Anesth Analg 2003;96:238-244
© 2003 International Anesthesia Research Society
NEUROSURGICAL ANESTHESIA
S(+)-Ketamine Attenuates Myogenic Motor-Evoked Potentials at or Distal to the Spinal  -Motoneuron
Kai-Michael Scheufler, MD*,
Christof Thees, MD ,
Joachim Nadstawek, MD, PhD, and
Josef Zentner, MD, PhD*
*Department of NeurosurgeryUniversity of Freiburg, Freiburg, Germany; and
Department of Anesthesiology and Intensive Care MedicineUniversity of Bonn, Bonn, Germany
Address correspondence and reprint requests to Kai-Michael Scheufler, MD, Abt. Allgemeine Neurochirurgie, Universitätsklinikum Freiburg, Breisacher Str. 64, D-79106 Freiburg, Germany. Address e-mail to scheufle{at}nz11.ukl.uni-freiburg.de
 |
Abstract
|
|---|
We investigated the effect of S(+)-ketamine on spinal cord evoked potentials (ESCPs) and myogenic motor-evoked potentials after electrical stimulation of the motor cortex in a rabbit model. This study was designed to characterize the relationship between ESCP characteristics and corresponding changes in compound muscle action potentials (CMAPs) derived from fore and hind limbs. Direct (D) and indirect (I) corticospinal volleys (ESCP) from the upper and lower thoracic spinal cord, recorded by two bipolar epidural electrodes, were assessed during IV administration of 0.02, 0.05, 0.1, and 0.2 mg · kg-1 · min-1 of S(+)-ketamine, each before and after neuromuscular blockade (0.4 mg/kg of cisatracurium), in 16 New Zealand White rabbits after single-pulse bipolar electrical stimulation of the motor cortex at 50 (threshold), 60, and 70 V. CMAP amplitudes at fore and hind limbs were significantly suppressed (P < 0.01) during infusion at 0.1 and 0.2 mL · kg-1 · min-1, whereas neither corresponding D- nor I-waves were altered. Similar findings were obtained during variation of stimulus amplitude (50–70 V). Multivariate regression analysis of CMAP amplitudes and various ESCP characteristics demonstrated no apparent interparametric association. These findings indicate that S(+)-ketamine modulates CMAP independent from corticospinal D- and I-wave-mediated facilitation at or distal to the spinal  -motoneuron.
IMPLICATIONS: S(+)-Ketamine combines several anesthetic properties suitable for total IV neuroanesthesia, including minimal effects on neurophysiological monitoring. Recording of neural and myogenic responses after electrical stimulation of the motor cortex indicates that S(+)-ketamine modulates myogenic motor-evoked potentials by a peripheral mechanism at or distal to the spinal -motoneuron.
|
Introduction
|
|---|
Intraoperative assessment of motor-evoked potentials (MEPs) after both electrical and magnetoelectrical stimulation is progressively gaining acceptance because of increasing success in obtaining stable recordings under general anesthesia (1–3). This success, leading to progressive implementation of MEP monitoring into clinical practice, results mainly from the development of suitable total IV anesthetic regimens, which are based on systematic investigations in animal models (4,5). Among various IV anesthetics considered suitable for both electrophysiological monitoring and neurosurgical anesthesia, racemic ketamine has not been regarded as a first-choice anesthetic because of emergence delirium and hallucinatory states observed during clinical use (6). However, the introduction of its enantiomer S(+)-ketamine, which has been reported to induce fewer clinical side effects and to have favorable neurovascular (7) and pharmacokinetic (8) properties, has renewed interest in this drug for use in neuroanesthesia, especially in view of its neuroprotective effects (9,10). Although it is known that ketamine induces moderate dose-dependent suppression of myogenic MEPs without any major effect on evoked spinal cord potentials (ESCPs), the exact relationship between these two responses has not been characterized in detail. We therefore evaluated S(+)-ketamine’s modulatory interactions with generation and conduction of evoked responses after electrical stimulation of the motor cortex in a standardized rabbit model (2,4,5).
