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Pediatric Anesthesiology: Research Reports

Dose-Dependent Suppression of the Electrically Elicited Stapedius Reflex by General Anesthetics in Children Undergoing Cochlear Implant Surgery

Crawford, Mark W. MBBS, FRCPC*; White, Michelle C. MBChB, DCH, FRCA*; Propst, Evan J. MSc, MD; Zaarour, Christian MD*; Cushing, Sharon MD; Pehora, Carolyne RN, MN*; James, Adrian L. DM, FRCS; Gordon, Karen A. PhD; Papsin, Blake C. MD, FRCSC

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doi: 10.1213/ane.0b013e31819bdfd5
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Cochlear implants stimulate the auditory nerve electrically to allow hearing in individuals with sensorineural deafness.1 The appropriate range of implant stimulation is guided by various auditory evoked responses that can be measured during cochlear implant surgery and postoperatively. Intraoperative measurements are generally favored in children because they eliminate the need for patient cooperation. The intraoperative electrically evoked stapedius reflex threshold (ESRT) and evoked compound action potential (ECAP) are used to guide implant settings in many centers.1–4

The stapedius reflex, an autonomic reflex that protects the ear from the effects of loud noise, is evoked electrically during cochlear implantation to determine the loudest sound that can be tolerated without causing discomfort (the maximum comfort level, MCL).1–4 An MCL set too high causes discomfort that may adversely affect the child’s ability to adapt to the cochlear implant. The ECAP is used to determine the hearing threshold, the minimum acoustic stimulus perceived as sound1–4; if set too high, normal levels of speech may be inaudible thereby under-utilizing the ability of the implant to enable hearing. Adjusting implant stimulation limits to the patient’s individual dynamic range (the range between the hearing threshold and the MCL) is essential for the successful use of a cochlear implant.

An ideal anesthetic technique for cochlear implant surgery is one that has no effect on the measured evoked auditory responses.5 It has been suggested that some general anesthetics can elevate the threshold of the electrically or acoustically elicited stapedius reflex6–10; however, no study has evaluated the dose-related effects of drugs currently used for maintenance of anesthesia on the ESRT and ECAP. The primary aim of the present study was to evaluate the dose-dependent effects of sevoflurane, desflurane, isoflurane, and propofol on the intraoperative ESRT and ECAP in children undergoing cochlear implant surgery.

METHODS

With approval from the Research Ethics Board at the Hospital for Sick Children, Toronto, written informed consent was obtained from the parents or guardians of 44 children aged 6 mo to 17 yr who were scheduled for cochlear implantation. Assent was obtained from children older than 7 yr. The children were ASA physical status I or II, fasting, and unpremedicated. All had bilateral, severe to profound sensorineural hearing loss and were approved for cochlear implant surgery by the Hospital for Sick Children’s Cochlear Implant team. Children with a history of adverse reaction to any study drug were excluded from this prospective study.

Randomization

Each child was randomly assigned using a table of random numbers to one of four anesthetic regimens consisting of sevoflurane, desflurane, isoflurane, or propofol. Those randomized to receive a volatile anesthetic underwent a second randomization to determine the sequence for administration of three different end-tidal anesthetic concentrations corresponding to 0, 0.75, and 1.50 age-adjusted minimum alveolar concentration (MAC).11,12 Randomized group assignments and concentration sequences were kept in sealed, opaque, sequentially numbered envelopes that were opened after consent/assent was obtained.

Anesthetic Management

On arrival to the operating room, standard intraoperative monitors (pulse oximetry, noninvasive arterial blood pressure, electrocardiogram) were applied and baseline values recorded. General anesthesia was induced with nitrous oxide and sevoflurane (inspired concentration, 6%) or propofol 4 mg/kg depending on patient preference, followed by fentanyl 2 μg/kg. After loss of consciousness, the patients’ lungs were ventilated with oxygen via a face mask. Rocuronium 0.6 mg/kg was administered to facilitate tracheal intubation. Anesthesia was maintained with 70% nitrous oxide administered in oxygen via a pediatric circle breathing circuit, remifentanil infusion (0.3–0.5 μg · kg−1 · min−1) titrated according to hemodynamic responses, and bolus IV midazolam 0.1 mg/kg. Ventilation was controlled to maintain normocapnia. A Bispectral Index monitor (BIS® A-2000, XP platform, Aspect Medical Systems, Natick, MA) was applied using a disposable strip electrode (BIS® quantro electrode, Aspect Medical Systems) after induction of anesthesia, and values were recorded at the time of measurement of the auditory thresholds.

