Pedro L. Gambús

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

The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers.

Background Unresolved issues with propofol include whether the pharmacokinetics are linear with dose, are influenced by method of administration (bolus vs. infusion), or are influenced by age. Recently, a new formulation of propofol emulsion, containing disodium edetate (EDTA), was introduced in the United States. Addition of EDTA was found by the manufacturer to significantly reduce bacterial growth. This study investigated the influences of method of administration, infusion rate, patient covariates, and EDTA on the pharmacokinetics of propofol. Methods Twenty‐four healthy volunteers aged 26–81 yr were given a bolus dose of propofol, followed 1 h later by a 60‐min infusion. Each volunteer was randomly assigned to an infusion rate of 25, 50, 100, or 200 micro gram [center dot] kg‐1 [center dot] min‐1. Each volunteer was studied twice under otherwise identical circumstances: once receiving propofol without EDTA and once receiving propofol with EDTA. The influence of the method of administration and of the volunteer covariates was explored by fitting a three‐compartment mamillary model to the data. The influence of EDTA was investigated by direct comparison of the measured concentrations in both sessions. Results The concentrations of propofol with and without EDTA were not significantly different. The concentration measurements after the bolus dose were significantly underpredicted by the parameters obtained just from the infusion data. The kinetics of propofol were linear within the infusion range of 25–200 micro gram [center dot] kg‐1 [center dot] min‐1. Age was a significant covariate for Volume2 and Clearance2, as were weight, height, and lean body mass for the metabolic clearance. Conclusions These results demonstrate that method of administration (bolus vs. infusion), but not EDTA, influences the pharmacokinetics of propofol. Within the clinically relevant range, the kinetics of propofol during infusions are linear regarding infusion rate.

The Influence of Age on Propofol Pharmacodynamics

BACKGROUND The authors studied the influence of age on the pharmacodynamics of propofol, including characterization of the relation between plasma concentration and the time course of drug effect. METHODS The authors evaluated healthy volunteers aged 25-81 yr. A bolus dose (2 mg/kg or 1 mg/kg in persons older than 65 yr) and an infusion (25, 50, 100, or 200 microg x kg(-1) x min(-1)) of the older or the new (containing EDTA) formulation of propofol were given on each of two different study days. The propofol concentration was determined in frequent arterial samples. The electroencephalogram (EEG) was used to measure drug effect. A statistical technique called semilinear canonical correlation was used to select components of the EEG power spectrum that correlated optimally with the effect-site concentration. The effect-site concentration was related to drug effect with a biphasic pharmacodynamic model. The plasma effect-site equilibration rate constant was estimated parametrically. Estimates of this rate constant were validated by comparing the predicted time of peak effect with the time of peak EEG effect. The probability of being asleep, as a function of age, was determined from steady state concentrations after 60 min of propofol infusion. RESULTS Twenty-four volunteers completed the study. Three parameters of the biphasic pharmacodynamic model were correlated linearly with age. The plasma effect-site equilibration rate constant was 0.456 min(-1). The predicted time to peak effect after bolus injection ranging was 1.7 min. The time to peak effect assessed visually was 1.6 min (range, 1-2.4 min). The steady state observations showed increasing sensitivity to propofol in elderly patients, with C50 values for loss of consciousness of 2.35, 1.8, and 1.25 microg/ml in volunteers who were 25, 50, and 75 yr old, respectively. CONCLUSIONS Semilinear canonical correlation defined a new measure of propofol effect on the EEG, the canonical univariate parameter for propofol. Using this parameter, propofol plasma effect-site equilibration is faster than previously reported. This fast onset was confirmed by inspection of the EEG data. Elderly patients are more sensitive to the hypnotic and EEG effects of propofol than are younger persons.

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.

Propofol Dosing Regimens for ICU Sedation Based upon an Integrated Pharmacokinetic- Pharmacodynamic Model

Background The pharmacology of propofol infusions administered for long-term sedation of intensive care unit (ICU) patients has not been fully characterized. The aim of the study was to develop propofol dosing guidelines for ICU sedation based on an integrated pharmacokinetic–pharmacodynamic model of propofol infusions in ICU patients. Methods With Institutional Review Board approval, 30 adult male medical and surgical ICU patients were given target-controlled infusions of propofol for sedation, adjusted to maintain a Ramsay sedation scale score of 2–5. Propofol administration in the first 20 subjects was based on a previously derived pharmacokinetic model for propofol. The last 10 subjects were given propofol based on a pharmacokinetic model derived from the first 20 subjects. Plasma propofol concentrations were measured, together with sedation score. Population pharmacokinetic and pharmacodynamic parameters were estimated by means of nonlinear regression analysis in the first 20 subjects, then prospectively tested in the last 10 subjects. An integrated pharmacokinetic–pharmacodynamic model was used to construct dosing regimens for light and deep sedation with propofol in ICU patients. Results The pharmacokinetics of propofol were described by a three-compartment model with lean body mass and fat body mass as covariates. The pharmacodynamics of propofol were described by a sigmoid model, relating the probability of sedation to plasma propofol concentration. The pharmacodynamic model for propofol predicted light and deep levels of sedation with 73% accuracy. Plasma propofol concentrations corresponding to the probability modes for sedation scores of 2, 3, 4, and 5 were 0.25, 0.6, 1.0, and 2.0 &mgr;g/ml. Predicted emergence times in a typical subject after 24 h, 72 h, 7 days, and 14 days of light sedation (sedation score = 3 → 2) with propofol were 13, 34, 198, and 203 min, respectively. Corresponding emergence times from deep sedation (sedation score = 5 → 2) with propofol were 25, 59, 71, and 74 h. Conclusions Emergence time from sedation with propofol in ICU patients varies with the depth of sedation, the duration of sedation, and the patient’s body habitus. Maintaining a light level of sedation ensures a rapid emergence from sedation with long-term propofol administration.