|
Methods
|
|---|
The institutional animal investigation committee approved all animal procedures. Sixteen adult male New Zealand White rabbits (Charles River Laboratories, Kißlegg, Germany) weighing between 3.5 and 4 kg were fasted overnight and anesthetized by IM injection of S(+)-ketamine (10 mg/kg; Parke-Davis, Berlin, Germany) and xylazine (7 mg/kg; Bayer, Leverkusen, Germany), followed by continuous IV infusion of S(+)-ketamine (0.05 mg · kg-1 · min-1) and midazolam (0.08 mg · kg-1 · min-1; Hoffmann-La Roche, Grenzach-Wyhlen, Germany) to provide adequate anesthesia for surgical manipulation. Midazolam and xylazine were discontinued after the surgical procedure at least 45 min before commencing with any electrophysiological recordings; anesthesia was provided exclusively by IV administration of S(+)-ketamine at 0.02 mg · kg-1 · min-1 during the baseline recording period. Cisatracurium (0.4 mg/kg, Tracrium®; Glaxo-Wellcome, Bad-Oldeslohe, Germany) was administered IV before intubation. The lungs were ventilated with oxygen and air to maintain arterial blood oxygen partial pressure (PaO2) at 100–120 mm Hg and end-tidal carbon dioxide pressure (ETCO2) between 35 and 40 mm Hg (CIV 101; Columbus Instruments, Columbus, OH). Mean arterial blood pressure was monitored continuously in the descending aorta, and central venous pressure was recorded in the inferior vena cava. Three-lead electrocardiograms were obtained via needle electrodes placed in the lateral chest wall. Continuous recording of mean arterial blood pressure, heart rate, and neuromuscular transmission was performed by using a customized monitor setup (CS/3; Datex-Ohmeda, Duisburg, Germany) with synchronous data transfer to a personal computer (ICU Pilot; CMA, Solna, Sweden). PaO2 and arterial blood carbon dioxide partial pressure (PaCO2), as well as arterial pH, were assessed regularly (ABL, Radiometer, Copenhagen, Denmark) and kept within their physiological ranges (PaCO2, 35 ± 4.4 mm Hg; pH, 7.37 ± 0.06). Fluid administration was adjusted by hourly determination of central venous pressure and urine output to maintain euvolemia. Brain temperature was measured by a thermocouple (GMS, Kiel-Mielkendorf, Germany), placed within the cerebral cortex contralateral to the stimulation electrodes, and maintained at 36.5°C–37.5°C by corresponding adjustments of body temperature (continuous rectal temperature assessment) with a thermal blanket.
Animals were placed prone on a custom bench, and their heads were fixed in a stereotactic three-pin headrest. A trephination was performed, exposing the parasagittal frontoparietal region (randomly assigned to either the right or left hemisphere) for epidural placement of 2 custom-made silver-plate electrodes (diameter, 1.5 mm) separated by 1.5 cm in sagittal orientation. Electrode impedances were kept at <10 k . Compound muscle action potentials (CMAP) were recorded with hypodermic needle electrodes (Nicolet Biomedical, Kleinostheim, Germany) placed in the flexor and extensor muscle groups of both fore limbs (FL) (brachioradialis and triceps) and hind limbs (HL) (gastrocnemius and tibialis anterior) in a belly-tendon montage. After laminectomy at thoracic spine levels T8 or T9, 2 pediatric bipolar pacemaker electrodes (Ossypka, Lörrach, Germany) with a lead separation of 10 mm were introduced into the epidural space at the cervicothoracic junction (upper thoracic spinal cord; UTSC) and thoracolumbar junction (lower thoracic spinal cord; LTSC) under fluoroscopic guidance for recording of ESCPs. Recording electrode impedances <5 k were accepted. Standard electrophysiological equipment (SpiritTM Evoked Potential System; Nicolet Biomedical) was used to register MEPs. Bandpass filters were set to 1 Hz to 3 kHz, and the notch filter was deactivated. Constant-voltage stimulation was used at threshold (T) intensity (50 V), T + 20% (60 V), and T + 40% (70 V), with a rectangular monophasic pulse of 200 µs duration (Digitimer D180; Digitimer Ltd., Hertfordshire, UK). T (50 V) was defined as the stimulation amplitude producing a myogenic potential  50 µV in at least 50% of 10 repetitive stimulations. All traces were independently reviewed by two single-blinded investigators. MEP amplitudes were measured from peak to peak as well as from peak to baseline, whereas latencies were defined as the interval between the first stimulation artifact and the onset of the MEP. Transsynaptically relayed (i.e., indirect [I]) waves resemble a series of low-amplitude deflections ( 40 µV throughout our experiments) derived from variable, sequential activation of a number of cortical motoneurons by excitatory cortical interneurons as a result of epidural electrical stimulation. I-waves are preceded by a high-amplitude (60 µV) unrelayed (i.e., direct [D]) wave component within the ESCP, resulting from depolarization of corticospinal tract axons at or even distal to the axonal hillock (depending on the stimulus amplitude). The D-wave complex was usually bifid (M-shaped), with an initial distinct spike (D1a) and a smaller consecutive wavelike component (D1b, reaching  45%–60% of D1a amplitude). Each component was analyzed individually.