Surgery and Neural Monitoring

Cochlear implant surgery was performed via a small postauricular incision, as described.13,14 Briefly, this surgery entails elevating subperiosteal flaps, drilling the mastoid bone to gain access to the basal turn of the cochlea, and inserting the cochlear implant electrode array via a cochleostomy. The Nucleus Freedom cochlear implant device (Cochlear Corporation, Melbourne, Australia), which uses Neural Response Telemetry, was used to elicit and record responses from the auditory system. The middle ear space was entered from the mastoid cavity through a posterior tympanotomy to provide surgical access to the cochlea and a clear view of the stapedius muscle. Cochlear implants had 22 active electrodes with Electrode 22 inserted at the apical end of the cochlea and Electrode 1 at the basal end. In the Neural Response Telemetry system, biphasic current pulses are delivered to an intracochlear electrode in a monopolar stimulation mode, which activated the auditory nerve to generate an ECAP. A second intracochlear electrode, typically located two electrodes away, is used to sample the voltage of the ECAP, which is transmitted to an external coil and captured by the Neural Response Telemetry software. Current pulses were biphasic, 25 μs in duration, and delivered at 80 Hz by Electrode 20 at the apical end, Electrode 9 at the middle and Electrode 3 at the basal end of the array. Facial nerve activity was monitored throughout the procedure, using an electrical probe positioned on the horizontal portion of the facial nerve in the middle ear to confirm its integrity (Nerve Integrity Monitoring System, Medtronic, Minneapolis, MN).

Determination of the Auditory Thresholds

Stimuli were generated using an electrode positioned at the apical end of the cochlear implant array (Electrode 20), a mid-array electrode (Electrode 9), and an electrode at the basal end of the array (Electrode 3). Current level was measured in current units (CUs) as defined by the cochlear implant programming software. Electrical pulse trains of 500 ms (number of pulses per burst, 450; stimulus pulse width, 25 μs; interstimulus interval, 7 μs) were delivered in a stepwise manner, first in increments of 10 CU and subsequently in decrements of 5 CU to bracket the ESRT. Movement of the ipsilateral stapedius muscle was identified by the implant surgeon using direct microscopic observation.15 The surgeon was blinded to anesthetic drug and concentration and indicated when he judged a stapedius reflex to occur. The ESRT was defined as the lowest level of stimulation at which a stapedius reflex was detected visually.

The ECAP was measured at the electrode located two electrode positions apical to the stimulating electrode on the intracochlear array. The stimulating current, delivered at 80 Hz, was decreased in steps of 10 CUs until the electrical response could no longer be visualized by the audiologist. The lowest level of stimulation at which a wave could be detected visually was defined as the threshold. Both the surgeon and audiologist were blinded to the anesthetic drug and concentration sequence. The anesthesiologist was blinded to the applied current stimulus.

Study Protocol

The auditory thresholds were determined after insertion of the intracochlear electrode array, at least 90 min after induction of anesthesia, at which time adductor pollicis train-of-four activity had recovered fully. For children randomized to receive volatile anesthesia, auditory thresholds were determined at each of the three concentrations in the randomized sequence. A 10 to 15-min period of stable end-tidal concentration was allowed after each change in inspired concentration to achieve equilibration of alveolar and effect-site concentrations. For those randomized to receive propofol, the auditory thresholds were determined at each of three targeted blood concentrations of propofol (0, 1.5, and 3.0 μg/mL) administered in sequence. Propofol was administered as an initial IV dose followed by an infusion to incrementally achieve the target blood concentrations.16,17 Before threshold determination, a 5 to 8-min period was allowed after each increment in propofol dose to achieve equilibration of blood and effect-site concentrations. As a secondary outcome, we evaluated the effect of nitrous oxide on evoked responses by repeating the auditory thresholds both without and with 70% nitrous oxide during continued administration of propofol to achieve a target propofol concentration of 3.0 μg/mL, allowing at least 5 min of stable end-tidal nitrous oxide concentration for equilibration after each change in inspired concentration.

