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Recent advances in extracorporeal therapies

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Recent advances in extracorporeal therapies

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Recent advances in extracorporeal therapies

  1. 1. R cn a vne iet croel ea i ee td a csn x aop rat rpe r h s
  2. 2. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 e6 Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apmeReview ArticleRecent advances in extracorporeal therapiesShamik H. Shah*ISN Fellow, Department of Nephrology, Apollo Hospitals, Gandhinagar, Ahmedabad, Gujarat 382428, Indiaarticle info abstractArticle history: Continuous renal replacement therapies (CRRT) started as continuous arterio-venous he-Received 31 December 2012 modialysis (CAVH)2 in the 1970s. Since then, the last 4 decades have seen numerous im-Accepted 3 January 2013 provements in extracorporeal therapies. Some of the notable improvements have been theAvailable online 22 January 2013 development of veno-venous therapies, the development of special low resistance filters with special geometry and fibers and improved machine safety with the use of micro-Keywords: processors and sensors.Hemoperfusion Classic extracorporeal therapies have focused on the removal of small solutes for effi-Polymyxin B cacy. However, it is well known that the characteristics of some solutes make their removalHigh cut off (HCO) membranes difficult. Also, limitations in efficiency of dialysis membranes, advances in hemadsorptionCytokine binding therapies and the development of newer filters have led to the application of extracorporeal ther- apies in the management of patients with multi-organ failure and sepsis, refractory con- gestive heart failure, acute neurologic injury, liver failure and patients with various other ailments. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.1. Introduction advances in hemadsorption and the development of newer filters have led to the application of extracorporeal therapies inDr. Willem Kolff is considered to be the father of extrac- the management of patients with multi-organ failure andorporeal therapies. This young Dutch physician constructed sepsis, refractory congestive heart failure, acute neurologicthe first dialyzer in 1943.1 injury, liver failure and patients with various other ailments. Continuous renal replacement therapies (CRRT) started as In this article, we will look at some of the recent advancescontinuous arterio-venous hemodialysis (CAVH)2 in the 1970s. in extracorporeal therapies in the management of suchSince then, the last 4 decades have seen numerous improve- patients.ments in extracorporeal therapies. Some of the notable im-provements have been the development of veno-venoustherapies, the development of special low resistance filters 2. Sepsiswith special geometry and fibers and improved machinesafety with the use of microprocessors and sensors. Sepsis is responsible for more than 20% of ICU admissions. Classic extracorporeal therapies have focused on the Despite recent advances in therapy, the mortality remainsremoval of small solutes for efficacy. However, it is well known disappointingly high.3that the characteristics of some solutes make their removal At present, it is believed that the sepsis syndrome reflectsdifficult. Also, limitations in efficiency of dialysis membranes, an imbalance of pro- and anti-inflammatory mediators, * Tel.: þ91 9924449956. E-mail address: shamik.shah@yahoo.com.0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.http://dx.doi.org/10.1016/j.apme.2013.01.003
  3. 3. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 e6 3resulting in immunodysregulation. Either group of mediators have published their experience in myoglobinuric acute kid-can be present in excess, in different compartments, and at ney injury.12 In patients with myoglobinuric acute kidneydifferent times.4 The abnormal “peak concentrations” of me- injury, HCO membranes have been found to reduce serumdiators is believed to be pathogenic. It is this state of systemic myoglobin levels up to 50%.13“hyperinflammation” that is injurious to many different or-gans, including the kidneys. This excessive response by the 2.3. Cytokine binding therapiesbody is associated with the production of inflammatory mol-ecules (“mediators”), which circulate in the blood and cause This therapy is based on biocompatible, highly porous poly-tissue and organ damage. These molecules are much larger in mer beads that can actively capture and absorb cytokines inmolecular weight (approximately 5e50 kDa) than conven- the À10 to 50 kDa range by pore capture and adsorption. Thetional uremic molecules (e.g., urea, creatinine) and are poorly therapy is flexible as it is compatible with standard hemodi-removed by standard high-flux membranes. alysis machines. It also aims to reduce cytokines and mitigate cytokine storm that is associated with multiple organ failure2.1. Hemoperfusion with polymyxin B and death in critical care illness. These columns, such as CytoSorb, CYT-860-DHP, Lixelle,Hemoperfusion is a process to remove a toxic substance from CTR-001 and MPCF-X, have excellent adsorption rates for in-a patient’s blood by pumping the blood over an absorbent flammatory cytokines such as TNF-alpha, IL-1beta, IL-6 andsurface. The inside of a column is packed with polystyrene IL-8.14fibers coated with the antibiotic polymyxin B. This material Various animal models have demonstrated a beneficialhas a high affinity for endotoxin and as blood passes through effect on inflammatory response and survival.15,16the column, endotoxin is tightly adsorbed onto the polymyxin In addition to sepsis, these columns have been successfullyB coated fibers. This process is known as direct hemoperfu- utilized in treatment of idiopathic thrombocytopenic pur-sion with polymyxin (DHP-PMX) and has been certified for use pura17 and digoxin intoxication18 and dialysis relatedin Europe since 1998 and in Japan since 2004. amyloidosis.19 Several prospective randomized controlled trials (RCTs)have been conducted in European countries. The first RCT,performed in six European academic medical centers in 2005,5 2.4. Coupled plasma filtration and adsorption (CPFA)concluded that PMX-DHP is associated with improved hemo-dynamic status and cardiac function. Coupled plasma filtrationeadsorption (CPFA) is an extrac- Subsequently, a meta-analysis of PMX-DHP was presented orporeal therapy that uses plasma filtration associated within Italy in 2007.6 This systematic review found positive effects an adsorbent cartridge and hemofiltration in post dilution toof PMX-DHP on mean arterial pressure and dopamine/dobut- remove cytokines and inflammatory mediators associatedamine use, PaO2/FiO2 ratio, endotoxin removal, and mortality. with septic shock and severe sepsis.However, like most trials on extracorporeal therapies, none of In in-vitro studies conducted by Livigni et al, the resin usedthe studies was double-blinded. The EUPHAS study,7 a multi- in the CPFA adsorptive cartridge showed higher than 80%center randomized controlled trial (RCT) performed in ten adsorption under both static and dynamic conditions for: IL-Italian intensive care units in 2009, found that PMX-DHP 1a, IL-6, IL-8, MIP-1a and MIP-1b, TNFa, MCP, myoglobin.20improved 28-day survival, blood pressure, vasopressor A small randomized trial by Hu et al21 in 14 patientsrequirement, and degree of organ failure. showed that CPFA could be superior to high volume hemofil- Two more RCTs, the ABDO-MIX and EUPHRATES studies, tration (HVHF) in improving the clinical manifestations andthe primary end points of which are 28-day mortality, were eliminating inflammatory mediators.started in Europe and the United States at the end of 2010 and In patients with severe acute pancreatitis, 1 group of pa-will hopefully provide more answers. tients was treated with continuous veno-venous hemofiltra- tion (CVVH). The other group received CPFA with CVVH and2.2. High cut off (HCO) membranes was found to be superior in terms of oxygenation index (PaO2/ FiO2), mean arterial pressure, serum amylase, blood urea ni-A new generation of hemodialysis membranes with molecular trogen and 28-day mortality.22weight cut-offs closer to that of the native kidney (65 kDa) has Fifty-five septic patients were enrolled in an Italianled to work assessing their potential utility across several multi-centric study.23 Every patient had four CPFA treat-different clinical scenarios. ments. The investigators evaluated hemodynamic parame- HCO membranes effectively remove cytokines from blood. ters, norepinephrine dosage, PaO2/FiO2 ratio, plasma IL-6,Treatment using HCO membranes has beneficial effects on and procalcitonin (PCT). They concluded that CPFA mayimmune cell function and increases survival in animal models improve hemodynamic status and respiratory function byof sepsis. In-vitro studies have shown that high cut-off hae- plasma filtration and adsorption of proinflammatorymofilters achieve high clearances for inflammatory mediators mediators.like IL-6 and TNF-a.8,9 Preliminary clinical studies show that Turani et al enrolled 77 patients in a study comparing CPFAHCO membranes decrease plasma cytokine levels and the with continuous veno-venous hemodialysis (CVVHDF). Theneed for vasopressor therapy.10 authors found that CPFA was more efficient than CVVHDF in Clinicians are now using these membranes for the treat- removing IL-6 and procalcitonin (PCT) and in improving he-ment of myeloma kidney11 and rhabdomyolysis. Premru et al modynamic status.24