Individual I-waves display slight latency shifts (0.05–0.08 ms) and variable morphology (bifid shape) within successive recordings, rendering the usual averaging algorithms (resulting in marked attenuation of averaged I-waves) impractical. Therefore, quantitative analysis of individual I-waves (termed I1–In by order of their occurrence) required latency-gated identification and subsequent assessment of any individual wavelet’s amplitude within each recording. Temporal coherence of distinct I-waves appearing in succession at the UTSC and LTSC was mandatory for reliable identification of individual wavelets. Inconsistencies between recordings at the UTSC and LTSC, prohibiting definite, latency-gated assignment of a given wavelet to a consistently traceable peak within the I-wave complex (Fig. 1), resulted in its exclusion from analysis. I-waves at the LTSC were not recruited for quantitative evaluation because of their complex, often bifid morphology (Fig. 1).
View larger version (25K):
[in this window]
[in a new window]
|
Figure 1. Top, Original nonaveraged recordings from one animal, showing myogenic (CMAP from FL and HL) and neurogenic responses (ESCP from the UTSC and LTSC) elicited by bipolar anodal electrical stimulation of the motor cortex with a single shock at 70 V. Note that the last I-wave (I5) within the ESCP recorded at UTSC is hidden by the paraspinal muscle artifact. Bottom, ESCPs from the UTSC (upper trace) and LTSC (lower trace) recorded after neuromuscular blockade. Typical D-waves consist of an initial high-amplitude spike (D1a) followed by a consecutive wavelike component (D1b). The I-wave complex consists of five distinct low-amplitude wavelets (I1–I5). Late I-waves are distinguished from noise by tracing the temporal coherence of individual wavelets recorded in succession at UTSC and LTSC, allowing latency-gated assignment of individual I-waves to a consistent traceable peak within the I-wave complex. CMAP = compound muscle action potential; ESCP = evoked spinal cord potential; FL = fore limb; HL = hind limb; UTSC = upper thoracic spinal cord; LTSC = lower thoracic spinal cord.
|
|
Baseline values were established at an infusion rate of 0.02 mg · kg-1 · min-1 of S(+)-ketamine before sequential dose escalation to 0.05, 0.1, and 0.2 mg · kg-1 · min-1. A minimum of 3 h for equilibration of plasma levels was allowed after each change of infusion rate before commencing with MEP recordings. Two series of experiments were conducted at each infusion rate—the first series without and the second series with neuromuscular blockade (cisatracurium 0.4 mg/kg)—to eliminate the ESCP’s paravertebral muscle artifact. Analysis of reference ESCP under muscular blockade was conducted to 1) preclude missing additional I-waves hidden within the paraspinal CMAP and 2) to increase the signal to noise ratio for quantitative analysis of ESCP. After completion of the second series, restoration of neuromuscular transmission was assessed by serial analysis of myogenic responses (CMAP amplitude at the HL) to sciatic nerve stimulation (train of four) until complete recovery of CMAP amplitudes (observed within <60 min). Four recordings were evaluated for any stimulation intensity level (50 to 60 to 70 V, each with and without neuromuscular blockade) at each infusion rate. Animals were killed by intracardial injection of 50 mmol of KCl after the administration of thiopental 200 mg.
