vancomycin在使用持續性低效率血液透析過濾(SLEDD-f) 的病人之藥品動態學與劑量學研究

Abstract

目的： 持續型低效率血液透析過濾(sustained low efficiency daily diafiltration，SLEDD-f)結合了間斷型血液透析(intermittent hemodialysis，IHD)與連續型腎臟替代療法(continuous renal replacement therapy，CRRT)的技術與優點，主要用在加護病房內併發腎衰竭的重症病人。而外科加護病房的病人常有傷口及導管，增加革蘭氏陽性菌感染的機會。在多重抗藥性金黃色葡萄球菌(methiciilin-resistant Staphylococcus aureus，MRSA)造成的感染，vancomycin是首選的用藥。SLEDD-f使用高穿透性透析膜(high-flux dialyzer membrane)，可能導致vancomycin被移除而使血中濃度不足。另外，vancomycin可能被透析膜吸附，增加一次SLEDD-f期間移除的量。因此，本研究的目的在觀察觀察以SLEDD-f做腎臟替代療法的病人，vancomycin的藥品動態學參數，同時評估一次SLEDD-f療程中，有多少比例的vancomycin會被移除，以及透過體外試驗，評估有多少量的vancomycin會被透析膜吸附。藉由以上的資料，找出在這群病人的適當給藥劑量。 方法： 本研究收入17位病人。收納條件為18歲以上，因任何原因導致腎衰竭而須使用SLEDD-f作為腎臟替代療法，且同時使用vancomycin做為感染的預防或治療之患者。vancomycin的給藥劑量與間隔由醫師或藥師決定，在起始劑量或第四劑以上後開始抽血。vancomyicn的給藥時間為SLEDD-f開始前15個小時，靜脈輸注2小時。抽血的時間為靜脈輸注結束後0、1、2、4、9個小時，SLEDD-f開始後0、2、4小時、SLEDD-f一結束時、SLEDD-f結束後1、2、3小時，共抽12個時間點的血，以FPIA測量濃度。 SLEDD-f使用的透析膜材質為helixone，表面積為1.4 m2。血液流速(QB) 200 mL/min，透析液流速(QD) 300 mL/min，超過濾速率(UFR)與補充液流速依病人所需的脫水量設定，透析時間為8小時。每2個小時收集透析期間的流出液，評估一次SLEDD-f療程所移除vancomycin的量。利用藥品動態學軟體WinNonlin中的Non-compartment模式來分析vancomycin的藥品動態學。

結果及討論： 本研究共收納16位男性，1位女性，共有10位病人被排除，排除的原因如下：1 位由於血行動力學不穩定更改腎臟替代療法，1位由於簽署放棄急救同意書而取消腎臟替代療程，1位由於腎功能恢復而取消腎臟替代療程，1位由於病危自動出院而取消腎臟替代療程，1位於簽署受試者同意書後決定退出試驗，另外2位分別因SLEDD-f開始前後的血中濃度收集不完全而無法分析其藥品動態學參數。但僅有9位男性、1位女性納入數據分析。這10位病人年齡介於33-73歲，平均55.7±12.6歲，體重介於54.2-90.6 kg，平均71.2±12.0 kg。以SLEDD-f做為腎臟替代療法的原因，8位為急性腎衰竭(acute renal failure，ARF)，4位為末期腎病(end stage renal disease，ESRD)。vancomycin的劑量介於500-1000 mg，平均8.7±2.8 mg/kg。1位病人在速效劑量後進行抽血，11位病人在第四劑給藥以上進行抽血。SLEDD-f設定方面，UFR平均2247.9±288.6 mL/hr，補充液流速平均1936.0±320.7 mL/hr。 8小時的SLEDD-f療程可移除455.7±90.7 mg的vancomycin (325.3-610.0 mg)，佔給藥劑量的78.0±18.1% (33.2-96.1%)。SLEDD-f前後血中濃度下降57.5±14.9%，若考慮反彈現象(rebound)，則下降47.2±12.2%。rebound發生的時間介於SLEDD-f結束後1-3個小時，rebound的百分比介於透析結束時血中濃度的4.6-28.8%。SLEDD-f一開始時，血中濃度平均16.5±4.2 mg/L，SLEDD-f一結束時，血中濃度平均6.9±2.5 mg/L，低於建議的8 mg/L以上。 SLEDD-f前後藥品動態學參數的差異：排除速率常數(elimination rate constant，k)：0.01 ± 0.01 vs. 0.11 ± 0.06 hr-1、半衰期(half-life，t1/2)：583.8± 1037.8 (43.0-3465.0) vs. 7.7 ± 3.0 (2.9-11.5) hr及廓清率(clearance，CL)：0.05± 0.07(0.00-0.22) vs. 1.5± 0.4 (0.8-2.2) mL/min/kg。體外試驗的結果顯示，在8小時內，全血溶液中的vancomycin濃度的變化均落在FPIA測量的誤差範圍內，顯示透析膜吸附vancomycin導致的濃度下降，低於FPIA偵測的範圍，因此在設計給藥劑量時，可將此部分忽略。 在以SLEDD-f作為腎臟替代療法，同時需以vancomycin做為感染的治療或預防的病人，vancomycin應在透析之後給予，給藥的頻率應依據SLEDD-f頻率調整。在未曾給藥的病人，可給予15-20 mg/kg的速效劑量，10-12 mg/kg的維持劑量。

