Biomedical subjects

Thomas Bouillon

Publications and source records attributed to Thomas Bouillon.

6 recordsLinked to original sources

PubMed2006

The well-being model: a new drug interaction model for positive and negative effects.

BACKGROUND: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. METHODS: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs. RESULTS: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed. CONCLUSIONS: The model is consistent with clinical knowledge and supports previously published experimental results on optimal drug combinations. This new framework improves understanding of the characteristics of drug combinations used in clinical practice and can be used in clinical research to identify optimal drug dosing.

Drug Interactions↗

PubMed2005

Compartmental pharmacokinetics of dantrolene in adults: do malignant hyperthermia association dosing guidelines work?

Dantrolene is the only drug proven effective for prevention and treatment of malignant hyperthermia (MH). Current dosing recommendations are based on noncompartmental analyses and are largely empiric. They are also divergent, as evidenced by differing recommendations from the Malignant Hyperthermia Association of the United States (MHAUS) and European Sources. We determined the compartmental pharmacokinetics of dantrolene, simulated the concentration time course based on currently recommended dosing, and suggest an optimal regimen. Nine volunteers (55-89 kg) received IV infusions of dantrolene (5 mg/kg over 30 min followed by 0.05 mg.kg(-1) . h(-1) for 5 h). Venous blood samples were drawn for up to 60 h, and dantrolene plasma concentrations were determined by reverse phase, high-performance liquid chromatography. One, two, and three compartmental models were fitted to the data, and a covariate analysis was performed. All calculations were performed with NONMEM using the population approach. The data were adequately described by a two-compartment model with the following typical variable values (median +/- se): volumes of distribution V1= 3.24 +/- 0.61 L; V2= 22.9 +/- 1.53 L; plasma clearance CL el= 0.03 +/- 0.003 L/min; and distributional clearance CL dist= 1.24 +/- 0.22 L/min. All parameters were scaled linearly with weight. Simulations of European recommendations for treatment of MH lead to plasma concentrations converging to 14-18 mg/L within 24 h. Simulating MHAUS guidelines (intermittent bolus administration) yielded peak and trough plasma concentrations ranging from 6.7-22.6 mg/L. Based on our findings, we propose an infusion regimen adjusted to the initial bolus dose(s) required to control symptoms. This strategy maintains the individualized therapeutic concentrations and improves stability of plasma concentrations.

Adult↗

PubMed2004

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.

Adult↗

PubMed2004

A new closed-loop control system for isoflurane using bispectral index outperforms manual control.

BACKGROUND: Automatic control of depth of hypnosis using the Bispectral Index (BIS) can help to reduce phases of inadequate control. Automated BIS control with propofol or isoflurane administration via an infusion system has recently been described, a comparable study with isoflurane administration via a vaporizer had not been conducted yet. Our hypothesis was that our new model based closed-loop control system can safely be applied clinically and maintains the BIS within a defined target range better than manual control. METHODS: Twenty-three patients, American Society of Anesthesiologists risk class I-III, scheduled for decompressive spinal surgery were randomized into groups with either closed-loop or manual control of BIS using isoflurane. An alfentanil target-controlled infusion was adjusted according to standard clinical practice. The BIS target was set to 50 during the operation. The necessity of human intervention in the control system and events of inadequate sedation (BIS <40 or BIS >60) were counted. The number of phases of inadequate control, defined as BIS >/=65 for more than 3 min, were recorded. The performance of the controller was assessed by several indicators (mean absolute deviation and median absolute performance error) and measured during the skin incision phase, the subsequent low flow phase, and the wound closure phase. Recovery profiles of both groups were compared. RESULTS: No human intervention was necessary in the closed-loop control group. The occurrence of inadequate BIS was quantified with the mean and median values of the area under the curve and amounted to 0.360 and 0.088 for the manual control group and 0.049 and 0.017 for the closed-loop control group, respectively. In the manual control group nine phases of inadequate control were recorded, compared with one in the closed-loop control group, 10.3% to 0.5% of all observed anesthesia time. During all phases the averages of the performance parameters (mean absolute deviation and median absolute performance error) were more than 30% smaller in closed-loop control than in manual control (P < 0.05 between groups). CONCLUSIONS: Closed-loop control with BIS using isoflurane can safely be applied clinically and performs significantly better than manual control, even in phases with abrupt changes of stimulation that cannot be foreseen by the control system.

Adolescent↗

PubMed2003

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.

Adult↗

PubMed2002

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.

Adult↗