure to isoflurane were approximately three times greater than values obtained in awake swine before anesthesia. In contrast, swine given I-653 had no detectable elevation in plasma fluoride concentration immediately after anesthesia, but a 17% (P less than 0.05) increase in plasma fluoride ion concentration 4 hours after anesthesia. These results imply that I-653 is metabolized less than is isoflurane in swine.

We determined the anesthetic potencies of a new fluorinated anesthetic, I-653, and isoflurane in pigs as a preliminary to a study of the relative cardiovascular and electroencephalographic effects of these agents. Clamps were sequentially applied to the dew claw and/or tail of each animal to determine the minimum alveolar concentration (MAC) that suppressed movement in response to each of these stimuli. MAC obtained by clamping the tail (8.28 +/- 1.34% [mean +/- standard deviation] for I-653 and 1.65 +/- 0.36% for isoflurane) was more variable and lower than MAC obtained by clamping the dew claw (10.00 +/- 0.94% for I-653 and 2.04 +/- 0.19% for isoflurane). We conclude that the type of stimulus applied affects the MAC value obtained for I-653 and isoflurane. Clamping the tail is not a supramaximal stimulus in pigs; a greater stimulus is provided by clamping the dew claw.