课件：ICU中的血液净化治疗：最新进展.ppt

Blood Purification in the ICU: State of the Art ICU中的血液净化治疗：最新进展,A/Prof. Rinaldo Bellomo Austin & Repatriation Medical Centre Melbourne Australia,Similarities between sepsis and renal failure 感染与肾功能衰竭之间的相似之处,“Uremia” 尿毒症 Organ dysfunction induces “toxemia” 器官功能不全导致的“毒血症” “Toxemia” induces widespread injury 毒血症导致的广泛损伤 The mediators of “toxemia” are ill-defined 关于毒血症的因子定义是错误的 Continuous removal beneficial 持续清除是有益的 Use Hemofiltration 使用血滤,“Septicemia” 败血症 Organ dysfunction induces “toxemia” 器官功能不全导致的“毒血症” “Toxemia” induces widespread injury 毒血症导致的广泛损伤 The mediators of “toxemia” are ill-defined 关于毒血症的因子定义是错误的 Continuous removal beneficial ? 持续地清除是否有益？ Use Hemofiltration? 是否可使用血滤？,The Mediators of Sepsis (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 (MW5,000), Phospholipase 其它：Vasoactive intestinal peptide,血管活性药物，内皮素，心肌抑制因子小于5千道尔顿，磷脂酶,The CRRT Membranes,Nominal Pore size: 20- 30 kD 普通孔径为23万道尔顿 Highly absorptive capacity 高黏附性 Can bind many mediators in vitro 在体外试验中可以黏附许多因子 Can bind mediators in vivo 在体内试验中也可以黏附细胞因子 Can filter some mediators in vitro Can filter some mediators in vivo 在体内及体外试验均可滤出一定的因子,CRRT and complement CRRT与补体,ng/ml for C3a (/ 10 for C5a),Time on CVVH at 2L / h UF rate,p 0.001,p 0.01,C3a SC = 0.2 C5a SC = 0.02,Hoffman et al. Intensive Care Med 1996,TNF levels: CVVH vs. CVVHD,p 0.02,PATIENTS,% Change,No TNF in UF!,J Kellum, Crit Care Med 1998,High Volume Hemofiltration,The term was first used by Grootendorst in 1992 这一术语是在1992年，由Grootendorst 首次提出的 Animal experiments in pigs (weight 36-39 kg) 所选动物为体重在3639公斤的猪 Blood flow 300 ml/min UF flow 6000 ml/hr Replacement fluid given pre-filter Polysulfone filters (Amicon, USA) 多聚砜膜 IV endotoxin over 30 minutes,HVHF and RVEF右室,p0.001,Grootendorst et al, Intensive Care Med 1992,HVHF and MAP,p0.001,Grootendorst et al, Intensive Care Med 1992,Effect of septic UF on MAP,2L Normal UF,2L LPS UF,Change in MAP (mmHg),Grootendorst et al, J Crit Care 1993,p 0.05,Effect of HVHF on ischemic gut injury,HVHF,No CVVH,Gut injury score,Mucosal injury 粘膜损伤,Sloughing 腐烂,Ulcers 溃疡,Perforation 穿孔,p 0.05,Grootendorst et al. Shock 1994,HVHF,HVHF may be beneficial in human septic shock 高容量血滤可能对感染性休克病人有益 If Hct of 30% and blood flow of 300 ml/min and pre-dilution.small solute clearance = approx. 60-70 ml/min (110ml/kg/hr) 假设HCT30，血流速度300ml/min,而且采用前置换那么小分子物质的清除率（SC）6070ml/min(110ml/kg/hr) In 70 kg patient in pre-dilutionneed about 11 L/hr of UF rate.less if post-dilution but need big blood flows (400 ml/min) 在一个70公斤的病人进行前置换时，超滤量（UF）11L/hr，小于后置换，但后置换需要更大的血流速度（400ml/min）,HVHF,11L/hr of UF is technically demanding/very difficult in human beings 病人身上实现11L/hr的超滤量，在技术上是极难实现的 Can we achieve similar results at lower UF rates? 是否我们能够使用较小一点的超滤量而达到相似的治疗效果呢？ Dog experiment in 20 kg dogs and UF rate of 2000ml/min (blood flow 200 ml and pre-dilution) 在体重为20KG的狗身上，使用2L/hr的超滤量（血流速度为200ml/min并采用前置换） Small solute clearance = approx. 80 ml/kg/hr 小分子物质的清除率（SC）80ml/kg/hr,Change in MAP after IV LPS,Time after IV LPS (minutes),MAP (mmHg),p 0.05,Bellomo et al AJRCCM 2000; 161: 1429-1436,HVHF vs. CVVH,10 patients with septic shock and ARF Noradrenaline dependent Randomized to 8 hrs of HVHF (6L/hr) or CVVH (1L/hr) in random order Physiological outcome: hemodynamic response Biological outcome: Complement and cytokines 这里是一项10个病人的试验，他们均患有感染中毒性休克和急性肾功能衰竭 去甲肾、8小时6、1L/hr血滤 生理指标：血流动力学的影响 生物学指标：补体系统和细胞因子,Technique for HVHF,Filtral 16 (1.6 m2)- AN 69 membrane Blood flow: 300 ml/min Catheter: 13.5 Fr double lumen Niagara (Bard) Replacement fluid: 2 L/hr pre and 4L/hr post Anticoagulation: heparin/protamine regional approach Buffer: lactate 使用乳酸盐作为缓冲剂 Estimate small solute clearance: approx. 85 ml/min (70 ml/kg/hr) 评价小分子物质的清除率85ml/min(70ml/kg/hr),Cole, Bellomo et al. Intensive Care Med 2001; 27: 978-986,Norepinephrine Requirements: HVHF vs. CVVH,Change (g/min) over 8 h.,p 0.02,Cole, Bellomo et al. Intensive Care Med 2001 ; 27: 978-986,% Change in Norepinephrine Dose: HVHF vs CVVH,% change over 8 h.,Cole, Bellomo et al. Intensive Care Med 2001 ; 27: 978-986,C3a: HVHF (6 L) vs. CVVH (1 L),ng /ml,p 0.017,*,*,TIME (hrs.),Cole, Bellomo et al. Intensive Care Med 2001 ; 27: 978-986,C5a: HVHF (6 L) vs. CVVH (1 L),ng/ml,Time (hrs.),*,*,*,p0.017,Cole, Bellomo et al. Intensive Care Med 2001,IL-10 during CVVH,pg / ml,TIME (hrs),HVHF,Cole, Bellomo et al. Intensive Care Med 2001,CVVH,HVHF: C3a: Serum vs. UF concentration,ng/ml,TIME (hrs.),Maximum C3a Clearance = 3.3 mil/min,Cole, Bellomo et al. Intensive Care Med 2001,TNF: HVHF vs. CVVH,pg / ml,TIME (hrs.),Cole, Bellomo et al. Intensive Care Med 2001,IL-8: HVHF vs. CVVH,pg / ml,TIME (hrs.),*,p 0.05,Cole, Bellomo et al. Intensive Care Med 2001,Conclusions,HVHF has beneficial short term effects in human septic shock similar to those in animals 高容量血滤对感染中毒性休克病人在一段时间内是有益的，这一点与动物试验结果类似 With AN69 and molecules 8-9 kD it results in adsorptive removal, not filtration of inflammatory mediators 使用AN69的滤器，对于分子量89千道尔顿的物质主要是靠黏附来清除，而不是靠滤出 There is now a rationale for phase II studies 现在可以进行二期临床试验,Short Term-Very HVHF,Patrick Honore et al. (Crit Care Med 2000; 28: 3581-3587) 20 patients in severe refractory septic shock 20例严重的难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小时HVHF（血流450ml/min,1.6m2多聚砜膜，后置换，UF8750ml/hr） Approx. small solute clearance: 116ml/kg/hr 小分子物质的清除率116ml/kg/hr,Results,11 responders (rapid increase in CI, MVSO2, pH7.3 and 50% reduction in adrenaline dose) 11例有反应的病人 9 of 11 responders survived Responders weighed less : 66 vs. 83 kg 有反应的病人体重较无反应者体重偏轻 Responders got more UF: 