Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy.

BACKGROUND: The purpose of this investigation was to describe the pharmacodynamic interaction between propofol and remifentanil for probability of no response to shaking and shouting, probability of no response to laryngoscopy, Bispectral Index (BIS), and electroencephalographic approximate entropy (AE). METHODS: Twenty healthy volunteers received either propofol or remifentanil alone and then concurrently with a fixed concentration of remifentanil or propofol, respectively, via a target-controlled infusion. Responses to shaking and shouting and to laryngoscopy were assessed multiple times after allowing for plasma effect site equilibration. The raw electroencephalogram and BIS were recorded throughout the study, and AE was calculated off-line. Response surfaces were fit to the clinical response data using logistic regression or hierarchical response models. Response surfaces were also estimated for BIS and AE. Surfaces were visualized using three-dimensional rotations. Model parameters were estimated with NONMEM. RESULTS: Remifentanil alone had no appreciable effect on response to shaking and shouting or response to laryngoscopy. Propofol could ablate both responses. Modest remifentanil concentrations dramatically reduced the concentrations of propofol required to ablate both responses. The hierarchical response surface described the data better than empirical logistic regression. BIS and AE are more sensitive to propofol than to remifentanil. CONCLUSIONS: Remifentanil alone is ineffective at ablating response to stimuli but demonstrates potent synergy with propofol. BIS and AE values corresponding to 95% probability of ablating response are influenced by the combination of propofol and remifentanil to achieve this endpoint, with higher propofol concentrations producing lower values for BIS and AE.

Mixed-effects modeling of the intrinsic ventilatory depressant potency of propofol in the non-steady state.

BACKGROUND: Despite the ubiquitous use of propofol for anesthesia and conscious sedation and numerous publications about its effect, a pharmacodynamic model for propofol-induced ventilatory depression in the non-steady state has not been described. To investigate propofol-induced ventilatory depression in the clinically important range (at and below the metabolic hyperbola while carbon dioxide is accumulating because of drug-induced ventilatory depression), the authors applied indirect effect modeling to Paco2 data at a fraction of inspired carbon dioxide of 0 during and after administration of propofol. METHODS: Ten volunteers underwent determination of their carbon dioxide responsiveness by a rebreathing design. The parameters of a power function were fitted to the end-expiratory carbon dioxide and minute ventilation data. The volunteers then received propofol in a stepwise ascending pattern with use of a target-controlled infusion pump until significant ventilatory depression occurred (end-tidal pressure of carbon dioxide > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 microg/ml. Propofol pharmacokinetics and the Paco2 were determined from frequent arterial blood samples. An indirect response model with Bayesian estimates of the pharmacokinetics and carbon dioxide responsiveness in the absence of drug was used to describe the Paco2 time course. Because propofol reduces oxygen requirements and carbon dioxide production, a correction factor for propofol-induced decreasing of carbon dioxide production was included. RESULTS: The following pharmacodynamic parameters were found to describe the time course of hypercapnia after administration of propofol (population mean and interindividual variability expressed as coefficients of variation): F (gain of the carbon dioxide response), 4.37 +/- 36.7%; ke0, CO2, 0.95 min-1 +/- 59.8%; baseline Paco2, 40.9 mmHg +/- 12.8%; baseline minute ventilation, 6.45 l/min +/- 36.3%; kel, CO2, 0.11 min-1 +/- 34.2%; C50,propofol, 1.33 microg/ml +/- 49.6%; gamma, 1.68 +/- 21.3%. CONCLUSION: Propofol at common clinical concentrations is a potent ventilatory depressant. An indirect response model accurately described the magnitude and time course of propofol-induced ventilatory depression. The indirect response model can be used to optimize propofol administration to reduce the risk of significant ventilatory depression.

A model of the ventilatory depressant potency of remifentanil in the non-steady state.

BACKGROUND: The C50 of remifentanil for ventilatory depression has been previously determined using inspired carbon dioxide and stimulated ventilation, which may not describe the clinically relevant situation in which ventilatory depression occurs in the absence of inspired carbon dioxide. The authors applied indirect effect modeling to non-steady state Paco2 data in the absence of inspired carbon dioxide during and after administration of remifentanil. METHODS: Ten volunteers underwent determination of carbon dioxide responsiveness using a rebreathing design, and a model was fit to the end-expiratory carbon dioxide and minute ventilation. Afterwards, the volunteers received remifentanil in a stepwise ascending pattern using a computer-controlled infusion pump until significant ventilatory depression occurred (end-tidal carbon dioxide [Peco2] > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 ng/ml. Remifentanil pharmacokinetics and Paco2 were determined from frequent arterial blood samples. An indirect response model was used to describe the Paco2 time course as a function of remifentanil concentration. RESULTS: The time course of hypercarbia after administration of remifentanil was well described by the following pharmacodynamic parameters: F (gain of the carbon dioxide response), 4.30; ke0 carbon dioxide, 0.92 min-1; baseline Paco2, 42.4 mmHg; baseline minute ventilation, 7.06 l/min; kel,CO2, 0.08 min-1; C50 for ventilatory depression, 0.92 ng/ml; Hill coefficient, 1.25. CONCLUSION: Remifentanil is a potent ventilatory depressant. Simulations demonstrated that remifentanil concentrations well tolerated in the steady state will cause a clinically significant hypoventilation following bolus administration, confirming the acute risk of bolus administration of fast-acting opioids in spontaneously breathing patients.

