13 February 2008
Charles F Minto & Thomas W Schnider
Approximately ten years ago we published covariate-adjusted population pharmacokinetic-pharmacodynamic models for remifentanil.[1-5] These now frequently cited manuscripts were based on work done during our post-doctoral fellowship in the research laboratory of Professors Don Stanski and Steven Shafer at Stanford University.
We are honored that Fresenius-Kabi and Cardinal Health decided to use the structural component of our population pharmacokinetic-pharmacodynamic models as the basis for their effect-site target controlled infusion pumps for propofol and remifentanil. However, we frequently receive detailed questions from clinicians about these pumps. Our only link to Fresenius-Kabi and Cardinal Health is through our published papers. We were not involved in the development of either pump, we are not consultants to either company, and we do not receive royalties from either company.
During our post-doctoral fellowship in Anesthesiology and Clinical Pharmacology at Stanford our interest was, in part, examining the influence of age on pharmacokinetics. Therefore, we studied a wide range of adult ages. We were not interested in weight per se, and we therefore limited our studies to adults of typical weight. Nevertheless, weight proved to be a covariate of propofol and remifentanil pharmacokinetics. We found better results with lean body mass (LBM) than with weight itself, and so the propofol and remifentanil pharmacokinetics were LBM adjusted, using an algorithm published by Professor James.
It turns out the the James equations behave oddly in very obese patients. The equations have the shape of an upside down parabola. Beyond a certain weight, they predict that the lean body mass gets smaller as patients get larger. For example, the James equations calculate the lean body mass of a 70 kg, 175 cm man as 56.5 kg. However, the equations calculate the lean body mass of a 280 kg, 175 cm man as **MINUS** 20 kg! (Spreadsheet example will be uploaded).
We didn’t realize this when we incorporated lean body mass into our model, as we had no obese patients in our study. However, clinicians take care of patients who may be sufficiently obese that their weight puts them on the downward limb of James equations. This is a potential problem.
Cardinal Health and Fresenius-Kabi have developed similar approaches to dealing with this issue. Fresenius-Kabi limits the use of our models to patients with a body mass index (BMI) of less than 35 kg/m2 in women and 42 kg/m2 in men. This is why the user interface on the Fresenius-Kabi pump turns grey when attempting to use TCI mode in very obese patients. Similar, although not identical, limits also exist on the Cardinal Health pump.
This is an interim solution to the problem of using our models in very obese patients. We are now working on developing a new set of pharmacokinetics for propofol and remifentanil that correctly accounts for extremes of weight as well as extremes of age. Indeed, that is one of the major goals of the Open TCI initiative.
While this is underway, we express our appreciation to Cardinal Health and Fresenius-Kabi for being innovators in the implementation of pharmacokinetically sophisticated devices to improve the care of our patients. We also express our appreciation to these companies, and to our academic colleagues, for their assistance and for their patience while we develop more robust covariate-adjusted models for propofol and remifentanil.
Charles & Thomas
- Minto C, Schnider T, Egan T, Youngs E, Lemmens H, Gambus P, Billard V, Hoke J, Moore K, Hermann D, Muir K, Mandema J, Shafer S: Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997; 86:10–23 PMID: 9009935
- Minto C, Schnider T, Shafer S: Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. Anesthesiology 1997; 86:24–33 PMID: 9009936
- Schnider T, Minto C, Gambus P, Andresen C, Goodale D, Shafer S, Youngs E: The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology 1998; 88:1170–82 PMID: 9605675
- Schnider T, Minto C, Shafer S, Gambus P, Andresen C, Goodale D, Youngs E: The influence of age on propofol pharmacodynamics. Anesthesiology 1999; 90:1502–16 PMID: 10360845
- Minto C, Schnider T, Gregg K, Henthorn T, Shafer S: Using the time of maximum effect site concentration to combine pharmacokinetics and pharmacodynamics. Anesthesiology 2003; 99:324–33 PMID: 12883405
- James WPT: Research on obesity. London: Her Majesty’s Stationary Office, 1976
- Bouillon T, Shafer S: Does size matter? Anesthesiology 1998; 89:557–60 PMID: 9743389