Data are expressed as mean ± SD. Two-sample significance of data was tested with the Mann-Whitney U-test. Pearson’s correlation was used to describe the relationships between single variables. Multivariate regression analysis was used to describe the interdependence between several different variables. Nonparametric analysis of variance (Kruskal-Wallis test, median test) was used to describe differences in distribution among the various groups. Statistical significance was assumed for P < 0.05. All statistical analyses were performed with the Statistica 5.0 package (StatSoft, Hamburg, Germany).
|
Results
|
|---|
The mean MEP latencies of 7.3 ± 0.16 ms (FL), 10.8 ± 0.22 ms (HL), 1.76 ± 0.25 ms (D1a, UTSC), 2.22 ± 0.26 ms (D1b, UTSC), 2.13 ± 0.31 ms (D1a, LTSC), and 2.64 ± 0.29 ms (D1b, LTSC) observed under baseline anesthesia did not change significantly during S(+)-ketamine dose escalation. Table 1 gives an overview on MEP amplitudes. The latencies of individual I-waves (n = 4.72 ± 0.41) at UTSC were 3.67 ± 0.22 ms (I1), 4.08 ± 0.27 ms (I2), 4.84 ± 0.42 ms (I3), 5.86 ± 0.49 ms (I4), and 6.88 ± 0.56 ms (I5). D1b and I5 (UTSC and LTSC) were inconsistent, especially during stimulation at T intensity (50 V) in combination with fast infusion rates of S(+)-ketamine (0.2 mg · kg-1 · min-1). However, this association did not reach statistical significance (P > 0.39). Whereas both CMAP and ESCP latencies, D-wave characteristics (D1a and D1b amplitude, D1b/D1a ratio), and the number of I-waves were significantly influenced neither by stimulation intensity nor by infusion rate (P > 0.1), CMAP attenuation was dependent on both stimulation intensity and S(+)-ketamine dosage.
During stimulation at 70 and 60 V, significant attenuation of CMAP recorded from FL and HL (P < 0.01) occurred between baseline (0.02 mL · kg-1 · min-1) and 0.1 as well as 0.2 mL · kg-1 · min-1 (differences among 0.05, 0.1, and 0.2 mL · kg-1 · min-1 were not significant). Baseline ESCP amplitudes (D1a and D1b) at UTSC were suppressed minimally (not significant) after the infusion speed was increased from 0.1 to 0.2 mL · kg-1 · min-1. Likewise, insignificant changes in ESCP amplitude (P > 0.22) were observed at LTSC (Fig. 2).
View larger version (43K):
[in this window]
[in a new window]
|
Figure 2. Bar graph illustrating the relationship between the S(+)-ketamine plasma infusion rate (0.02–0.2 mg · kg-1 · min-1) and the relative amplitude of myogenic MEPs (compared with baseline) recorded from the fore and hind limbs as well as neurogenic MEPs (D1a amplitude) recorded from the UTSC and LTSC. The dose-dependent progressive attenuation of myogenic MEP (CMAP) without corresponding alterations in neurogenic potential (ESCP) characteristics is independent from stimulation amplitude. **Statistically significant differences between groups within brackets; n = 16; mean ± SD. D1a = initial spike component of the D-wave; CMAP = compound muscle action potential; ESCP = evoked spinal cord potential; MEP = motor-evoked potential; UTSC = upper thoracic spinal cord; LTSC = lower thoracic spinal cord.
|
|
At T stimulation intensity (50 V), CMAP amplitudes recorded from FL were significantly reduced at infusion rates of 0.1 and 0.2 mL · kg-1 · min-1 (P < 0.01) compared with 0.02 mL · kg-1 · min-1 (baseline). At HL, CMAP amplitudes varied between baseline and 0.05, 0.1, and 0.2 mL · kg-1 · min-1 (P < 0.01).
Neither the number of I-waves nor the D-wave morphology (amplitude of D1a and D1b, D1b/D1a ratio) was related to stimulus intensity. Nonparametric assessment of the correlation between individual variables (Spearman’s rank correlation) and multivariate regression analysis (Table 2) of CMAP and ESCP characteristics (CMAP amplitudes, D1a and D1b amplitudes, number of I-waves) excluded significant interdependencies between any of the investigated MEP variables except for CMAP amplitudes at FL and HL (r = 0.52; P < 0.01). Therefore, changes in myogenic MEP were neither associated with nor predicted by corresponding alterations of ESCP waveforms.
