Anomalies in target-controlled infusion: an analysis after 20 years of clinical use.

Although target-controlled infusion has been in use for more than two decades, its benefits are being obscured by anomalies in clinical practice caused by a number of important problems. These include: a variety of pharmacokinetic models available in open target-controlled infusion systems, which often confuse the user; the extrapolation of anthropomorphic data which provokes anomalous adjustments of dosing by such systems; and the uncertainty of regulatory requirements for the application of target-controlled infusion which causes uncontrolled exploitation of drugs and pharmacokinetic models in target-controlled infusion devices. Comparison of performance of pharmacokinetic models is complex and mostly inconclusive. However, a specific behaviour of a model in a target-controlled infusion system that is neither intended nor supported by scientific data can be considered an artefact or anomaly. Several of these anomalies can be identified in the current commercially available target-controlled infusion systems and are discussed in this review.

The influence of target concentration, equilibration rate constant (ke0 ) and pharmacokinetic model on the initial propofol dose delivered in effect-site target-controlled infusion.

One advantage of effect-site target-controlled infusion is the administration of a larger initial dose of propofol to speed up the induction of anaesthesia. This dose is determined by the combination of the pharmacokinetic model parameters, the target setting and the blood-effect time-constant, ke0 . With the help of computer simulation, we determined the ke0 values required to deliver a range of initial doses with three pharmacokinetic models for propofol. With an effect site target of 4 µg.ml(-1) , in a 35-year-old, 170-cm tall, 70-kg male subject, the ke0 values delivering a dose of 1.75 mg.kg(-1) with the Marsh, Schnider and Eleveld models were 0.59 min(-1) , 0.20 min(-1) and 0.26 min(-1) , respectively. These ke0 values have the attractive feature that, when used to simulate the administration schemes used in two previous studies, predicted effect site concentrations at loss of consciousness were close to those required for maintenance of anaesthesia.

Sevoflurane-enriched blood cardioplegia: the intramyocardial delivery of a volatile anesthetic.

Myocardial ischemia/reperfusion injury is a major problem in cardiac surgery, characterized by an enhanced inflammatory response postoperatively. Sevoflurane has anti-inflammatory effects and may attenuate this injury. This study describes a novel approach to using sevoflurane as a local anti-inflammatory drug and not as an anesthetic. Therefore, a pediatric oxygenator with a sevoflurane vaporizer was integrated into the blood cardioplegia system of an adult bypass system. In addition, a gas blender was implemented to regulate pO2 and pCO2 concentrations in the cardioplegia. This proof-of-principle study was tested in vivo and shows that it is feasible to deliver sevoflurane locally while regulating O2 and CO2 concentrations. Moreover, this set-up enables one to use only the specific cardioprotective features of sevoflurane. Inflammatory responses were attenuated, both locally (i.e. the heart) as well as systemically through intramyocardial delivery of sevoflurane.

Cardiospecific sevoflurane treatment quenches inflammation but does not attenuate myocardial cell damage markers: a proof-of-concept study in patients undergoing mitral valve repair.

BACKGROUND: Inflammation is considered a key mediator of complications after cardiac surgery. Sevoflurane has been shown to quench inflammation and to provide cardioprotection in preclinical studies. Clinical studies using sevoflurane confirm this effect on inflammation but do not consistently show clinical benefits. This paradox may indicate that the contribution of inflammation to postoperative sequalae is less than commonly thought or that systemic doses are too low in their local concentration. To test the latter, we evaluated the effects of intramyocardial sevoflurane delivery. METHODS: Selective myocardial sevoflurane delivery was performed during aortic cross-clamping in patients undergoing valve surgery (n=11). Results were compared with a control group not receiving sevoflurane (n=10). A reference group (n=5) was added to evaluate the effects of systemic sevoflurane delivery. Paired arterial and myocardial venous blood samples were collected at various time points post-reperfusion. Inflammatory mediators and myocardial cell damage were studied. RESULTS: Intramyocardial delivery was superior to systemic delivery in attenuation of interleukin-6 and interleukin-8 (-44% and -25%, respectively; both P=0.001). Myocardial and systemic sevoflurane delivery effectively suppressed surgery-related inflammatory responses including postoperative C-reactive protein levels when compared with controls [63 (47-99) (P=0.01) and 58 (56-81) (P=0.04) compared with 107 (79-144) mg litre(-1)]. Sevoflurane treatment did not reduce postoperative troponin T, creatine kinase, and creatine kinase-MB values. CONCLUSIONS: This proof-of-concept study suggests that intramyocardial delivery compared with the systemic delivery of sevoflurane more strongly attenuates the systemic inflammatory response after cardiopulmonary bypass without reducing postoperative markers of myocardial cell damage. CLINICAL TRIAL REGISTRATION: Nederlands Trial Register NTR2089.

A novel technique to determine an 'apparent ke0 ' value for use with the Marsh pharmacokinetic model for propofol.

Debate continues over the most appropriate blood-brain equilibration rate constant (ke0) for use with the Marsh pharmacokinetic model for propofol. We aimed to define the optimal ke0 value. Sixty-four patients were sedated with incremental increases in effect-site target concentration of propofol while using six different ke0 values within the range 0.2-1.2 min(-1). Depth of sedation was assessed by measuring visual reaction time. A median 'apparent ke0' value of 0.61 min(-1) (95% CI 0.37-0.78 min(-1)) led to the greatest probability of achieving a stable clinical effect when the effect-site target was fixed at the effect-site concentration displayed by the target-controlled infusion system, at the time when a desired depth of sedation had been reached. By utilising a clinically relevant endpoint to derive this value, inter-individual pharmacokinetic and pharmacodynamic variability may be accounted for.

Predictive performance of computer-controlled infusion of remifentanil during propofol/remifentanil anaesthesia.

BACKGROUND: The predictive performance of the available pharmacokinetic parameter sets for remifentanil, when used for target-controlled infusion (TCI) during total i.v. anaesthesia, has not been determined in a clinical setting. We studied the predictive performance of five parameter sets of remifentanil when used for TCI of remifentanil during propofol anaesthesia in surgical patients. METHODS: Remifentanil concentration-time data that had been collected during a previous pharmacodynamic interaction study in 30 female patients (ASA physical status I, aged 20-65 yr) who received a TCI of remifentanil and propofol during lower abdominal surgery were used in this evaluation. The remifentanil concentrations predicted by the five parameter sets were calculated on the basis of the TCI device record of the infusion rate-time profile that had actually been administered to each individual. The individual and pooled bias [median performance error (MDPE)], inaccuracy [median absolute performance error (MDAPE)], divergence and wobble of the remifentanil TCI device were determined from the pooled and intrasubject performance errors. RESULTS: A total of 444 remifentanil blood samples were analysed. Blood propofol and remifentanil concentrations ranged from 0.5 to 11 micro g ml(-1) and 0.1 to 19.6 ng ml(-1) respectively. Pooled MDPE and MDAPE of the remifentanil TCI device were -15 and 20% for the parameter set of Minto and colleagues (Anesthesiology 1997; 86: 10-23), 1 and 21%, -6 and 21%, and -6 and 19% for the three parameter sets described by Egan and colleagues (Anesthesiology 1996; 84: 821-33, Anesthesiology 1993; 79: 881-92, Anesthesiology 1998; 89: 562-73), and -24 and 30% for the parameter set described by Drover and Lemmens (Anesthesiology 1998; 89: 869-77). CONCLUSIONS: Remifentanil can be administered by TCI with acceptable bias and inaccuracy. The three pharmacokinetic parameter sets described by Egan and colleagues resulted in the least bias and best accuracy.