Background: Sustained slow low efficiency daily diafiltration (SLEDD-f) is a conceptual and technical hybridization of continuous renal replacement therapy (CRRT) and intermittent hemodialysis (IHD). It is an increasingly used modality of renal replacement therapy for patients in intensive care unit (ICU) with acute or chornic renal failure. Vancomycin, a member of glycopeptides antibiotics, is commonly used in ICU patients for prevent or treat methicillin-resistant Staphylococcus aureas (MRSA) infection. Since the pore size of high-flux dialyzer membrane is much larger than vancomycin, post dialysis supplement dose may be required. Several studies have demonstrated that intermittent hemodilaysis with high-flux dialyzer membrane removed significant amount of vancomycin, and once weekly dose is not appropriate. However, until now, there is no relavent study on the effect of SLEDD-f on vancomycin pharmacokinetics. Therefore, the purpose of this study is to understand the pharmacokinetic of vancomycin in these patients and the amount of vancomycin removed during one course of 8-hr SLEDD-f, in order to determine an appropriate dose regimen for patients requiring SLEDD-f as renal replacement therapy. Patients and methods: Patients who used SLEDD-f as renal replacement therapy and also vancomycin for infection control or prevention were included. Vancomycin dose regimen was decided by ICU doctor or pharmacist. Serum concentration was measured after lodiang dose or the 4th doses. Vancomyicn infusion was started 15 hours before SLEDD-f start. Blood samples were drawn from arterial line at 0, 1, 2, 5, 9 hours after completion of vancomycin infusion, predialysis, 2, 4 hours after dialysis started, at the end of dialysis, 1, 2 and 3 hours after completion of dialysis. Serum vancomycin concentration was measured with fluorescence polarization immunoassay (FPIA). A high-flux helixone membrane (F60X, Fresenius) with surface area of 1.4 m2 was used for SLEDD-f. Blood flow was 200 mL/min, and dialysate flow was 300 mL/min. Ultrafiltration rate was determined by the doctor. Dialysis duration was 8 hours. Effluent (the combination of dialysate and ultrafiltrate) was collected every two hours to measure the amount of vancomycin removed during one course of SLEDD-f. Pharmacokinetic parameters were analyzed with WinNonlin professional version 4.1. Results and discussion: 17 patients were included into this study; 7 patients drop out for unstable hemodynamics (1), sign DNR (do not resuscitation) (1), renal function recovery (1), against advice discharge (1), withdraw from the study and uncomplete blood samples collection (2); only 9 males and 1 female were included for data analysis. They aged from 33-73 years, (mean±standard deviation: 55.7±12.6). The average body weight was 71.2±12.0 kg. 8 patients received SLEDD-f because of acute renal failure (ARF) and 4 for end-stage renal disease (ESRD). Vancomycin dose ranged from 500-1000 mg (mean±standard deviation: 8.7±2.8 mg/kg). Blood samples were obtained after loading dose for 1 patient and maintenance dose for 9 patients. During 8 hours of SLEDD-f, 455.7±90.7 mg of vancomycin was removed, accounted for about 78.0±18.1% (33.2-96.1%) of vancomycin dose infused. Serum concentraiton decreased by 57.5±14.9% after 8 hour of SLEDD-f, and taking into consideration of the post-dialysis rebound, the concentration decreased by 47.2±12.2%. Time of rebound ranged between 1-3 hours, and the percentage of rebond ranged from 4.6-28.8% of post dialysis concentraiton. Serum concentraiotn before SLEDD-f started was 16.5±4.2 mg/L, and concentration at the end of SLEDD-f was 6.9±2.5 mg/L, lower than the therapeutic level defined in this study (> 8 mg/L). The pharmacokinetic parameters before SLEDD-f started and during SLEDD- f were quite different: elimination rate constatnt (k) before and during dialysis, 0.01 ± 0.01 vs. 0.11 ± 0.06 hr-1, half-life (t1/2), 583.8± 1037.8 (43.0-3465.0) vs. 7.7 ± 3.0 (2.9-11.5) hr. Total clearance (CLT) before dialysis was 0.05± 0.07(0.00-0.22) mL/min/kg. Dialysis clearance (dialysance, CLD) was 1.5± 0.4 (0.8-2.2) mL/min/kg. In vitro experiment showed that during 8 hour of study, the absolute amount of vancomyicn adsorbed on the dialyzer membrane was minimal, so it can be ignored in clinical practice. Conclusion: Significant amount of vancomycin is removed during SLEDD-f, thus, post dialysis supplement dose is recommended. For patients requiring SLEDD-f as renal replacement therapy, a 15-20 mg/kg loading dose, followed by a 10-12 mg/kg maintenance dose given at the end of each dialysis is an acceptable dose regimen.