ICU中的血液凈化治療以及最新進(jìn)展

1、Blood Purification in the ICU: State of the ArtICU中的血液凈化治療以及最新進(jìn)展Similarities between sepsis and renal failure感染與腎功能衰竭之間的相似之處“Uremia”尿毒癥Organ dysfunction induces “toxemia”器官功能不全導(dǎo)致的“毒血癥”“Toxemia” induces widespread injury毒血癥導(dǎo)致的廣泛損傷The mediators of “toxemia” are ill-defined關(guān)于毒血癥的因子定義是錯(cuò)誤的Continuous remo

2、val beneficial持續(xù)清除是有益的Use Hemofiltration使用血濾“Septicemia”敗血癥Organ dysfunction induces “toxemia”器官功能不全導(dǎo)致的“毒血癥”“Toxemia” induces widespread injury毒血癥導(dǎo)致的廣泛損傷The mediators of “toxemia” are ill-defined關(guān)于毒血癥的因子定義是錯(cuò)誤的Continuous removal beneficial ?持續(xù)地清除是否有益？Use Hemofiltration? 是否可使用血濾？The Mediators of Sepsi

3、s (the Humoral Theory of Sepsis)TNF (MW 17,500-trimer)IL-1 (MW 17,000); IL-8 (MW9,000); IL-6 (MW22,000)Complement: Factor D (MW 25,000), C3a, C5a (MW 11,500)Eicosanoids: TxB2, PGE2 (MW 500)PAF: MW 600血小板活化因子Others: VIP, vasopressin, endorphin, myocardial depressant factors (MW400 ml/min)在一個(gè)70公斤的病人進(jìn)行

4、前置換時(shí)，超濾量（UF）11L/hr，小于后置換，但后置換需要更大的血流速度（400ml/min）HVHF11L/hr of UF is technically demanding/very difficult in human beings病人身上實(shí)現(xiàn)11L/hr的超濾量，在技術(shù)上是極難實(shí)現(xiàn)的Can we achieve similar results at lower UF rates?是否我們能夠使用較小一點(diǎn)的超濾量而達(dá)到相似的治療效果呢？Dog experiment in 20 kg dogs and UF rate of 2000ml/min (blood flow 200 ml a

5、nd pre-dilution)在體重為20KG的狗身上，使用2L/hr的超濾量（血流速度為200ml/min并采用前置換）Small solute clearance = approx. 80 ml/kg/hr小分子物質(zhì)的清除率（SC）80ml/kg/hrChange in MAP after IV LPSTime after IV LPS (minutes)MAP(mmHg)Bellomo et al AJRCCM 2000; 161: 1429-1436HVHF vs. CVVH10 patients with septic shock and ARFNoradrenaline depe

6、ndentRandomized to 8 hrs of HVHF (6L/hr) or CVVH (1L/hr) in random orderPhysiological outcome: hemodynamic responseBiological outcome: Complement and cytokines這里是一項(xiàng)10個(gè)病人的試驗(yàn)，他們均患有感染中毒性休克和急性腎功能衰竭去甲腎、8小時(shí)6、1L/hr血濾生理指標(biāo)：血流動(dòng)力學(xué)的影響生物學(xué)指標(biāo)：補(bǔ)體系統(tǒng)和細(xì)胞因子Technique for HVHFFiltral 16 (1.6 m2)- AN 69 membraneBlood flow

7、: 300 ml/minCatheter: 13.5 Fr double lumen Niagara (Bard)Replacement fluid: 2 L/hr pre and 4L/hr postAnticoagulation: heparin/protamine regional approachBuffer: lactate使用乳酸鹽作為緩沖劑Estimate small solute clearance: approx. 85 ml/min (70 ml/kg/hr)評(píng)價(jià)小分子物質(zhì)的清除率85ml/min(70ml/kg/hr)Cole, Bellomo et al. Intens

8、ive Care Med 2001; 27: 978-986 Norepinephrine Requirements: HVHF vs. CVVHChange (g/min)over 8 h.Cole, Bellomo et al. Intensive Care Med 2001 ; 27: 978-986 % Change in NorepinephrineDose: HVHF vs CVVH% change over 8 h.Cole, Bellomo et al. Intensive Care Med 2001 ; 27: 978-986 C3a: HVHF (6 L) vs. CVVH

9、 (1 L)ng /ml*TIME (hrs.)Cole, Bellomo et al. Intensive Care Med 2001 ; 27: 978-986 C5a: HVHF (6 L) vs. CVVH (1 L)ng/mlTime (hrs.)*Cole, Bellomo et al. Intensive Care Med 2001IL-10 during CVVHpg / mlTIME (hrs)HVHFCole, Bellomo et al. Intensive Care Med 2001CVVHHVHF:C3a: Serum vs. UF concentrationng/m

10、lTIME (hrs.)Maximum C3a Clearance = 3.3 mil/min Cole, Bellomo et al. Intensive Care Med 2001TNF: HVHF vs. CVVHpg / mlTIME (hrs.)Cole, Bellomo et al. Intensive Care Med 2001IL-8: HVHF vs. CVVHpg / mlTIME (hrs.)*Cole, Bellomo et al. Intensive Care Med 2001ConclusionsHVHF has beneficial short term effe

