The performance of compartmental and physiologically based recirculatory pharmacokinetic models for propofol: a comparison using bolus, continuous, and target-controlled infusion data.

BACKGROUND: With the growing use of pharmacokinetic (PK)-driven drug delivery and/or drug advisory displays, identifying the PK model that best characterizes propofol plasma concentration (Cp) across a variety of dosing conditions would be useful. We tested the accuracy of 3 compartmental models and 1 physiologically based recirculatory PK model for propofol to predict the time course of propofol Cp using concentration-time data originated from studies that used different infusion schemes. METHODS: Three compartmental PK models for propofol, called the "Marsh," the "Schnider," and the "Schüttler" models, and 1 physiologically based recirculatory model called the "Upton" model, were used to simulate the time course of propofol Cp. To test the accuracy of the models, we used published measured plasma concentration data that originated from studies of manual (bolus and short infusion) and computer-controlled (target-controlled infusion [TCI] and long infusion) propofol dosing schemes. Measured/predicted (M/P) propofol Cp plots were constructed for each dataset. Bias and inaccuracy of each model were assessed by median prediction error (MDPE) and median absolute prediction error (MDAPE), respectively. RESULTS: The M/P propofol Cp in the 4 PK models revealed bias in all 3 compartmental models during the bolus and short infusion regimens. In the long infusion, a worse M/P propofol Cp at higher concentration was seen for the Marsh and the Schüttler models than for the 2 other models. Less biased M/P propofol Cp was found for all models during TCI. In the bolus group, after 1 min, a clear overprediction was seen for all 3 compartmental models for the entire 5 min; however, this initial error resolved after 4 min in the Schnider model. The Upton model did not predict propofol Cp accurately (major overprediction) during the first minute. During the bolus and short infusion, the Marsh model demonstrated worse MDPE and MDAPE compared with the 3 other models. During short infusion, MDAPE for the Schnider and Schüttler models was better than the Upton and the Marsh models. All models showed similar MDPE and MDAPE during TCI simulations. During long infusion, the Marsh and the Schüttler models underestimated the higher plasma concentrations. CONCLUSION: When combining the performance during various infusion regimens, it seems that the Schnider model, although still not perfect, is the recommended model to be used for TCI and advisory displays.

Response surface modeling of the interaction between propofol and sevoflurane.

BACKGROUND: Propofol and sevoflurane display additivity for gamma-aminobutyric acid receptor activation, loss of consciousness, and tolerance of skin incision. Information about their interaction regarding electroencephalographic suppression is unavailable. This study examined this interaction as well as the interaction on the probability of tolerance of shake and shout and three noxious stimulations by using a response surface methodology. METHODS: Sixty patients preoperatively received different combined concentrations of propofol (0-12 microg/ml) and sevoflurane (0-3.5 vol.%) according to a crisscross design (274 concentration pairs, 3 to 6 per patient). After having reached pseudo-steady state, the authors recorded bispectral index, state and response entropy and the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy. For the analysis of the probability of tolerance by logistic regression, a Greco interaction model was used. For the separate analysis of bispectral index, state and response entropy suppression, a fractional Emax Greco model was used. All calculations were performed with NONMEM V (GloboMax LLC, Hanover, MD). RESULTS: Additivity was found for all endpoints, the Ce(50, PROP)/Ce(50, SEVO) for bispectral index suppression was 3.68 microg. ml(-1)/ 1.53 vol.%, for tolerance of shake and shout 2.34 microg . ml(-1)/ 1.03 vol.%, tetanic stimulation 5.34 microg . ml(-1)/ 2.11 vol.%, laryngeal mask airway insertion 5.92 microg. ml(-1) / 2.55 vol.%, and laryngoscopy 6.55 microg. ml(-1)/2.83 vol.%. CONCLUSION: For both electroencephalographic suppression and tolerance to stimulation, the interaction of propofol and sevoflurane was identified as additive. The response surface data can be used for more rational dose finding in case of sequential and coadministration of propofol and sevoflurane.

Early phase pharmacokinetics but not pharmacodynamics are influenced by propofol infusion rate.