132 ml/kg/min vs. 107 ml/kg/min 那么有反应的病人UF则要高于无反应者 Responders were treated earlier: 6.5 vs. 13.8 hrs 同时也发现，有反应的病人治疗要早于无反应者,Comments 注解,但这一试验本身存在问题： No controls No randomization No predefined criteria of response 没有预先制定有反应组的诊断标准 However. Provocative study 研究是具有煽动性的 Findings consistent with expectations 与期望的结果一致,2019/8/22,29,可编辑,Conclusions,We have no consensus definition for the term “HVHF” but we have several phase I studies suggesting that “more” UF might be better. 我们没有关于高容量血滤的一致定义，但是我们已经从一些一期临床试验报道中看到，UF越大，疗效越好 We have limited understanding of mechanisms, dose and duration, however, and no markers like urea 我们对于其机制的了解非常有限，剂量，时间，而且我们除了尿素没有任何可以取而代之的指标 This is a promising and exciting area of research. We now need a phase II trial. 这是一个非常有前途和令人兴奋的领域。我们现在需要进行的是二期临床试验,Why not plasma exchange? 为什么不选择血浆置换？,Fresh frozen plasma (FFP) is available in limited amounts FFP的数量非常有限 If done continuously, after a while one is removing the FFP given 如果持续进行，在很短的时间内就会耗竭所有的血浆 FFP contains many of the proteins we want to remove. Intermittent therapy is unlikely to be enough FFP中含有很多我们希望清除的蛋白。间断的治疗未必充足 No effect in Phase Ib trial (Reeves et al. Crit Care Med 1999; 27: 2096-2104) 从如下一b期临床试验中反应的结果是无效的,Why Coupled Plasma Filtration Adsorption (CPFA)? 为什么选择联合血浆滤过黏附,All plasma becomes available for “purification” 体内所有的血浆都变得可以用于净化治疗 Therapy can be continuous 治疗可以持续 No interaction between cells and adsorptive cartridges 细胞与吸附罐之间没有相互反应,CPFA: Ex-vivo testing - Cytokine adsorption,Tetta et al. Nephrol Dial Transplant 1998; 13: 1458-64,Resin: XAD 1600,CPFA in animal models,Test whether biochemical findings translate into clinical effects 检测生化方面的发现是否在临床上产生效果 Assess magnitude of clinical effects 评价大量的临床效果 Assess nature of clinical effects 评价效果的本质 Exclude major unexpected adverse events 排除主要的负面反应事件 Deal with unexpected technical problems 处理难以预料的技术问题,CPFA in the rabbit - TNF adsorption,U/mil,Tetta et al. Crit Care Med 2000; 28: 1526-1533,CPFA in the rabbit,% survival,p =0.004,Days,Tetta et al. Crit Care Med 2000; 28: 1526-1533,Phase I trial of CPFA,10 patients Single ICU MODS + ARF + high cardiac output + hypotensive + norepinephrine infusion Random allocation to CPFA + CVVHD or to CVVHD alone each for 10 hours with cross over 按照交叉随机方案，进行10小时的CPFACVVHD,或10小时的CVVHD治疗,Outcome measures,Primary: decreased need for norepinephrine and/or increased arterial pressure 主要观察终点：去甲肾上腺素剂量的下降和/或动脉血压的升高 Secondary: a) decreased levels of TNF and IL-10 b) improved monocyte response to LPS 增加了单核细胞对LPS的敏感性,Hemodialyzer,Blood In 100-200 ml/min,Blood Out,CVVHD (Treatment B) 治疗B,Dialysate In 30 ml/min,Dialysate Out + Uf 2-8 ml/min,Sorbent,Plasmafilter,Dialysate Out + Uf 2-8 ml/min,Dialysate In 30 ml/min,Blood Out,Plasmafiltrate 30-40 ml/min,Hemodialyzer,Blood In 100-200 ml/min,CPFA (Treatment A) 治疗A,Sampling point,Site 1,Site 2,Site 3,Site 4,Site 5,Site 6,Site 7,Ronco, Brendolan, Lonnemann, Bellomo, et al. Crit Care Med 2002; 30: 1250-1255,Change in MAP during 10 hours of CPFA,P0.05,P0.05,Ronco, Brendolan, Lonnemann, Bellomo et al. Crit Care Med 2002,这一图形显示：,AB,AB,AB,AB,AB,AB,BA,BA,BA,BA,Changes in norepinephrine requirements,P0.05,p0.05,Survival: 9 out 10 patients which on died?,t0,t10,In-vitro monocyte responsiveness to LPS 单核细胞在体外对LPS的反应,t10,Crit Care Med 2002; 30: 1250-1255,Single pass sorbent effect,体外试验证实，血液通过黏附器后，对LPS的反应性增加，产生TNF 的水平增加,0,100,300,500,700,900,TNF a (pg/ml),Post + anti-IL-10,1100,Post alone,Pre + anti-IL-10,*,Pre alone,*,*,Spontaneous TNF production by whole blood after incubation with PF,Green = t0,Black = t10,Crit Care Med 2002; 30: 1250-1255,当血液通过吸附以后对PF的反应明显增加了，更容易产生TNF ,Conclusions,There is a biologic rationale for CPFA 从生物学原理的角度上讲，CPFA是可行的 There is ex-vivo evidence of adsorption 在体外试验中，有证据表明黏附的存在 There is animal evidence of increased survival 动物试验的证据支持其可以正加存活率 A Phase I trial shows beneficial hemodynamic effects in humans with septic shock 一期临床试验显示出其对感染中毒性休克的病人血流动力学的改善,Problems with CPFA,Plasmafilter can take limited blood flows 血浆滤器的血流速度是有限的 Limited blood flow = limited PF rate 有限的血流有限的PF Limited PF rate = limited clearance 有限的PF有限的清除率 Even with 100% adsorption, clearance can only be 30-35 ml/min 即使黏附作用是100，但清除率只能是3035ml/min We may need more 我们要的不止这些,Super High Flux Filters (nominal pore size = 100 kD) 超高通量滤器,Easier to use Do not need complex CPFA circuit Cheaper Can be used by anyone If combined with HVHF may offer “best value” 如果结合HVHF，可能更据价值,Clearances (ml/min) of cytokines and albumin in 1L/hr ultrafiltration(ml/min) 1L/hr超滤量时，细胞因子及蛋白的清除,Polyamide super high-flux filter 多聚酰胺高通量滤器,Note low IL-8 clearance,Uchino, Bellomo et al. Intensive Care Med 2002; 28: 651-655,Figure 2B: Clearances (ml/min) of cytokines and albumin in 6L/hr UF (ml/min),Polyamide SHF filter + HVHF 聚酰胺超高通量滤器HVHF,Loss of SC with increased UF rate and time,Uchino, Bellomo et al. Intensive Care Med 2002; 28: 651-655,Figure 2A: Clearances of cytokines and albumin in 1L/hr ultrafiltration (ml/min),Cellulose triacetate SHF filter + HVHF 三醋酸纤维素高通量滤器HVHF,Low clearance for MW,Uchino, Bellomo et al. Int J Artif Organs 2002; 25: 27-32,Figure 2B: Clearances of cytokines and albumin in 6L/hr ultrafiltration (ml/min),Cellulose triacetate SHF filter + HVHF,Loss of SC,Observations 观测结果,Polyamide and cellulose triacetate are different. Polyamide is better. 多聚酰胺膜效果较好 Increasing UF rate increases clearance but decreases SC Time effect small 时间对它的影响较少 Albumin losses sustainable 蛋白的丢失是可以忍受的 Highest cytokine removal ever reported! 这是迄今为止所有报道中细胞因子清除得最多的,Can we dialyze cytokines? 我们是否真正能够对细胞因子透析？,Hemofiltration requires h