Effects of remifentanil on processing of auditory stimuli: a combined MEG/EEG study.

Remifentanil (Ultiva(®)) is a potent ultra-short acting mu-opioid receptor agonist used for perioperative pain treatment and anaesthesia. So far, it is not known how sensitive the cognitive processing of auditory perception elicited by the mismatch negativity (MMN) paradigm is to opioids. The present exploratory study investigated how the opioid remifentanil modulates different stages of auditory processing as reflected in the MMN(m) and P3a(m). We recorded electroencephalography (EEG) and magnetoencephalography (MEG) during auditory stimulation under remifentanil or placebo infusion in 20 healthy participants. For the MMN, a gender effect was found for tones deviating in frequency (± 10%) from the standard tone. Remifentanil increased the amplitude of the frequency MMN at F3 in females but not in males. No effect of treatment was found for the MMN(m) or the novel P3a(m). These results suggest that while the bottom-up stimulus change detection system for auditory stimuli appears to be relatively insensitive to opioids, the automatic attention switch caused by the change detection seems to be modulated by the opioid system in females. The multiple deviant paradigm including novel sounds is a promising tool for investigating pharmacological manipulation of different stages of auditory processing. Furthermore, combining the two techniques will yield more specific information about the drug effects on MMN(m).

Spectral entropy as a measure of hypnosis and hypnotic drug effect of total intravenous anesthesia in children during slow induction and maintenance.

BACKGROUND: We evaluated whether spectral entropy (SpE) can measure the depth of hypnosis and the hypnotic drug effect in children during total intravenous anesthesia. METHODS: Sixty healthy children, aged 3-16 yr, were studied. Anesthesia was induced with an increasing target controlled infusion of propofol, and maintained by a stable remifentanil infusion and variable concentrations of target controlled infusion propofol. Depth of hypnosis was assessed according to the University of Michigan Sedation Scale (UMSS). Estimated plasma (C(p)) and pseudo effect site (C(eff)) propofol concentrations reflected the hypnotic drug effect. Patients were stratified to three age groups. The correlations between SpE versus UMSS, C(p), and C(eff) were analyzed by Prediction Probability (P(k)). The pharmacodynamic relationship between SpE and C(p), and the differences of SpE values between the age groups at the corresponding UMSS levels, were studied. RESULTS: Respective mean P(k) values for the youngest, middle, and oldest age groups were: 1) during induction: SpE versus UMSS 0.87, 0.87, and 0.93; SpE versus C(p) 0.92, 0.95, and 0.97; and SpE versus C(eff) 0.88, 0.94, and 0.95; 2) during maintenance: SpE versus C(eff) 0.86, 0.75, and 0.81. The pharmacodynamic analysis determined an association between SpE and C(p) that followed the E(max) model closely. There were significant differences in SpE values between age groups at corresponding UMSS sedation levels. CONCLUSIONS: SpE measures the level of hypnosis and hypnotic drug effect in children during total intravenous anesthesia. There is an age dependency associated with SpE. Anesthesia should not be steered solely on the basis of SpE.

The Narcotrend index indicates age-related changes during propofol induction in children.

BACKGROUND: The Narcotrend electroencephalogram monitor is designed to measure hypnotic state during anesthesia. We performed this study to evaluate the effectiveness and reliability of the Narcotrend monitor in assessing hypnotic state and loss of consciousness (LOC) during propofol anesthesia induction in children. METHODS: Sixty-two children, aged 1-5 (n = 17), 6-12 (n = 23), and 13-16 (n = 21) yr, scheduled for elective surgery were studied. The patients were premedicated with oral midazolam 0.5 mg/kg. After IV access, propofol target controlled infusion (TCI) was started with 0.5 microg/mL and increased by 0.5 microg/mL increments every 2 min until the child did not respond to any verbal command or physical stimuli. A manual scheme was used for children weighing <15 kg. Hypnotic state was measured every minute from the start of the propofol infusion using the University of Michigan Sedation Scale (UMSS). LOC was defined as a transition of UMSS scale value 2 to 3. The Narcotrend index (NI) was recorded before the start of induction and during the whole study period. NI values were noted simultaneously, yet independently of the sedation measurements. Prediction probability (PK) was used to assess the correspondence between NI and UMSS. Sensitivity and specificity of NI for differentiating between consciousness and unconsciousness were calculated. NI values at specific UMSS levels were compared between the different age groups and the relationships between TCI propofol concentrations and sedation levels were assessed using correlation analysis. RESULTS: A PK-value of 0.84 (95% CI [0.80-0.88]) of NI was calculated from the data for the detection of LOC. Similarly, a PK value of 0.82 (95% CI [0.78-0.86]) indicated agreement between NI and UMSS values. The average NI values differed between successive UMSS sedation levels 0 and 1 and levels 1 and 2 (P < 0.01). In the youngest age group, the NI discriminated between UMSS levels 2 and 3, in the second age group between levels 1 and 2 and 2 and 3, and in the oldest age group between 0 and 1. Furthermore, the NI values differed significantly between age groups at UMSS levels 1-4 (P < 0.005), with the NI values being higher in younger compared with older children. The average NI value at LOC was 68. For the detection of consciousness, a sensitivity of 0.67 and specificity of 0.79 were achieved. Spearman correlation coefficients indicated higher association between TCI propofol concentrations and UMSS (0.96) than between NI and UMSS (-0.68). CONCLUSIONS: During propofol induction in children, the Narcotrend electroencephalogram monitor was capable of following changes in the sedation level of children to some extent, but also had a relatively high probability (0.18) of incorrectly predicting changes in conscious state. Therefore, the monitor should not solely be used to guide sedation and anesthesia. NI was age-dependent and younger children had higher NI-values than older children at the same level of sedation.