BACKGROUND: Conventional compartmental pharmacokinetic models wrongly assume instantaneous drug mixing in the central compartment, resulting in a flawed prediction of drug disposition for the first minutes, and the flaw affects pharmacodynamic modeling. This study examined the influence of the administration rate and other covariates on early phase kinetics and dynamics of propofol by using the enlarged structural pharmacokinetic model. METHODS: Fifty patients were randomly assigned to one of five groups to receive 1.2 mg/kg propofol given with the rate of 10 to 160 mg . kg(-1). h(-1). Arterial blood samples were taken frequently, especially during the first minute. The authors compared four basic pharmacokinetic models by using presystemic compartments and the time shift of dosing, LAG time. They also examined a sigmoidal maximum possible drug effect pharmacodynamic model. Patient characteristics and dose rate were obtained to test the model structure. RESULTS: Our final pharmacokinetic model includes two conventional compartments enlarged with a LAG time and six presystemic compartments and includes following covariates: dose rate for transit rate constant, age for LAG time, and weight for central distribution volume. However, the equilibration rate constant between central and effect compartments was not influenced by infusion rate. CONCLUSIONS: This study found that a combined pharmacokinetic-dynamic model consisting of a two-compartmental model with a LAG time and presystemic compartments and a sigmoidal maximum possible drug effect model accurately described the early phase pharmacology of propofol during infusion rate between 10 and 160 mg . kg(-1). h(-1). The infusion rate has an influence on kinetics, but not dynamics. Age was a covariate for LAG time.

Manual versus target-controlled infusion remifentanil administration in spontaneously breathing patients.

BACKGROUND: The combination of propofol-remifentanil for procedural deep sedation in spontaneously breathing patients is characterized by the frequent incidence of side effects, especially respiratory depression. These side effects may be due to either the drug combination or the drug delivery technique. Target-controlled infusion (TCI) might optimize drug delivery. In this prospective, randomized, double-blind study in patients undergoing elective colonoscopy, we thus tried to answer two questions: first, if adding remifentanil to propofol surpasses the disadvantages of the combination of these two products, and second, if administration of remifentanil via TCI decreases the incidence of side effects, compared to manually controlled administration. METHODS: Patients undergoing elective colonoscopy were randomly assigned to receive remifentanil via manually controlled continuous infusion (MCI) (0.125 microg x kg(-1) x min(-1) for 2 min followed by a continuous infusion of 0.05 microg x kg(-1) x min(-1)), TCI remifentanil (1 ng/mL), or placebo (normal saline either as TCI or manual infusion of equivalent rate). All patients received TCI propofol, adjusted to a target concentration level that provided deep sedation in which patients were not responsive to verbal commands, but maintained spontaneous ventilation without assistance. RESULTS: Significantly more patients in the placebo group showed movement, cough and hiccup, which transiently interfered with the examination. There were no clinically significant differences in hemodynamic or recovery variables among all groups. Remifentanil administered via TCI resulted in a decrease in propofol requirements. The incidence of hypopnea and apnea was less frequent when remifentanil was administered via TCI compared to MCI (TCI n = 7, MCI n = 16, P < 0.05). CONCLUSION: The combination of remifentanil and propofol for deep sedation in spontaneously breathing patients, offered better conditions for colonoscopy than propofol used as a single drug. Remifentanil administered via TCI resulted in a decrease in propofol dosing and in a lower incidence in apnea and respiratory depression (TCI n = 7, MCI n = 16, P < 0.05), compared to manually controlled administration of remifentanil.

The accuracy and clinical feasibility of a new bayesian-based closed-loop control system for propofol administration using the bispectral index as a controlled variable.