  4. 4. 4 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 e6 treated with ultrafiltration had a more pronounced reduction3. Extracorporeal carbon dioxide removal in signs and symptoms of HF and a significant decrease in(ECCO2R) plasma aldosterone and NT-proBNP levels than the diuretic group. The ultrafiltration group also showed a significantExtracorporeal membrane carbon dioxide removal is used to improvement in stroke volume index, cardiac index, cardiactreat respiratory failure in critically ill patients. The aim is to power output and various other criteria.remove excess carbon dioxide from the blood. The patient willstill need to receive oxygen by mechanical ventilation. Blood isdrawn from the circulation and passed through a synthetic 6. CRRT in acute neurologic injurymembrane, where carbon dioxide is removed, before it isreturned to the circulation. Little is known about the effects of hemodialysis on the Kolobow et al25 first described the use of veno-venous injured brain, however; concern exists over the use of inter-carbon dioxide removal (VVCO2R) in an experimental sheep mittent hemodialysis in patients with acute brain injury (ABI)model. Since then, a number of studies have shown that due to its hemodynamic effects and increased intracranialECCO2R effectively allows the decoupling of oxygenation from pressure (ICP) associated with therapy. Continuous renalCO2 removal. replacement therapy (CRRT) has become the preferred In a study by Terragni et al,26 VV-ECCO2R successfully method of renal support in these patients.treated hypercapnic acidosis in all patients and allowed the CRRT is an option for the treatment of hypervolemia and inprotective ventilation strategy to continue. The study also theory may improve intracranial compliance.demonstrated a reduction in bronchoalveolar inflammatory Fletcher et al35 report a case of traumatic brain injury withcytokines (IL-6, IL-8, IL-1b, IL-Ra) after 72 h of ventilation. In refractory intracranial hypertension in which continuousanother study,27 the authors reported a reduction in mortality hemofiltration was found useful because of gentle removal ofin relation to a retrospective comparator group. fluid, solutes, and inflammatory cytokines. There have been short case series and anecdotal reports of Another small case series36 also reports the beneficial ef-use in diverse clinical scenarios like near-fatal asthma, com- fects of CRRT in patients with refractory intracranialbined head and chest injury, as a bridge to transplant and in hypertension.facilitating weaning and transfer of patients. 7. Liver failure4. Cell binding therapies An accumulation of both water-soluble and water-insoluble,Researchers have hypothesized that exposing circulating protein-bound, metabolic waste products occurs in patientsblood to cells outside the body would add antimicrobial or with acute or acute on chronic liver failure. Conventionalinflammation modulating properties. Such bioartificial de- extracorporeal blood purification techniques based on dif-vices may help in critical differentiated transport and improve fusion and/or convection may only eliminate small molecularendocrine and metabolic functions of the kidney.28 weight, water-soluble compounds. In recent years, fractio- Altrichter et al have published their experience of a pilot nated plasma separation and adsorption (FPSA) has beenstudy of 10 patients with septic shock in which they demon- introduced for extracorporeal liver support therapy.strated reduced need for pressor support and improvements Oppert et al37 have published data about 23 patients trea-in biomarkers of sepsis.29 ted with FPSA with the Prometheus system. In 40 sessions, this therapy significantly reduced bilirubin levels and accor- ded a survival rate of 26%. However, in another randomized5. Hemofiltration in congestive heart failure study,38 the results were not that encouraging. Huang et al39 conducted a prospective, randomized con-Extracorporeal ultrafiltration (UF) is found to be useful in pa- trolled study to evaluate the effects of plasma exchange (PE)tients with refractory congestive heart failure (rCHF). It has with molecular adsorbent