Ann L. G. Vanluchene

BACKGROUND: The authors compared the behavior of two calculations of electroencephalographic spectral entropy, state entropy (SE) and response entropy (RE), with the A-Line ARX Index (AAI) and the Bispectral Index (BIS) and as measures of anesthetic drug effect. They compared the measures for baseline variability, burst suppression, and prediction probability. They also developed pharmacodynamic models relating SE, RE, AAI, and BIS to the calculated propofol effect-site concentration (Ceprop). METHODS: With institutional review board approval, the authors studied 10 patients. All patients received 50 mg/min propofol until either burst suppression greater than 80% or mean arterial pressure less than 50 mmHg was observed. SE, RE, AAI, and BIS were continuously recorded. Ceprop was calculated from the propofol infusion profile. Baseline variability, prediction of burst suppression, prediction probability, and Spearman rank correlation were calculated for SE, RE, AAI, and BIS. The relations between Ceprop and the electroencephalographic measures of drug effect were estimated using nonlinear mixed effect modeling. RESULTS: Baseline variability was lowest when using SE and RE. Burst suppression was most accurately detected by spectral entropy. Prediction probability and individualized Spearman rank correlation were highest for BIS and lowest for SE. Nonlinear mixed effect modeling generated reasonable models relating all four measures to Ceprop. CONCLUSIONS: Compared with BIS and AAI, both SE and RE seem to be useful electroencephalographic measures of anesthetic drug effect, with low baseline variability and accurate burst suppression prediction. The ability of the measures to predict Ceprop was best for BIS.

BACKGROUND: Several new measures based on the regularity of the electroencephalogram signal for the assessment of depth of anesthesia/sedation have been proposed recently. In this study we analyze the influence of remifentanil and electroencephalogram frequency content of the performance of a set of such measures. METHODS: Forty-five patients with American Society of Anesthesiologists physical status I were randomly allocated to one of three groups according to the received dose of predicted effect compartment-controlled remifentanil (0, 2, and 4 ng/ml). All 45 patients received stepwise increased effect site concentration-controlled dose of propofol. At every step of propofol increase, the Observer's Assessment of Alertness/Sedation score was assessed. The following measures were calculated from the electroencephalographic signal: spectral entropy, approximate entropy, Higuchi fractal dimension, Lempel-Ziv complexity, relative beta ratio, and SyncFastSlow measure. RESULTS: The behavior of the electroencephalogram-based measures is highly sensitive to the frequency content of the signal and the dose of remifentanil. The prediction probability with respect to the Observer's Assessment of Alertness/Sedation score of the most discriminative measure, the Higuchi fractal dimension, dropped from 0.90 (electroencephalographic frequency band 6-47 Hz, no remifentanil) to 0.55 when the frequency band was changed to 0.5-19 Hz and to 0.83 when remifentanil concentration was increased to 4 ng/ml. The coeffect of remifentanil on electroencephalographic regularity is bimodal depending on the frequency band of the signal. CONCLUSIONS: Cutting off high frequencies from the electroencephalogram and increased remifentanil concentration deteriorate the performance of the electroencephalogram-based entropy/complexity measures as indicators of the depth of propofol sedation.

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.

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.