At completion of ESRT and ECAP measurements, the study ended and anesthesia was maintained with remifentanil and either a volatile anesthetic or propofol at the discretion of the anesthesiologist. Morphine 0.15 mg/kg was administered for postoperative analgesia and ondansetron 0.1 mg/kg for prophylaxis against postoperative nausea and vomiting.

Statistical Analysis

The primary outcome for this study was the threshold of the electrically ESRT. Sample size was estimated a priori assuming a standard deviation for intraoperative ESRT measurements of 15 CU, based on a retrospective review of separate pilot data. For a two-tailed α of 0.05 and a β of 0.2, we estimated that 10 patients per group would be required to demonstrate a clinically relevant within-group difference of 20 CU. Forty-four patients were enrolled assuming 10% dropouts. Within-group measures of the auditory thresholds were compared using one-way repeated-measures analysis of variance and Student–Newman–Keuls post hoc test. Kruskal– Wallis one-way analysis on ranks was used to compare demographic data. One-way analysis of variance was used for comparison of intraoperative outcomes. Least-squares linear regression analysis was used to evaluate the relationship between age and ESRT. P < 0.05 was considered statistically significant. Data are presented as mean ± sd or median and range, as appropriate. All statistical analyses were conducted using GraphPad Prism version 4.0 for Macintosh (GraphPad Software, San Diego, CA).

RESULTS

Forty-four consecutive patients undergoing cochlear implant surgery were recruited. Stapedius reflex thresholds could be established in 40 children. Four patients were withdrawn because determination of the threshold was not possible, either as a result of suspected surgical disruption of the stapedius muscle or tendon (three patients) or anatomic variation (one patient). Data analysis was performed on the remaining 40 patients.

Patient demographics are shown in Table 1. No significant differences among groups were found in terms of age, weight, dose of remifentanil, dose of midazolam, or time interval from midazolam administration to ESRT determination (Table 1). Overall median age and weight were 4.0 yr (range, 0.7–17.2 yr) and 16.4 kg (range, 7.7–72 kg), respectively. Median duration of hearing loss was 2.2 yr (range, 0.6–17.1 yr). All children had profound hearing loss. Hearing loss was genetic (21 children), secondary to prematurity (two children), intracranial bleed (one child), Mondini malformation (one child), Modiolar deficiency (one child), or of unknown etiology (14 children).

Table 1
Table 1:
Demographics and Intraoperative Data

Dose-related effects of the anesthetics on the ESRT are shown in Figure 1. The ESRT increased significantly with increasing end-tidal concentration of each volatile anesthetic (Figs. 1A–C). This finding was consistent across Electrodes 20, 9, and 3. The relationship between ESRT and dose of volatile anesthetic was linear for most electrodes (Figs. 1A–C). The ESRT was completely abolished at an end-tidal concentration of 0.75 MAC in three patients (one in the desflurane group and two in the isoflurane group) even with application of the maximum stimulating current. At an end-tidal concentration of 1.5 MAC, the ESRT was completely abolished in 18 patients (five in the sevoflurane group, six in the desflurane group, and seven in the isoflurane group). For these 21 patients, therefore, a threshold elevation occurred but could not be quantified. For the purpose of statistical analysis, a threshold value of 255 CU, the maximum stimulating current delivered by the cochlear implant device, was assigned to those patients in whom the ESRT was completely abolished.

Figure 1.
Figure 1.:
Dose-related effects of volatile anesthetics (A–C) and propofol (D) on the electrically elicited stapedius reflex (ESRT). Individual data and mean ± sd are shown. *P < 0.001 compared with baseline. †P < 0.001 compared with baseline and P < 0.01 compared with 0.75 MAC. ‡P < 0.05 compared with baseline. **P < 0.01 compared with baseline.

The ESRT was relatively unaffected by propofol (Fig. 1D). There was a small but statistically significant increase in ESRT at each target concentration of propofol (Fig. 1D). At a target concentration of 3.0 μg/mL, the ESRT increased on average by only 10% compared with baseline measurements acquired before administration of propofol. In no patient was the ESRT completely abolished by propofol. Omission of nitrous oxide had no affect on the ESRT (Fig. 1D).