|
Discussion
|
|---|
The phencyclidine derivative S(+)-ketamine, a stereoisomer of racemic ketamine, combines twofold greater analgesic and hypnotic effects with shorter recovery times in comparison to racemic ketamine (11). Racemic ketamine has a mean elimination half-life of 2.6 hours and a low plasma binding of 12% (6). In our model, each infusion rate was maintained constant for a period between 1 and 2 half-times (three to five hours). Whereas construction of a pharmacological dose-response curve would require steady-state plasma concentrations (which can be attained only after approximately four half-times), the context-sensitive half-life of S(+)-ketamine (regarding its effects on MEP) was considerably less than 20 minutes after bolus administration (2). The effect of bolus administration of S(+)-ketamine on MEP compares well with the results reported in this study (2). Because we intended to relate our findings to those of a previous study (12), we chose a very similar dose-escalation protocol using continuous infusion of S(+)-ketamine. Although the distribution volume of ketamine enantiomers is not stereoselective (8,13), some of their specific interactions with different neurotransmitter receptor systems are (14,15). Norketamine, the main metabolite of ketamine, is a highly soluble noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist (11,15), promoting cerebral protection against ischemic (10) and excitotoxic cerebral damage mediated by glutamate release (9).
The neurophysiological effects of S(+)-ketamine include activation and inhibition of various neurotransmitter receptor and effector systems, including the NMDA receptor (11,16), the opioid receptors µ,  ,  , and  (17,18), and sodium and potassium channels within the central nervous system (CNS) (6,19) and peripheral nerves (20). Ketamine is also a potent inhibitor of nicotinic acetylcholine receptors (21). Although its anesthetic and analgesic effects have been ascribed to interaction with the NMDA receptor (16), ketamine also inhibits neuronal activity in spinal dorsal horn cells (22). In addition, this substance also influences systemic circulation by increasing sympathetic outflow to muscles (23). Stable myogenic MEPs have been obtained by using total IV anesthesia with ketamine and fentanyl in a similar rabbit model (4). Similarly, racemic ketamine has been demonstrated to exert minimal suppressive effects on neurogenic MEPs in primates with IV infusion rates up to 0.2 mg · kg-1 · min-1, even when it is combined with additional administration of 50% inspiratory nitrous oxide for the maintenance of baseline anesthesia (12). However, nitrous oxide by itself produces significant dose-dependent suppression of both neurogenic and myogenic MEP (5). To investigate exclusively the specific effects of S(+)-ketamine on MEP, we used midazolam for additional sedation only during the surgical procedure, discontinuing infusion 45 minutes ahead of MEP baseline recording. With midazolam at the infusion rate and duration used in our study, no significant side effects on MEP were expected (2). Our results generally confirm the findings reported by Ghaly et al. (23), who demonstrated maintenance of corticospinal D-volleys and virtually all spinal I-waves during the administration of racemic ketamine at various hypnotic doses. Although these combined results indicate that the effect of S(+)-ketamine on ESCP is comparable to that of racemic ketamine, previous investigations (4,12) have not provided conclusive data regarding the relationship between ESCP and corresponding myogenic MEP.
According to the current physiological concept of MEP generation and facilitation, attenuation of myogenic potentials by various IV and volatile anesthetics is related to dose-dependent suppression of polysynaptic corticospinal I-volleys generated by cortical motoneurons in response to synchronized discharge of excitatory cortical interneurons after single-pulse stimulation and progressive reduction of D-wave amplitude and number in case of multiple D-waves resulting from repetitive cortical stimulation (2,5,24). For single cortical stimulation, this concept of D- and I-wave-mediated activation of spinal -motoneurons maintains that progressive amplitude reduction of the latest I-wave(s) within the ESCP will finally result in suppression of myogenic activity, with a presumably nonlinear transfer function between temporal and spatial convergence of corticospinal volley input and -motoneuron output (24). However, the exact mechanisms involved in the modulation of myogenic MEPs by ketamine, especially regarding D- and I-wave-mediated activation of spinal -motoneurons, have thus far remained elusive, mainly because of the difficulties encountered in the quantitative evaluation of ESCP. Improvements in the quality of ESCP recording, correlating signals from different recording sites and obtaining reference ESCPs after complete muscle relaxation, enabled us to address this specific issue. Single-pulse T and supra-T electrical stimulation of the motor cortex were used to assess the effect of S(+)-ketamine on D-waves and all successive I-waves within the resultant ESCP, without the typical artifacts (e.g., multiple D-waves truncating the initial I-wave complex) observed during multipulse stimulation. Although application of a single stimulus to the motor cortex readily evokes spinal -motoneuron discharge by generation of a single D-wave and multiple I-waves, a single direct corticospinal tract stimulation (producing a single D-wave only) is ineffective without precontraction (i.e., facilitation) of target muscles, even without any pharmacological suppression of the motor system (24).
