Jan H. Baars

In Ausgabe AINS 1/13 wurde unter der Rubrik Fachwissen Anästhesiologie – Topthema: Awareness der Name des Autors Bosch, Matthias J falsch angegeben – der Autor heißt richtig Posch, Matthias J. Dies wurde im Originalartikel korrigiert.

Potentiation of inhibitory transmissions in the spinal cord is considered to be an important mechanism for the mediation of the immobilizing effects of anesthetics. However, the depressant effects on motoneurons could be counterbalanced by presynaptic effects that inhibit the depressant pathways. Here we investigated the effect of sevoflurane on a disynaptic inhibitory pathway onto motoneurons in a human reflex model. The study was performed with 9 volunteers receiving sevoflurane anesthesia (end tidal: 0.8% sevoflurane). Reciprocal inhibition was estimated from the depression of the H-reflex following a conditioning stimulation of the muscle spindle afferents from the tibialis anterior muscle. Measurements were performed before, during and after drug administration. The inhibition (mean ± SE) amounted to 15.4% ± 6.8%, 1.9% ± 4.2% and 15.7% ± 8.8% for measurements before, during and after sevoflurane administration, respectively. Differences between the anesthetic state and the two controls were statistically significant (mixed-effect ANOVA, p<0.01). Sevoflurane reduces reciprocal Ia-inhibition on motoneurons in humans. These findings seem to contradict the accepted view that sevoflurane enhances inhibitory synaptic transmission. This contradiction might be explained by the inhibitory actions of sevoflurane within the disynaptic pathway prior to the final glycinergic transmission onto the motoneuron. Our results suggest that even in presumably simple pathways, postsynaptic effects of anesthetics could be superimposed by their presynaptic effects.

Background: The predominant target of anesthetics to suppress movement responses to noxious stimuli is located in the spinal cord. Although volatile anesthetics appear to produce immobility by actions on the ventral rather than the dorsal horn, the site of action of propofol remains unclear. Methods: In a crossover design, the authors compared in 13 volunteers the effects of sevoflurane and propofol on the amplitudes of the H reflex, which is mediated exclusively in the ventral horn and a withdrawal reflex (RIII Reflex), which integrates dorsal and ventral horn function. The concentrations were adjusted according to a Dixon up-and-down approach, depending on movement responses to tetanic stimulation. Results: Sevoflurane and propofol concentrations ranged from 1.2 to 1.6 Vol% and 3 to 6 mg/l, respectively. Sevoflurane reduced the H reflex amplitude significantly to 66 +/- 17% (mean +/- SD) of its control values. Propofol did not significantly reduce the H reflex. The reductions under the two drugs differed significantly. The RIII reflex amplitude was significantly reduced to 19 +/- 10% and 27 +/- 12% (mean +/- SD) of the control values by sevoflurane and propofol, respectively. The reductions did not differ between the drugs. Conclusions: Probably because of the polysynaptic relay, the attenuation of the withdrawal reflex exceeds the attenuation of the H reflex. Sevoflurane produces a larger inhibitory effect on the H reflex than propofol, which confirms that the ventral horn is a more important target for volatile anesthetics, whereas effects of propofol on this site of action are rather limited. Our findings indirectly suggest for propofol a relatively stronger effect within the dorsal horn.

RESEARCH on spinal effects of anesthetics has become a focus of interest since the spinal cord was identified more than a decade ago as the primary target mediating the suppression of movement in response to noxious stimulation during the anesthetic state. In rats, neither decerebration1 nor hypothermic transsection2 between the brain and the spinal cord altered the anesthetic requirements to suppress movement responses to noxious stimuli. It is commonly accepted that volatile anesthetics interact in the central nervous system with different ligand gated ion channels, at least glutamate, γ-aminobutyric acid type A (GABA^A), and glycine receptors.3 Although the primary molecular targets have been partly identified, the mechanisms by which anesthetics suppress movement responses are still not fully understood. Human in vivo studies have shown that the suppression of spinal motoneuron excitability, as assessed using the monosynaptic H reflex by volatile anesthetics and nitrous oxide, correlates well with the suppression of movement responses to noxious stimuli,4–6 which underlines the importance of anesthetic effects on the “final common pathway” for motor output in respect to the suppression of movement to noxious stimuli. In vitro studies on spinal cord slices have given evidence that anesthetics inhibit spinal motoneuron excitability by both presynaptic and postsynaptic actions.7–9 The relative contribution of presynaptic and postsynaptic effects, however, is not known.

