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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: firstname.lastname@example.org/$ 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
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 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
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