BACKGROUND: Closed-loop control of the hypnotic component of anesthesia has been proposed in an attempt to optimize drug delivery. Here, we introduce a newly developed Bayesian-based, patient-individualized, model-based, adaptive control method for bispectral index (BIS) guided propofol infusion into clinical practice and compare its accuracy and clinical feasibility under direct observation of an anesthesiologist versus BIS guided, effect compartment controlled propofol administration titrated by the anesthesiologist during ambulatory gynecological procedures. METHODS: Forty ASA patients were randomly allocated to the closed-loop or manual control group. All patients received midazolam 1 mg IV and alfentanil 0.5 mg IV before induction. In the closed-loop control group, propofol was administered using the previously described closed-loop control system to reach and maintain a target BIS of 50. In the manual control group, the propofol effect-site concentration was adapted at the discretion of the anesthesiologist to reach and maintain a BIS as close as possible to 50. Induction characteristics, performance, and robustness during maintenance and recovery times were compared. Hemodynamic and respiratory stability were calculated as clinical feasibility parameters. RESULTS: The closed-loop control system titrated propofol administration accurately resulting in BIS values close to the set point. The closed-loop control system was able to induce the patients within clinically accepted time limits and with less overshoot than the manual control group. Automated control resulted in beneficial recovery times. Our closed-loop control group showed similar acceptable clinical performance specified by similar hemodynamic, respiratory stability, comparable movement rates, and quality scores than the manual control group. CONCLUSIONS: The Bayesian-based closed-loop control system for propofol administration using the BIS as a controlled variable performed accurate during anesthesia for ambulatory gynecological procedures. This control system is clinical feasibility and can be further validated in clinical practice.

Long-term pressure monitoring with arterial applanation tonometry: a non-invasive alternative during clinical intervention?

Arterial tonometry is a non-invasive technique for continuous registration of arterial pressure waveforms. This study aims to assess tonometric blood pressure recording (TBP) as an alternative for invasive long-term bedside monitoring. A prospective study was set up where patients undergoing neurosurgical intervention were subjected to both invasive (IBP) and non-invasive (TBP) blood pressure monitoring during the entire procedure. A single-element tonometric pressure transducer was used to better investigate different inherent error sources of TBP measurement. A total of 5.7 hours of combined IBP and TBP were recorded from three patients. Although TBP performed fairly well as an alternative for IBP in steady state scenarios and some short-term variations, it could not detect relevant long-term pressure variations at all times. These findings are discussed in comparison to existing work. Physiological alterations at the site of TBP measurement are highlighted as a potentially important source of artifacts. It is concluded that at this point arterial tonometry remains not enough understood for long-term use during a delicate operative procedure. Physiological changes at the TBP measurement site deserve further investigation before tonometry technology is to be considered as an non-invasive alternative for long-term clinical monitoring.

Estimation of optimal modeling weights for a Bayesian-based closed-loop system for propofol administration using the bispectral index as a controlled variable: a simulation study.

BACKGROUND: Implementing Bayesian methods in a model-based closed-loop system requires the integration of a standard response model with a patient-specific response model. This process makes use of specific modeling weights, called Bayesian variances, which determine how the specific model can deviate from the standard model. In this study we applied simulations to select the Bayesian variances yielding the optimal controller for a Bayesian-based closed-loop system for propofol administration using the Bispectral Index (BIS) as a controlled variable. METHODS: The relevant Bayesian variances determining the modeling process were identified. Each set of such Bayesian variances represents a potential controller. The set, which will result in optimal control, was estimated using calculations on a simulated population. We selected 625 candidate sets. Similar to our previous closed-loop performance study, we applied a simulation protocol to evaluate controller performance. Our population consisted of 416 virtual patients, generated using population characteristics from previous work. A BIS offset trajectory similar to a surgical case was used. RESULTS: We were able to develop, describe, and optimize the parameter setting for a patient-individualized model-based closed-loop controller using Bayesian optimization. Selection of the optimal set yields a controller performing with the following median absolute prediction errors at BIS targets 30, 50, and 70: 12.9 +/- 2.87, 7.59 +/- 0.74, and 5.76 +/- 1.03 respectively. CONCLUSIONS: We believe this system can be introduced safely into clinical testing for both induction and maintenance of anesthesia under direct observation of an anesthesiologist.

Postoperative results after desflurane or sevoflurane combined with remifentanil in morbidly obese patients.

