Kotaro Kaneda

Population pharmacokinetics of a propofol bolus administered in patients with major burns

OBJECTIVE In operating theaters and burn units, propofol is commonly used for sedation and anesthesia in patients with major burns. This study determined the population pharmacokinetics of propofol in burns and identified clinically significant covariates. METHOD Seventeen adults, age 42±10 (mean±SD) years, with 41±19% total body surface area burns, were enrolled at 16±14 days after-burn. Non-burn adults (n=19) served as controls. After an intravenous bolus of 2mg/kg propofol, the plasma concentration was determined at designated times for up to 4.5h. Concentration-time profiles were analyzed using nonlinear mixed-effect modeling. RESULTS A three-compartment model gave the best fit. The volume of distribution of the central compartment (V(1)) was considerably greater in the burned than non-burned group (48.4 L vs. 27.6 L, respectively). The clearances of the central (CL(1)) and slow peripheral (CL(3)) compartments were higher in burn patients (4.2 L/min vs. 1.7 L/min and 3.6 L/min vs. 1.1 L/min, respectively). Adding the covariates BURN to V(1), CL(1), and CL(3) and WT (weight) to CL(1) significantly improved the model performance. CONCLUSION The pharmacokinetic characteristics of a propofol bolus administered in patients with major burns were enhanced clearance and expanded volume of distribution. BURN and WT were the important covariates. For sedation or anesthesia induction, a higher than recommended dose of propofol may be required to maintain therapeutic plasma drug concentrations in patients with severe burns. Vigilance regarding the burned individual and careful titration of hypnotics to the desired effect cannot be overemphasized.

Comparative population pharmacokinetics of fentanyl using non-linear mixed effect modeling: burns vs. non-burns.

OBJECTIVE Fentanyl is a commonly used analgesic and sedative for the burned in the operating theater as well as the burn care units. The aim of this study was to characterize fentanyl population pharmacokinetics in burns and to identify clinically significant covariates. METHOD Twenty adults, aged 37+/-3 years, with 49+/-4% (mean+/-S.E.) total body surface area burn, were enrolled at 17+/-3 days after the injury. Twenty non-burn adults served as controls. After an intravenous bolus of 200 mcg fentanyl, the plasma concentrations were sequentially determined up to 4.5 h. Concentration-time profiles were subjected to non-linear mixed effect modeling. Cardiac indices were estimated with esophageal Doppler monitor. RESULTS Burned patients have higher cardiac index than the non-burned. Three-compartment model was the best fit. The volumes of distribution were considerably expanded in all three compartments (27.9 L vs. 63.4 L, 64.7 L vs. 92.9 L, 153 L vs. 301 L, respectively) compared to the non-burned. BURN was the single most important covariate significantly improving the model. CONCLUSION The primary effect of burn trauma on fentanyl pharmacokinetics is substantially expanded volumes of distribution, i.e., dilutional. Difference in simulation, however, was insufficient to explain the augmented resistance to fentanyl, implying the importance of titrating analgesics to the clinical effect.

Population Pharmacokinetics and Pharmacodynamics of Brief Etomidate Infusion in Healthy Volunteers

This study established the pharmacokinetic and pharmacodynamic relationships of the bispectral index (BIS) and Observers Assessment of Alertness/Sedation (OAA/S) scale with effect site drug concentrations during and after brief etomidate infusion. Eighteen American Society of Anesthesiologists status I or II volunteers received etomidate (0.2%) infusion at 5 mg/min until the loss of eyelash reflexes, and spontaneous recovery was allowed. Data for plasma etomidate concentrations, BIS, and OAA/S were collected every minute and analyzed by NONMEM. A 2‐compartment pharmacokinetic model and a pharmacodynamic sigmoid Emax model fit the data best, with volumes of distribution at central and peripheral compartments of 4.45 and 74.90 L, respectively, and systemic and intercompartmental clearances of 0.63 and 3.16 L/min, respectively. t1/2ke0 was 1.550 min. EC50 values were 0.526 and 0.554 μg/mL, and gamma values were 2.25 and 6.24 for BIS and OAA/S, respectively. The prediction probability between OAA/S and BIS was 0.8. The slopes of the curves suggest that BIS is a better monitor of depth of sedation and hypnosis, whereas OAA/S may be more useful for monitoring sleep versus wakefulness. These results should be interpreted within the context of short‐term etomidate infusion of less than 10 minutes.

