Departments of Anesthesiology, Statistics, Pediatrics, and Biomedical Engineering, University of Florida Colleges of Medicine and Engineering, Gainesville, Florida, USA
* Corresponding author. University of Alabama, Department of Anesthesiology, University of Alabama at Birmingham, Jefferson Tower, Room 920, 619 South 19th Street, Birmingham, AL 35249-0001, USA. E-mail: froelich{at}uab.edu
Accepted for publication November 18, 2004.
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Abstract |
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Methods. We studied the Diprifusor model (Marsh Pharmacokinetics and a Graseby® 3400 infusion pump) in 18 human volunteers at two sedative target plasma concentrations (0.5 and 1.0 µg ml1). Twenty minutes after infusion start or change and 20 min after discontinuation of the infusion plasma propofol concentrations were measured using liquid chromatographymass spectroscopy (LC-MS). Plasma propofol concentrations were compared with concentrations predicted by the TCI system. Agreement of those two measures (precision and bias) was determined using regression analysis.
Results. We found little systematic bias but poor precision. When setting the TCI system to deliver a plasma concentration of 1.0 µg ml1 one can predict the actual plasma concentration with 95% confidence only within a range of 0.441.38 µg ml1.
Conclusions. This finding helps to explain differences in responses to propofol sedation; pharmacokinetic variability appears to be an important factor.
Keywords: anaesthetics, i.v., propofol ; anaesthetic techniques, computer-assisted continuous infusion ; equipment, infusion pump ; model, computer ; pharmacokinetics, model ; statistics, regression analysis
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Introduction |
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TCI systems are based on a three compartment pharmacokinetic model; these compartments are the central compartment (blood or plasma), highly perfused tissue (heart, brain, muscle) and poorly perfused tissue (adipose tissue, bone). At equilibrium, the drug moves from one compartment to another at a constant rate based on inter-compartmental distribution rate constants. These rate constants are used to mathematically predict plasma and brain (effect site) concentrations.
The pharmacokinetics of propofol have been comprehensively studied in the past.13 The pharmacokinetic variability of propofol has been the concern of many investigator and efforts have been made to adjust for some of the sources of this biologic variability (age, body weight, pre-existing medical conditions, genetic, and environmental factors). Therefore, various investigators have refined the infusion model to maximize predictive accuracy of propofol plasma or brain concentration.4 5 The most popular of these models developed by Marsh and colleagues6 was chosen for the commercially available Diprifusor® (Astra Zeneca). This model was found to have good delivery performance in a recent laboratory report when hypnotic propofol concentrations are chosen.7 However, when applied to clinical care TCI systems it may not be as accurate as suggested previously.8 9
TCI systems are used for clinical practice as well as research; in many studies investigators use predicted propofol values as a surrogate for actual plasma concentrations.1012 The accuracy of the Diprifusor® model has been investigated at anaesthestic (hypnotic) doses of propofol but little information is available on the precision of the Diprifusor® over the sedative dosage range.
The aim of this study is to determine precision and bias of the Diprifusor® model at sedative concentrations.
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Subjects and methods |
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An i.v. line for propofol infusion was placed in one arm and a sampling i.v. line was inserted in the other. Subjects 318 received propofol in two sedative effect site concentrations, 1.0 (moderate sedation) and 0.5 (mild sedation) µg ml1. The first two subjects were started on a slightly higher dose for both levels (1.5, 1.2, and 0.75 µg ml1). In order to avoid potential problems with over-sedation, doses were reduced and kept consistent at 1.0 and 0.5 µg ml1 starting with subject 3. The study was designed to alternate mild and moderate sedation with a no drug infusion control condition necessary to obtain psychophysical measurements that are reported separately. There were three of four time points per subject during which blood samples were obtained (illustrated and in Fig. 1). A total of 66 blood samples were obtained and compared with the calculated concentration provided by the TCI software.
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Data were analysed using regression analysis. Measured propofol plasma concentration (LC-MS, gold standard) was the response variable (Y) and the propofol plasma concentration predicted by Stanpump was used as explanatory variable (X).