11、cts in human septic shock similar to those in animals高容量血濾對(duì)感染中毒性休克病人在一段時(shí)間內(nèi)是有益的，這一點(diǎn)與動(dòng)物試驗(yàn)結(jié)果類似With AN69 and molecules 8-9 kD it results in adsorptive removal, not filtration of inflammatory mediators使用AN69的濾器，對(duì)于分子量89千道爾頓的物質(zhì)主要是靠黏附來(lái)清除，而不是靠濾出There is now a rationale for phase II studies現(xiàn)在可以進(jìn)行二期臨床試驗(yàn)Short T

12、erm-Very HVHFPatrick Honore et al. (Crit Care Med 2000; 28: 3581-3587)20 patients in severe refractory septic shock20例嚴(yán)重的難以控制的感染中毒性休克病人4 hours of HVHF (blood flow 450 ml/min, 1.6 m2 Fresenius polysulfone filter, bicarbonate buffer, post-dilution, UF rate 8750 ml/hr)4小時(shí)HVHF（血流450多聚砜膜，后置換，UF8750ml/hr）

13、Approx. small solute clearance: 116ml/kg/hr小分子物質(zhì)的清除率116ml/kg/hrResults11 responders (rapid increase in CI, MVSO2, pH7.3 and 50% reduction in adrenaline dose)11例有反應(yīng)的病人9 of 11 responders survivedResponders weighed less : 66 vs. 83 kg有反應(yīng)的病人體重較無(wú)反應(yīng)者體重偏輕Responders got more UF: 132 ml/kg/min vs. 107 ml/kg/

14、min那么有反應(yīng)的病人UF則要高于無(wú)反應(yīng)者Responders were treated earlier: 6.5 vs. 13.8 hrs同時(shí)也發(fā)現(xiàn)，有反應(yīng)的病人治療要早于無(wú)反應(yīng)者Comments注解但這一試驗(yàn)本身存在問(wèn)題：No controlsNo randomizationNo predefined criteria of response沒(méi)有預(yù)先制定有反應(yīng)組的診斷標(biāo)準(zhǔn)However.Provocative study研究是具有煽動(dòng)性的Findings consistent with expectations與期望的結(jié)果一致ConclusionsWe have no consensus

15、definition for the term “HVHF” but we have several phase I studies suggesting that “more” UF might be better.我們沒(méi)有關(guān)于高容量血濾的一致定義，但是我們已經(jīng)從一些一期臨床試驗(yàn)報(bào)道中看到，UF越大，療效越好We have limited understanding of mechanisms, dose and duration, however, and no markers like urea我們對(duì)于其機(jī)制的了解非常有限，劑量，時(shí)間，而且我們除了尿素沒(méi)有任何可以取而代之的指標(biāo)This

16、is a promising and exciting area of research. We now need a phase II trial.這是一個(gè)非常有前途和令人興奮的領(lǐng)域。我們現(xiàn)在需要進(jìn)行的是二期臨床試驗(yàn)Why not plasma exchange?為什么不選擇血漿置換？Fresh frozen plasma (FFP) is available in limited amountsFFP的數(shù)量非常有限If done continuously, after a while one is removing the FFP given如果持續(xù)進(jìn)行，在很短的時(shí)間內(nèi)就會(huì)耗竭所有的血漿F

17、FP contains many of the proteins we want to remove. Intermittent therapy is unlikely to be enoughFFP中含有很多我們希望清除的蛋白。間斷的治療未必充足No effect in Phase Ib trial (Reeves et al. Crit Care Med 1999; 27: 2096-2104)從如下一b期臨床試驗(yàn)中反應(yīng)的結(jié)果是無(wú)效的Why Coupled Plasma Filtration Adsorption (CPFA)?為什么選擇聯(lián)合血漿濾過(guò)黏附All plasma becomes

18、 available for “purification”體內(nèi)所有的血漿都變得可以用于凈化治療Therapy can be continuous治療可以持續(xù)No interaction between cells and adsorptive cartridges細(xì)胞與吸附罐之間沒(méi)有相互反應(yīng)CPFA: Ex-vivo testing - Cytokine adsorptionTetta et al. Nephrol Dial Transplant 1998; 13: 1458-64Resin: XAD 1600CPFA in animal modelsTest whether biochemi

19、cal findings translate into clinical effects檢測(cè)生化方面的發(fā)現(xiàn)是否在臨床上產(chǎn)生效果Assess magnitude of clinical effects評(píng)價(jià)大量的臨床效果Assess nature of clinical effects評(píng)價(jià)效果的本質(zhì)Exclude major unexpected adverse events排除主要的負(fù)面反應(yīng)事件Deal with unexpected technical problems處理難以預(yù)料的技術(shù)問(wèn)題CPFA in the rabbit - TNF adsorptionU/milTetta et al.

