Background: The pharmacodynamics of propofol and remifentanil alone have been described extensive... more Background: The pharmacodynamics of propofol and remifentanil alone have been described extensively. Although they are commonly administered together for clinical anesthesia, very few studies about their pharmacodynamic interactions are available (1, 2 ...
IEEE Transactions on Automation Science and Engineering, 2000
Monitored anesthesia care (MAC) is increasingly used to provide patient comfort for diagnostic an... more Monitored anesthesia care (MAC) is increasingly used to provide patient comfort for diagnostic and minor surgical procedures. The drugs used in this setting can cause profound respiratory depression even in the therapeutic concentration range. Titration to effect suffers from the difficulty to predict adequate analgesia prior to application of a stimulus, making titration to a continuously measurable side effect an attractive alternative. Exploiting the fact that respiratory depression and analgesia occur at similar drug concentrations, we suggest to administer opioids and propofol during MAC using a feedback control system with transcutaneously measured partial pressures of CO (P tcCO ) as the controlled variable. To investigate this dosing paradigm, we developed a comprehensive model of human metabolism and cardiorespiratory regulation, including a compartmental pharmacokinetic and a pharmacodynamic model for the fast acting opioid remifentanil. Model simulations are in good agreement with ventilatory experimental data, both in presence and absence of drug. Closed-loop simulations show that the controller maintains a predefined CO target in the face of surgical stimulation and variable patient sensitivity. It prevents dangerous hypoventilation and delivers concentrations associated with analgosedation. The proposed control system for MAC could improve clinical practice titrating drug administration to a surrogate endpoint and actively limiting the occurrence of hypercapnia/hypoxia. Note to Practitioners-We describe a system minimizing the risks associated with the delivery of respiratory depressants to spontaneously breathing patients during medical procedures. In this setting, several factors can contribute to the occurrence of patient injuries: overdosing leading to profound respiratory depression, especially in the nonsteady state (bolus administration); inadequate monitoring of physiological parameters; delayed or inadequate resuscitation. We propose to monitor the respiratory gases (O CO ) as effective indicators of the patient's ventilatory state and to automatically titrate drug delivery based on this information. We tested the performance of the control system in a software environment with a comprehensive mathematical model of human metabolism and cardiorespiratory regulation. Using a P tcCO setpoint of 50 mmHg, the system delivered drug concentrations in the accepted therapeutic range for analgesia and prevented the occurrence of severe (transient and steady-state) respiratory depression, coping with interindividual variability. Since the drugs and the hardware necessary for the proposed system are commercially available, developing a medical device for the automatic delivery of sedatives/analgesics would be relatively inexpensive. In our opinion, the safety of monitored anesthesia care, especially when performed by non-anesthesiologists, would be profoundly enhanced. Future research will be directed towards the design of an algorithm for robust detection of sensor malfunction and the clinical evaluation of the device.
Objective: To analyse fenoterol-induced tachycardia and hypokalaemia, the most important and most... more Objective: To analyse fenoterol-induced tachycardia and hypokalaemia, the most important and most frequent adverse effects of tocolytic therapy with 2 -adrenoceptor agonists in females of childbearing age. Methods: The study was performed as a double blind, randomised, placebo controlled, cross over trial. Seven healthy women aged 22-38 y, received intravenous infusions of fenoterol at 3 different rates within the therapeutic range for tocolysis (0.5,1.0, and 2.0 µg·min 91 ) and placebo. The time courses of the plasma concentrations of fenoterol and potassium, and the heart rate were analysed with mixed effects pharmacokinetic-pharmacodynamic ( PKPD) modeling using NONMEM. Results: The plasma concentration-time course followed a linear two compartment model. Fenoterolinduced tachycardia was described by a linear concentration-effect model with baseline. The estimated baseline and slope parameters were 78 beats ·min 91 and 0.032 beats · min 91 ·µg 91 · l, respectively. Fenoterol-induced hypokalaemia could be described by a physiological indirect response model including feedback; the Estimated basal plasma potassium concentration was 3.93 mmol ·l 91 and the slope factor for the fenoterol-induced relative increase in the efflux of potassium from the extracellular space was 6.22 * 10 94 ng ·l 91 . Conclusion: The estimated population parameters permitted calculation of the expected time course of tachycardia and hypokalaemia in women after the initiation of tocolysis with fenoterol over the clinically relevant concentration range, and prediction of its variability. Based on simulation, our model predicted that a continous infusion of 2.0 µg · min 91 (highest rate examined) would increase heart rate to 113 beats·min 91 at steady state and lower the plasma potassium concentration to 2.77 mmol· l 91 1.5 h after beginning the infusion. Thereafter, the plasma potassium concentration would slowly return to normal.
