Probability to tolerate laryngoscopy and noxious stimulation response index as general indicators of the anaesthetic potency of sevoflurane, propofol, and remifentanil.

BACKGROUND: The probability to tolerate laryngoscopy (PTOL) and its derivative, the noxious stimulation response index (NSRI), have been proposed as measures of potency of a propofol-remifentanil drug combination. This study aims at developing a triple drug interaction model to estimate the combined potency of sevoflurane, propofol, and remifentanil in terms of PTOL. We compare the predictive performance of PTOL and the NSRI with various anaesthetic depth monitors. METHODS: Data from three previous studies (n=120) were pooled and reanalysed. Movement response after laryngoscopy was observed with different combinations of propofol-remifentanil, sevoflurane-propofol, and sevoflurane-remifentanil. A triple interaction model to estimate PTOL was developed. The NSRI was derived from PTOL. The ability of PTOL and the NSRI to predict observed tolerance of laryngoscopy (TOL) was compared with the following other measures: (i) effect-site concentrations of sevoflurane, propofol, and remifentanil (CeSEVO, CePROP, and CeREMI); (ii) bispectral index; (iii) two measures of spectral entropy; (iv) composite variability index; and (v) surgical pleth index. RESULTS: Sevoflurane and propofol interact additively, whereas remifentanil interacts in a strongly synergistic manner. The effect-site concentrations of sevoflurane and propofol at a PTOL of 50% (Ce50; se) were 2.59 (0.13) vol % and 7.58 (0.49) µg ml(-1). A CeREMI of 1.36 (0.15) ng ml(-1) reduced the Ce50 of sevoflurane and propofol by 50%. The common slope factor was 5.22 (0.52). The PTOL and NSRI predict the movement response to laryngoscopy best. CONCLUSIONS: The triple interaction model estimates the potency of any combination of sevoflurane, propofol, and remifentanil expressed as either PTOL or NSRI.

Compartmental pharmacokinetics of nefopam during mild hypothermia.

BACKGROUND: Nefopam is a non-opioid, non-steroidal, centrally acting analgesic which has an opioid-sparing effect. It also reduces the threshold (triggering core temperature) for shivering without causing sedation or respiratory depression. The drug is therefore useful as both an analgesic and to facilitate induction of therapeutic hypothermia. However, compartmental pharmacokinetics during hypothermia are lacking for nefopam. METHODS: We conducted a prospective, randomized, blinded study in eight volunteers. On two different occasions, one of two nefopam concentrations was administered and more than 30 arterial blood samples were gathered during 12 h. Plasma concentrations were determined using gas chromatography/mass spectrometry to investigate the pharmacokinetics of nefopam with non-linear mixed-effect modelling. RESULTS: A two-compartment mammillary model with moderate inter-individual variability and inter-occasional variability independent of covariates was found to best describe the data [mean (SE): V(1)=24.13 (2.8) litre; V(2)=183.34 (13.5) litre; Cl(el)=0.54 (0.07) litre min(-1); Cl(dist)=2.84 (0.42) litre min(-1)]. CONCLUSIONS: The compartmental data set describing a two-compartment model was determined and could be implemented to drive automated pumps. Thus, work load could be distributed to a pump establishing and maintaining any desired plasma concentration deemed necessary for a treatment with therapeutical hypothermia.

Hypnotic and opioid anesthetic drug interactions on the CNS, focus on response surface modeling.

This chapter will present the conceptual and applied approaches to capture the interaction of anesthetic hypnotic drugs with opioid drugs, as used in the clinical anesthetic state. The graphic and mathematical approaches used to capture hypnotic/opiate anesthetic drug interactions will be presented. This chapter is not a review article about interaction modeling, but focuses on specific drug interactions within a quite narrow field, anesthesia.

[Effect compartment equilibration and time-to-peak effect. Importance of a pharmacokinetic-pharmacodynamic principle for the daily clinical practice]. / Wirkortäquilibration, Anschlagzeit, "time to peak effect". Bedeutung pharmakokinetisch-dynamischer Prinzipien für die tägliche klinische Praxis.

