使用體外膜氧合術(ECMO)的成人其萬古黴素(vancomycin)藥品動態學及劑量學研究

Abstract

目的： 體外膜氧合術(extracorporeal membrane oxygenation、ECMO)主要是用在預期性可恢復的心肺衰竭病人。由於多重抗藥性的金黃色葡萄球菌(MRSA)的感染日益增加，vancomycin經常用在ECMO的病人作為感染的預防及治療。ECMO在使用時需要外加液體(priming volume)，而使用ECMO的病人其腎功能可能變差，加上vancomycin也會吸附在ECMO的管路上而造成損失。因此本研究的目的為研究ECMO在成人的使用是否會對vancomycin的藥品動態學(pharmacokinetics)產生影響，並進一步找出vancomycin在使用ECMO的成人及加護病房(intensive care unit、ICU)病人的給藥建議及峰濃度(Cpeak)的最適當抽血時間。 方法： 本研究收入ECMO及control兩組病人，每組各12位病人。ECMO組病人的收納條件為大於等於18歲使用vancomycin的ECMO病人，如果同時接受連續性靜脈取代療法(continuous renal replacement therapy、CRRT)、血液透析(hemodialysis、HD)及嚴重燒傷的病人（> 30-40 % BSA）則排除。Control組的收納及排除條件和ECMO組的病人相同，除了ECMO的使用之外，且將兩組的年齡、性別及腎功能配對(match)，使兩組病人在這些因子的分佈相似。 Vancomycin的給法方面，可選擇給予15 mg/kg的起始劑量，維持劑量依Rodvold法給予，如果病人腎功能正常(CLCr ≥ 50 mL/min)也可給予500 mg q6h或1000 mg q12h的維持劑量。在第四劑（或更多劑）給藥後開始抽取病人血中vancomycin濃度，依據給藥間隔的不同，每個病人抽5-9個點的血中濃度，並利用non-compartment model來分析PK parameters。 利用Sawchuk and Zaske’s method所得到的PK parameters和Non-compartment model 得到的PK parameters的相關性來決定Cpeak的最適當抽血時間。 結果及討論： ECMO及control兩組的k ：0.088 ± 0.055 vs. 0.125 ± 0.096 hr-1、t1/2：11.13 ± 9.08 vs. 10.15 ± 9.08 hr、CL：1.18 ± 0.71 vs. 1.45 ± 0.82 mL/min/kg及Vss：0.84 ± 0.24 vs. 0.83 ± 0.30 L/kg，並沒有統計上顯著的差異。Priming volume對於vancomycin Vd的影響並沒有臨床上的意義，而在使用ECMO的病人，其腎臟灌流會減少而導致CLvancomycin的減少，t1/2的增加。將ECMO分為離心式及滾輪式幫浦來分析，兩種幫浦的藥品動態學和各別的control組相比結果同上。比較兩種血液幫浦，使用滾輪式幫浦的病人其k顯著的較小（0.110 ± 0.057 vs. 0.049 ± 0.021, p=0.035）， t1/2顯著的較大（7.99 ± 3.88 vs. 16.62 ± 8.30, p=0.04。使用滾輪式幫浦的病人Vss也較大，然未達統計意義。 CLCr和CLvancomycin有顯著的線性關係，以全部病人的資料來分析可得到：CLvancomycin = 0.019*CLCr – 0.18 (r=0.73,R2= 0.53,p <0.001)，而將兩組病人分開分析，在control組的病人(r = 0.78)其線性關係較ECMO組的病人(r = 0.61)要好。 Vancomycin在ICU病人(CLCr ≥ 40 mL/min/1.73m2)的使用，建議以15 mg/kg給予病人起始劑量，並以maintenance dose (mg/kg/24hr) = 0.5472*CLCr (mL/min/1.73m2) – 5.184估算病人的維持劑量，以CLCr (mL/min/1.73m2)來決定病人的τ (hrs)，CLCr ≥ 100、τ = 6，80 ≤ CLCr ≤ 99、τ =8、40 ≤ CLCr ≤ 79、τ =12。或是以CL(mL/min/kg) = 0.019*CLCr(mL/min/1.73m2) – 0.18；k (hr-1) = 0.0017*CLCr (mL/min/1.73m2) – 0.029、Vd (L/kg)= CL*60/(k*1000) 來預測ICU病人的PK parameters，並藉由此預測的PK parameters估算病人所需的劑量。 建議在給vancomycin至少四個劑量後對病人進行血中濃度監測，由於在ECMO的病人其CLCr和CLvancomycin的線性相關性較差，因此對於使用ECMO的病人可以更早做濃度監測，之後藉由濃度監測所獲得的PK parameters來調整vancomycin的劑量。不管有無使用ECMO的病人皆建議以藥品輸注結束後2小時的血中濃度作為Cpeak。如此可使SZ method得到的PK parameters有較好的預測性。之後根據SZ method所獲得的PK parameters來調整各個病人的vancomycin劑量以達到較適當的治療。 關鍵字：萬古黴素、藥品動態學(藥動學)、體外膜氧合術、重症照護、劑量學、成人

