本文選題：超濾 + 體外循環(huán)��； 參考：《北京協(xié)和醫(yī)學(xué)院》2014年博士論文

【摘要】：研究總體思路： 體外循環(huán)技術(shù)使得心臟手術(shù)得到很大發(fā)展,但非生理性的血液轉(zhuǎn)流過程伴隨著潛在的危害�；颊哐号c體外循環(huán)管道異物表面接觸可引起炎性反應(yīng),導(dǎo)致毛細(xì)血管通透性增加。體外循環(huán)開始后,患者出現(xiàn)稀釋性的血紅蛋白降低及血清蛋白降低,導(dǎo)致炎性毛細(xì)血管滲漏,液體向組織間隙轉(zhuǎn)移,出現(xiàn)組織水腫及終末器官灌注不良。血液稀釋技術(shù)雖能增加體外循環(huán)期間組織灌注,允許在低流量甚至循環(huán)停止時使用深低溫保護(hù)器官免受缺血損傷,并且減少體外循環(huán)過程中對異體血的需求。過度的血液稀釋可能增加血容量,導(dǎo)致充血性心力衰竭或腎功能衰竭。 超濾作為體外循環(huán)中的一項(xiàng)常用技術(shù),1979年Darup等人報(bào)道了在體外循環(huán)中使用超濾技術(shù)。20世紀(jì)80年代,研究報(bào)道了體外循環(huán)中使用超濾可濾除體內(nèi)多余的水分,有改善患者術(shù)后的心功能、肺功能、神經(jīng)功能、減少輸血、減輕炎癥反應(yīng)等優(yōu)勢。超濾除了其改善患者生理狀態(tài)等優(yōu)勢的同時,研究報(bào)道了其可濾出各種藥物,如麻醉藥、阿片類藥物、肌松藥、抗生素等等。超濾對于體外循環(huán)中抗生素濃度的影響目前研究報(bào)道較少。心臟手術(shù)中由于體外循環(huán)轉(zhuǎn)流、低溫、血液稀釋等因素使機(jī)體對外源性感染源的抵抗力下降,在心臟手術(shù)中常規(guī)應(yīng)用抗生素預(yù)防感染成為外科醫(yī)生普遍接受的常規(guī)。在體外循環(huán)下內(nèi)環(huán)境發(fā)生極大的變化,各種抗生素的藥代動力學(xué)和藥效動力學(xué)亦隨之發(fā)生改變。抗生素的用藥策略在體外循環(huán)下的心臟手術(shù)中是否仍然合適是一個研究的熱點(diǎn)。體外循環(huán)中影響抗生素的因素包括血液稀釋、低溫、血流動力學(xué)改變、藥物代謝器官血液灌注的改變、藥物與體外循環(huán)管路的接觸以及超濾等等。本研究擬從模擬體外循環(huán)模型、小兒平衡超濾、及成人深低溫停循環(huán)選擇性腦灌注下兩種超濾策略幾個方面探討超濾在心臟手術(shù)中對抗生素及炎性因子的影響。為今后制定更合理的藥物使用策略提供依據(jù)。 第一部分本研究使用體外循環(huán)模擬管路模擬體外循環(huán)過程,排除了臨床研究中患者的個體差異、病情的差異及手術(shù)過程中的不可控因素,只關(guān)注于超濾技術(shù)對體外轉(zhuǎn)流過程中抗生素濃度的影響。實(shí)驗(yàn)中管路預(yù)充、排氣、降溫、體外循環(huán)、肝素的使用與臨床方案完全相同。分別從加藥口加入頭孢替安與頭孢美唑兩種抗生素。使用平衡超濾過程中在不同時間點(diǎn)留取血標(biāo)本及濾液標(biāo)本檢測抗生素濃度,方法為高壓液相技術(shù)。通過這一部分離體實(shí)驗(yàn),探索超濾技術(shù)是否可以濾除血漿中的抗生素,以及超濾過程中血漿抗生素濃度的變化,及影響因素。離體實(shí)驗(yàn)的結(jié)果可為進(jìn)一步臨床研究提供理論依據(jù)。 第二部分離體研究中證實(shí)了平衡超濾可呈劑量依賴性濾除血液中的抗生素。但臨床上各種因素復(fù)雜多變,在患兒個體差異、病情差異、術(shù)中狀況的差異下離體研究的結(jié)果是否可以在臨床研究中得到證實(shí)是本研究的重點(diǎn)。