Utility of nociceptive flexion reflex threshold and bispectral index to predict movement responses under propofol anaesthesia.

INTRODUCTION: The nociceptive flexion reflex threshold (NFRT) is a promising tool to monitor analgesia during general anaesthesia. Clinical studies have shown that the NFRT allows to predict movement responses to painful stimuli under a combined anaesthetic regime of sedative and opioid agents. Experimental studies indicated that the NFRT is also able to predict such movement responses under an exclusively sedative regime like propofol mono-anaesthesia. Therefore, we performed this study to investigate the ability of the NFRT to predict movement responses to painful stimuli in patients during a clinical propofol mono-anaesthesia. METHODS: We investigated 140 cardiac surgery patients during their postoperative phase under propofol mono-anaesthesia. NFRT and bispectral index (BIS) were determined in each patient right before endotracheal suctioning or painful electrical test stimulation. Prediction probabilities were calculated to quantify how accurate each measure is able to predict movement responses to the stimuli. RESULTS: The 124 patients included in the analysis received a median propofol dosage of 3.2 (2.5-3.9) [median (IQR)] mg/kg/h. The included patients showed 287 movement responses after a total of 725 investigated stimuli. The prediction probabilities for positive movement responses were 0.63 (95%CI: 0.59-0.67) for the NFRT and 0.69 (95%CI: 0.65-0.73) for the BIS. CONCLUSIONS: The NFRT allows the prediction of movement responses under propofol mono-anaesthesia, which confirms its utility as a monitor to predict movement responses under general anaesthesia. The BIS allows an even more accurate prediction, although it does not reflect the physiological structures of movement suppression, but correlates closely with the dose of propofol. TRIAL REGISTRATION: German clinical trial register (DRKS00003062, Deutsches Register Klinischer Studien).

[Neuromonitoring and awareness]. / Awareness - Stellenwert des Neuromonitorings von Analgesie und Hypnose.

Awareness is a rare but in some cases severe complication of general anesthesia. In clinical practice vegetative signs such as sweating, lacrimation, tachycardia and hypertension are used to assess the anesthetic depth. Awareness however may also occur without any of these signs. Different systems based on the electroencephalogram (EEG) have been developed to monitor hypnosis. Some studies have shown that the use of EEG based monitor systems can reduce the incidence of awareness in patients of high risk. A similar reduction of the incidence was reached in studies using protocols based on concentrations of volatile anesthetics. Other systems to monitor anesthetic depth have been developed, but their influence on awareness has not yet been investigated sufficiently. Further studies are needed to clarify their impact concerning the incidence of awareness.

Comparison of trigeminal and spinal modulation of pain and nociception.

Modulation of pain and nociception by noxious counterstimulation, also called "diffuse noxious inhibitory controls" or DNIC-like effect, is often used in studies of pain disorders. It can be elicited in the trigeminal and spinal innervation areas, but no study has previously compared effects in both innervation areas. Therefore, we performed a study comparing DNIC-like effects on the nociceptive flexion reflex (NFR) and the nociceptive blink reflex as well as the respective pain sensations. In 50 healthy volunteers, the blink reflex elicited with a concentric electrode and the NFR were recorded before and after immersion of the contralateral hand in cold water. Responses were recorded as the subjective pain sensation and the reflex size. The cold water immersion of the contralateral hand elicited a reduction of both subjective pain sensation and reflex amplitude following the stimulation of both reflexes. However, there were no strong correlations between the individual reductions of both subjective pain sensation and reflex amplitude for both reflexes, and neither when results of the two reflexes were compared with each other. The dissociation between DNIC-like effects on pain and on nociception, which had been found previously already for the NFR, implies that both effects need to be studied separately.

Effects of sevoflurane and propofol on the nociceptive withdrawal reflex and on the H reflex.

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.

Variability comparison of the composite auditory evoked potential index and the bispectral index during propofol-fentanyl anesthesia.

