Recent advances in extracorporeal therapies

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Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
Review Article
Recent advances in extracorporeal therapies
Shamik H. Shah*
ISN Fellow, Department of Nephrology, Apollo Hospitals, Gandhinagar, Ahmedabad, Gujarat 382428, India
article info abstract
Article 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 the
Available 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 removal
High cut off (HCO) membranes difficult. Also, limitations in efficiency of dialysis membranes, advances in hemadsorption
Cytokine 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 in
Dr. Willem Kolff is considered to be the father of extrac- the management of patients with multi-organ failure and
orporeal therapies. This young Dutch physician constructed sepsis, refractory congestive heart failure, acute neurologic
the 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 advances
continuous arterio-venous hemodialysis (CAVH)2 in the 1970s. in extracorporeal therapies in the management of such
Since 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-venous
therapies, the development of special low resistance filters 2. Sepsis
with special geometry and fibers and improved machine
safety 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 remains
removal of small solutes for efficacy. However, it is well known disappointingly high.3
that the characteristics of some solutes make their removal At present, it is believed that the sepsis syndrome reflects
difficult. 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. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 e6 3
resulting 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 kidney
different times.4 The abnormal “peak concentrations” of me- injury, HCO membranes have been found to reduce serum
diators 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 therapies
body 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 in
molecular weight (approximately 5e50 kDa) than conven-
the À10 to 50 kDa range by pore capture and adsorption. The
tional 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 failure
2.1. 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 and
surface. The inside of a column is packed with polystyrene
IL-8.14
fibers coated with the antibiotic polymyxin B. This material
Various animal models have demonstrated a beneficial
has a high affinity for endotoxin and as blood passes through
effect on inflammatory response and survival.15,16
the column, endotoxin is tightly adsorbed onto the polymyxin
In addition to sepsis, these columns have been successfully
B 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 related
in 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 with
in Italy in 2007.6 This systematic review found positive effects an adsorbent cartridge and hemofiltration in post dilution to
of PMX-DHP on mean arterial pressure and dopamine/dobut- remove cytokines and inflammatory mediators associated
amine 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 used
the 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.20
improved 28-day survival, blood pressure, vasopressor A small randomized trial by Hu et al21 in 14 patients
requirement, 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 and
the 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 and
2.2. 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.22
weight cut-offs closer to that of the native kidney (65 kDa) has Fifty-five septic patients were enrolled in an Italian
led 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 may
immune cell function and increases survival in animal models improve hemodynamic status and respiratory function by
of sepsis. In-vitro studies have shown that high cut-off hae- plasma filtration and adsorption of proinflammatory
mofilters 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 CPFA
HCO membranes decrease plasma cytokine levels and the with continuous veno-venous hemodialysis (CVVHDF). The
need 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 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 reduction
3. 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 significant
Extracorporeal membrane carbon dioxide removal is used to improvement in stroke volume index, cardiac index, cardiac
treat 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 will
still need to receive oxygen by mechanical ventilation. Blood is
drawn from the circulation and passed through a synthetic 6. CRRT in acute neurologic injury
membrane, where carbon dioxide is removed, before it is
returned 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 intracranial
ECCO2R effectively allows the decoupling of oxygenation from pressure (ICP) associated with therapy. Continuous renal
CO2 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 in
protective 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 with
cytokines (IL-6, IL-8, IL-1b, IL-Ra) after 72 h of ventilation. In refractory intracranial hypertension in which continuous
another study,27 the authors reported a reduction in mortality hemofiltration was found useful because of gentle removal of
in 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 intracranial
bined head and chest injury, as a bridge to transplant and in hypertension.
facilitating weaning and transfer of patients.
7. Liver failure
4. 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 patients
blood to cells outside the body would add antimicrobial or with acute or acute on chronic liver failure. Conventional
inflammation 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 molecular
endocrine 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 been
study 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 randomized
5. 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) on
been 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 effectively
reduce, 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 reduction
and fewer heart failure (HF) rehospitalizations than IV di- 8. Conclusion
uretics in 200 hospitalized patients. The authors observed that
despite similar fluid loss with UF and continuous diuretic There have been tremendous innovations and developments
infusion, fewer HF rehospitalizations equivalents occurred in extracorporeal therapies over the past few decades. Rapid
only with UF. Removal of isotonic fluid by UF compared with strides are being made in diverse therapeutic areas. Newer
hypotonic 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 convincing
were randomly assigned to diuretics or ultrafiltration. Patients manner. To that end, many large trials are under way. In this

5. a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 2 e6 5
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Conflicts of interest digoxin intoxication by haemoperfusion with specific
columns for b2-microgloblin-adsorption (Lixelleä) in
The author has none to declare. a maintenance haemodialysis patient. Nephrol Dial Transplant.
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