Valerie Billard

Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil I. Model development

BackgroundPrevious studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodyn

A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect

The effects of anesthetic drugs on electroencephalograms (EEG) have been studied to develop the EEG as a measure of anesthetic depth. Bispectral analysis is a new quantitative technique that measures the consistency of the phase and power relationships and returns a single measure, the bispectral index. The purpose of this study was to compare the performance of the bispectral index, version 1.1, with other spectral analysis EEG measures of drug effect for three commonly used anesthetic drugs.

A comparison of propofol and remifentanil target-controlled infusions to facilitate fiberoptic nasotracheal intubation.

INTRODUCTION: Successful fiberoptic intubation requires both patient comfort and good intubating conditions. In this study we compared the efficacy and ease of titration of propofol (P) and remifentanil (R) target-controlled infusions (TCI) during fiberoptic intubation. METHODS: Sixty patients requiring fiberoptic nasotracheal intubation were randomized to receive (P) or (R) effect-site TCI. After topical anesthesia, TCI was set to 2.5 &mgr;g/mL (P) or 1.5 ng/mL (R) then titrated by 1 &mgr;g/mL (P) or 0.5 ng/mL (R) increments according to patient reactions. Targets and level of sedation were recorded at each step as well as total dose, number of adjustments, intubating conditions, discomfort, and recall assessed after surgery. RESULTS: Intubation duration, success rate, and number of increments did not differ between groups. Intubating conditions were good in both groups, with a final target of 3.9 ± 1.4 &mgr;g/mL (P) or 2.4 ± 0.8 ng/mL (R) (total dose 142 ± 55 mg and 77 ± 27 &mgr;g, respectively). There was no difference in minimal Spo2 and maximal end-tidal CO2 after intubation. No laryngospasm or significant hemodynamic instability was observed. There was one major hypoxemia due to obstructive apnea in group P. Patients in group P were significantly more sedated and less cooperative. Recall was more frequent in group R, whereas pain scores were equally low in both groups. CONCLUSION: Both R and P TCI can be rapidly titrated to achieve good intubating conditions and patient comfort. R allows for more patient cooperation, making it safer when spontaneous ventilation is paramount.

ORG 9487 Neuromuscular Block at the Adductor Pollicis and the Laryngeal Adductor Muscles in Humans

Background: ORG 9487 is a new steroidal nondepolarizing muscle relaxant with a rapid onset of action. This study was designed to determine the neuromuscular blocking profile of ORG 9487 at the adductor muscles of the larynx and the adductor pollicis. Methods: In 30 adults, anesthesia was induced with propofol (2–5 mg/kg) and fentanyl (2–3 micro gram/kg). After train‐of‐four stimulation, the block of the laryngeal adductor muscles was evaluated by measuring the pressure changes in the cuff of the tracheal tube placed between the vocal cords, and the force of the contraction of the adductor pollicis was measured with a force transducer. Patients were randomly allocated to receive ORG 9487 at intravenous bolus doses of 0.75, 1.5 or 2 mg/kg (n = 10 in each group). Results: Time to peak effect was significantly shorter at the vocal cords than at the adductor pollicis muscle (P < 0.001). Onset time at the vocal cords was 62 +/‐ 16 s, 62 +/‐ 13 s, and 52 +/‐ 14 s (mean +/‐ SD) after doses of 0.75, 1.5, and 2 mg/kg, respectively (not significant). Onset time at the adductor pollicis muscle was 126 +/‐ 33 s, 96 +/‐ 20 s, and 82 +/‐ 21 s after 0.75, 1.5, and 2 mg/kg doses, respectively (P <0.001). Maximum block was significantly less intense at the vocal cords than at the adductor pollicis muscle (69 +/‐ 15% vs. 94 +/‐ 4% after 0.75 mg/kg; 86 +/‐ 7% vs. 97 +/‐ 4% after 1.5 mg/kg; and 91 +/‐ 5% vs. 99 +/‐ 1% after 2 mg/kg). After 1.5 mg/kg duration to 25%, recovery was 3.7 +/‐ 2.2 min versus 10.2 +/‐ 2.5 min at the vocal cords and the adductor pollicis muscle, respectively, and 75% recovery occurred at 9.7 +/‐ 3.7 min at the vocal cords and at 18.3 +/‐ 5.2 min at the adductor pollicis muscle. Conclusions: ORG 9487 has a rapid onset of action at the laryngeal adductor and the adductor pollicis muscles. Onset and duration of action are faster at the vocal cords than at the adductor pollicis muscle. However, the maximum block obtained at the laryngeal muscles was less than at the adductor pollicis, regardless of the dose of ORG 9487.

Does spectral entropy reflect the response to intubation or incision during propofol-remifentanil anesthesia?