Background: In vitro studies indicate that the primary molecular targets of propofol in the spinal cord are gamma-aminobutyric acid (GABA) type A receptors. Because of the complexity of the central nervous system, specific GABA-mediated effects have not yet been isolated in humans. Here, the authors used heteronymous Ia facilitation of the soleus H-reflex from the femoral nerve as a specific pathway involving GABA to demonstrate a presynaptic GABA-mediated effect of propofol in humans. Methods: The study was performed in 10 volunteers aged 23-32 yr. The soleus H-reflex was evoked by stimulation of the tibial nerve in the popliteal fossa. The stimulation current was adjusted to yield an unconditioned H-reflex of 15% of the maximal muscle response to electric stimulation of the tibial nerve. The soleus H-reflex was conditioned by stimulating Ia afferents from the quadriceps femoris in the femoral triangle. The stimulus was applied 0.3-0.4 ms after the onset of facilitation, to assure a purely monosynaptic excitatory postsynaptic potential from quadriceps Ia afferents to the soleus motoneuron. At least 45 conditioned (femoral and tibial) and unconditioned (only tibial) stimuli were applied in random order. The authors compared the amount of heteronymous H-reflex facilitation under a concentration of 2 microg/ml propofol with control values obtained before and after the propofol infusion. Results: H-reflex facilitation due to the conditioning stimulus during propofol administration was significantly (P < 0.05, t test) decreased by an average of 43% in all patients in comparison with the control values. Conclusions: Although alternative explanations such as supraspinal effects cannot be ruled out completely, the findings of this study are most likely explained by a specific presynaptic effect of propofol. Strong evidence form neurophysiologic studies indicates that this effect is mediated by the GABA type A receptors.

The spinal cord is an important site of anaesthetic action because it mediates surgical immobility. During anaesthesia with volatile anaesthetics, it has been shown that the suppression of the spinal H-reflex correlates with surgical immobility. To evaluate whether the H-reflex could also be a possible candidate for monitoring immobility during propofol anaesthesia, this study assessed the concentration-dependent suppression of the H-reflex by propofol. To discriminate different effect sites, the individual concentration response-curves and the t(1/2ke0) of the H-reflex have been compared with those of two EEG parameters. In 18 patients, anaesthesia was induced and maintained with propofol infused using a target-controlled infusion pump at stepwise increasing and decreasing plasma concentrations between 0.5 and 4.5 mg/l. The H-reflex of the soleus muscle was recorded at a frequency of 0.1 Hz. Calculated propofol concentrations and H-reflex amplitude were analysed in terms of a pharmacokinetic-pharmacodynamic (PKPD) model with a sigmoid concentration-response function. For slowly increasing propofol concentrations, computer fits of the PKPD model for H-reflex suppression by propofol yielded the following median parameters: EC50 1.1 (0.8-1.7) mg/l, slope parameter 2.4 (2.0-3.7), and a t(1/2ke0) of 6.7 (2.8-7.5, 25-75% quantiles) min. For the bispectral index, the t(1/2ke0) was 2.2 (1.8-3.1) min and for the spectral edge frequency at the 95th percentile of the power spectrum 2.8 (1.9-3.2) min. Propofol, unlike sevoflurane, suppresses the spinal H-reflex at concentrations far lower than the C50 skin incision. The differences in t(1/2ke0)-values indicate the presence of different effect compartments for effects on the H-reflex and the EEG.