This allows a more flexible calibration than the BlandAltman method13 used in other medical publications because it allows a true calibration equation. Bland and Altman consider as errors any literal YX difference. Thus, the BlandAltman method forces the line to have a slope equal to 1.0 and allows an intercept term (which they call bias). If the regression line produces a slope near 1.0 and an intercept near 0.0, then regression will be very similar to BlandAltman with only a very minor loss of two degrees of freedom for error. However, if the regression line has slope or intercept moderately different from 1.0 and 0.0, respectively, then the regression line will produce a more reliable predictor of the gold standard than the method described by Bland and Altman. Both a linear and a quadratic regression model were tested.
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Results |
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Results of the regression analysis are displayed in Table 1. The regression coefficients for the linear regression were an intercept of 0.09, a slope b of 0.82 and a root mean square (RMS) error of 0.24. The coefficient of determination, R2, was 0.59. The SD of all blood propofol levels was 0.37 µg ml1. The SD of the Diprifusor® model was 0.24 µg ml1. The precision of the Diprifusor® can also be described in terms of confidence. If we set our Diprifusor infusion pump to deliver 1.0 µg ml1, we can be 95% confident that our measured propofol concentration will be between 0.44 and 1.38 µg ml1; this wide range illustrates the lack of precision (Fig. 2).
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Discussion |
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Information about the precision of propofol TCI is important because this model is widely applied as a surrogate for plasma propofol concentration both for clinical16 and research applications.11 17 A study by Kaike and colleagues18 exemplifies this potential problem; investigators used propofol TCI to predict levels of propofol anaesthesia in 16 subjects to study regional cerebral blood flow as measured by positron emission tomography. Taking predicted propofol levels as surrogate for actual (measured) propofol levels introduces error, which is compounded by the subsequent analysis of regional cerebral blood flow. Disregard for the propofol measurement error certainly presents a challenge for this and many similar studies.
The focus of our study on the sedative dose range and the chosen precision analysis requires comment. Several infusion pumps have been used for the study of TCI performance characteristics. Traditionally the Harvard 22 pump is used. Unfortunately, the latter pump is not approved for clinical use. We therefore selected an infusion pump, the Graseby 3400 pump, which is approved for clinical use. Many pumps used clinically tend to be less accurate at low infusion rates and it is recommended to check infused volumes predicted by software with actually delivered volumes (read at the syringe). We made this comparison before each change in the infusion rate and found the Graseby 3400 pump to perform accurately to within 1 ml of the infused volume. Another point of discussion relates to the evaluation of pump performance. Rather than focusing on a single time point, many investigators are also interested in pump performance over time. A comprehensive method to evaluate computer assisted infusions using temporal characteristics like divergence and wobble has been described by Varvel and co-workers.12 In the present study, we observed data from several subjects at three time points. Thus, only part of the analysis described by Varvel and colleaguesprecision and biasis suitable for our experiment. Precision and bias are derived from a regression analysis and are described using traditional statistical terms.
Another point of discussion relates to blood sampling. Many investigators use arterial blood sampling for pharmacological studies as opposed to venous sampling. One might postulate that arterial propofol sampling might have resulted in a more precise agreement of predicted and measured propofol levels because tissue uptake of propofol might result in an arterio-venous concentration difference and potentially also a difference in the variability of measured propofol concentrations. This issue has been studied by Johnston and colleagues19 who did not find a significant difference in either variance or mean propofol concentrations when comparing arterial and arterialized venous sampling. We used simple venous sampling and sampled from a large antecubital vein without the use of a tourniquet at a comfortable room temperature to avoid subjects shivering. This is a potential limitation of our study results. However, one would expect a systematic bias towards higher (or lower) measured propofol concentrations if tissue extraction indeed were to be a major confounder.
In summary, this study addresses a simple question; what is the precision of the Diprifusor® model 20 min after a sedative infusion is started or changed? We detected that the actual dose delivered has a wide estimated range (0.441.38 µg ml1 if 1 µg ml1 is targeted); thus, the predicted concentration is not very precise. This finding aids us in understanding why patients appear to react differently to comparable sedative doses of propofol and alerts researchers to use actual rather than predicted propofol levels.
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Footnotes |
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References |
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