Can bispectral index monitoring predict recovery of consciousness in patients with severe brain injury

Background:The probability of recovering consciousness in acute brain-injured patients depends on central nervous system damage and complications acquired during their stay in the intensive care unit. The objective of this study was to establish a relation between the Bispectral Index (BIS) and other variables derived from the analysis of the electroencephalographic signal, with the probability of recovering consciousness in patients in a coma state due to severe cerebral damage. Methods:Twenty-five critically ill, unconscious brain-injured patients from whom sedative drugs were withdrawn at least 24 h before BIS recording were prospectively studied. BIS, 95% spectral edge frequency, burst suppression ratio, and frontal electromyography were recorded for 20 min. The neurologic condition of the patients was measured according to the Glasgow Coma Score (GCS). Patients were followed up for assessment of recovery of consciousness for 6 months after the injury. The studied variables were compared between the group of patients who recovered consciousness and those who did not recover. Their predictive ability was evaluated by means of the Pk statistic. Univariate and multivariate logistic regression was used to model the relation between variables and probability of recovery of consciousness. Cross-validation was used to validate the proposed model. Results:There were statistically significant differences between the group of patients who recovered consciousness and those who did not with respect to BISmax, BISmin, BISmean, and BISrange, frontal electromyography, signal quality index values, and GCSBIS. The Pk (SE) values were 0.99 (0.01) for electromyelography, 0.96 (0.05) for BISmax, 0.92 (0.05) for BISmean, 0.92 (0.06) for BISrange, and 0.82 (0.09) for GCSBIS. The odds ratio for BISmax in the logistic regression model was 1.17 (95% confidence interval, 1.1–1.35). Cross-validation results reported a high-accuracy median absolute cross-validation performance error of 3.06% (95% confidence interval, 1–22.15%) and a low-bias median cross-validation performance error of 0.84% (0.56–2.12%). Conclusions:The study of BIS and other electrophysiologic and clinical variables has enabled construction and cross-validation of a model relating BISmax to the probability of recovery of consciousness in patients in a coma state due to a severe brain injury, after sedation has been withdrawn.

Validation of the Alfentanil Canonical Univariate Parameter as a Measure of Opioid Effect on the Electroencephalogram

Background Several parameters derived from the multivariate electroencephalographic (EEG) signal have been used to characterize the effects of opioids on the central nervous system. These parameters were formulated on an empirical basis. A new statistical method, semilinear canonical correlation, has been used to construct a new EEG parameter (a certain combination of the powers in the EEG power spectrum) that correlates maximally with the concentration of alfentanil at the effect site. To date, this new canonical univariate parameter (CUP) has been tested only in a small sample of subjects receiving alfentanil.

Modeling of the Sedative and Airway Obstruction Effects of Propofol in Patients with Parkinson Disease undergoing Stereotactic Surgery

Background Functional stereotactic surgery requires careful titration of sedation since patients with Parkinson disease need to be rapidly awakened for testing. This study reports a population pharmacodynamic model of propofol sedation and airway obstruction in the Parkinson disease population. Methods Twenty-one patients with advanced Parkinson disease undergoing functional stereotactic surgery were included in the study and received propofol via target-controlled infusion to achieve an initial steady state concentration of 1 &mgr;g/ml. Sedation was measured using the Ramsay Sedation Scale. Airway obstruction was measured using a four-category score. Blood samples were drawn for propofol measurement. Individual pharmacokinetic profiles were constructed nonparametrically using linear interpolation. Time course of sedation and respiratory effects were described with population pharmacodynamic models using NONMEM. The probability (P) of a given level of sedation or airway obstruction was related to the estimated effect-site concentration of propofol (Ce) using a logistic regression model. Results The concentrations predicted by the target-controlled infusion system generally exceeded the measured concentrations. The estimates of C50 for Ramsay scores 3, 4, and 5 were 0.1, 1.02, and 2.28 &mgr;g/ml, respectively. For airway obstruction scores 2 and 3, the estimates of C50 were 0.32 and 2.98 &mgr;g/ml, respectively. Estimates of ke0 were 0.24 and 0.5 1/min for the sedation and respiratory effects, respectively. Conclusions The pharmacokinetic behavior of propofol in patients with Parkinson disease differs with respect to the population from which the model used by the target-controlled infusion device was developed. Based on the results from the final models, a typical steady state plasma propofol concentration of 0.35 &mgr;g/ml eliciting a sedation score of 3 with only minimal, if any, airway obstruction has been defined as the therapeutic target.