Correlation of approximate entropy, bispectral index, and spectral edge frequency 95 (SEF95) with clinical signs of "anesthetic depth" during coadministration of propofol and remifentanil.

BACKGROUND: Several studies relating electroencephalogram parameter values to clinical endpoints using a single (mostly hypnotic) drug at relatively low levels of central nervous system depression (sedation) have been published. However, the usefulness of a parameter derived from the electroencephalogram for clinical anesthesia largely depends on its ability to predict the response to stimuli of different intensity or painfulness under a combination of a hypnotic and an (opioid) analgesic. This study was designed to evaluate the predictive performance of spectral edge frequency 95 (SEF95), BIS, and approximate entropy for the response to increasingly intense stimuli under different concentrations of both propofol and remifentanil in the therapeutic range. METHODS: Ten healthy male and ten healthy female volunteers were studied during coadministration of propofol and remifentanil. After having maintained a specific target concentration for 10 min, the depth of sedation-anesthesia was assessed using the responsiveness component of the Observer's Assessment of Alertness/Sedation (OAA/S) rating scale, which was modified by adding insertion of a laryngeal mask and laryngoscopy. The electroencephalogram derived parameters approximate entropy, bispectral index, and SEF95 were recorded just before sedation level was assessed. RESULTS: The prediction probability values for approximate entropy were slightly, but not significantly, better than those for bispectral index, SEF95, and the combination of drug concentrations. A much lower prediction ability was observed for tolerance of airway manipulation than for hypnotic endpoints. CONCLUSION: Approximate entropy revealed informations on hypnotic and analgesic endpoints using coadministration of propofol and remifentanil comparable to bispectral index, SEF95, and the combination of drug concentrations.

Non-steady state analysis of the pharmacokinetic interaction between propofol and remifentanil.

BACKGROUND: The pharmacokinetics of both propofol and remifentanil have been described extensively. Although they are commonly administered together for clinical anesthesia, their pharmacokinetic interaction has not been investigated so far. The purpose of the current investigation was to elucidate the nature and extent of pharmacokinetic interactions between propofol and remifentanil. METHODS: Twenty healthy volunteers aged 20-43 yr initially received either propofol or remifentanil alone in a stepwise incremental and decremental fashion a target controlled infusion. Thereafter, the respective second drug was infused to a fixed target concentration in the clinical range (0-4 microg/ml and 0-4 ng/ml for propofol and remifentanil, respectively) and the stepwise incremental pattern repeated. Frequent blood samples were drawn for up to 6 h for propofol and 40 min for remifentanil after the end of administration and assayed for the respective drug concentrations with gas chromatography-mass spectrometry. The time courses of the measured concentrations were fitted to standard compartmental models. Calculations were performed with NONMEM. After having established the individual population models for both drugs and an exploratory analysis for hypothesis generation, pharmacokinetic interaction was identified by including an interaction term into the population model and comparing the value of the objective function in the presence and absence of the respective term. RESULTS: The concentration-time courses of propofol and remifentanil were described best by a three- and two-compartment model, respectively. In the concentration range examined, remifentanil does not alter propofol pharmacokinetics. Coadministration of propofol decreases the central volume of distribution and distributional clearance of remifentanil by 41% and elimination clearance by 15%. This effect was not concentration-dependent in the examined concentration range of propofol. CONCLUSIONS: Coadministration of propofol decreases the bolus dose of remifentanil needed to achieve a certain plasma-effect compartment concentration but does not alter the respective maintenance infusion rates and recovery times to a clinically significant degree.

Pharmacokinetic study of FFP photochemically treated with amotosalen (S-59) and UV light compared to FFP in healthy volunteers anticoagulated with warfarin.

BACKGROUND: To date, no clinical trials have characterized FFP infusion efficacy, and infusion still carries infectious risk. This single-blinded crossover study compared postinfusion kinetics of FVII in photochemically treated FFP to standard FFP. STUDY DESIGN AND METHODS: Subjects donated plasma by apheresis. Half of the collected plasma was treated with the psoralen amotosalen hydrochloride (S-59) and UVA light, and half were prepared as standard plasma. Subjects received warfarin over 4 days to lower FVII levels. On Day 4, subjects received 1 L of either treated or standard FFP. After 2 weeks, subjects underwent a regimen identical to that with the other type of FFP. RESULTS: After warfarin ingestion, the mean FVII concentration was 0.33 IU per mL. Both types of FFP exhibited comparable FVII kinetics, with a mean peak increment of 0.10 to 0.12 IU per mL occurring at the end of infusion. The effect disappeared after 8 hours. DISCUSSION: Study data of warfarin-treated healthy volunteers demonstrate that psoralen plus UV-treated FFP provides an equivalent in vivo coagulation response to control plasma. A 1-L dose of FFP in adults may provide an initial increment of 0.10 IU per mL of FVII. In the absence of bleeding, FVII levels return to baseline after 8 hours.