在嬰幼兒心臟手術(shù)中由于患兒體重小、血液稀釋嚴(yán)重,因而超濾技術(shù)廣泛應(yīng)用于濾除體內(nèi)多余的水分及炎性因子。但超濾對抗生素的影響尚無存爭議。本研究選取單純房間隔缺損及室間隔缺損矯治術(shù)的患兒,隨機(jī)分為平衡超濾組及非平衡超濾組,在超濾前、超濾后分別取血標(biāo)本進(jìn)行炎性因子及抗生素濃度檢測,并留取濾液標(biāo)本檢測炎性因子及抗生素濃度。本部分的目的是探索平衡超濾對兒科心臟手術(shù)中血漿炎性因子及抗生素濃度的影響,以及對術(shù)中血?dú)饧捌渌笜?biāo)的影響。 第三部分深低溫停循環(huán)下的主動脈弓置換手術(shù)由于患者病情重、手術(shù)復(fù)雜、體外循環(huán)時間長及深低溫停循環(huán)的打擊,患者發(fā)生炎性反應(yīng)激活、缺血再灌注損傷及酸中毒。深低溫停循環(huán)手術(shù)中常需使用大劑量超濾來調(diào)節(jié)改善內(nèi)環(huán)境,濾除多余水分及炎性因子。美國胸外科學(xué)會指南對心臟外科手術(shù)中的預(yù)防性應(yīng)用抗生素的劑量和間隔給了推薦性意見,然而未納入主動脈置換手術(shù)及心臟移植手術(shù)。而深低溫停循環(huán)手術(shù)中抗生素的藥代動力學(xué)及藥效動力學(xué)缺乏研究證據(jù)。深低溫停循環(huán)下的主動脈弓置換手術(shù)中超濾對于抗生素的影響文獻(xiàn)報(bào)道較少。前期離體及小兒心臟手術(shù)中的發(fā)現(xiàn)是否能在成人深低溫停循環(huán)的情況下得以證實(shí)是第三部分的重點(diǎn)。本研究中分別采用常規(guī)超濾和體外循環(huán)過程中全程超濾兩種不同的超濾管理技術(shù),探索超濾技術(shù)對炎性因子及抗生素濃度的影響。 第一部分離體模型下研究平衡超濾技術(shù)對抗生素濃度的影響 背景與目的心外科手術(shù)常規(guī)預(yù)防性使用抗生素防止圍術(shù)期感染。然而體外循環(huán)對內(nèi)環(huán)境產(chǎn)生的極大干擾,使得抗生素的分布和代謝發(fā)生變化,其中平衡超濾技術(shù)對體內(nèi)抗生素濃度的影響尚不清楚。因此本研究擬在體外模擬模型下,研究平衡超濾技術(shù)是否能對圍術(shù)期血漿抗生素濃度產(chǎn)生影響。 方法建立體外循環(huán)體外模擬環(huán)路,包括回流室、膜肺、嬰兒動脈濾器。血液濃縮器安裝在動脈濾器和儲血室之間。新鮮全血與乳酸林格氏液預(yù)充體外循環(huán)管路,并保持最終紅細(xì)胞壓積在24-28%。頭孢替安(320mg)和頭孢咪唑(160mg)一次性加入循環(huán)管路中。30分鐘體外循環(huán)后開始零平衡超濾,通過Hoffman鉗維持動脈管路壓力約100mmHg。超濾速度控制在12mL/min。使用勃脈力A持續(xù)滴入管路維持紅細(xì)胞壓積。平衡超濾過程中每5分鐘采取血漿和超濾液標(biāo)本,使用高壓液相色譜檢測技術(shù)分別動態(tài)監(jiān)測頭孢替安和頭孢美唑的藥物濃度。 結(jié)果頭孢替安和頭孢美唑在不同時點(diǎn)的超濾液中均可檢測到。血漿中抗生素的濃度隨著超濾液量的增加呈線性降低。超濾結(jié)束時,血漿頭孢替安濃度為104.96±44.36μg/ml,大約為初始濃度的44.38%±7.42%(初始濃度238.95±101.12μg/ml)(p0.001)；而血漿頭孢美唑濃度降低至25.76±14.78μg/ml,約為初始濃度的49.69%±10.49%(初始濃度51.49±28.03μg/ml)(p0.001)；超濾液中頭孢替安的含量為總給藥量的27.16%±12.17%,頭孢美唑的含量占總給藥量的7.74%±4.17%。