Target-Controlled Continuous Infusion for Antibiotic Dosing:Proof-of-Principle in an In-silico Vancomycin Trial in Intensive Care Unit Patients

Objectives: In this in-silico study, we investigate the clinical utility of target-controlled infusion for antibiotic dosing in an intensive care unit setting using vancomycin as a model compound. We compared target-controlled infusion and adaptive target-controlled infusion, which combines target-controlled infusion with data from therapeutic drug monitoring, with conventional (therapeutic drug monitoring-based) vancomycin dosing strategies. Methods: A clinical trial simulation was conducted. This simulation was based on a comprehensive database of clinical records of intensive care unit patients and a systematic review of currently available population-pharmacokinetic models for vancomycin in intensive care unit patients. Dosing strategies were compared in terms of the probability of achieving efficacious concentrations as well as the potential for inducing toxicity. Results: Adaptive target-controlled infusion outperforms rule-based dosing guidelines for vancomycin. In the first 48h of treatment, the probability of target attainment is significantly higher for adaptive target-controlled infusion than for the second-best method (Cristallini). Probability of target attainments of 54 and 72% and 47 and 59% for both methods after 24 and 48h, respectively. Compared to the Cristallini method, which is characterized by a probability of attaining concentrations above 30mg.L-1>65% in the first few hours of treatment, adaptive target-controlled infusion shows negligible time at risk and a probability of attaining concentrations above 30mg.L-1 not exceeding 25%. Finally, in contrast to the other methods, the performance of target-controlled infusion is consistent across subgroups within the population. Conclusions: Our study shows that adaptive target-controlled infusion has the potential to become a practical tool for patient-tailored antibiotic dosing in the intensive care unit

Patient-maintained sedation for oral surgery using a target-controlled infusion of propofol - a pilot study

OBJECTIVE: To assess the safety and efficacy of a new patient-maintained propofol system for conscious sedation in dentistry. DESIGN: Prospective clinical trial SETTING: Department of Sedation, Glasgow Dental Hospital and School, 2001 SUBJECTS AND METHODS: Patients scheduled for oral surgery with conscious sedation. Exclusions included ASA IV -V, inability to use the handset, opioid use and severe respiratory disease. INTERVENTIONS: Patients were given intravenous propofol to a level of 1.0 microg/ml (reducing from 1.5 microg/ml) using a target controlled infusion system, they then controlled their sedation level by double-clicking a handset which on each activation increased the propofol concentration by 0.2 microg/ml. MAIN OUTCOME MEASURES: Oxygen saturation, patient satisfaction, and surgeon satisfaction. RESULTS: Twenty patients were recruited, 16 female and four male. Nineteen patients completed sedation and treatment successfully. Mean lowest oxygen saturation was 94%. No patients were over-sedated. All patients successfully used the system to maintain a level of sedation adequate for their comfort. Patient and surgeon satisfaction were consistently high. CONCLUSIONS: Initial experience with this novel system has confirmed safety, patient satisfaction and surgeon satisfaction

An analytical study of standard propofol- sufentanil target controlled infusion protocols for total intravenous anaesthesia requirements in an Indian population using bispectral index monitoring

Background: Target controlled infusion (TCI) is an automated and regulated total intravenous anaesthesia delivering device. On the basis of western pharmacokinetic and pharmacodynamic models it delivers a calculated dosage of intravenous anaesthetic drugs to achieve an ideal anaesthetic plane. The depth of anaesthesia is judged by monitors such as bispectral index (BIS) monitors which gives a rough estimate whether the TCI is delivering more or less.Methods: This analytical study was carried out on 100 patients between 20 to 60 years of age in a teaching hospital. Simultaneous BIS monitoring and TCI were set on these patients. If BIS values went below 45 the target concentration was decreased by 0.5μg/ml and if it was more than Injection propofol was supplemented manually and the changes were collected and analyzed.Results: On analyses and comparison of the data with a western study it was found that the duration of surgery was similar in both studies. With the help of “t” test based on normal distribution it was found that group having BIS 60 was more statistically significant in the Indian population.Conclusions: Depth of anaesthesia was assessed with neurological monitor, BIS, at the time of administration of Target controlled infusion (TCI) and data acquired was compared with data from a western study. The two groups had similar anaesthetic depth levels with the same infusion protocols of Target controlled infusion (TCI)