BACKGROUND:Spectral entropy is an electroencephalogram-based monitoring technique with a frequency band enlarged to include the electromyogram spectrum, which is intended to help to assess analgesia. Although its correlation with hypnosis has been shown, its performance during a noxious stimulation and the influence of neuromuscular blockade have not been described. METHODS:In this prospective, open, multicenter study, 105 patients received propofol then remifentanil target-controlled infusion for induction of anesthesia, with randomized remifentanil targets ranging from 2 to 8 ng/mL. Half of the patients received neuromuscular blockade. Intubation and incision were used as standard noxious stimulations, motor or hemodynamic responses were recorded, and spectral entropy values before and after stimulations were compared between responders and nonresponders. RESULTS:No difference was found in response entropy (RE), state entropy (SE), or (RE − SE) between patients with or without hemodynamic response to stimulations. Patients with motor response to intubation had higher values of RE, SE, and (RE − SE) both before and after the intubation than patients with no response. These results were confirmed by a prediction probability analysis, showing a significant but weak predictive value of entropy for motor response only. CONCLUSIONS:Entropy predicted a motor response to noxious stimulations but not a hemodynamic response, which limits its usefulness for assessing the analgesic component of anesthesia in paralyzed patients. High values (RE >55) before the stimulation should be avoided in order to decrease the risk of motor response, but lower values might not prevent this response when the opioid concentration is insufficient, despite an adequate hypnosis.

Pharmacokinetics of intravenous dynorphin A(1–13) in opioid-naive and opioid-treated human volunteers*

Dynorphin A(1–13) is a fragment of the endogenous opioid neuropeptide dynorphin A. Previous research suggested that intravenously administered dynorphin A(1–13) has the ability to modulate morphine‐induced analgesia. We designed this study to characterize the disposition of intravenous dynorphin immunoreactivity in humans and to determine whether concomitant long‐term opioid therapy influenced the pharmacokinetics or side‐effects profile of dynorphin A(1–13).

Does the EEG Measure Therapeutic Opioid Drug Effect

In this chapter we discuss the extent to which the EEG reflects therapeutic opioid drug effect. For the hypnotics, the EEG has been used to control the depth of anesthesia via closed-loop administration. These systems will be discussed in the chapters by Professors Schwilden [1, 2] (median frequency) and Kenny (auditory-evoked potentials). That computerized systems are able to satisfactorily administer hypnotics based on direct feedback from EEG-derived measures suggests that the EEG is, in fact, a very reasonable measure of hypnotic drug effect. Thus, we will focus here on the EEG as a measure of the therapeutic effect of opioids.

Influence of real-time Bayesian forecasting of pharmacokinetic parameters on the precision of a rocuronium target-controlled infusion

SummaryIntroductionBayesian forecasting has been shown to improve the accuracy of pharmacokinetic/pharmacodynamic (PK/PD) models by adding measured values to a population model. It could be done in real time for neuromuscular blockers (NMB) using measured values of effect. This study was designed to assess feasibility and benefit of Bayesian forecasting during a rocuronium target-controlled infusion (TCI).MethodsAfter internal review board (IRB) approval and informed consent, 21 women scheduled for breast plastic surgery were included. Anesthesia was maintained with propofol, alfentanil, and controlled ventilation through a laryngeal mask. Rocuronium was delivered in TCI with Stanpump software and the Plaud population model. The target effect was 50% blockade until insertion of breast prosthesis; thereafter it was set to 0%. Response to train of four (TOF) at adductor pollicis was recorded using a force transducer. In ten patients, drug delivery was based on the population model. In the others, repeated measures values were entered in the software, and the PK model was adjusted to minimize the error in predicted effect. Model precision was compared between groups using mean prediction error and mean absolute prediction error.ResultsAt target 50%, model accuracy was not improved with Bayesian adjustments; conversely, post-infusion errors were significantly decreased. The first two measures had the most influence on the model changes.DiscussionBelow clinical utility, such adjustments may be used to explore cofactors influencing interindividual and intraindividual variability in NMB dose-response relationship. Similar tools may also be developed for drugs in which a quantitative effect is available, such as electroencephalography (EEG) for hypnotics.ImplicationReal-time Bayesian forecasting combining measured values of effect with a population model is suitable to guide NMB-agent delivery using Stanpump software.

Computer-Controlled Infusion of Neuromuscular Blocking Agents

Neuromuscular blocking agents are useful in anaesthesia and in intensive care medicine to paralyse patients for anaesthetic (intubation and ventilation) or surgical procedures. The level of neuromuscular blockade required depends on the procedure. When it is insufficient, neuromuscular blocking agents become useless, movement or coughing may occur and may be harmful to the patient e.g. during eye- or neurosurgery, or during peritoneal closure. On the other hand, overdose of neuromuscular blocking agents has few side effects as long as amnesia is provided and artificial ventilation is controlled. Its main consequences are a delayed recovery and a useless increase of drug consumption and costs.

Influence of Age and Gender on the Pharmacokinetics and Pharmacodynamics of Remifentanil: I. Model Development

Background Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short‐acting opioid remifentanil. Methods Sixty‐five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant‐rate infusion of 1 to 8 micro gram [centered dot] kg sup ‐1 [centered dot] min sup ‐1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y. Results The parameters for the simple three‐compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were ke0 = 0.516 min sup ‐1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic‐pharmacodynamic model performed better than did the simple model when applied prospectively. Conclusions This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.