The purpose of the present study was to determine the pharmacokinetics of the micro-agonist opioi... more The purpose of the present study was to determine the pharmacokinetics of the micro-agonist opioid pirinitramide (piritramide) after prolonged administration. Nine patients requiring intensive care therapy and artificial ventilation for several days received piritramide with a median infusion rate of 5 mg h(-1) (range 4.8-10 mg h(-1)) for a median period of 69.9 h (range 49-89 h) for analgesia and sedation. After the end of the infusion, frequent arterial blood samples were withdrawn for 96 h and assayed for piritramide using a gas chromatographic method. Standard compartmental models were fitted to the individual concentration-time courses to characterize the elimination of piritramide after prolonged administration. The concentration-time course after the end of the infusion was adequately described with a three-compartment model in eight patients and a two-compartment model in one patient (standard two-stage geometric mean and 16-84% quantile: volumes of distribution V1 = 47.9 (26.8-85.8)L, V2 = 402 (241-672)L, V3 = 332 (124-885)L; clearances Cl1 = 66.5 (53.2-83.0)Lh(-1), Cl2 = 215 (125-369)Lh(-1), Cl3 = 18.4 (9.2-36.8) Lh(-1)). Both the steady-state volume of distribution (782 L) and the terminal elimination half-life (17.4 h) were larger than predicted from single bolus pharmacokinetic studies (412.5 L and 10.4 h, respectively), the context-sensitive half-time after more than 72 h of administration was 32% shorter than predicted (285 vs. 420 min). Despite increasing terminal elimination half-life and volume of distribution at steady state (increasing drug load for a given plasma concentration), the context-sensitive half-time of piritramide after 3 days of administration is lower than predicted from bolus kinetics, making the drug a suitable candidate for intensive care unit analgesia.
Despite the ubiquitous use of propofol for anesthesia and conscious sedation and numerous publica... more 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. 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. 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%. 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.
The pharmacokinetics of both propofol and remifentanil have been described extensively. Although ... more 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. 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. 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. 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.
Background: The question whether some opioids exert less respiratory depression than others has n... more Background: The question whether some opioids exert less respiratory depression than others has not been answered conclusively. We applied pharmacokinetic/pharmacodynamic (PKPD) modeling to obtain an estimate of the C 50 for the depression of CO 2 elimination as a measure of the respiratory depressant potency of alfentanil and piritramide, two opioids with vastly different pharmacokinetics and apparent respiratory depressant action. Methods: Twenty-three patients received either alfentanil (2.3 mgÁkg À1 Ámin À1 , 14 patients, as published previously) or piritramide (17.9 mgÁkg À1 Ámin À1 , nine patients) until significant respiratory depression occurred. Opioid pharmacokinetics and the arterial PCO 2 (PaCO 2 ) were determined from frequent arterial blood samples. An indirect response model accounting for the respiratory stimulation due to increasing PaCO 2 was used to describe the PaCO 2 data. Results: The following pharmacodynamic parameters were estimated with NONMEM [population means and interindividual variability (CV)]: k elCO2 (elimination rate constant of CO 2 ) 0.144 (-) min À1 , F (gain of the CO 2 response) 4.0 (fixed according to literature values) (28%), C 50 (both drugs) 61.3 mg l À1 (41%), k eo alfentanil 0.654 (-) min À1 and k eo piritramide 0.023 (-) min À1 . Assigning separate C 50 values for alfentanil and piritramide did not improve the fit compared with a model with the same C 50 . Conclusion: Since the C 50 values did not differ, both drugs are equally potent respiratory depressants. The apparently lower respiratory depressant effect of piritramide when compared with alfentanil is caused by slower equilibration between the plasma and the effect site. Generalizing our results and based on simulations we conclude that slowly equilibrating opioids like piritramide are intrinsically safer with regard to respiratory depression than rapidly equilibrating opioids like alfentanil.
Background: The Anesthetic Conserving Device (Ana-ConDa s ) uncouples delivery of a volatile anes... more Background: The Anesthetic Conserving Device (Ana-ConDa s ) uncouples delivery of a volatile anesthetic (VA) from fresh gas flow (FGF) using a continuous infusion of liquid volatile into a modified heat-moisture exchanger capable of adsorbing VA during expiration and releasing adsorbed VA during inspiration. It combines the simplicity and responsiveness of high FGF with low agent expenditures. We performed in vitro characterization of the device before developing a population pharmacokinetic model for sevoflurane administration with the Ana-ConDa s , and retrospectively testing its performance (internal validation). Materials and methods: Eighteen females and 20 males, aged 31-87, BMI 20-38, were included. The end-tidal concentrations were varied and recorded together with the VA infusion rates into the device, ventilation and demographic data. The concentration-time course of sevoflurane was described using linear differential equations, and the most suitable structural model and typical parameter values were identified. The individual pharmacokinetic parameters were obtained and tested for covariate relationships. Prediction errors were calculated.