Pharmacokinetic Characteristics of Bolus‐Administered Mannitol in Patients Undergoing Elective Craniotomy

To better understand mannitol pharmacokinetics, the authors constructed and compared population models for high‐ versus low‐dose bolus infusions in humans. Patients (aged 18–75, American Society of Anesthesiologists physical status 1–3) scheduled for elective craniotomy with an anticipated need for intraoperative mannitol were randomly assigned to receive either 0.5 (n = 10) or 1.0 (n = 12) g/kg of 20% mannitol over 15 minutes. Serial blood samples were collected at the predetermined intervals over 12 hours. Plasma mannitol concentrations were measured by gas chromatography and subjected to pharmacokinetic analysis; a 3‐compartment model best described mannitol disposition characteristics. Weight and dose were the important covariates for rapid peripheral volume of distribution (V2) and central clearance (CL1), respectively. Estimated population means were 2.80, 8.86, and 12.0 L for central (V1), rapid (V2), and slow (V3) volumes of distribution, respectively. Clearances of the central compartments (CL1) were 0.07 versus 0.04 L/min in the high‐ versus low‐dose group, respectively. Thus, mannitol kinetics can be considered as nonlinear. Clearances of the rapid peripheral (CL2) and slow peripheral compartments (CL3) were identical (2.07 and 0.16 L/min) in both. The current weight‐based dosing guidelines yielded greater than expected plasma drug concentrations in obese patients.

361: PRECISION OF AN INTRAVASCULAR TEMPERATURE MANAGEMENT SYSTEM IN PCAS VICTIMS

Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) hours after ROSC. Secondary outcomes included association between vasopressor use, recurrent CAs and survival to discharge. Results: Of the 501 patients screened, 58 were included in the analysis of which only 10 patients received epinephrine. Average age was 62 ± 17 years, and 50% were female. When adjusted for confounders, epinephrine was not associated with reduced CA recurrence (OR 0.37, 95%CI 0.03-4.9, p=0.450). Vasopressor use also was not associated with reduced CA recurrence, however AV nodal blockers were associated with reduced recurrence (OR 0.08, 95%CI 0.01-0.81, p=0.033) and anti-arrhythmics were associated with an increased recurrence (OR 13.1, 95%CI 1.38-124.10, p=0.025). Only use of antiarrhythmics was associated with reduced survival to discharge (OR 0.08, 95%CI 0.010.99, p=0.047). Conclusions: Epinephrine use after CA is not associated with recurrent CA, and use of any agent to achieve MAP goals may be reasonable. The adjusted analysis revealed that use of antiarrhythmic and AV nodal blocking agents after initial CA may impact outcomes, and thus warrants prospective investigation.

Efficacy of Bedside Learning in Emergency and Critical Care Medicine for Undergraduate Students

【背景】山口大学の救急医学卒前教育は侵襲学と重症患者管理学を中心に行われてきた．【目的】救急医学の臨床実習で他の講座の臨床実習では習得しにくい知識や考え方をどのように習得しているか明らかにする．【対象】平成17年５月から平成18年10月に救急医学の臨床実習［ポリクリニック（ポリクリ）あるいはクリニカル・クラークシップ（クリクラ）］を受けた医学部５年生と６年生159人．【方法】１）臨床実習開始時に各講義担当者が作成したプール問題から毎回異なる試験（プレテスト）を行い，２週間後の終了時に同問題の試験（ポストテスト）を行い，その点数の変化を調べた（10点満点）．２）前半に救急を回るグループ（前期グループ）と他科の臨床実習を先に終了したグループ（後期グループ）とでプレテストの成績を比較した．３）同時期に臨床実習に参加したポリクリとクリクラの学生間でプレテストの点数を比較した．４）プレテストで特に正解の得られにくい問題を検討した．【結果】プレテストの点数は6.2±1.4（平均±標準偏差），ポストテストの点数は7.8±1.3で，有意にポストテストの点数が高かった（86名，p<0.001）．前期グループ（36名）の点数（6.1±1.5）と後期グループ（41名）の点数（6.3±1.3）に有意差はなかった．ポリクリ学生（34名）の点数（5.5±1.7）とクリクラ学生（39名）の点数（6.1±1.4）に有意差はなかった．プレテストで正解の得られにくかった問題は，外傷の初期評価と治療，ショックの治療に関する問題であった．【結語】救急医学の臨床実習は外傷，ショックなどの他の講座で教えることの少ない領域を含んでおり卒前教育に不可欠である．学生は２週間の臨床実習で救急医学に関する知識や考え方を習得していた．