Because myogenic responses were consistently obtained at all stimulation intensities and ketamine concentrations, we consider the mechanisms mentioned above to be functional in our model and, thus, relevant for interpreting the effects of S(+)-ketamine observed in this study. No significant association between alterations in ESCP morphology (amplitudes of D- and I-waves, number of I-volleys) and corresponding dose-dependent suppression of CMAP amplitudes recorded from muscle groups of the upper and lower limbs were observed after incremental IV administration of S(+)-ketamine at four different infusion rates. We therefore conclude that S(+)-ketamine, and likely also racemic ketamine, may attenuate myogenic MEPs by mechanisms distal to the generation and conduction of corticospinal D- and I-volleys. Rather, temporal and spatial summation of excitatory postsynaptic potentials at the spinal -motoneuron appears to be inhibited, suggesting modulating effects on the activity of spinal interneurons, similar to the action of opioids (2,18,22). Additional effects may result from interference with peripheral nerve conduction (20) or neuromuscular transmission (25). Ketamine may affect the temporal summation of ESCP at the -motoneuron by changing its membrane time constant and therefore increase the rate of ESCP decay. Spinal -motoneuron discharge may also be affected by presynaptic inhibition of neurotransmitter release from the terminals of corticospinal tract axons. Experimental data suggest that ketamine reduces neuromuscular transmission by noncompetitive inhibition of NMDA receptors at the neuromuscular junction (25). Because both glutamate and acetylcholine are released into the synaptic cleft to mediate neuromuscular transmission, dose-dependent suppression of myogenic MEPs could potentially rely exclusively on this mechanism. However, ketamine has also been demonstrated to block axonal conduction by nonstereoselective blockade of sodium and potassium channels in peripheral nerve membranes (20). Although specific modulation of these ion channels and the NMDA receptor by ketamine may vary with respect to their localization in the CNS and peripheral nervous system, the investigated variables of axonal conductance within the central motor pathways (ESCP amplitudes and latencies) were not changed by different doses of ketamine throughout our study. Therefore, the anesthetic and analgesic effects of S(+)-ketamine are not linearly related to its suppressing effects on myogenic MEPs. The hypothetical mechanisms of peripheral interactions of S(+)-ketamine resulting in dose-dependent attenuation of myogenic MEPs warrant further investigation, targeting the specific action of ketamine enantiomers on spinal motor and inhibitory interneuronal systems, motor nerve conduction, and neuromuscular transmission.
|
Acknowledgments
|
|---|
Supported by grants from the Deutsche Forschungsgemeinschaft Ze 267/3-1.
|
References
|
|---|
- Kawaguchi M, Inoue S, Kakimoto M, et al. The effect of sevoflurane on myogenic motor-evoked potentials induced by single and paired transcranial electrical stimulation of the motor cortex during nitrous oxide/ketamine/fentanyl anesthesia. J Neurosurg Anesthesiol 1998; 10: 131–6.[Web of Science][Medline]
- Scheufler KM, Zentner J. Total intravenous anesthesia for intraoperative monitoring of motor evoked potentials: an integral view combining clinical and experimental data. J Neurosurg 2002; 96: 571–9.[Web of Science][Medline]
- Sihle-Wissel M, Scholz M, Cunitz G. Transcranial magnetic-evoked potentials under total intravenous anaesthesia and nitrous oxide. Br J Anaesth 2000; 85: 465–7.[Abstract/Free Full Text]
- Sakamoto T, Kawaguchi M, Inoue S, Furuya H. Suppressive effect of nitrous oxide on motor evoked potentials can be reversed by train stimulation in rabbits under ketamine/fentanyl anaesthesia, but not with additional propofol. Br J Anaesth 2001; 86: 395–402.[Abstract/Free Full Text]
