Mand'ák J, Pojar M, Maláková J, Lonsk V, Palicka V, Zivný P
Department of Cardiac Surgery, Charles University, Faculty of Medicine and University Hospital, Hradec Kralove, Czech Republic.
Perfusion. 2007 Mar;22(2):129-36. doi: 10.1177/0267659107080116.
Wound and mediastinal infections are still very serious complications of open-heart surgery, in spite of the use of prophylactic antibiotics. The use of cardiopulmonary bypass (CPB) is associated with profound physiological changes affecting the pharmacokinetic behaviour of antibiotics. The aim of this pilot study was to monitor the tissue concentrations of cephuroxime (prophylactic antibiotic) in skeletal muscle during cardiac surgery using CPB by interstitial microdialysis. These concentrations were compared with plasma concentrations of cephuroxime.
Nine adult patients operated on using CPB were enrolled in this study. Cephuroxime was used as a prophylactic antibiotic (1st dose - 3 g of cefuroxime i.v. with anesthesia induction, 2nd dose - 1.5 g i.v. after CPB with protamine sulphate, 3rd dose - 1.5 g i.v. 8 hours after the surgery). Interstitial microdialysis was performed by probe CMA 60 (CMA Microdialysis AB, Sweden) inserted into the patient's deltoid muscle. Concentrations of cephuroxime in dialysates and in plasma were determined by the modified fluid chromatography method. The unbound cephuroxime fraction in plasma was obtained by using an ultrafiltration method. Samples of dialysates were collected at the following intervals: before CPB, each 30 minutes of CPB, at the end of CPB. Samples of blood were collected at these intervals: incision, start of CPB, each 30 minutes of CPB, at the end of CPB, at the end of surgery. Concentrations of cephuroxime in tissue were corrected by in vivo recoveries of the microdialysis probes.
Plasma concentrations of cephuroxime were 163.5 +/- 40.1, 79.3 +/- 17.4, 73.7 +/- 16.8, 66.1 +/- 18.3, 57.0 +/- 10.9, 120.7 +/- 29.9 (mg L(-1)) and concentrations of free plasma fraction of cephuroxime were 119.5 +/- 35.2, 67.8 +/- 15.5, 66.0 +/- 12.5, 54.8 +/- 12.2, 49.6 +/- 9.8, 102.6 +/-26.0 (mg L(-1)). The concentrations of cephuroxime in dialysates were 44.3 +/- 15.7, 36.1 +/- 11.6, 31.9 +/- 9.3, 34.6 +/- 12.3, 27.6 +/-12.9, 56.7 +/- 17.6 (mg L(-1)). The mean in vivo recovery of cephuroxime in this study was 30%. Corrected concentrations (calculated by in vivo recovery) of cephuroxime in skeletal muscle were 148, 120, 106, 115, 92, 189 (mg L(-l)).
Our preliminary results show that CPB can modify the time course of cephuroxime plasma and tissue concentrations. A decrease in plasma drug concentrations occurred at the start of CPB and lasted until CPB ended. An increase in plasma concentrations corresponds to the second drug dose after CPB. The concentrations of cephuroxime in skeletal muscle (corrected by recovery) during CPB are higher than plasma concentrations. It is influenced by important changes during CPB; closely associated with hemodilution, a shift of intravascular volume, solutes and albumin to the extravascular space and inconstant protein binding of cephuroxime during operation.
尽管使用了预防性抗生素，但伤口感染和纵隔感染仍是心脏直视手术非常严重的并发症。体外循环（CPB）的使用会引起深刻的生理变化，影响抗生素的药代动力学行为。本初步研究的目的是通过组织间微透析监测CPB心脏手术期间头孢呋辛（预防性抗生素）在骨骼肌中的组织浓度，并将这些浓度与头孢呋辛的血浆浓度进行比较。
本研究纳入了9例接受CPB手术的成年患者。头孢呋辛用作预防性抗生素（第1剂 - 麻醉诱导时静脉注射3g头孢呋辛，第2剂 - CPB后用硫酸鱼精蛋白时静脉注射1.5g，第3剂 - 术后8小时静脉注射1.5g）。通过插入患者三角肌的CMA 60探针（瑞典CMA微透析公司）进行组织间微透析。采用改良液相色谱法测定透析液和血浆中头孢呋辛的浓度。通过超滤法获得血浆中未结合的头孢呋辛分数。在以下时间间隔收集透析液样本：CPB前、CPB期间每30分钟、CPB结束时。在这些时间间隔收集血液样本：切口时、CPB开始时、CPB期间每30分钟、CPB结束时、手术结束时。组织中头孢呋辛的浓度通过微透析探针的体内回收率进行校正。
头孢呋辛的血浆浓度分别为163.5±40.1、79.3±17.4、73.7±16.8、66.1±18.3、57.0±10.9、120.7±29.9（mg/L），头孢呋辛血浆游离分数的浓度分别为119.5±35.2、67.8±15.5、66.0±12.5、54.8±12.2、49.6±9.8、102.6±26.0（mg/L）。透析液中头孢呋辛的浓度分别为44.3±15.7、36.1±11.6、31.9±9.3、34.6±12.3、27.6±12.9、56.7±17.6（mg/L）。本研究中头孢呋辛的平均体内回收率为30%。骨骼肌中头孢呋辛的校正浓度（通过体内回收率计算）分别为148、120、106、115、92、189（mg/L）。
我们的初步结果表明，CPB可改变头孢呋辛血浆和组织浓度的时间进程。CPB开始时血浆药物浓度降低，并持续至CPB结束。血浆浓度升高与CPB后第二次给药相对应。CPB期间骨骼肌中头孢呋辛的浓度（经回收率校正）高于血浆浓度。这受到CPB期间重要变化的影响；与血液稀释、血管内容积、溶质和白蛋白向血管外间隙的转移以及手术期间头孢呋辛不恒定的蛋白结合密切相关。