Contrary to the situation in "classical" clinical pharmacology, non-steady state phenomena play a fundamental role for clinical pharmacology in anesthesia. Their understanding is of tantamount importance for the safe and efficient application of drugs relevant to anesthesia. Concepts like optimised target-controlled infusion (TCI), effect compartment targeting and the small margin of error tolerable during maintained spontaneous ventilation, force the anesthesiologist to acquire a firm understanding of the difference between the concentration time course at the effect side vs. time course of the plasma concentration. The underlying concepts, their application for the rational use of muscle relaxants, propofol with TCI systems, volatile anaesthetics and opioids will be discussed.

Onset of propofol-induced burst suppression may be correctly detected as deepening of anaesthesia by approximate entropy but not by bispectral index.

The bispectral index (BIS) is a complex EEG variable that combines several disparate descriptors of the EEG into a single value. Approximate entropy is a novel EEG measure that quantifies the regularity of a data time series such as EEG. We report two patients in which the EEG effect of propofol was quantified very similarly by BIS and approximate entropy. However, at the beginning of burst suppression of the EEG, BIS did not indicate an increased anaesthetic drug effect, while approximate entropy did.

Shannon entropy applied to the measurement of the electroencephalographic effects of desflurane.

BACKGROUND: The Shannon entropy is a standard measure for the order state of sequences. It quantifies the degree of skew of the distribution of values. Increasing hypnotic drug concentrations increase electroencephalographic amplitude. The probability density function of the amplitude values broadens and flattens, thereby changing from a skew distribution towards equal distribution. We investigated the dose-response relation of the Shannon entropy of the electroencephalographic amplitude values during desflurane monoanesthesia in comparison with previously used electroencephalographic parameters. METHODS: Electroencephalographic records previously obtained in 12 female patients during gynecologic laparotomies were reanalyzed. Between opening and closure of the peritoneum, desflurane vapor settings were varied between 0.5 and 1.6 minimum alveolar concentration. Electroencephalographic Shannon entropy, approximate entropy, median electroencephalographic frequency, SEF 95, total power, log total power, and Bispectral Index were determined, and their correlations with the desflurane effect compartment concentration, obtained by simultaneous pharmacokinetic-pharmacodynamic modeling, were compared. RESULTS: The electroencephalographic Shannon entropy increased continuously over the observed concentration range of desflurane. The correlation of the Shannon entropy (R2 = 0.84+/-0.08, mean +/- SD) with the desflurane effect compartment concentrations is similar to approximate entropy (R2 = 0.85+/-0.12), SEF 95 (R2 = 0.85+/-0.10), and Bispectral Index (R2 = 0.82+/-0.13) and is more statistically significant than median frequency (R2 = 0.72+/-0.17), total power (R2 = 0.67+/-0.18), and log total power (R2 = 0.80+/-0.09). CONCLUSIONS: The Shannon entropy seems to be a useful electroencephalographic measure of anesthetic drug effect.

Bispectral index (BIS) and burst suppression: revealing a part of the BIS algorithm.

OBJECTIVE: The bispectral index (BIS) is a complex EEG parameter which integrates several disparate descriptors of the EEG into a single variable. One of the subparameters incorporated in the BIS is the suppression ratio, quantifying the percentage of suppression during burst suppression pattern. The exact algorithm used to synthetize the information to the BIS value is unpublished and still unknown. This study provides insight into the integration of the suppression ratio into the BIS algorithm. METHODS: EEG data of 10 healthy volunteers during propofol infusion were analyzed. Propofol concentrations were ramped up to 4 predetermined concentrations (1, 2, 3, 4, 6, 8, 9, or 12 microg/ml) using a computer controlled infusion pump (STANPUMP). EEG recordings were performed with an Aspect A-1000 EEG monitor (Version 3.22). The relationship of the processed EEG variables bispectral index and suppression ratio, calculated by the Aspect A-1000 monitor, was analyzed. RESULTS: Up to 40% suppression ratio the average BIS values remained constant regardless of suppression ratios (r = 0.13). Beyond a suppression ratio of 40%, BIS and suppression ratio were invariably linearly correlated (r = -1). At a suppression ratio > or = 40% the BIS value could be calculated as BIS = 50 - suppression ratio/2. CONCLUSIONS: Suppression ratio values > 40% are linearly correlated with BIS values from 30 to 0. An increasing anesthetic drug effect resulting in an increase of the duration of suppression to a suppression ratio up to 40% is not adequately reflected by the BIS value.