Target-Controlled Infusion of Cefepime in Critically Ill Patients:single center experience

Attainment of appropriate pharmacokinetic-pharmacodynamic (PK-PD) targets for antimicrobial treatment is challenging in critically ill patients, particularly for cefepime, which exhibits a relative narrow therapeutic-toxic window compared to other beta-lactam antibiotics. Target-controlled infusion (TCI) systems, which deliver drugs to achieve specific target drug concentrations, have successfully been implemented for improved dosing of sedatives and analgesics in anesthesia. We conducted a clinical trial in an intensive care unit (ICU) to investigate the performance of TCI for adequate target attainment of cefepime. Twenty-one patients treated with cefepime according to the standard of care were included. Cefepime was administered through continuous infusion using TCI for a median duration of 4.5 days. TCI was based on a previously developed population PK model incorporating the estimated creatinine clearance based on the Cockcroft-Gault formula as the input variable to calculate cefepime clearance. A cefepime blood concentration of 16 mg/liter was targeted. To evaluate the measured versus predicted plasma concentrations, blood samples were taken (median of 10 samples per patient), and total cefepime concentrations were measured using ultraperformance liquid chromatography-tandem mass spectrometry. The performance of the TCI system was evaluated using Varvel criteria. Half (50.3%) of the measured cefepime concentrations were within +/- 30% around the target value of 16 mg liter(-1). The wobble was 11.4%, the median performance error (MdPE) was 21.1%, the median absolute performance error (MdAPE) was 32.0%, and the divergence was -3.72% h(-1). Based on these results, we conclude that TCI is useful for dose optimization of cefepime in ICU patients

Modeling of the Sedative and Airway Obstruction Effects of Propofol in Patients with Parkinson Disease undergoing Stereotactic Surgery

BACKGROUND: Functional stereotactic surgery requires careful titration of sedation since patients with Parkinson disease need to be rapidly awakened for testing. This study reports a population pharmacodynamic model of propofol sedation and airway obstruction in the Parkinson disease population. METHODS: Twenty-one patients with advanced Parkinson disease undergoing functional stereotactic surgery were included in the study and received propofol target-controlled infusion to achieve an initial steady state concentration of 1 microg/ml. Sedation was measured using the Ramsay Sedation Scale. Airway obstruction was measured using a four-category score. Blood samples were drawn for propofol measurement. Individual pharmacokinetic profiles were constructed nonparametrically using linear interpolation. Time course of sedation and respiratory effects were described with population pharmacodynamic models using NONMEM. The probability (P) of a given level of sedation or airway obstruction was related to the estimated effect-site concentration of propofol (Ce) using a logistic regression model. RESULTS: The concentrations predicted by the target-controlled infusion system generally exceeded the measured concentrations. The estimates of C(50) for Ramsay scores 3, 4, and 5 were 0.1, 1.02, and 2.28 microg/ml, respectively. For airway obstruction scores 2 and 3, the estimates of C(50) were 0.32 and 2.98 microg/ml, respectively. Estimates of k(e0) were 0.24 and 0.5 1/min for the sedation and respiratory effects, respectively. CONCLUSIONS: The pharmacokinetic behavior of propofol in patients with Parkinson disease differs with respect to the population from which the model used by the target-controlled infusion device was developed. Based on the results from the final models, a typical steady state plasma propofol concentration of 0.35 microg/ml eliciting a sedation score of 3 with only minimal, if any, airway obstruction has been defined as the therapeutic target

Target Controlled infusion of opioids for bariatric surgery and morphine loading dose

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Propofol and children--what we know and what we do not know.

The pharmacokinetics of propofol are relatively well described in the pediatric population. Recent work has confirmed the validity of allometric scaling for predicting propofol disposition across different species and for describing pediatric ontogenesis. In the first year of life, allometric models require adjustment to reflect ontogeny of maturation. Pharmacodynamic data for propofol in children are scarcer, because of practical difficulties in data collection and the limitations of currently available depth of anesthesia monitors for pediatric use. Hence, questions relating to the comparative sensitivity of children to propofol, and differences in time to peak effect relative to adults, remain unanswered. K(eo) half-lives have been determined for pediatric kinetic models using time to peak effect techniques but are not currently incorporated into commercially available target-controlled infusion pumps