re-circulating system (MARS) onbeen seen that after UF, right atrial pressure and pulmonary patients with acute on chronic liver failure and hepatic en-wedge pressure decrease, pulmonary and peripheral edema cephalopathy. They found that PE þ MARS therapy effectivelyreduce, mechanical lung function improves and diuretic effi- reduces serum bilirubin levels and is more cost effective.cacy is restored.30e32 In the UNLOAD33 trial, UF produced greater fluid reductionand fewer heart failure (HF) rehospitalizations than IV di- 8. Conclusionuretics in 200 hospitalized patients. The authors observed thatdespite similar fluid loss with UF and continuous diuretic There have been tremendous innovations and developmentsinfusion, fewer HF rehospitalizations equivalents occurred in extracorporeal therapies over the past few decades. Rapidonly with UF. Removal of isotonic fluid by UF compared with strides are being made in diverse therapeutic areas. Newerhypotonic urine by diuretics more effectively reduced total developments have made the possibility of multi-organ sup-body sodium in congested HF patients. port therapy a reality. In another trial,34 thirty patients with decompensated HF All of these approaches are yet to be proven in a convincingwere randomly assigned to diuretics or ultrafiltration. Patients manner. To that end, many large trials are under way. In this
  5. 5. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 e6 5exciting new realm of extracorporeal therapies, nephrologists endotoxin-induced shock in rats. Ther Apher Dial. 2006should join hands with colleagues from other specialties and Feb;10(1):49e53.lead the way. 17. Takenaka T, Suzuki H. Lixelle ameliorates idiopathic thrombocytopenic purpura. Nephrol Dial Transplant. 2003 May 1;18(5):1032e1033. 18. Kaneko T, Kudo M, Okumura T, et al. Successful treatment ofConflicts of interest digoxin intoxication by haemoperfusion with specific columns for b2-microgloblin-adsorption (Lixelleä) inThe author has none to declare. a maintenance haemodialysis patient. Nephrol Dial Transplant. 2001 Jan 1;16(1):195e196. 19. Kuragano T, Inoue T, Yoh K, et al. Effectiveness of beta(2)- microglobulin adsorption column in treating dialysis-relatedreferences amyloidosis: a multicenter study. Blood Purif. 2011;32(4):317e322. 20. Livigni S, Silengo D, Maio M, et al. Characterization of the 1. Kolff WJ. The artificial kidney. J Mt Sinai Hosp N Y. 1947 coupled plasma filtration-adsorption resin cartridge JuleAug;14(2):71e79. adsorptive capacity for cytokines and inflammatory 2. Kramer P, Wigger W, Rieger J, Matthaei D, Scheler F. mediators: adsorption profiles from septic patient plasma [Arteriovenous haemofiltration: a new and simple method for and in vitro endotoxin-stimulated whole blood. Crit Care. treatment of over-hydrated patients resistant to diuretics]. 2007;11(suppl 2):118. Klin Wochenschr. 1977 Nov 15;55(22):1121e1122. 21. Hu D, Sun S, Zhu B, et al. Effects of coupled plasma filtration 3. Martin GS. Sepsis, severe sepsis and septic shock: changes in adsorption on septic patients with multiple organ incidence, pathogens and outcomes. Expert Rev Anti Infect dysfunction syndrome. Ren Fail. 2012;34(7):834e839. Ther. 2012 Jun;10(6):701e706. 22. He C, Zhang L, Shi W, et al. Coupled plasma filtration 4. Ronco C, Bonello M, Bordoni V, et al. Extracorporeal therapies adsorption combined with continuous veno-venous in non-renal disease: treatment of sepsis and the peak hemofiltration treatment in patients with severe acute concentration hypothesis. Blood Purif. 2004;22(1):164e174. pancreatitis. J Clin Gastroenterol; 2012 Oct 17. 5. Vincent JL, Laterre PF, Cohen J, et al. A pilot-controlled study 23. Turani F, Falco M, Natoli S, et al. Coupled plasma filtration of a polymyxin B-immobilized hemoperfusion cartridge in and adsorption in septic shock: a multicentric experience. Crit patients with severe sepsis secondary to intra-abdominal Care. 2010;14(suppl 1):412. infection. Shock. 2005 May;23(5):400e405. 24. Turani F, Falco M, Barchetta R, Candidi F, Marinelli A, Di 6. Cruz DN, Perazella MA, Bellomo R, et al. Effectiveness of Corato C. Different effect of CVVHDF and coupled plasma polymyxin B-immobilized fiber column in sepsis: filtration and adsorption on IL-6 and procalcitonin in sepsis. a systematic review. Crit Care. 2007;11(2):R47. Crit Care. 2011;15(suppl 1):117. 7. Cruz DN, Antonelli M, Fumagalli R, et al. Early use of 25. Kolobow T, Borelli M, Spatola R, Tsuno K, Prato P. Single polymyxin B hemoperfusion in abdominal septic shock: the catheter veno-venous membrane lung bypass in the EUPHAS randomized controlled trial. JAMA. 2009 Jun treatment of experimental ARDS. ASAIO Trans. 