BACKGROUND: This randomized prospective study with blinded postanesthesia care unit (PACU) observers compared the recovery profiles in morbidly obese patients who received sevoflurane or desflurane for maintenance of anesthesia in combination with a remifentanil target controlled infusion (TCI). METHODS: 50 morbidly obese patients scheduled for laparoscopic gastric banding were included to receive BIS-guided sevoflurane or desflurane anesthesia with BIS-triggered inhalation boli in combination with remifentanil TCI. In the PACU, the following recovery scores were investigated: Modified Aldrete score, a modified Observers' Assessment of Alertness/Sedation Scale (OAA/S), pain numerical rating scale (NRS), oxygen saturation (SpO(2)) and postoperative nausea and vomiting (PONV). RESULTS: OAA/S and NRS pain scores showed a similar evolution in both groups from the moment of PACU admission up to 120 minutes after admission. In both groups, patients showed no serious hypoxemia during PACU stay. Incidence of PONV was shorter lasting in the sevoflurane group compared to the desflurane group. CONCLUSIONS: No clinically relevant difference was found in recovery in the PACU between morbidly obese patients anesthetized with desflurane or sevoflurane. Both agents resulted in satisfactory recovery in morbidly obese patients.

Remifentanil used to supplement propofol does not improve quality of sedation during spontaneous respiration.

STUDY OBJECTIVE: To evaluate whether the use of remifentanil to supplement propofol during spontaneous respiration confers any benefits in terms of quality of sedation and recovery, or in terms of reduction in propofol requirements. DESIGN: Prospective, randomized, double-blind study. SETTING: University hospital. PATIENTS: 50 ambulatory adult ASA physical status I and II patients scheduled for total colonoscopy. INTERVENTIONS: Patients were randomized to receive either propofol alone or propofol plus remifentanil 0.1 microg/kg/min, while independently maintaining spontaneous respiration. MEASUREMENTS: Cardiovascular and respiratory variables were measured before induction and at 1-minute intervals thereafter. Recovery from anesthesia was assessed using simple verbal commands and the Steward Post Recovery Score. Patient satisfaction was measured with a visual analog scale. Computer simulation was used to calculate the effect-site concentrations of propofol and remifentanil. MAIN RESULTS: The depressant effects on blood pressure and respiratory function were significantly higher when propofol and remifentanil were combined. Although the addition of remifentanil resulted in a decrease of propofol usage, recovery of anesthesia was faster and patient satisfaction was higher when using propofol alone. CONCLUSIONS: The addition of remifentanil to propofol during spontaneous ventilation offered no benefits compared with the use of propofol alone.

A new method for evaluating the performance of depth-of-hypnosis indices - the D-value.

An alternative statistic, the D-value, is presented for the evaluation of the performance of EEG-based depth-of-hypnosis measures against the Observers' Assessment of Alertness/Sedation scale. The measures considered here are spectral entropy, approximate entropy, Lempel-Ziv complexity and Higuchi fractal dimension. The study is based on recordings from 45 patients, divided into three groups of 15 recordings each. Patients of Group I received no remifentanil while patients of Groups II and III received 2 and 4 ng/ml effect compartment controlled remifentanil. All the patients received stepwise increased dose of propofol. The study shows that the D-value is a promising and flexible statistic for the evaluation of the discriminative power of the EEG measures with respect to the OAA/S scale. The D-value indicates well the dependence of the performance of the measures on the EEG frequency band as well as on remifentanil concentration.

Influence of administration rate on propofol plasma-effect site equilibration.