Background. The immobilizing effects of volatile anaesthetics are primarily mediated at the spinal level. A suppression of recurrent spinal responses (F-waves), which reflect spinal excitability, has been shown for propofol. We have assessed the concentration-dependent F-wave suppression by propofol and related it to the logistic regression curve for suppression of movement to noxious stimuli and the effect on the bispectral index™ (BIS™). The predictive power of drug effects on F-waves and BIS for movement responses to noxious stimuli was tested. Methods. In 24 patients anaesthesia was induced and maintained with propofol infused by a target controlled infusion pump at stepwise increasing and decreasing plasma concentrations between 0.5 and 4.5 mg litre⁻¹. The F-waves of the abductor hallucis muscle were recorded at a frequency of 0.2 Hz. BIS values were recorded continuously. Calculated propofol concentrations and F-wave amplitude and persistence were analyzed in terms of a pharmacokinetic–pharmacodynamic (PK/PD) model with a simple sigmoid concentration–response function. Motor responses to tetanic electrical stimulation (50 Hz, 60 mA, 5 s, volar forearm) were tested and the EC_50tetanus was calculated using logistic regression. Results. For slowly increasing propofol concentrations, computer fits of the PK/PD model for the suppression by propofol yielded a median EC₅₀ of 1.26 (0.4–2.3) and 1.9 (1.0–2.8) mg litre⁻¹ for the F-wave amplitude and persistence, respectively. These values are far lower than the calculated EC₅₀ for noxious electrical stimulation of 3.75 mg litre⁻¹. This difference results in a poor prediction probability of movement to noxious stimuli of 0.59 for the F-wave amplitude. Conclusions. F-waves are almost completely suppressed at subclinical propofol concentrations and they are therefore not suitable for prediction of motor responses to noxious stimuli under propofol mono-anaesthesia.

Background. Decreased spinal excitability contributes to the immobilizing effects of halogenated ethers during general anaesthesia. Recurrent spinal responses such as F-waves reflect spinal excitability and are suppressed by volatile anaesthetics. To evaluate whether F-waves are suitable for monitoring immobility, the concentration-dependent effects of sevoflurane on F-waves were compared with effects on the Bispectral Index™ (BIS™). The predictive power of all parameters for movement responses to noxious stimuli was tested. In addition, the effect of the noxious stimulus itself on F-waves was investigated. Methods. In 28 patients, F-waves were recorded during sevoflurane anaesthesia at a frequency of 0.2 Hz at the lower limb. To insert a laryngeal mask, the sevoflurane concentration was initially increased to ∼4%, which caused a complete extinction of F-waves. The sevoflurane concentration was then reduced until the F-waves recovered. BIS and spectral edge frequency (SEF₉₅) were recorded continuously. The t_1/2ke0 and EC₅₀ values of the F-wave persistence and amplitude were calculated using a standard pharmacokinetic–pharmacodynamic model. During decreasing sevoflurane concentration motor responses to tetanic electrical stimulation (50 Hz, 60 mA, 5 s, volar forearm) were tested in seven patients and MAC_tetanus was calculated using logistic regression. Results. Sevoflurane reduces the F-wave amplitude with an EC₅₀ of 0.79 vol% at a far lower concentration than the calculated MAC_tetanus (1.5 vol%), whereas the F-wave persistence yields an EC₅₀ of 1.4 vol%. Spinal and EEG parameters predicted the motor responses to movement better than chance alone, but did not differ significantly from each other. Conclusion. F-waves, especially the F-wave amplitude, cannot be used to predict movement to noxious stimuli during sevoflurane anaesthesia because they are almost completely suppressed at subclinical sevoflurane concentrations. Either the particular motoneurone pool (the largest motoneurones) assessed by F-waves is not involved in generating movement to painful stimuli or direct effects on motoneurone excitability are not involved in the suppression of movement to painful stimuli by sevoflurane.