Skin impedance correlates to sedation grade, plasma propofol concentrations and bispectral index during a target-controlled infusion of propofol.

BACKGROUND AND OBJECTIVE: Sympathetic activity, measured as changes in electrical skin impedance, may be used to assess the adequacy of general anaesthesia. The aim of this prospective study was to evaluate electrical skin impedance in comparison with bispectral index values and the Observer's Assessment of Alertness and Sedation (OAAS) scale during propofol infusion. METHODS: Electrical skin impedance was measured with an electrosympathicograph. In 22 patients and eight healthy volunteers, anaesthesia was induced and maintained with propofol that was administered via a target-controlled infusion pump at increasing plasma concentrations. Bispectral index, electrosympathicograph and OAAS values were compared at six successive predicted target plasma concentrations (T 1-6: 0, 1.3, 1.7, 2.0, 2.4 and 2.8 microg ml(-1)). RESULTS: The changes in the electrical skin impedance measured with the assistance of the electrosympathicograph correlated with the changes in bispectral index values at each measurement time point and during the whole course (P < 0.0001), with the target plasma propofol concentrations (P < 0.0001), and with the OAAS scale (P < 0.0001). CONCLUSION: The observed correlations between electrical skin impedance, predicted plasma concentrations of propofol and OAAS scale appear to justify further investigation of skin impedance as a depth of anaesthesia monitor.

Auricular acupuncture for dental anxiety: a randomized controlled trial.

Auricular acupuncture can be an effective treatment for acute anxiety, but there is a lack of direct comparisons of acupuncture to proven standard drug treatments. In this study we compared the efficacy of auricular acupuncture with intranasal midazolam, placebo acupuncture, and no treatment for reducing dental anxiety. Patients having dental extractions (n = 67) were randomized to (i) auricular acupuncture, (ii) placebo acupuncture, and (iii) intranasal midazolam and compared with a no treatment group. Anxiety was assessed before the interventions, at 30 min, and after the dental extraction. Physiological variables were assessed continuously. With the no treatment group as control, the auricular acupuncture group, and the midazolam group were significantly less anxious at 30 min as compared with patients in the placebo acupuncture group (Spielberger Stait-Trait Anxiety Inventory X1, P = 0.012 and <0.001, respectively). In addition, patient compliance assessed by the dentist was significantly improved if auricular acupuncture or application of intranasal midazolam had been performed (P = 0.032 and 0.049, respectively). In conclusion, both, auricular acupuncture and intranasal midazolam were similarly effective for the treatment of dental anxiety.

Implicit memory varies as a function of hypnotic electroencephalogram stage in surgical patients.

UNLABELLED: Previous studies have observed a correlation of implicit memory with certain electroencephalogram (EEG) measures during anesthesia. Here, we tested the relationship between hypnotic depth determined by computer system (Narcotrend(TM)) and implicit memory in anesthetized patients, assessed by a postoperative reading speed test. Thirty-two patients undergoing laparoscopic herniotomy and 30 age-matched volunteer controls were included the study. All patients received IV midazolam 2-3 mg followed by an induction dose of propofol and remifentanil. The anesthesia was maintained with propofol and remifentanil infusions and cisatracurium. Each patient was exposed to 2 of 4 stories, repeated 6 times. The first story was presented during light to moderate hypnotic EEG stages, and the second story was presented during deep hypnosis. Presentation of stories was balanced between patients and hypnotic stages. The controls listened to the two stories without receiving anesthesia. The reading speed for the previously presented stories and two new stories was measured approximately 7 h later with a computer program. No signs of inadequate anesthesia were observed, and no explicit memories of intraoperative events were revealed by a structured interview. No change of reading speed was observed for words presented during deep hypnotic stages. In contrast, an increased reading speed of 20 ms per word was found for content words (i.e., nouns, verbs, and adjectives), but not for function words (conjunctions, prepositions, and so on), presented during light to moderate hypnotic stages. Increased reading speed for semantically rich content words indicates that anesthetized patients are able to process acoustic information during light and moderate, but not deep, hypnosis. IMPLICATIONS: In this study, implicit memory was observed during general anesthesia at light to moderate, but not deep, hypnotic stages. Hypnotic stages were determined by a commercial electroencephalogram device, and implicit memory was measured by using a postoperative reading speed task. During lighter phases of anesthesia, patients should be protected against acoustic information that could negatively influence their postoperative outcome.