結(jié)論平衡超濾能夠?yàn)V出血液中的抗生素,其濾出量與蛋白結(jié)合率顯著相關(guān)；超濾技術(shù)對于圍術(shù)期抗生素的血藥濃度具有顯著影響,因而術(shù)中抗生素的應(yīng)用策略應(yīng)考慮此影響因素。 第二部分嬰幼兒心臟手術(shù)中平衡超濾對炎性因子及抗生素濃度的影響 背景與目的體外循環(huán)管路預(yù)充液對于小兒來說會造成比較嚴(yán)重的血液稀釋,因而超濾技術(shù)在兒科心臟手術(shù)中成為常規(guī)應(yīng)用以濾除體內(nèi)多余水分以及體外循環(huán)預(yù)充液,及減少炎性因子。然而由于超濾對抗生素也有濾除作用,且兒童心臟手術(shù)中超濾對抗生素的濾除作用研究報(bào)道較少。為證實(shí)第一部分離體研究的結(jié)果,本部分研究探討平衡超濾對行體外循環(huán)的嬰幼兒體內(nèi)炎性因子及抗生素血藥濃度的影響,為臨床抗生素的指導(dǎo)用藥提供理論依據(jù)。 方法選取2012年7月-2013年5月期間于本院心臟外科接受房間隔缺損、室間隔缺損矯治手術(shù)的先天性心臟病患兒,心功能Ⅰ-Ⅱ,入選患者隨機(jī)分成平衡超濾組(Balanced Ultrafiltration, BU F)和非平衡超濾組(non-Balanced Ultrafiltration, NBUF),于胸部切皮前30分鐘通過靜脈給予頭孢美唑0.03mg/kg。分別于體外循環(huán)轉(zhuǎn)流開始前(t1),超濾前(t2),體外循環(huán)結(jié)束后5分鐘(t3),抽取t1、t2、t3時刻動脈血測定血?dú)饧澳z體滲透壓,并留取血液和超濾液標(biāo)本。使用酶聯(lián)免疫吸附法(ELISA)檢測炎性介質(zhì)指標(biāo)包括白細(xì)胞介素(Interleukin, IL)-1、IL-6、IL-10、中性粒細(xì)胞彈性蛋白酶(Neutrophil Elastase, NE)以及腫瘤壞死因子(Tumor Necrosis Factor, TNF)-a,使用高壓液相色譜檢測技術(shù)檢測抗生素濃度。 結(jié)果停體外循環(huán)后,IL-1、IL-6、IL-10、TNF-α及NE的血漿濃度較超濾前顯著升高(p0.05)。IL-1、IL-6、NE停體外循環(huán)時兩組之間的血漿濃度無顯著差別(p0.05)。IL-10、TNF-α停體外循環(huán)時血漿濃度在BUF組低于NBUF組(p0.05)。濾液中可檢測到所有這幾種炎性因子的存在,各種炎癥介質(zhì)在濾液中的濃度在兩組之間未見差別(p0.05)。BUF組,血漿頭孢美唑由超濾前初始濃度72.03±23.77μg/ml降低至停止體外循環(huán)時40.04±12.38μg/ml(53.47%±13.60%)。在NBUF組,停止體外循環(huán)時血漿頭孢美唑由超濾前的初始濃度80.04±30.30μg/ml降低至58.02±18.86μg/ml(69.11%±9.0%)。兩組間血漿抗生素濃度的減少量之間的差別有統(tǒng)計(jì)學(xué)意義(p=0.018)=BUF組超濾液中頭孢美唑總含量占總給藥量的7.25%±3.83%,NBUF組超濾液中頭孢美唑總含量占總給藥量的2.83%±1.71%,兩組之間有顯著差異(p=0.004)。 結(jié)論平衡超濾可選擇性濾除血漿中的炎癥介質(zhì)。體外循環(huán)中超濾的使用確切可以濾除血液中的抗生素,且平衡超濾的使用增加了抗生素在濾液中的濾出量。 