Keisuke Sawada

Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients derivation of dosing weight: (pharmacokinetic mass)

Background: The currently available pharmacokinetic models for fentanyl were derived from normal weight patients and were not scaled to body weight. Their application to obese patients may cause overprediction of the plasma concentration of fentanyl. This study examined the influence of body weight on the predictive accuracy of two models (Anesthesiology 1990; 73:1091–102 and J Pharmacol Exp Ther 1987; 240:159–66). Further, we attempted to derive suggested dosing mass weights for fentanyl that improved predicted accuracy. Method: Seventy patients undergoing major elective surgery with total body weight (TBW) <85 kg and body mass index <30 (Group L) and 39 patients with TBW ≥85 kg and body mass index >30 (Group O) were studied. In Group L and Group O, the mean TBW was 69 kg, and 125 kg, respectively and the mean body mass index in Group L and Group O was 24 and 44, respectively. Fentanyl infusion was used during surgery and postoperatively for analgesia. Plasma fentanyl concentrations were measured and predicted concentrations were obtained by computer simulation; 465 pairs of measured and predicted values were obtained. Results: The influence of TBW on the performance errors of the original two models was examined with nonlinear regression analysis. Shafer error versus TBW showed a highly significant negative relationship (R squared = 0.689, P < 0.001); i.e., the Shafer model systematically overestimated fentanyl concentration as weight increased. The Scott and Stanski model showed greater variation (R squared = 0.303). We used the exponential equation for Shafer performance error versus TBW to derive suggested dosing weights (“pharmacokinetic mass”) for obese patients. The pharmacokinetic mass versus TBW curve was essentially linear below 100 kg (with slope of 0.65) and approached a plateau above 140 kg. For patients weighing 140 to 200 kg, dosing weights of 100–108 kg are projected. Total body clearance (ml/min) showed a strong linear correlation with pharmacokinetic mass (r = 0.793; P < 0.001), whereas the relationship with TBW was nonlinear. Conclusion: Actual body weight overestimates fentanyl dose requirements in obese patients. Dosing weight (pharmacokinetic mass) derived from the nonlinear relationship between prediction error and TBW proved to have a linear relationship with clearance.

Recovery of heart rate variability profile in patients after coronary artery surgery

We examined the different characteristics of heart rate variability (HRV) to define the time course of HRV profile after coronary artery surgery (CAS).Spectral analysis of HRV was performed on a 512-s segment of R-R intervals of the electrocardiogram on the preoperative day and on Postoperative Days 1, 2, 3, 4, 5, 6, 7, 14, 21, and 28. Power spectral area was divided into low (0.04-0.15 Hz; LF)-and high (0.15-0.5 Hz; HF)-frequency components. Fractal slope and sympathovagal slope of 1/f characteristics of HRV were determined in two different frequency ranges (from 0.01 to 0.15 Hz and from 0.01 to 0.5 Hz, respectively). Three recovery profiles of HRV were identified. Early HRV recovery profiles (Postoperative Days 1-6) included reduction in LF, HF, and sympathovagal slope, as well as an increase in fractal slope. Subsequent HRV recovery profiles (Postoperative Days 7-21) revealed reductions in LF, HF, and sympathovagal slope. Fractal slope became normal. Later HRV recovery profiles (Postoperative Day 28) demonstrated that all spectral components of HRV remained reduced, but sympathovagal and fractal slopes became normal. These changes in the HRV profile after CAS suggest significant postoperative alterations in cardiovascular homeostasis with significant but incomplete recovery during the first 28 postoperative days. Implications: Heart rate variability reflects normal neural regulation of cardiac function. This variability remains depressed as long as 28 days after coronary artery bypass surgery, but can recover as early as 1 wk postoperatively. Despite implied loss of normal neural regulation of cardiac function, a specific correlation between depressed heart rate variability and outcomes was not performed. (Anesth Analg 1997;85:713-8)

Clinical applications of fentanyl pharmacokinetics and pharmacodynamics: roles of fentanyl in anesthesia

1 Department of Anesthesiology, New York Medical College, Valhalla, New York 10595, USA 2 Department of Anesthesiology and Intensive Care, Hamamatsu University School of Medicine, Hamamatsu 431-31, Japan 3 Department of Anesthesiology, Hirosaki University School of Medicine, Hirosaki 036, Japan 4 Department of Anesthesiology and Acute Medicine, Aichi Medical University, Yazako, Nagakute-cho, Aichi 480-1195, Japan 5 Department of Anesthesiology and Intensive Care, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan