馬帥 丁峰
摘 要 1977年Kramer開展了全球首例連續(xù)性動(dòng)脈-靜脈血液濾過(guò),標(biāo)志著連續(xù)性腎臟替代治療(continuous renal replacement therapy, CRRT)就此問(wèn)世。CRRT起步階段沿用了很多維持性血液透析領(lǐng)域的技術(shù)、設(shè)備,影響治療效果。隨著CRRT技術(shù)不斷發(fā)展,現(xiàn)已生產(chǎn)出專為危重癥患者設(shè)計(jì)的CRRT平臺(tái),在危重癥患者中的使用率大幅提高,成為急性腎損傷患者的主要治療手段之一。近年來(lái),重癥醫(yī)學(xué)不斷發(fā)展,“腎臟替代”不再是CRRT的唯一治療目的,不局限于腎臟的多器官支持治療技術(shù)發(fā)展迅速。CRRT技術(shù)雖已在全球范圍內(nèi)得到廣泛應(yīng)用,但其仍存在一些挑戰(zhàn)和不確定性,如何解決這些問(wèn)題是CRRT領(lǐng)域今后的主要研究方向。
關(guān)鍵詞 血液凈化 連續(xù)性腎臟替代治療 急性腎損傷 膿毒癥
中圖分類號(hào):R692.5; R459.5 文獻(xiàn)標(biāo)志碼:A 文章編號(hào):1006-1533(2018)09-0003-03
Continuous renal replacement therapy: past, present and future*
MA Shuai, DING Feng**
(Division of Nephrology, Shanghai Ninth Peoples Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China)
ABSTRACT In 1977, Peter Kramer launched the worlds first continuous arterial-venous hemofiltration, marking the birth of continuous renal replacement therapy (CRRT). In the initial stage of CRRT, a lot of technologies and equipment for maintenance dialysis were used, which affected the therapeutic effect. With the continuous development of CRRT technology, CRRT platforms specially designed for critically ill patients have been produced. The use of CRRT in critically ill patients has been greatly increased and become one of the main treatments for patients with acute kidney injury. In recent years, critical care medicine has progressed and “renal replacement” is no longer the sole purpose of treatments since the concept of multiple organ support therapy is proposed. There still exist a number of challenges and uncertainties though CRRT has been widely used worldwide. How to solve these problems is still the main research direction in the future.
KEy WORDS blood purification; continuous renal replacement therapy; acute kidney injury; sepsis