第三部分全程超濾對深低溫停循環(huán)下主動脈弓置換手術(shù)中血漿炎性因子及抗生素濃度的影響 背景與目的深低溫停循環(huán)下的主動脈弓置換手術(shù)中,由于手術(shù)時間長并且需要經(jīng)歷低溫及缺血等嚴(yán)重的打擊,從而引起機(jī)體酸堿平衡紊亂及氧化應(yīng)激損傷,并產(chǎn)生大量炎性因子。因而常規(guī)使用超濾技術(shù)濾除循環(huán)內(nèi)多余水分,調(diào)節(jié)電解質(zhì)及酸堿平衡,濾除炎性因子。然而,由于超濾可濾除抗生素,且與超濾的劑量呈正相關(guān),因此在深低溫停循環(huán)手術(shù)中大量的超濾可能會對抗生素血藥濃度產(chǎn)生影響。因而本實(shí)驗(yàn)擬研究深低溫停循環(huán)下不同超濾技術(shù)對術(shù)中抗生素濃度、炎癥反應(yīng)程度以及術(shù)后感染等臨床指標(biāo)的影響。 方法納入需深低溫停循環(huán)下行主動脈弓置換手術(shù)的患者,隨機(jī)分為兩組：全程組(主動脈阻斷10分鐘后開始全程超濾至停止體外循環(huán)),復(fù)溫組(開始復(fù)溫時開始超濾至停止體外循環(huán))。切皮前靜脈給予頭孢呋辛1.5g,體外循環(huán)轉(zhuǎn)流2小時追加0.75g。分別于體外循環(huán)轉(zhuǎn)流開始升主動脈阻斷后10分鐘(T1)、體外循環(huán)轉(zhuǎn)流2小時(T2)、停體外循環(huán)時(T3),及停體外循環(huán)后4小時(T4)抽取動脈血4ml。體外循環(huán)結(jié)束時收集超濾液標(biāo)本5ml,記錄超濾液總量。使用高壓液相色譜法檢測抗生素濃度。使用酶聯(lián)免疫吸附法(ELISA)檢測炎性介質(zhì)指標(biāo)包括白細(xì)胞介素(IL)-1、IL-6、IL-10、中性粒細(xì)胞彈性蛋白酶(NE)以及腫瘤壞死因子(TNF)-α。 結(jié)果全程組血漿頭孢呋辛濃度從體外循環(huán)開始時94.23±30.21μg/ml,下降到體外循環(huán)2個小時的74.69±21.90μg/ml(下降17.86±11.52%)(p0.05)。復(fù)溫組血漿頭孢呋辛濃度從體外循環(huán)開始時85.63±32.76μg/ml,下降到體外循環(huán)2小時的73.68±22.86μg/ml(下降12.16%±6.85%)(p0.05),兩組之間差異無統(tǒng)計(jì)學(xué)意義(p=0.083)。停體外循環(huán)后血漿頭孢呋辛濃度全程組106.90±61.34μg/ml,復(fù)溫組129.32±63.70μg/ml;停體外循環(huán)4個小時血漿頭孢呋辛濃度全程組152.75±98.30μg/mL,復(fù)溫組189.77±119.03μg/mL;兩組間無統(tǒng)計(jì)學(xué)差異(p0.05)。IL-1和TNF-α的血漿濃度在整個過程中變化不顯著(p0.05)。lL-6、IL-10及NE的血漿濃度在體外循環(huán)2小時的時候無顯著變化,而在停體外循環(huán)時顯著升高(p0.05)。IL-10血漿濃度從停體外循環(huán)時的319.03±67.51ng/L下降到停體外循環(huán)4小時的148.57±83.28ng/L(p0.05),IL-6及NE停體外循環(huán)4小時濃度未見顯著下降(p0.05)。但各個時點(diǎn)每種炎性因子的濃度在兩組間無顯著差異(p0.05)。 結(jié)論兩種超濾方法對血漿頭孢呋辛濃度的影響未見顯著差別,因此在本給藥策略下可以給患者保證足夠的血藥濃度。全程超濾可以濾除更多的炎性因子,但對血漿炎性因子的影響并未優(yōu)于復(fù)溫后超濾。
[Abstract]:Overall thinking :