The ECAP was unaffected by the concentration of volatile anesthetic or propofol (Figs. 2A–D). Bispectal Index values decreased by comparable amounts with increasing MAC multiples of the volatile anesthetics (Fig. 3). Stepwise increases in the propofol dose resulted in reductions in Bispectal Index values that were comparable with those caused by the volatile anesthetics (Fig. 3). No significant correlation was found between age (Fig. 4) or duration of deafness (Fig. 5) and ESRT values obtained at baseline before administration of the volatile anesthetics or propofol. No adverse reaction to study drugs or other complication resulted from participation in this study.

Figure 2.
Figure 2.:
Dose-related effects of volatile anesthetics (A–C) and propofol (D) on the electrically elicited compound action potential (ECAP). Individual data and mean ± sd are shown. No statistically significant differences were found within groups.
Figure 3.
Figure 3.:
Effect of sevoflurane, desflurane, isoflurane, and propofol on the Bispectral Index. Individual data and mean ± sd are shown.
Figure 4.
Figure 4.:
Scatterplot showing the relationship between age and baseline ESRT (Electrode 9). No significant correlation was found.
Figure 5.
Figure 5.:
Scatterplot showing the relationship between duration of deafness and baseline ESRT (Electrode 9). No significant correlation was found.

DISCUSSION

The limits of cochlear implant stimulation can be reliably set to the patient’s individual dynamic range through subjective psychophysical tasks that children may not have the attention span or language skills to perform. In young children, programming the cochlear implant using objective measures obtained while the child is anesthetized is generally necessary.1 In many pediatric centers, the intraoperative ESRT and ECAP are used to determine the upper and lower limits, respectively, of the dynamic range of stimulation.1–4 We sought to evaluate the dose-related effects of sevoflurane, desflurane, isoflurane, and propofol on the evoked responses. The results show that the volatile anesthetics caused marked suppression of the stapedius reflex even at an end-tidal concentration of 0.75 MAC. Complete suppression was found in 7.5% of patients at an end-tidal concentration of 0.75 MAC and in 52% at an end-tidal concentration of 1.5 MAC. In contrast, propofol minimally affected the ESRT when infused at rates that caused equipotent depression of the Bispectral Index value. Clinically, volatile anesthetic-induced suppression of the stapedius reflex could result in overestimation of the MCL, causing discomfort postoperatively that could adversely affect the child’s adaptation to the implant.

Makhdoum et al.6 studied the effect of sequential increases in halothane or isoflurane concentration on the ESRT in a small cohort of children undergoing cochlear implantation. A trend toward an increase in ESRT with increasing concentration of volatile anesthetic was described, although no statistical analysis of the data was presented. A similar trend was reported after administration of a single dose of sevoflurane, desflurane, or propofol/sufentanil in a small cohort of adult patients, although this did not achieve statistical significance probably because of a Type II statistical error.10 Bissinger et al.8 investigated the effect of various anesthetic regimens on the acoustically elicited stapedius reflex threshold in adults with normal hearing. Isoflurane 1.5 MAC completely abolished the reflex, whereas midazolam and ketamine showed little effect; however, comparison with the present data is not possible given that the intensity of electrical stimulation is considerably greater than that of acoustic stimulation. In other retrospective studies, a significant positive correlation between methohexital dose and the intraoperative ESRT,5 and between halothane but not isoflurane concentration and the intraoperative ESRT,7 has been described in adults. Methodological limitations, including retrospective design and lack of appropriate power or statistical analysis, hamper interpretation of many of these previous studies.

The mechanism underlying the dose-dependent reflex suppression is speculative. The neuronal organization of the stapedius reflex arc is polysynaptic and includes the auditory nerve as the afferent limb; central auditory brainstem connections involving the ventral cochlear nucleus, trapezoid body and medial superior olive; and efferent motoneurons that course with the facial nerve to the stapedius muscle.18 Volatile anesthetics depress synaptic conduction more than axonal conduction. Accordingly, oliogosynaptic pathways are minimally affected, whereas polysynaptic pathways are exquisitely sensitive to anesthetic concentration.19,20 A depressant effect of the anesthetics on the stapedius muscle itself may also account for our findings. Volatile anesthetics act at the neuromuscular junction by binding to protein sites within the pore of the nicotinic acetylcholine receptor thereby blocking ion flow resulting in channel blockade.21,22 Alternatively, anesthetic molecules may bind elsewhere on the receptor to induce a conformational change to a nonconducting state.22 That the ECAP was unaffected by anesthesia is consistent with the fact that this is an axonal response and suggests that the site of anesthetic action on the ESRT is unlikely to be the auditory nerve. Further studies to evaluate auditory brainstem and efferent limb responses are needed to help elucidate the site of anesthetic action.