- Zentner J, Thees C, Pechstein U, et al. Influence of nitrous oxide on motor-evoked potentials. Spine 1997; 22: 1002–6.[Web of Science][Medline]
- Rhoney DH, Parker D. Use of sedative and analgesic agents in neurotrauma patients: effects on cerebral physiology. Neurol Res 2001; 23: 237–59.[Web of Science][Medline]
- Engelhard K, Werner C, Mollenberg O, Kochs E. S(+)-ketamine/propofol maintain dynamic cerebrovascular autoregulation in humans. Can J Anaesth 2001; 48: 1034–9.[Web of Science][Medline]
- Geisslinger G, Hering W, Thomann P, et al. Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method. Br J Anaesth 1993; 70: 666–71.[Abstract/Free Full Text]
- Himmelseher S, Pfenninger E, Georgieff M. The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons. Anesth Analg 1996; 83: 505–12.[Abstract]
- Reeker W, Werner C, Mollenberg O, et al. High-dose S(+)-ketamine improves neurological outcome following incomplete cerebral ischemia in rats. Can J Anaesth 2000; 47: 572–8.[Web of Science][Medline]
- Liu HT, Hollmann MW, Liu WH, et al. Modulation of NMDA receptor function by ketamine and magnesium: part I. Anesth Analg 2001; 92: 1173–81.[Abstract/Free Full Text]
- Henthorn TK, Krejcie TC, Niemann CU, et al. Ketamine distribution described by a recirculatory pharmacokinetic model is not stereoselective. Anesthesiology 1999; 91: 1733–43.[Web of Science][Medline]
- Yamakura T, Sakimura K, Shimoji K. The stereoselective effects of ketamine isomers on heteromeric N-methyl-D-aspartate receptor channels. Anesth Analg 2000; 91: 225–9.[Abstract/Free Full Text]
- Zeilhofer HU, Swandulla D, Geisslinger G, Brune K. Differential effects of ketamine enantiomers on NMDA receptor currents in cultured neurons. Eur J Pharmacol 1992; 213: 155–8.[Web of Science][Medline]
- Oye I, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 1992; 260: 1209–13.[Abstract/Free Full Text]
- Hirota K, Okawa H, Appadu BL, et al. Stereoselective interaction of ketamine with recombinant mu, kappa, and delta opioid receptors expressed in Chinese hamster ovary cells. Anesthesiology 1999; 90: 174–82.[Web of Science][Medline]
- Finck AD, Ngai SH. Opiate receptor mediation of ketamine analgesia. Anesthesiology 1982; 56: 291–7.[Web of Science][Medline]
- Frenkel C, Urban BW. Molecular actions of racemic ketamine on human CNS sodium channels. Br J Anaesth 1992; 69: 292–7.[Abstract/Free Full Text]
- Brau ME, Sander F, Vogel W, Hempelmann G. Blocking mechanisms of ketamine and its enantiomers in enzymatically demyelinated peripheral nerve as revealed by single-channel experiments. Anesthesiology 1997; 86: 394–404.[Web of Science][Medline]
- Tassonyi E, Charpantier E, Muller D, et al. The role of nicotinic acetylcholine receptors in the mechanisms of anesthesia. Brain Res Bull 2002; 57: 133–50.[Web of Science][Medline]
- Suzuki R, Matthews EA, Dickenson AH. Comparison of the effects of MK-801, ketamine and memantine on responses of spinal dorsal horn neurones in a rat model of mononeuropathy. Pain 2001; 91: 101–9.[Web of Science][Medline]
- Kienbaum P, Heuter T, Pavlakovic G, et al. S(+)-ketamine increases muscle sympathetic activity and maintains the neural response to hypotensive challenges in humans. Anesthesiology 2001; 94: 252–8.[Web of Science][Medline]
- Ghaly RF, Ham JH, Lee JJ. High-dose ketamine hydrochloride maintains somatosensory and magnetic motor evoked potentials in primates. Neurol Res 2001; 23: 881–6.[Web of Science][Medline]
- Deletis V, Rodi Z, Amassian VE. Neurophysiological mechanisms underlying motor evoked potentials in anesthetized humans. II. Relationship between epidurally and muscle recorded MEPs in man. Clin Neurophysiol 2001; 112: 445–52.[Web of Science][Medline]
- Koyuncuoglu H, Kara I, Gunel MA, et al. N-methyl-D-aspartate antagonists, glutamate release inhibitors, 4-aminopyridine at neuromuscular transmission. Pharmacol Res 1998; 37: 485–91.[Web of Science][Medline]
Accepted for publication September 25, 2002.
|
Top
Abstract
Introduction