In vitro circulation , cardiac surgery has been greatly developed , but the non - physiologic blood transfer process is accompanied by potential hazards . The patient ' s blood is in contact with the foreign body surface of the extracorporeal circulation pipeline to cause inflammatory reaction , which leads to an increase in capillary permeability . After the start of the extracorporeal circulation , the patient has decreased hemoglobin and decreased serum protein , resulting in inflammatory capillary leak , fluid - to - tissue clearance transfer , tissue edema and poor perfusion of the terminal organ .

ultrafiltration is used as a common technique in cardiopulmonary bypass . In 1979 , Darup et al . reported the use of ultrafiltration in cardiopulmonary bypass . In the 1980s , it was reported that the use of ultrafiltration in cardiopulmonary bypass could filter out the excess water in the body , improve the cardiac function , pulmonary function , nerve function , reduce blood transfusion and alleviate inflammatory response .

In the first part , this study used extracorporeal circulation to simulate the cardiopulmonary bypass . It excluded the individual difference of the patients , the difference of the condition and the uncontrollable factors in the course of surgery . It was only concerned with the effect of ultrafiltration on the concentration of antibiotics in the process of extracorporeal circulation .

In the study of the second part , it was proved that the balanced ultrafiltration can filter the antibiotics in the blood in dose - dependent manner . But the clinical factors are complicated . The results of the ex vivo study can be proved to be the focus of this study in the clinical study .

In this study , the effects of ultrafiltration on inflammatory factors and antibiotic concentration were investigated in this study .

Study on the effect of balanced ultrafiltration on the concentration of antibiotics in the first separated model

BACKGROUND & OBJECTIVE To prevent perioperative infections with antibiotics . However , the effects of balanced ultrafiltration on the concentration of antibiotics in the perioperative period are not clear due to the great interference caused by cardiopulmonary bypass . Therefore , it is proposed to study whether the balance ultrafiltration technology can influence the plasma antibiotic concentration in perioperative period .

Methods The extracorporeal circulation line of extracorporeal circulation was established , including reflux chamber , membrane lung and infant arterial filter . The blood concentrator was installed between the arterial filter and the reservoir . Fresh whole blood was pre - filled with lactated ringer ' s liquid in extracorporeal circulation line . The pressure of the final red blood cells was maintained at 24 - 28 % . The pressure of the final red blood cells was maintained at 12 mL / min . The plasma and ultrafiltrate samples were collected every 5 minutes during ultrafiltration . Plasma and ultrafiltrate were taken every 5 minutes during ultrafiltration , and the drug concentrations of ceftean and cefmetazole were dynamically monitored by high pressure liquid chromatography .