BACKGROUND: The authors hypothesized a difference in plasma-effect site equilibration, depicted by a first-order constant k(e0), depending on the injection rate of propofol. METHODS: Sixty-one patients received 2.5 mg/kg propofol given as a bolus or as a 1-, 2-, or 3-min infusion. The Bispectral Index was used to monitor drug effect. Propofol predicted plasma concentration was calculated using a three-compartment model and the effect site concentration over time as the convolution between the predicted plasma concentration and the disposition function of the effect site concentration. The authors evaluated the influence of the infusion rate on the k(e0) by comparing the model with one k(e0) for all groups with models estimating different k(e0) values for each group. The authors also assessed the accuracy of two pharmacokinetic models after bolus injection. RESULTS: The best model based was a fixed (Bispectral Index > or = 90) plus sigmoidal model (Bispectral Index < 90) with two values of k(e0), one for the bolus (t(1/2) k(e0) = 1.2 min) and one for the infusions (t(1/2) k(e0) = 2.2 min). However, the tested pharmacokinetic models poorly predicted the arterial concentrations in the first minutes after bolus injection. Simulations showed the requirement for two k(e0) values for bolus and infusion was mostly a compensation for the inaccurate prediction of arterial concentrations after a bolus. CONCLUSION: Propofol plasma-effect site equilibration occurs more rapidly after a bolus than after rapid infusion, based on the electroencephalogram as a drug effect measure, mostly because of misspecification of the pharmacokinetic model in the first minutes after bolus.

Comparison of three disposable extraglottic airway devices in spontaneously breathing adults: the LMA-Unique, the Soft Seal laryngeal mask, and the Cobra perilaryngeal airway.

BACKGROUND: The authors compared three disposable extraglottic airway devices in spontaneously breathing anesthetized adults: the LMA-Unique (LMA-U; The Laryngeal Mask Company, San Diego, CA), the Soft Seal laryngeal mask (SS-LM; Portex Ltd., Hythe, United Kingdom), and the Cobra perilaryngeal airway (Cobra-PLA; Engineered Medical Systems, Inc. Indianapolis, IN). METHODS: Three hundred twenty consecutive adults (American Society of Anesthesiologists physical status I-III; aged 18-80 yr) were randomly allocated for airway management with one of the three devices. Anesthesia was with fentanyl-propofol for induction and a sevoflurane-nitrous oxide-oxygen-fentanyl mixture for maintenance. Intraoperative data were collected by an unblinded observer about ease of insertion, effective airway time, oropharyngeal leak pressure, anatomical position (determined with a rigid endoscope), intracuff pressure changes, and airway trauma. Data were collected by a blinded observer about sore throat, dysphagia, and dysphonia 2 h after surgery. RESULTS: Insertion was easier with the LMA-U and SS-LM than with the Cobra-PLA (P < 0.02), but the overall failure rates were similar. Effective airway times were similar among groups. Oropharyngeal leak pressure was lower with the LMA-U than with the SS-LM and Cobra-PLA (P < 0.001). Intracuff pressure increased during surgery with all extraglottic airway devices. Anatomical position was better with the Cobra-PLA than with the SS-LMA (P < 0.001) and better with the SS-LM than with LMA-U (P < 0.001). Blood staining was detected more frequently with the Cobra-PLA than with the LMA-U and SS-LM (P < 0.001), but there were no differences in airway morbidity. CONCLUSION: The LMA-U and SS-LM are easier to insert and cause less trauma than the Cobra-PLA, but the Cobra-PLA has a more effective seal than the LMA-U and better endoscopically determined anatomical position than the LMA-U and SS-LM.

Closed loops in anaesthesia.

Closed-loop systems are able to make their own decisions and to try to reach and maintain a preset target. As a result, they might help the anaesthetist to optimise the titration of drug administration without any overshoot, controlling physiological functions and guiding monitoring variables. Thanks to the development of fast computer technology and more reliable pharmacological effect measures, the study of automation in anaesthesia has regained popularity. This short review focuses on the most recently developed and tested feedback systems in anaesthesia. Various new approaches for controlling the administration of intravenous and inhaled hypnotic-anaesthetic drugs have recently been published. For analgesics, a framework for further research has been presented in the literature. For other drugs, such as muscle relaxants and haemodynamic agents, only short reviews can be found. Until now, most of these systems have had to be under development. The challenge is now fully to establish the safety, efficacy, reliability and utility of closed-loop anaesthesia so that it can be adopted in the clinical setting. Besides, their role in optimising the controlled variables and control models, these systems have to be tested in extreme circumstances in order to test their robustness.