The current study posed several challenges, both ethical and logistic. First, we sought to minimize any prolongation of anesthetic time because of repeated measurement of auditory thresholds while still allowing sufficient time for equilibration of blood and effect-site anesthetic concentrations. Given the reported t1/2keO values for the anesthetics, at least 10 min of stable end-tidal concentration in the case of the volatile anesthetics23–25 and at least 5 min for propofol26 allowed 3 half-times for equilibration. It was explained to parents and patients during the informed consent that the study would prolong anesthetic time accordingly. Second, it is not possible to acquire baseline measurements in the awake state. We used midazolam as the basal anesthetic because this drug minimally affected the ESRT.9 Because the maintenance anesthetic regimen was standardized, any effect of the basal anesthetic would be applied equally to all groups. Third, when evaluating the effects of volatile and IV anesthetics, it is important to administer equipotent doses. The lack of plasma propofol concentration measurements is a limitation of the current study; however, Bispectral Index values decreased by comparable amounts with increasing concentrations of propofol and volatile anesthetics (Fig. 3), suggesting that stepwise changes in depth of anesthesia were similar among groups. There are, however, limitations to the use of Bispectral Index as a measure of depth of anesthesia. Bispectral Index values are variable at any given depth of anesthesia and are dependent on the anesthetic used.27–29

Fourth, to control for possible effects of muscle fatigue, time, and residual effects of induction drugs, we randomized the sequence of volatile anesthetic concentration, although this was not possible for propofol. That the results were consistent regardless of the volatile anesthetic concentration sequence suggests that these potential confounders did not affect measurement of auditory thresholds in the present study. Fifth, evaluating the effect of nitrous oxide could not be truly blinded because two additional ESRT measurements were needed; however, this was a secondary outcome in the present study. The results suggest that omission of nitrous oxide had no significant effect on the evoked responses, in contrast to the depression of somatosensory and motor evoked potentials associated with this drug when used in combination with other anesthetics.19,20

The age at which children are scheduled to undergo cochlear implantation is decreasing given evidence that shortening the period of auditory deprivation improves long-term outcome.30 Children implanted at 5 yr or younger perform better in auditory and speech understanding tests than their older counterparts, and those implanted younger than 2 yr of age perform even better.30 Initial setting of the dynamic range of stimulation is difficult in infants and young children because of their limited cooperation and communication abilities. Measurements in awake children are subjective as they rely on behavioral response methods of audiometry. For example, determination of the hearing threshold relies on observing movement or a verbal response to the stimulus and determination of the MCL requires application of progressively higher levels of stimulation until the child shows an adverse response, which exposes the child to the risk of over-stimulation and may lead to rejection of the implant. Objective rather than behavioral methods are increasingly being used to determine the limits of the dynamic range of stimulation. Knowledge of the effects of anesthetics on these objective measures is important to optimize the outcome of pediatric cochlear implantation.

The present findings also have clinical implications regarding the choice of drugs used to facilitate induction of controlled hypotension, which is often requested by the implant surgeon to improve the quality of the surgical field. Our results imply that the common practice of using volatile anesthetics to induce hypotension should be avoided during cochlear implant surgery. At the doses required to induce hypotension, the volatile anesthetics would be expected to cause profound depression or complete abolition of the stapedius reflex. Clinically, we have found that remifentanil infusion, titrated to the desired mean arterial blood pressure during anesthesia with propofol and nitrous oxide, provides satisfactory surgical conditions.

In conclusion, setting the appropriate limits of implant stimulation to achieve an optimum dynamic range is essential to the success of cochlear implant surgery. The results of the current study indicate that even sub-MAC concentrations of volatile anesthetics can markedly suppress or completely abolish the stapedius reflex, potentially causing an erroneously high MCL that could compromise the outcome of cochlear implantation. In contrast, propofol and nitrous oxide administered during remifentanil infusion had little or no effect on the auditory thresholds and are therefore recommended for the determination of auditory thresholds during pediatric cochlear implant surgery.

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