Results Ceftean and cefmetazole could be detected in ultrafiltrate with different concentration . The concentration of antibiotic in plasma decreased linearly with the increase of ultrafiltrate . At the end of ultrafiltration , the concentration of ceftetiam was 104.96 鹵 44.36渭g / ml , which was 44.38 % 鹵 7.42 % ( initial concentration 238.95 鹵 101.12 渭g / ml ) ( p0.001 ) .
The concentration of cefmetazole decreased to 25.76 鹵 14.78 渭g / ml , which was 49.69 % 鹵 10.49 % ( initial concentration 51.49 鹵 28.03 渭g / ml ) ( p0.001 ) .
The content of ceftean in ultrafiltrate was 27.16 % 鹵 12.17 % of the total dosage , and the content of cefmetazole accounts for 7.74 % 鹵 4.17 % of the total dose . Conclusion Balance ultrafiltration can filter out the antibiotics in blood , and its filtrate amount is related to the protein binding rate .
The ultrafiltration technique has a significant effect on the plasma concentration of antibiotics in perioperative period , and the application strategy of antibiotics should consider this effect .

Effect of balanced ultrafiltration on inflammatory factor and antibiotic concentration in the second part of infant ' s heart surgery

BACKGROUND & OBJECTIVE To study the effect of ultrafiltration on the anti - inflammatory factors and the concentration of antibiotics in infants with cardiopulmonary bypass , and to provide a theoretical basis for the guidance of clinical antibiotics .

Methods The blood gas and colloid osmotic pressure were measured by enzyme - linked immunosorbent assay ( ELISA ) . Blood gas and colloid osmotic pressure were measured by using enzyme linked immunosorbent assay ( ELISA ) . The concentration of antibiotics was detected by enzyme linked immunosorbent assay ( ELISA ) .

The plasma concentrations of IL - 1 , IL - 6 , IL - 10 , TNF - 偽 and NE increased significantly ( p < 0.05 ) . The plasma concentrations of IL - 1 , IL - 6 and NE decreased to 58.02 鹵 18.86 渭g / ml ( 53.47 % 鹵 13.60 % ) .

Conclusion Balance ultrafiltration can selectively remove the inflammatory mediators in the plasma . The use of ultrafiltration in extracorporeal circulation can filter out the antibiotics in the blood , and the use of balanced ultrafiltration increases the leaching of antibiotics in the filtrate .

Effect of the third part of the whole course ultrafiltration on the plasma inflammatory factor and antibiotic concentration in aortic arch replacement surgery under deep and low temperature circulatory arrest

Background and Objective To study the effects of ultrafiltration on the concentration of antibiotics , the degree of inflammatory response and post - operative infection in patients with deep and low temperature circulatory arrest due to the long operative time and the need to undergo severe blows such as low temperature and ischemia .

Methods The patients were randomly divided into two groups : the whole course group ( after 10 minutes of aortic cross - cutting ) , the whole course was ultrafiltered to stop the extracorporeal circulation , and the arterial blood was collected 4 hours after the cardiopulmonary bypass ( T1 ) , the cardiopulmonary bypass was 2 hours ( T2 ) , the extracorporeal circulation was stopped ( T3 ) , and the total amount of the ultrafiltrate was recorded after the cardiopulmonary bypass . The indexes of inflammatory media were detected by enzyme linked immunosorbent assay ( ELISA ) including interleukin ( IL ) -1 , IL - 6 , IL - 10 , neutrophil elastase ( NE ) and tumor necrosis factor ( TNF ) - 偽 .

The plasma concentrations of IL - 6 , IL - 10 and NE decreased from 319.03 鹵 32.76渭g / ml and 189.77 鹵 19.03 渭g / ml at the beginning of cardiopulmonary bypass . There was no significant difference between the two groups ( p = 0.083 ) . The plasma concentrations of IL - 1 and TNF - 偽 decreased from 319.03 鹵 67.51ng / ml to 148.57 鹵 83.28ng / ml in cardiopulmonary bypass ( p = 0.083 ) .

Conclusion There are no significant differences in the effects of two ultrafiltration methods on plasma ceftiofur concentration . Therefore , it is possible to ensure adequate plasma concentration for patients under the present administration strategy . The whole course ultrafiltration can filter more inflammatory factors , but the effect of ultrafiltration on plasma inflammatory factors is not superior to ultrafiltration after rewarming .
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R726.1

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