The effects of ketamine and rocuronium on the A-Line auditory evoked potential index, Bispectral Index, and spectral entropy monitor during steady state propofol and remifentanil anesthesia.

BACKGROUND: The authors studied the effects of ketamine and rocuronium on the Bispectral Index, A-Line auditory evoked potential index, state entropy, and response entropy during a calculated steady state anesthesia with propofol and remifentanil. METHODS: After ethics committee approval, 42 patients were allocated to four groups. Baseline measurements were performed after implementing a calculated steady state anesthesia with propofol and remifentanil. The control group received no additional medication. The ketamine group received a bolus and continuous infusion of ketamine. The rocuronium group received a bolus of rocuronium. The rocuronium-ketamine group received both. All data were stored during 15 min after baseline. After inspection of the raw data, the authors conducted an explorative statistical analysis. RESULTS: No significant changes were found in the control group for any of the monitors. Mean values decreased in the rocuronium group for the A-Line auditory evoked potential index, Bispectral Index, and response entropy, but not for state entropy. In the ketamine group, the A-Line auditory evoked potential index and Bispectral Index did not change significantly, but state and response entropy increased. In the rocuronium-ketamine group, the A-Line auditory evoked potential index and Bispectral Index did not decrease as found in the rocuronium group. Response and state entropy increased significantly. CONCLUSIONS: The response of all monitors after ketamine administration is not affected by simultaneous administration of rocuronium. Interpretation of all studied indices must be done cautiously while taking into account the clinical setting during measurement.

AQUAVAN injection, a water-soluble prodrug of propofol, as a bolus injection: a phase I dose-escalation comparison with DIPRIVAN (part 1): pharmacokinetics.

BACKGROUND: AQUAVAN Injection (AQ) (GPI 15715; Guilford Pharmaceutical Inc., Baltimore, MD) is a water-soluble prodrug of propofol (PropofolGPI). This study aimed to explore the pharmacokinetics of AQ, PropofolGPI, and formate (a metabolite of AQ) and to compare them with the pharmacokinetics of propofol lipid emulsion (PropofolD). METHODS: After ethics committee approval, 36 healthy volunteers were randomly allocated into six cohorts (male/female: 3/3) and given a single bolus of AQ (5, 10, 15, 20, 25, or 30 mg/kg). For comparison, an equipotent dose (as measured by the Bispectral Index) of PropofolD was given to the same subjects 1 week later. For both drugs, blood samples were collected (1-480 min) to analyze AQ, PropofolGPI, PropofolD, and formate concentrations. Noncompartmental pharmacokinetic analyses were performed for all analytes. A population compartmental model was developed for AQ and PropofolGPI using NONMEM. The models were evaluated using simulations and bootstraps. RESULTS: The noncompartmental pharmacokinetic comparison revealed different dispositions of PropofolGPI and PropofolD. The maximum plasma concentration was lower for PropofolGPI than for PropofolD at equipotent doses, and apparent clearance and distribution volume were much higher for PropofolGPI than for PropofolD. Formate concentrations were similar when injecting both drugs and were not higher than baseline. Compartmental modeling revealed that the pharmacokinetic behavior of AQ and its liberated PropofolGPI was best described by a nonlinear, six-compartment model, composed of two three-compartment models connected to each other by hydrolysis of AQ to PropofolGPI. CONCLUSIONS: PropofolGPI showed different noncompartmental pharmacokinetics from PropofolD, hereby revealing the influence of the formulation. The combined model for AQ and PropofolGPI was best modeled by a nonlinear, six-compartment model.

AQUAVAN injection, a water-soluble prodrug of propofol, as a bolus injection: a phase I dose-escalation comparison with DIPRIVAN (part 2): pharmacodynamics and safety.