Background: The pharmacodynamics of propofol and remifentanil alone have been described extensive... more Background: The pharmacodynamics of propofol and remifentanil alone have been described extensively. Although they are commonly administered together for clinical anesthesia, very few studies about their pharmacodynamic interactions are available (1, 2 ...
IEEE Transactions on Automation Science and Engineering, 2000
Monitored anesthesia care (MAC) is increasingly used to provide patient comfort for diagnostic an... more Monitored anesthesia care (MAC) is increasingly used to provide patient comfort for diagnostic and minor surgical procedures. The drugs used in this setting can cause profound respiratory depression even in the therapeutic concentration range. Titration to effect suffers from the difficulty to predict adequate analgesia prior to application of a stimulus, making titration to a continuously measurable side effect an attractive alternative. Exploiting the fact that respiratory depression and analgesia occur at similar drug concentrations, we suggest to administer opioids and propofol during MAC using a feedback control system with transcutaneously measured partial pressures of CO (P tcCO ) as the controlled variable. To investigate this dosing paradigm, we developed a comprehensive model of human metabolism and cardiorespiratory regulation, including a compartmental pharmacokinetic and a pharmacodynamic model for the fast acting opioid remifentanil. Model simulations are in good agreement with ventilatory experimental data, both in presence and absence of drug. Closed-loop simulations show that the controller maintains a predefined CO target in the face of surgical stimulation and variable patient sensitivity. It prevents dangerous hypoventilation and delivers concentrations associated with analgosedation. The proposed control system for MAC could improve clinical practice titrating drug administration to a surrogate endpoint and actively limiting the occurrence of hypercapnia/hypoxia. Note to Practitioners-We describe a system minimizing the risks associated with the delivery of respiratory depressants to spontaneously breathing patients during medical procedures. In this setting, several factors can contribute to the occurrence of patient injuries: overdosing leading to profound respiratory depression, especially in the nonsteady state (bolus administration); inadequate monitoring of physiological parameters; delayed or inadequate resuscitation. We propose to monitor the respiratory gases (O CO ) as effective indicators of the patient's ventilatory state and to automatically titrate drug delivery based on this information. We tested the performance of the control system in a software environment with a comprehensive mathematical model of human metabolism and cardiorespiratory regulation. Using a P tcCO setpoint of 50 mmHg, the system delivered drug concentrations in the accepted therapeutic range for analgesia and prevented the occurrence of severe (transient and steady-state) respiratory depression, coping with interindividual variability. Since the drugs and the hardware necessary for the proposed system are commercially available, developing a medical device for the automatic delivery of sedatives/analgesics would be relatively inexpensive. In our opinion, the safety of monitored anesthesia care, especially when performed by non-anesthesiologists, would be profoundly enhanced. Future research will be directed towards the design of an algorithm for robust detection of sensor malfunction and the clinical evaluation of the device.
Objective: To analyse fenoterol-induced tachycardia and hypokalaemia, the most important and most... more Objective: To analyse fenoterol-induced tachycardia and hypokalaemia, the most important and most frequent adverse effects of tocolytic therapy with 2 -adrenoceptor agonists in females of childbearing age. Methods: The study was performed as a double blind, randomised, placebo controlled, cross over trial. Seven healthy women aged 22-38 y, received intravenous infusions of fenoterol at 3 different rates within the therapeutic range for tocolysis (0.5,1.0, and 2.0 µg·min 91 ) and placebo. The time courses of the plasma concentrations of fenoterol and potassium, and the heart rate were analysed with mixed effects pharmacokinetic-pharmacodynamic ( PKPD) modeling using NONMEM. Results: The plasma concentration-time course followed a linear two compartment model. Fenoterolinduced tachycardia was described by a linear concentration-effect model with baseline. The estimated baseline and slope parameters were 78 beats ·min 91 and 0.032 beats · min 91 ·µg 91 · l, respectively. Fenoterol-induced hypokalaemia could be described by a physiological indirect response model including feedback; the Estimated basal plasma potassium concentration was 3.93 mmol ·l 91 and the slope factor for the fenoterol-induced relative increase in the efflux of potassium from the extracellular space was 6.22 * 10 94 ng ·l 91 . Conclusion: The estimated population parameters permitted calculation of the expected time course of tachycardia and hypokalaemia in women after the initiation of tocolysis with fenoterol over the clinically relevant concentration range, and prediction of its variability. Based on simulation, our model predicted that a continous infusion of 2.0 µg · min 91 (highest rate examined) would increase heart rate to 113 beats·min 91 at steady state and lower the plasma potassium concentration to 2.77 mmol· l 91 1.5 h after beginning the infusion. Thereafter, the plasma potassium concentration would slowly return to normal.