連續(xù)性腎臟替代治療(continuous renal replacement therapy, CRRT)最初是作為不能耐受常規(guī)血液透析的血流動(dòng)力學(xué)不穩(wěn)定的急性腎衰竭患者的替代治療方案而研發(fā)的[1-2]。CRRT起步階段沿用了很多維持性血液透析領(lǐng)域的技術(shù)、設(shè)備,影響治療效果。隨著CRRT技術(shù)不斷發(fā)展,現(xiàn)已生產(chǎn)出專為危重癥患者設(shè)計(jì)的CRRT平臺(tái),在危重癥患者中的使用率大幅提高,成為急性腎損傷患者的一線治療手段之一,同時(shí)涵蓋至不局限于腎臟的多器官支持治療領(lǐng)域[3]。CRRT技術(shù)雖在全球范圍內(nèi)得到廣泛應(yīng)用,但其仍存在一些重大挑戰(zhàn)和不確定性[4],包括治療劑量、治療開始和終止時(shí)機(jī)、精準(zhǔn)的液體管理、抗凝方案等。在CRRT問(wèn)世40周年之際,本文回顧C(jī)RRT的發(fā)展歷程、探討現(xiàn)階段CRRT的局限性和未來(lái)CRRT的發(fā)展趨勢(shì)。
1 連續(xù)性動(dòng)脈-靜脈血液濾過(guò)(continuous arteriovenous hemofiltration, CAVH)時(shí)代
1977年Kramer開展了全球首例CAVH,用于治療急性腎衰竭患者[5]。他將濾器連接在患者的股動(dòng)脈和股靜脈間,利用動(dòng)、靜脈間的壓力差使血液以100 ml/min的速率流過(guò)濾器,產(chǎn)生的濾液被電解質(zhì)溶液替換。當(dāng)時(shí)主要使用間歇性血液透析治療急性腎衰竭患者,由于患者的血流動(dòng)力學(xué)不穩(wěn)定,死亡率非常高。CAVH可連續(xù)、緩慢進(jìn)行,對(duì)患者血流動(dòng)力學(xué)的影響較小。
CAVH在液體控制方面表現(xiàn)良好,但其不能充分清除尿素,特別是對(duì)有高分解代謝的危重癥患者[6]。為此,1984年Geronemus等[7]引入了連續(xù)性動(dòng)脈-靜脈血液透析(continuous arterio-venous hemodialysis, CAVHD)的概念,通過(guò)彌散機(jī)制提高尿素的清除率。此外,1985年Ronco等[8]開展了連續(xù)性動(dòng)脈-靜脈血液透析濾過(guò)(continuous arterio-venous hemodiafiltration, CAVHDF),通過(guò)對(duì)流和彌散機(jī)制相結(jié)合提高大、小分子溶質(zhì)的清除率。這一時(shí)期醫(yī)師們也認(rèn)識(shí)到了精確的液體平衡控制的重要意義。醫(yī)師們最初通過(guò)將濾液袋放置在不同的高度以改變其對(duì)濾器產(chǎn)生的負(fù)壓力,由此實(shí)現(xiàn)了對(duì)超濾量的手動(dòng)控制。同樣,置換液的輸送最初也是手動(dòng)調(diào)節(jié)的。以后隨著稱重傳感器、電子夾等的應(yīng)用,逐步產(chǎn)生了電腦控制的早期自動(dòng)液體平衡系統(tǒng),后者可通過(guò)感知重量變化調(diào)節(jié)跨膜壓,從而實(shí)現(xiàn)液體平衡的精準(zhǔn)化控制[9]。
2 連續(xù)性靜脈-靜脈血液濾過(guò)(continuous venovenous hemofiltration, CVVH)問(wèn)世
動(dòng)脈-靜脈回路的主要缺點(diǎn)包括:①需在動(dòng)脈穿刺置管,這勢(shì)必帶來(lái)一定的風(fēng)險(xiǎn);②整個(gè)體外循環(huán)依賴于動(dòng)脈壓力,一旦患者出現(xiàn)低血壓,體外循環(huán)的血流量將隨即減少,而沒(méi)有足夠的體外循環(huán)血流量,往往會(huì)導(dǎo)致治療間斷、治療效果下降,甚至治療失敗??紤]到上述風(fēng)險(xiǎn),伴隨著雙腔靜脈導(dǎo)管和蠕動(dòng)泵的應(yīng)用,更有效的CVVH、連續(xù)性靜脈-靜脈血液透析(continuous venovenous hemodialysis, CVVHD)和連續(xù)性靜脈-靜脈血液透析濾過(guò)(continuous veno-venous hemodiafiltration, CVVHDF)逐步替代了CAVH、CAVHD和CAVHDF[10]。這些改變提高了危重癥患者體外循環(huán)治療的安全性和治療效果,醫(yī)師們開始使用更高的血流量(>150 ml/min)和有更大膜面積的濾器(>1.0 m2),從而達(dá)到了更好地控制患者的高分解代謝狀態(tài)和其他嚴(yán)重的病理生理紊亂的目的[11]。