20、 Crit Care Med 2000; 28: 1526-1533CPFA in the rabbit% survivalpDaysTetta et al. Crit Care Med 2000; 28: 1526-1533Phase I trial of CPFA10 patientsSingle ICUMODS + ARF + high cardiac output + hypotensive + norepinephrine infusionRandom allocation to CPFA + CVVHD or to CVVHD alone each for 10 hours wit

21、h cross over按照交叉隨機(jī)方案，進(jìn)行10小時(shí)的CPFACVVHD,或10小時(shí)的CVVHD治療Outcome measuresPrimary: decreased need for norepinephrine and/or increased arterial pressure主要觀察終點(diǎn)：去甲腎上腺素劑量的下降和/或動(dòng)脈血壓的升高Secondary: a) decreased levels of TNF and IL-10 b) improved monocyte response to LPS增加了單核細(xì)胞對(duì)LPS的敏感性HemodialyzerBlood In100-200ml

22、/minBlood OutCVVHD (Treatment B)治療BDialysate In 30 ml/min Dialysate Out + Uf2-8 ml/minSorbentSorbent PlasmafilterDialysate Out + Uf 2-8 ml/minDialysate In 30 ml/min Blood OutPlasmafiltrate30-40 ml/minHemodialyzerBlood In100-200ml/minCPFA (Treatment A)治療A Sampling pointSite 1 Site 2 Site 3Site 4Site

23、5Site 6Site 7Ronco, Brendolan, Lonnemann, Bellomo, et al. Crit Care Med 2002; 30: 1250-1255Change in MAP during 10 hours of CPFAPRonco, Brendolan, Lonnemann, Bellomo et al. Crit Care Med 2002 這一圖形顯示：ABABABABABABBABABABAChanges in norepinephrine requirementsPpSurvival: 9 out 10 patients which on died

24、?t0t10In-vitro monocyte responsiveness to LPS單核細(xì)胞在體外對(duì)LPS的反應(yīng)t10Crit Care Med 2002; 30: 1250-1255Single pass sorbent effect體外試驗(yàn)證實(shí)，血液通過(guò)黏附器后，對(duì)LPS的反應(yīng)性增加，產(chǎn)生TNF 的水平增加0100300500700900TNF a (pg/ml)Post + anti-IL-101100Post alonePre + anti-IL-10*Prealone*Spontaneous TNF production by whole blood after incubat

25、ion with PFGreen = t0Black = t10Crit Care Med 2002; 30: 1250-1255當(dāng)血液通過(guò)吸附以后對(duì)PF的反應(yīng)明顯增加了，更容易產(chǎn)生TNF ConclusionsThere is a biologic rationale for CPFA從生物學(xué)原理的角度上講，CPFA是可行的There is ex-vivo evidence of adsorption在體外試驗(yàn)中，有證據(jù)表明黏附的存在There is animal evidence of increased survival動(dòng)物試驗(yàn)的證據(jù)支持其可以正加存活率A Phase I trial s

26、hows beneficial hemodynamic effects in humans with septic shock一期臨床試驗(yàn)顯示出其對(duì)感染中毒性休克的病人血流動(dòng)力學(xué)的改善Problems with CPFAPlasmafilter can take limited blood flows血漿濾器的血流速度是有限的Limited blood flow = limited PF rate有限的血流有限的PFLimited PF rate = limited clearance有限的PF有限的清除率Even with 100% adsorption, clearance can onl

27、y be 30-35 ml/min即使黏附作用是100，但清除率只能是3035ml/minWe may need more我們要的不止這些Super High Flux Filters (nominal pore size = 100 kD)超高通量濾器Easier to useDo not need complex CPFA circuitCheaperCan be used by anyoneIf combined with HVHF may offer “best value”如果結(jié)合HVHF，可能更據(jù)價(jià)值Clearances (ml/min) of cytokines and albu

28、min in 1L/hr ultrafiltration(ml/min)1L/hr超濾量時(shí)，細(xì)胞因子及蛋白的清除Polyamide super high-flux filter多聚酰胺高通量濾器Note low IL-8 clearanceUchino, Bellomo et al. Intensive Care Med 2002; 28: 651-655Figure 2B:Clearances (ml/min) of cytokines and albumin in 6L/hr UF (ml/min)Polyamide SHF filter + HVHF聚酰胺超高通量濾器HVHFLoss o

29、f SC with increased UF rate and timeUchino, Bellomo et al. Intensive Care Med 2002; 28: 651-655Figure 2A:Clearances of cytokines and albumin in 1L/hr ultrafiltration (ml/min)Cellulose triacetate SHF filter + HVHF三醋酸纖維素高通量濾器HVHFLow clearance for MWUchino, Bellomo et al. Int J Artif Organs 2002; 25: 2

30、7-32Figure 2B:Clearances of cytokines and albumin in 6L/hr ultrafiltration (ml/min)Cellulose triacetate SHF filter + HVHFLoss of SCObservations觀測(cè)結(jié)果Polyamide and cellulose triacetate are different. Polyamide is better.多聚酰胺膜效果較好Increasing UF rate increases clearance but decreases SCTime effect small時(shí)間對(duì)它的影響較少Albumin losses sustainable蛋白的丟失是可以忍受的Hi