BACKGROUND: Monitors of hypnotic depth help anesthesiologists to guide the anesthetic. The performance of different monitors depends on several factors, index variability at a steady state of hypnotic depth being one. We compared the recently introduced AAI1.6 with the established bispectral index (BIS), regarding index variability during stable values of propofol effect-site concentration. METHODS: After ethics committee approval and written informed consent, anesthesia was performed in 40 patients with propofol as the target controlled infusion and fentanyl. Variability of BIS and AAI1.6 was calculated during periods of constant predicted propofol effect compartment concentration and constant levels of surgical stimulation as the median absolute deviation (MAD) from the median value. A variability index was calculated as 1.48*MAD/(threshold - median value), with threshold being the division line between awake and asleep. Threshold crossing time was used to evaluate the performance in predicting return of consciousness. RESULTS: Variability index, however, was significantly larger for the AAI1.6, despite similar absolute variability measured as MAD. Lightening of anesthesia before recovery could be noticed earlier using the BIS than the AAI1.6, although consciousness was detected with a significantly higher Pk-value by the AAI1.6. CONCLUSION: Variability in relation to the difference between the median index value during anesthesia and the threshold necessary to detect consciousness with high sensitivity is higher for the AAI1.6 than for the BIS. This, as well as the steeper concentration-response function found for AAI1.6, impairs the performance of the AAI1.6 in predicting imminent return of consciousness during decreasing propofol concentrations. However, it makes AAI1.6 well suited to detect consciousness when it has occurred.

Easily applicable SEP-monitoring of the N20 wave in the intensive care unit.

In this technical note, a conveniently sized, single-channel somatosensory evoked potentials (SEP)-stimulation-recording unit for bedside use in the intensive care unit is presented. The validation of the SEP N20 wave in intensive care guidelines as initial parameter for the prognostic evaluation of cardiac arrest has increased the demand for a more widespread availability of SEP, outside the electrophysiological domain. A device with a simplified interface that safely guides the user through a complete examination and that includes artifact removal is a prerequisite for such more widespread use, in which expert interpretation can be reduced to a necessary minimum.

H-reflex depression by propofol and sevoflurane is dependent on stimulus intensity.

OBJECTIVE: The H-reflex has been widely used to investigate effects of drugs on motoneuron excitability in humans. However, up to now no systematic investigation has been done to examine the effects at different stimulus intensities. Here, the M. soleus recruitment curves were compared under influence of propofol and sevoflurane with control conditions to investigate these stimulus intensity dependent effects. METHODS: The study was performed in 10 volunteers for propofol and sevoflurane each, aged 23-32 years. The M. soleus H-reflex was evoked by stimulation of the tibial nerve. Recruitment curves were gained by increasing the stimulation current stepwise from below the threshold of a minimal H-reflex up to a maximal (m-response. Measurements were performed under the influence of the respective drug (2mg/l propofol, 0.8 vol% sevoflurane) and compared to control measurements before and after drug administration. RESULTS: The relative amount of depression of the H-reflex at high stimulus intensities is for both drugs significantly (p<0.001, Friedman's test) lower than at low stimulus intensities. CONCLUSIONS: Stimulus dependent effects have to be taken into consideration when experimental settings to investigate the effects of drugs on the H-reflex are being designed. According to the size principle of motoneuron excitation, it can also be assumed that under the influence of propofol and sevoflurane larger motoneurons are not depressed in the same amount as smaller motoneurons. SIGNIFICANCE: Different drug effects on the H-reflex at different stimulus intensities are not only of methodological importance, but also indicate different drug effects on motoneurons of different sizes.

Habituation of the nociceptive flexion reflex is dependent on inter-stimulus interval and stimulus intensity.

The nociceptive flexion reflex (NFR) has become a popular tool in experimental and clinical pain research. However, the gradual decrease of the reflex size during repeated application of stimuli, which is termed habituation, may reduce its validity and the comparability of studies. We investigated the degree of habituation at different inter-stimulus intervals (ISI) commonly used in clinical studies and the dependency of habituation on stimulus intensity. Thirty subjects each received 12 sets of 50 stimuli to elicit the NFR at ISI of 1, 3, 6 and 10s, each at stimulus intensities of 1 ×, 1.5 × and 2 × the individual NFR-threshold. For each of the sets, the habituation was calculated as the relative size of the average of the last 10 reflexes compared to the average of the first 10 reflexes. The influence of the factors ISI and stimulus intensity, as well as the factor interaction, was tested using a two-way analysis of variance (ANOVA). Analysis proved that influences of ISI and stimulus intensity on reflex habituation were significant (p < 0.01, two-way ANOVA), while the interaction between the two factors had no significant influence (p = 0.99). We conclude that habituation of the NFR is dependent on ISI and stimulus intensity. Lower stimulus intensities and shorter ISI lead to stronger habituation. Therefore, to ensure habituation is avoided during repeated elicitation of the NFR, stimulation should be conducted according to the ISI for the respective stimulus intensities presented here.