BACKGROUND: AQUAVAN Injection (AQ) (GPI 15715; Guilford Pharmaceuticals Inc., Baltimore, MD) is a water-soluble prodrug of propofol. The authors explored the pharmacodynamics and safety of AQ and compared it with propofol lipid emulsion (PropofolD). METHODS: After institutional review board approval, 36 volunteers with American Society of Anesthesiologists physical status of I were randomly allocated into six cohorts (male/female: 3/3 per cohort) and given a single bolus of AQ (5, 10, 15, 20, 25, or 30 mg/kg). A Bispectral Index monitor (Aspect Medical Systems Inc., Newton, MA) measured the hypnotic effect. The lowest Bispectral Index level (BISpeak) was recorded. One week later, PropofolD was given to the same subjects at 50 mg/min to reach a similar BISpeak. Heart rate, oxygen saturation measured by pulse oximetry, blood pressure, and side effects were monitored. Incidence and duration of apnea and loss (LOCverbal) and return of response to verbal command were measured. A population compartmental pharmacokinetic-pharmacodynamic model was developed for AQ using NONMEM and evaluated using simulations, leverage, and bootstrap analyses. RESULTS: In the higher dosages (cohorts 4-6), all subjects achieved LOCverbal. Similar times until LOCverbal were seen for AQ and PropofolD. A dose-related increase in duration of LOCverbal was longer for AQ than for PropofolD. AQ BISpeak occurred later than with PropofolD. Pain on injection was only present with PropofolD (12 of 36). With AQ, transient paresthesias and pruritus were seen. Hemodynamic profiles were similar for both drugs, except for an initial tachycardia after AQ administration. Dose-dependent apnea was more pronounced with PropofolD than with AQ. The AQ combined pharmacokinetic-pharmacodynamic profile was best described by a nonlinear, six-compartment pharmacokinetic model and an effect site compartment. A dependency of the ke0 value on the PropofolGPI plasma concentration was noted. CONCLUSION: Bolus administration of AQ achieves LOCverbal at a similar time as an equipotent amount of PropofolD but shows a longer time to BISpeak and prolonged pharmacodynamics. For both drugs, excellent drug safety was achieved, although there was a tendency of fewer and shorter duration of apneas for AQ.

New composite index based on midlatency auditory evoked potential and electroencephalographic parameters to optimize correlation with propofol effect site concentration: comparison with bispectral index and solitary used fast extracting auditory evoked potential index.

BACKGROUND: This study investigates the accuracy of a composite index, the A-Line(R) auditory evoked potentials index version 1.6 (AAI1.6; Danmeter A/S, Odense, Denmark), as a measure of cerebral anesthetic drug effect in a model for predicting a calculated effect site concentration of propofol (CePROP). The AAI1.6 algorithm extracts information from the midlatency auditory evoked potentials, the spontaneous electroencephalographic activity, and the detection of burst suppression. The former version of this monitor, the A-Line auditory evoked potential index version 1.5, is only based on fast extracted midlatency auditory evoked potential information. METHODS: After institutional ethics committee approval (University Hospital, Ghent, Belgium), informed consent was obtained from 13 patients (10 women, 3 men) with an American Society of Anesthesiologists physical status of I, aged 18-65 yr, who were scheduled to undergo ambulatory gynecologic or urologic surgery. The authors evaluated for Bispectral Index, A-Line auditory evoked potential index, version 1.5, AAI1.6 scaled from 0 to 100 and AAI1.6 scaled from 0 to 60, the interpatient stability at baseline, the detection of burst suppression, prediction probability, and correlation with CePROP, during a constant infusion of 1% propofol at 300 ml/h. The authors developed pharmacodynamic models relating the predicted CePROP to each measure of cerebral anesthetic drug effect. RESULTS: Bispectral Index had the lowest interindividual baseline variability. No significant difference was found with prediction probability analysis for all measures. Comparisons for correlation were performed for all indices. The AAI1.6 scaled to 60 had a significantly higher correlation with CePROP compared with all other measures. The AAI1.6 scaled to 100 had a significant higher correlation with CePROP compared with the A-Line auditory evoked potential index version 1.5 (P < 0.05) CONCLUSIONS: The authors found that the application of AAI1.6 has a better correlation with a calculated CePROP compared with a solitary fast extracting midlatency auditory evoked potential measure. Whether this improvement in pharmacodynamic tracing is accompanied by an improved clinical performance should be investigated using clinical endpoints.