1988 17;301(23):2445e2452. JaneMar;34(1):35e38. 8. Morgera S, Klonower D, Rocktaschel J, et al. TNF-a elimination ¨ 26. Terragni PP, Del Sorbo L, Mascia L, et al. Tidal volume lower with high cut-off haemofilters: a feasible clinical modality for than 6 ml/kg enhances lung protection: role of extracorporeal septic patients? Nephrol Dial Transplant. 2003 July carbon dioxide removal. Anesthesiology. 2009 1;18(7):1361e1369. Oct;111(4):826e835. 9. Mariano F, Fonsato V, Lanfranco G, et al. Tailoring high-cut- 27. Zimmermann M, Bein T, Arlt M, et al. Pumpless off membranes and feasible application in sepsis-associated extracorporeal interventional lung assist in patients with acute renal failure: in vitro studies. Nephrol Dial Transplant. acute respiratory distress syndrome: a prospective pilot 2005 June;20(6):1116e1126. study. Crit Care. 2009;13(1):R10.10. Haase M, Bellomo R, Baldwin I, et al. The effect of three 28. Humes HD, Mackay SM, Funke AJ, Buffington DA. Tissue different miniaturized blood purification devices on plasma engineering of a bioartificial renal tubule assist device: cytokine concentration in an ex vivo model of in vitro transport and metabolic characteristics. Kidney Int. endotoxinemia. Int J Artif Organs. 2008 Aug;31(8):722e729. 1999;55(6):2502e2514.11. Kanayama K, Ohashi A, Hasegawa M, et al. Comparison of 29. Altrichter J, Sauer M, Kaftan K, et al. Extracorporeal cell free light chain removal by four blood purification methods. therapy of septic shock patients with donor granulocytes: Ther Apher Dial. 2011 Aug;15(4):394e399. a pilot study. Crit Care. 2011;15(2):R82.12. Premru V, Kovac J, Buturovic-Ponikvar J, Ponikvar R. High 30. Silverstein ME, Ford CA, Lysaght MJ, Henderson LW. cut-off membrane hemodiafiltration in myoglobinuric Treatment of severe fluid overload by ultrafiltration. N Engl J acute renal failure: a case series. Ther Apher Dial. 2011 Med. 1974 Oct 10;291(15):747e751. Jun;15(3):287e291. 31. Simpson IA, Rae AP, Simpson K, et al. Ultrafiltration in the13. Albert C, Haase M, Bellomo R, Mertens PR. High cut-off and management of refractory congestive heart failure. Br Heart J. high-flux membrane haemodialysis in a patient with 1986 Apr;55(4):344e347. rhabdomyolysis-associated acute kidney injury. Crit Care 32. Canaud B, Leray-Moragues H, Garred LJ, et al. Slow Resusc. 2012 Jun;14(2):159e162. isolated ultrafiltration for the treatment of congestive14. Taniguchi T. Cytokine adsorbing columns. Contrib Nephrol. heart failure. Am J Kidney Dis Off J Natl Kidney Found. 2010;166:134e141. 1996;28(5):S67eS73.15. Tsuchida K, Yoshimura R, Nakatani T, Takemoto Y. Blood 33. Costanzo MR, Saltzberg MT, Jessup M, Teerlink JR, purification for critical illness: cytokines adsorption therapy. Sobotka PA. Ultrafiltration is associated with fewer Ther Apher Dial. 2006 Feb;10(1):25e31. rehospitalizations than continuous diuretic infusion in16. Tsuda K, Taniguchi T. Effects of extracorporeal treatment patients with decompensated heart failure: results from with Lixelle on the mortality and inflammatory responses to UNLOAD. J Card Fail. 2010 Apr;16(4):277e284.
  6. 6. 6 a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 e634. Giglioli C, Landi D, Cecchi E, et al. Effects of ULTRAfiltration failure in the intensive care unit. Ther Apher Dial. 2009 vs. DIureticS on clinical, biohumoral and haemodynamic Oct;13(5):426e430. variables in patients with deCOmpensated heart failure: the 38. Kribben A, Gerken G, Haag S, et al. Effects of fractionated ULTRADISCO study. Eur J Heart Fail. 2011 Mar;13(3):337e346. plasma separation and adsorption on survival in patients35. Fletcher JJ, Bergman K, Feucht EC, Blostein P. Continuous with acute-on-chronic liver failure. Gastroenterology. 2012 renal replacement therapy for refractory intracranial Apr;142(4):782e789. e3. hypertension. Neurocrit Care. 2009;11(1):101e105. 39. Huang YK, Tan DM, Xie YT, et al. Randomized36. Fletcher JJ, Bergman K, Carlson G, Feucht EC, Blostein PA. controlled study of plasma exchange combined with Continuous renal replacement therapy for refractory molecular adsorbent re-circulating system for the intracranial hypertension? J Trauma. 2010 Jun;68(6):1506e1509. treatment of liver failure complicated with hepatic37. Oppert M, Rademacher S, Petrasch K, Jorres A. Extracorporeal encephalopathy. Hepatogastroenterology. 2012 liver support therapy with Prometheus in patients with liver JuleAug;59(117):1323e1326.
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