Prediction of motor responses to surgical stimuli during bilateral orchiectomy of pigs using nociceptive flexion reflexes and the bispectral index derived from the electroencephalogram.

Movement responses to noxious stimuli during anaesthesia indicate nociception. Under experimental conditions consistent prediction of such movement responses has been achieved by the use of nociceptive flexion reflexes (NFRs). The aim of this study was to investigate the reliability of NFRs and the electroencephalogram bispectral index (BIS) in predicting motor responses to real surgical stimuli in pigs. The study was undertaken in 30 pigs undergoing bilateral orchiectomy under ketamine/azaperone anaesthesia. During the operation, movement responses to seven distinct surgical steps that provided noxious stimuli of different intensity were evaluated. Any movement response of limbs or the head was considered as a positive response. For each surgical step the values of NFRs and the BIS obtained just prior to the step were tested as predictors of movement responses. The prediction probability for movement responses was 0.58±0.04 for the BIS and 0.76±0.03 for the NFRs. It was concluded that NFRs but not the BIS can predict the effectiveness of ketamine anaesthesia in terms of the suppression of movement responses to surgical stimuli.

Investigation of threshold and magnitude criteria of the nociceptive blink reflex.

OBJECTIVE: The nociceptive blink reflex is a trigeminofacial brain-stem reflex which is used in pain research to evaluate the modulation of pain processing. To standardize the analysis of the reflex we investigated which electromyographic parameters show the best correlation with subjective pain ratings and should therefore be used for scoring blink reflex magnitude. Furthermore we investigated which parameters show the highest accuracy and reliability to define the blink reflex threshold. METHODS: Forty-six subjects each received 54 electrical stimuli to the supraorbital nerve at nine different stimulus intensities, which corresponded to pain ratings between 0 and 70 (scale 0-100). Multilevel modeling was performed to determine which electromyographic blink reflex parameter showed the best correlation with subjective pain ratings. To define the blink reflex threshold ROC analyses were performed, comparing different electromyographic blink reflex parameters with the judgment of expert raters for 2500 blink reflex recordings from this study and 1400 from another. RESULTS: The baseline-adjusted area under the curve showed the best correlation with subjective pain ratings. Seventy-six percent of the residual variance of the pain ratings could be explained by this parameter. The peak z score showed the highest accuracy in defining the blink reflex threshold and also the highest cut-point stability. CONCLUSIONS: We recommend the baseline-adjusted area under the curve for scoring the magnitude of the nociceptive blink reflex and the peak z score to define the nociceptive blink reflex threshold. SIGNIFICANCE: The here defined standardized criteria to score blink reflex magnitude and threshold improve the comparability and validity of blink reflex studies.

Presynaptic and postsynaptic effects of the anesthetics sevoflurane and nitrous oxide in the human spinal cord.

BACKGROUND: Reduced spinal excitability contributes to the suppression of movement responses to noxious stimuli during the anesthetic state. This study examines and compares presynaptic and postsynaptic effects of two anesthetics in the human spinal cord. METHODS: The authors tested two parameters during the administration of 0.8 vol% sevoflurane or 40 vol% nitrous oxide compared with control states before and after drug administration: (1) the size of the soleus H reflex (integrating presynaptic and postsynaptic effects) at increasing stimulus intensities (recruitment curve) and (2) the amount of presynaptic inhibition on Ia afferents of the quadriceps femoris, evaluated by the heteronymous facilitation of the soleus H reflex caused by a conditioning stimulation of the femoral nerve. The study was performed in 10 subjects for each drug. RESULTS: At the chosen concentrations, the maximum H reflex was reduced by 26.3 +/- 8.4% (mean +/- SD) during sevoflurane and by 33.5 +/- 15.6% during nitrous oxide administration. The averaged recruitment curves were similarly depressed under the influence of the two drugs. The reduction of H-reflex facilitation was significantly stronger for sevoflurane (28.8 +/- 20.0%) than for nitrous oxide administration (6.2 +/- 26.4%). CONCLUSIONS: These results demonstrate in humans presynaptic effects of the volatile anesthetic sevoflurane but not of nitrous oxide. A possible explanation for this difference may be the different potency of the respective drugs in enhancing gamma-aminobutyric acid type A receptor-mediated inhibition, because presynaptic inhibition in the spinal cord involves this receptor subtype.

Propofol increases presynaptic inhibition of ia afferents in the intact human spinal cord.

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.