The purpose of the present study was to determine the pharmacokinetics of the micro-agonist opioi... more The purpose of the present study was to determine the pharmacokinetics of the micro-agonist opioid pirinitramide (piritramide) after prolonged administration. Nine patients requiring intensive care therapy and artificial ventilation for several days received piritramide with a median infusion rate of 5 mg h(-1) (range 4.8-10 mg h(-1)) for a median period of 69.9 h (range 49-89 h) for analgesia and sedation. After the end of the infusion, frequent arterial blood samples were withdrawn for 96 h and assayed for piritramide using a gas chromatographic method. Standard compartmental models were fitted to the individual concentration-time courses to characterize the elimination of piritramide after prolonged administration. The concentration-time course after the end of the infusion was adequately described with a three-compartment model in eight patients and a two-compartment model in one patient (standard two-stage geometric mean and 16-84% quantile: volumes of distribution V1 = 47.9 (26.8-85.8)L, V2 = 402 (241-672)L, V3 = 332 (124-885)L; clearances Cl1 = 66.5 (53.2-83.0)Lh(-1), Cl2 = 215 (125-369)Lh(-1), Cl3 = 18.4 (9.2-36.8) Lh(-1)). Both the steady-state volume of distribution (782 L) and the terminal elimination half-life (17.4 h) were larger than predicted from single bolus pharmacokinetic studies (412.5 L and 10.4 h, respectively), the context-sensitive half-time after more than 72 h of administration was 32% shorter than predicted (285 vs. 420 min). Despite increasing terminal elimination half-life and volume of distribution at steady state (increasing drug load for a given plasma concentration), the context-sensitive half-time of piritramide after 3 days of administration is lower than predicted from bolus kinetics, making the drug a suitable candidate for intensive care unit analgesia.
Despite the ubiquitous use of propofol for anesthesia and conscious sedation and numerous publica... more 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. 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. 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%. 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.
The pharmacokinetics of both propofol and remifentanil have been described extensively. Although ... more 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. 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. 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. 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.
Background: The question whether some opioids exert less respiratory depression than others has n... more Background: The question whether some opioids exert less respiratory depression than others has not been answered conclusively. We applied pharmacokinetic/pharmacodynamic (PKPD) modeling to obtain an estimate of the C 50 for the depression of CO 2 elimination as a measure of the respiratory depressant potency of alfentanil and piritramide, two opioids with vastly different pharmacokinetics and apparent respiratory depressant action. Methods: Twenty-three patients received either alfentanil (2.3 mgÁkg À1 Ámin À1 , 14 patients, as published previously) or piritramide (17.9 mgÁkg À1 Ámin À1 , nine patients) until significant respiratory depression occurred. Opioid pharmacokinetics and the arterial PCO 2 (PaCO 2 ) were determined from frequent arterial blood samples. An indirect response model accounting for the respiratory stimulation due to increasing PaCO 2 was used to describe the PaCO 2 data. Results: The following pharmacodynamic parameters were estimated with NONMEM [population means and interindividual variability (CV)]: k elCO2 (elimination rate constant of CO 2 ) 0.144 (-) min À1 , F (gain of the CO 2 response) 4.0 (fixed according to literature values) (28%), C 50 (both drugs) 61.3 mg l À1 (41%), k eo alfentanil 0.654 (-) min À1 and k eo piritramide 0.023 (-) min À1 . Assigning separate C 50 values for alfentanil and piritramide did not improve the fit compared with a model with the same C 50 . Conclusion: Since the C 50 values did not differ, both drugs are equally potent respiratory depressants. The apparently lower respiratory depressant effect of piritramide when compared with alfentanil is caused by slower equilibration between the plasma and the effect site. Generalizing our results and based on simulations we conclude that slowly equilibrating opioids like piritramide are intrinsically safer with regard to respiratory depression than rapidly equilibrating opioids like alfentanil.
Background: The Anesthetic Conserving Device (Ana-ConDa s ) uncouples delivery of a volatile anes... more Background: The Anesthetic Conserving Device (Ana-ConDa s ) uncouples delivery of a volatile anesthetic (VA) from fresh gas flow (FGF) using a continuous infusion of liquid volatile into a modified heat-moisture exchanger capable of adsorbing VA during expiration and releasing adsorbed VA during inspiration. It combines the simplicity and responsiveness of high FGF with low agent expenditures. We performed in vitro characterization of the device before developing a population pharmacokinetic model for sevoflurane administration with the Ana-ConDa s , and retrospectively testing its performance (internal validation). Materials and methods: Eighteen females and 20 males, aged 31-87, BMI 20-38, were included. The end-tidal concentrations were varied and recorded together with the VA infusion rates into the device, ventilation and demographic data. The concentration-time course of sevoflurane was described using linear differential equations, and the most suitable structural model and typical parameter values were identified. The individual pharmacokinetic parameters were obtained and tested for covariate relationships. Prediction errors were calculated.
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Papers by T. Bouillon