Blockade of voltage-operated neuronal and skeletal muscle sodium channels by S(+)- and R(-)-ketamine.

UNLABELLED: Besides its general anesthetic effect, ketamine has local anesthetic-like actions. We studied the voltage- and use-dependent interaction of S(+)- and R(-)-ketamine with two different isoforms of voltage-operated sodium channels, with a special emphasis on the difference in affinity between resting and inactivated channel states. Rat brain IIa and human skeletal muscle sodium channels were heterologously expressed in human embryonic kidney 293 cells. S(+)- and R(-)-ketamine reversibly suppressed whole-cell sodium inward currents; the 50% inhibitory concentration values at -70 mV holding potential were 240 +/- 60 microM and 333 +/- 93 microM for the neuronal isoform and 59 +/- 10 microM and 181 +/- 49 microM for the skeletal muscle isoform. S(+)-ketamine was significantly more potent than R(-)-ketamine in the skeletal muscle isoform only. Ketamine had a higher affinity to inactivated than to resting channels. However, the estimated difference in affinity between inactivated and resting channels was only 8- to 10-fold, and the time course of drug equilibration between inactivated and resting channels was too fast to cause use-dependent block at 10 Hz up to a concentration of 300 microM. These results suggest that ketamine is less effective than lidocaine-like local anesthetics in stabilizing the inactivated channel state. IMPLICATIONS: Blockade of sodium channels by ketamine shows voltage dependency, an important feature of local anesthetic action. However, ketamine is less effective than lidocaine-like local anesthetics in stabilizing the inactivated state. Because it does not elicit phasic blockade at small concentrations, its ability to reduce the firing frequency of action potentials may be small.

Postoperative analgesia in infants and children.

PURPOSE OF REVIEW: Although postoperative analgesia in infants and children should be an integral part of the perioperative management, undertreatment of pain is not rare in clinical practice and may influence outcome and long term behaviour. Therefore, this review summarizes results of recent papers and discusses actual trends and future perspectives concerning postoperative pharmacologic pain therapy in infants and children. RECENT FINDINGS: A multimodal approach using locoregional anesthesia and systemic analgesics is a widely accepted technique. New developments include new local anesthetics with a wider margin of safety and more experience with adjuvants, catheter techniques and systemic analgesics. Replacement of bupivacaine with ropivacaine may be prudent especially for prolonged epidural infusion, use in neonates, impaired hepatic metabolic function, and anesthetic techniques requiring large dosage of local anesthetic. The limited duration of analgesia after single blocks can be prolonged by use of adjuvants (clonidine, ketamine), catheter techniques or early use of systemic analgesics. Non-opioids (acetaminophen, non-steroidal anti-inflammatory drugs) are appropriate for patients with mild to moderate pain or as a component of multimodal pain therapy. Patient- and nurse-controlled analgesia are convenient ways for opioid administration in infants and children. SUMMARY: The reviewed studies suggest that there are many reliable agents and techniques available to provide a safe and effective postoperative analgesia even in neonates and small infants.

Implicit memory for words played during isoflurane- or propofol-based anesthesia: the lexical decision task.

BACKGROUND: Unconscious processing of words during general anesthesia has been suggested after surgery with several tests of implicit memory. Patients can neither recall those words nor do they have explicit memories of other intraoperative events. It is unclear to what degree information is processed during general anesthesia and which tests are best suited to detect implicit memory. In the current study, a lexical decision paradigm not previously used to demonstrate implicit memory during anesthesia was used. METHODS: Sixty patients undergoing lumbar disc surgery were assigned to receive isoflurane infusion- or propofol infusion-based anesthesia combined with alfentanil infusions and a nitrous oxide-oxygen mixture. A control group of 10 medical students listened to tapes without receiving anesthesia. Two tapes, each containing a list of 30 low-frequency German nouns repeated for 15 min, were prepared, with half of the patients listening to tape A and the other half listening to tape B during the operation. Exposure time was 15 min from the time of skin incision onward. In the test phase, approximately 7 h later, words from lists A and B plus 60 nonwords were presented in random order by a computer program. Subjects were asked to indicate, by pressing one of two response buttons, whether the spoken word was or was not a legal German word (lexical decision). RESULTS: A recognition test revealed chance recognition for words presented during anesthesia. Lexical decision responses, however, were slightly faster to primed (previously presented) words than to unprimed (not previously presented) words when the entire group of patients was tested, suggesting a small implicit memory effect, which barely failed to reach the significance level. When the two medication groups were tested separately, no significant implicit memory effect could be ascertained statistically. The effects of previous exposure were much more pronounced in the control group. CONCLUSIONS: Balanced anesthesia techniques with isoflurane or propofol lead to only a minimal, statistically borderline implicit memory effect in the lexical decision paradigm.