The effects of acute isovolemic hemodilution on oxygenation during one-lung ventilation.

Data on the effects of isovolemic hemodilution (IH) on oxygenation during one-lung ventilation (OLV) are lacking. We studied 47 patients with hemoglobin >14 g/dL who were scheduled for lung surgery (17 with normal lung function [group NL], 17 with chronic obstructive pulmonary disease [COPD] [group COPD], and 13 with COPD as control for time/anesthesia effects [group CTRL]). Anesthesia was standardized. The tracheas were intubated with a double-lumen tube. Ventilatory settings and fraction of inspired oxygen remained constant. The study was performed with patients in the supine position before surgery. OLV was initiated for 15 min. Two-lung ventilation was reinstituted, and IH was performed (500 mL); an identical volume of hydroxyethyl starch was administered. Subsequently, OLV was again performed for 15 min. In group CTRL, the same sequences of OLV were performed without IH. At the end of each period of OLV, pulmonary mechanics and blood gases were recorded. Data were analyzed by analysis of variance (mean +/- sd). In group NL and group CTRL, the arterial oxygen partial pressure remained constant, whereas it decreased in group COPD from 119 +/- 21 mm Hg before IH to 86 +/- 16 mm Hg after IH (P <0.01). Mild IH impairs gas exchange during OLV in COPD patients, but not in patients with normal lung function.

Closed-loop control of anaesthesia.

PURPOSE OF REVIEW: Closed-loop systems are able to make decisions on their own and try to reach and maintain a preset target. As a result, they might help the anaesthesiologist in optimizing the titration of drug administration without overshooting, controlling physiological functions and guiding monitoring variables. Thanks to the development of fast computer technology and more reliable pharmacological effect measures, the study of automation in anaesthesia has regained popularity. RECENT FINDINGS: This short review focuses on the most recently developed and tested feed-back systems in anaesthesia. Various new approaches for controlling the administration of intravenous and inhaled hypnotic-anaesthetic drugs have been published recently. For analgesics, a framework for further research has been presented in the literature. For other drugs, such as muscle relaxants and haemodynamics, a short review can be found. SUMMARY: Until now, most of these systems are still under development. The challenge is now to establish fully the safety, efficacy, reliability and utility of closed-loop anaesthesia for its adoption into the clinical setting. Besides the optimization of controlled variables and control models, these systems have to be tested in extreme circumstances.

Performance evaluation of two published closed-loop control systems using bispectral index monitoring: a simulation study.

BACKGROUND: Although automated closed-loop control systems may improve quality of care, their safety must be proved under extreme control conditions. This study describes a simulation methodology to test automated controllers and its application in a comparison of two published controllers for Bispectral Index (BIS)-guided propofol administration. METHODS: A patient simulator was developed to compare controllers. Using input scripts to dictate patient characteristics, target BIS values, and the time course of surgical events, the simulator continuously monitors the infusion pump under control and generates BIS values as a composite of modeled response to drug, perceived stimulation, and random noise. The simulator formats the output stream of BIS data as input to the controller under test to emulate the serial output of the actual BIS monitor. A published model-based controller and a classic proportional integral derivative controller were compared when using the BIS value as a controlled variable. Each controller was tested using a set of 10 virtual patients undergoing a fixed surgical profile that was repeated with BIS targets set at 30, 50, and 70. Controller performance was assessed using median (absolute) prediction error, divergence, wobble, and percentage time within BIS target range metrics. RESULTS: The median prediction error was significantly smaller for the proportional integral derivative controller than for the model-based controller. The median absolute prediction error was smaller for the model-based controller than for the proportional integral derivative controller for each BIS target, reaching statistical significance for targets 30 and 50. CONCLUSIONS: When simulating closed-loop control of BIS using propofol, the use of a patient-individualized, model-based adaptive closed-loop system with effect site control resulted in better control of BIS compared with a standard proportional integral derivative controller with plasma site control. Even under extreme conditions, the modeled-based controller exhibited no behavioral problems.