Aims: Extracoporeal membrane oxygenation (ECMO) is indicated for patients with reversible cardiopulmonary failure. Due to the increasing infection rate of methicillin-resistant staphylococcus aureus (MRSA), vancomycin is often empirically used in patients receiving ECMO. Patients on ECMO required priming fluid (centrifugal pump: 850 mL, roller pump: 2000 mL). Studies showed that renal function in patients receiving ECMO altered transiently and vancomycin might be sequestrated by the circuit of ECMO. The objective of this study was to understand the effects of ECMO on pharmacokinetics of vancomycin in adult patients, so as to establish a dosing guildline for patients on ECMO and in ICU and decide the appropriate sampling time for monitoring peak concentration. Methods: This is a control study. Both ECMO and control groups recruited 12 patients. The inclusion criteria for ECMO group were patients greater than or equaled to 18 years-old and received ECMO and vancomycin simultaneously. Those who were on continuous renal replacement therapy (CRRT) or hemodialysis, or having severe burn (involved 30-40% body surface area) were excluded. The inclusion and exclusion criteria for control group were the same as ECMO group, except that they did not use ECMO. Control group was matched with ECMO group by age, sex and renal function. Vancomycin therapy might be initiated with or without a loading dose (LD) of 15 mg/kg. The maintenance dose was determined by Rodvold method. In patients with a creatinine clearance (CLCr) ≥ 50 mL/min, 500 mg q6h and 1000 mg q12h could be given. Serum vancomycin concentrations were determined after at least the fourth dose. Five to nine samples were taken depending on dosing interval and pharmacokinetic (PK) parameters were determined by fitting the data to non-compartment model. The PK parameters determined by Sawchuk and Zaske’s method were compared with those determined by non-compartment model. Through this comparison, the most appropriate sampling time for routine monitor of peak concentration was determined. Results and Discussion: The elimination rate constant (k), half life (t1/2), clearance (CLvancomycin) and volume distribution at steady state (Vss) of ECMO and control group were 0.088 ± 0.055 vs. 0.125 ± 0.096 hr-1, 11.13 ± 9.08 vs. 10.15 ± 9.08 hr, 1.18 ± 0.71 vs. 1.45 ± 0.82 mL/min/kg, 0.84 ± 0.24 vs. 0.83 ± 0.30 L/kg, respectively, and there was no statistically significant difference between the 2 groups. Priming volume of ECMO did not have important influence on Vss of ECMO. Reducing renal perfusion could reduce CLvancomycin and make t1/2 longer. After stratifing ECMO group according to centrifugal and roller pump, there was a significant difference in k (0.110 ± 0.057 vs. 0.049 ± 0.021, p=0.035) and t1/2 (7.99 ± 3.88 vs. 16.62 ± 8.30, p=0.04). Although Vss tended to be greater in patients using roller pump, there were no statistically significant differences between these 2 groups. There were also no statistically differences in PK parameters between the individual groups and their control. CLCr was a good predictor of CLvancomycin. Linear regression using all patient’s data showed that CLvancomycin = 0.019*CLCr – 0.18 (r=0.73, R2= 0.53, p <0.001). The linear relationship was more significant in control group (r = 0.78) than in ECMO group (r = 0.61). In National Taiwan University Hospital, Rodvold method was used to calculate empirical vancomycin maintenance dose. Due to the poor predictivity of the method, we recommended that a 15 mg/kg loading dose be given and an empirical maintenance dose determined by equation: maintenance dose (mg/kg/24hr) = 0.5472*CLCr (mL/min/1.73m2) – 5.184 developed according to CLCr and CLvancomycin in all patients in this study. The dosing intervals were determined according to CLCr (mL/min/1.73m2) : 6 hrs for CLCr ≥ 100; 8 hrs for 80 ≤ CLCr ≤ 99; 12 hrs for 40 ≤ CLCr ≤ 79. This equation could only be applied to patients with a CLCr greater than 40 mL/min/1.73m2. From this study, PK parameters might be estimated by CL(mL/min/kg) = 0.019*CLCr(mL/min/1.73m2) – 0.18、k(hr-1) = 0.0017*CLCr(mL/min/1.73m2) – 0.029、Vd(L/kg) = CL*60/(k*1000) and used these PK parameters to determine appropriate dose for individual patients. . After empirical dosing of vancomycin, pharmacokinetic monitoring should be performed after at least four doses, especially for patients receiving ECMO. The most appropriate sampling time for peak concentration was 2 hours after completion of infusion of vancomycin. After obtaining peak and trough concentration, Sawchuk and Zaske’s method provides a good estimate of PK parameters for adjusting vancomycin dosage. Key words：vancomycin、pharmacokinetics (PK)、extracoporeal membrane oxygenation (ECMO)、critical care、dosage、adult