最初,靜脈-靜脈回路利用當(dāng)時(shí)已有的技術(shù)(主要借鑒維持性血液透析技術(shù)),通過(guò)將多種模塊如血泵、超濾泵、抗凝裝置、液體回輸泵和壓力報(bào)警裝置等不斷疊加、組合,組成了被戲稱為呈“圣誕樹現(xiàn)象”的治療系統(tǒng)[3,12]。不過(guò),盡管這類系統(tǒng)具備了多項(xiàng)功能,但因各模塊相互獨(dú)立、并未予以集成,故可能產(chǎn)生錯(cuò)誤放大,有提高嚴(yán)重治療并發(fā)癥發(fā)生的風(fēng)險(xiǎn)。鑒于臨床上存在對(duì)能集成多種模塊、使用更加安全和便捷的設(shè)備的迫切需求,專業(yè)化的CRRT平臺(tái)應(yīng)運(yùn)而生。
3 專業(yè)化CRRT平臺(tái)
PRISMA是全球首個(gè)專為危重癥患者緊急腎臟替代治療所設(shè)計(jì)的專業(yè)化CRRT平臺(tái)[6,11]。這個(gè)平臺(tái)包含標(biāo)準(zhǔn)化的循環(huán)管路及濾器、4個(gè)嵌入式泵頭和3個(gè)獨(dú)立的重量監(jiān)測(cè)系統(tǒng),具備自動(dòng)預(yù)充功能,由集成電路控制,安全性和可操作性大大提高,幾乎可實(shí)現(xiàn)當(dāng)時(shí)各種CRRT模式。
此后,隨著大量臨床研究的開展,為了滿足治療劑量、治療模式和治療安全性的需求,第三代CRRT平臺(tái)不斷涌現(xiàn)[6,11,13-14]。這些平臺(tái)允許的最大血流量可達(dá)450 ml/min,最大透析液、置換液流量可達(dá)8 ~ 10 L/h,最大流出液流量可達(dá)20 ~ 25 L/h。血泵的精確度大大提高,血流量的控制誤差<2%。此外,這些平臺(tái)還具備完善的安全監(jiān)測(cè)系統(tǒng)和液體平衡控制系統(tǒng),每日液體平衡誤差<0.3%,且系統(tǒng)會(huì)每小時(shí)更新1次處方超濾量和實(shí)際超濾量,不斷修正,減少超濾誤差。同時(shí),用戶界面的出現(xiàn)也進(jìn)一步簡(jiǎn)化了操作,治療安全性提高。
4 廣義的CRRT——多臟器支持治療(multiorgan support therapy, MOST)
隨著重癥醫(yī)學(xué)的不斷發(fā)展,“腎臟替代”已不再是唯一治療目的,而是轉(zhuǎn)向利用體外循環(huán)技術(shù),通過(guò)多種治療途徑、多種治療模式相結(jié)合的方法達(dá)到不同的治療目的,實(shí)現(xiàn)MOST。1980年P(guān)aganini首次提出緩慢連續(xù)性超濾(slow continuous ultrafiltration, SCUF)的概念,期望在不使用透析液、置換液的前提下以對(duì)流機(jī)制清除溶質(zhì)和水分[15]。不過(guò),由于SCUF對(duì)溶質(zhì)清除不理想,這一技術(shù)并未隨即得到廣泛應(yīng)用。但隨著對(duì)容量負(fù)荷研究的不斷深入,現(xiàn)今SCUF已主要用于難治性心力衰竭、肺水腫等高容量負(fù)荷狀態(tài)患者的治療[16]。肝臟功能支持方面,目前主要應(yīng)用血漿置換、血液透析、血液濾過(guò)、血液灌流等血液凈化技術(shù),采用單獨(dú)或聯(lián)合治療模式清除各類毒素、糾正代謝紊亂、補(bǔ)充必需的有益物質(zhì)[17]。隨著白蛋白透析液概念的提出,連續(xù)性白蛋白凈化系統(tǒng)(continuous albumin purification system)、分子吸附再循環(huán)系統(tǒng)(molecular adsorbents recirculating system)和普羅米修斯系統(tǒng)(Prometheus system)等非生物型人工肝臟在臨床上也已用于肝衰竭患者的救治[17-19]。此外,體外膜肺氧合(extracorporeal membrane oxygenation)、體外二氧化碳清除(extracorporeal carbon dioxide removal)等體外生命支持技術(shù)不斷成熟,為危重癥患者的救治提供了更多的選擇[20-21]。