Comparison of the LMA Supreme™ with the LMA Proseal™ for airway management in patients anaesthetized in prone position

BACKGROUND The laryngeal mask airway (LMA) has been successfully used in patients in the prone position either for rescue or elective airway management. The reusable Proseal™ LMA (PLMA) and the single use Supreme™ LMA (SLMA) have been reported to be suitable for this purpose but few comparative data are available. In this study, we compared the clinical use of both devices in adult patients anaesthetized in the prone position. METHODS One hundred and twenty patients undergoing surgery in the prone position were randomized to receive either the PLMA or the SLMA for airway management. Patients positioned themselves in the prone position and after pre-oxygenation, anaesthesia was induced using a target-controlled i.v. infusion of propofol and remifentanil. All PLMAs and SLMAs were inserted by experienced anaesthetists using a guided and a standard technique respectively. Ease of facemask ventilation, time and number of attempts needed for insertion, quality of ventilation, airway seal pressure, fibreoptic view, and complications were compared. RESULTS There were no differences between groups in insertion time or first attempt success (100% vs. 98%). The PLMA required fewer manipulations (3% vs. 15%; P=0.02) to achieve effective ventilation and provided a higher seal pressure (mean [sd] 31 [4] vs. 27 [4] cm H2O; P<0.01). The fibrescopic view of the vocal cords was similar, although easier to achieve with the PLMA. The complication rate was low and similar between the groups. Blood was present on masks in 7% vs. 8% and sore throat in 3% vs. 5% of patients with the PLMA and SLMA, respectively. CONCLUSIONS Airway management in patients anaesthetized in the prone position was efficient with both devices, although the PLMA required fewer manipulations and achieved a higher seal pressure.

Modeling the Effect of Propofol and Remifentanil Combinations for Sedation-Analgesia in Endoscopic Procedures Using an Adaptive Neuro Fuzzy Inference System (ANFIS)

BACKGROUND:The increasing demand for anesthetic procedures in the gastrointestinal endoscopy area has not been followed by a similar increase in the methods to provide and control sedation and analgesia for these patients. In this study, we evaluated different combinations of propofol and remifentanil, administered through a target-controlled infusion system, to estimate the optimal concentrations as well as the best way to control the sedative effects induced by the combinations of drugs in patients undergoing ultrasonographic endoscopy. METHODS:One hundred twenty patients undergoing ultrasonographic endoscopy were randomized to receive, by means of a target-controlled infusion system, a fixed effect-site concentration of either propofol or remifentanil of 8 different possible concentrations, allowing adjustment of the concentrations of the other drug. Predicted effect-site propofol (Cepro) and remifentanil (Ceremi) concentrations, parameters derived from auditory evoked potential, autoregressive auditory evoked potential index (AAI/2) and electroencephalogram (bispectral index [BIS] and index of consciousness [IoC]) signals, as well as categorical scores of sedation (Ramsay Sedation Scale [RSS] score) in the presence or absence of nociceptive stimulation, were collected, recorded, and analyzed using an Adaptive Neuro Fuzzy Inference System. The models described for the relationship between Cepro and Ceremi versus AAI/2, BIS, and IoC were diagnosed for inaccuracy using median absolute performance error (MDAPE) and median root mean squared error (MDRMSE), and for bias using median performance error (MDPE). The models were validated in a prospective group of 68 new patients receiving different combinations of propofol and remifentanil. The predictive ability (Pk) of AAI/2, BIS, and IoC with respect to the sedation level, RSS score, was also explored. RESULTS:Data from 110 patients were analyzed in the training group. The resulting estimated models had an MDAPE of 32.87, 12.89, and 8.77; an MDRMSE of 17.01, 12.81, and 9.40; and an MDPE of −1.86, 3.97, and 2.21 for AAI/2, BIS, and IoC, respectively, in the absence of stimulation and similar values under stimulation. Pk values were 0.82, 0.81, and 0.85 for AAI/2, BIS, and IoC, respectively. The model predicted the prospective validation data with an MDAPE of 34.81, 14.78, and 10.25; an MDRMSE of 16.81, 15.91, and 11.81; an MDPE of −8.37, 5.65, and −1.43; and Pk values of 0.81, 0.8, and 0.8 for AAI/2, BIS, and IoC, respectively. CONCLUSION:A model relating Cepro and Ceremi to AAI/2, BIS, and IoC has been developed and prospectively validated. Based on these models, the (Cepro, Ceremi) concentration pairs that provide an RSS score of 4 range from (1.8 &mgr;g·mL−1, 1.5 ng·mL−1) to (2.7 &mgr;g·mL−1, 0 ng·mL−1). These concentrations are associated with AAI/2 values of 25 to 30, BIS of 71 to 75, and IoC of 72 to 76. The presence of noxious stimulation increases the requirements of Cepro and Ceremi to achieve the same degree of sedative effects.