嚴(yán)重感染是危重癥患者的常見問(wèn)題,現(xiàn)重癥監(jiān)護(hù)室患者的膿毒癥死亡率仍很高。膿毒癥患者的體內(nèi)會(huì)釋放大量細(xì)胞因子和炎癥介質(zhì),導(dǎo)致機(jī)體免疫功能紊亂、失衡。隨著細(xì)胞因子峰濃度假說(shuō)、閾值免疫調(diào)節(jié)假說(shuō)、炎癥因子流通假說(shuō)和細(xì)胞因子動(dòng)力學(xué)假說(shuō)的提出,通過(guò)血液凈化清除細(xì)胞因子和炎癥介質(zhì)已開始在膿毒癥治療中發(fā)揮重要作用[22-25]。目前,用于膿毒癥治療的血液凈化方法主要有高容量血液濾過(guò)(high-volume hemofiltration, HVHF)、多黏菌素B血液吸附、配對(duì)血漿濾過(guò)吸附(coupled plasma filtration and adsorption, CPFA)、高截流量血液濾過(guò)(high-cutoff hemofiltration, HCOHF)等。HVHF通過(guò)提高置換液流速、增加血液與置換液的交換來(lái)提高細(xì)胞因子和炎癥介質(zhì)的清除率[26]。近年來(lái),可吸附內(nèi)毒素的多黏菌素B血液吸附技術(shù)對(duì)膿毒癥患者的治療作用也得到了越來(lái)越多的關(guān)注[27]。CPFA系先將血漿與吸附劑接觸,待細(xì)胞因子和炎癥介質(zhì)被吸附后再將血漿與血細(xì)胞混合,接著通過(guò)第二個(gè)血液濾器來(lái)清除過(guò)量的液體和水溶性毒素[28]。HCOHF則通過(guò)提高濾過(guò)膜孔徑來(lái)提高炎癥介質(zhì)的清除率[29]。
5 CRRT的現(xiàn)況與未來(lái)
通過(guò)不斷發(fā)展與改進(jìn),最新一代的CRRT平臺(tái)已能保證治療的安全性和可靠性,CRRT已成為世界各國(guó)絕大多數(shù)標(biāo)準(zhǔn)化重癥監(jiān)護(hù)室中危重癥患者的主要治療方法。不過(guò),標(biāo)準(zhǔn)化的治療質(zhì)量評(píng)估,如治療劑量、治療開始和終止時(shí)機(jī)、精準(zhǔn)的液體管理、抗凝方案等,仍待得到更多臨床證據(jù)的支持?!凹毙酝肝鲑|(zhì)量倡議”(Acute Disease Quality Initiative)工作組提出了“精準(zhǔn)化CRRT”(precision CRRT)的概念[30-31],強(qiáng)調(diào)CRRT的個(gè)體化治療,根據(jù)患者的臨床狀況及時(shí)調(diào)整治療方案。精準(zhǔn)化的 CRRT治療需對(duì)治療參數(shù)、患者的生理信息進(jìn)行實(shí)時(shí)分析,工作量很大。因此,研發(fā)CRRT平臺(tái)的實(shí)時(shí)數(shù)據(jù)采集和自動(dòng)化生理信息反饋系統(tǒng)非常重要。
6 結(jié)語(yǔ)
CRRT已廣泛用于危重癥患者的治療。從動(dòng)脈-靜脈回路到靜脈-靜脈回路,從簡(jiǎn)單的設(shè)備模塊拼湊到具備專業(yè)功能的集成平臺(tái),從單一治療模式到現(xiàn)階段的新型、復(fù)雜治療模式,從單純的腎臟功能替代到多臟器支持治療,CRRT技術(shù)不斷得到發(fā)展。但其局限性仍不容忽視,解決這些問(wèn)題,CRRT將更安全、更有效。
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