Choice of Extracorporeal Therapies
Alessandra Brendolan and MD Dinna Cruz, MD, MPH
Department of Nephrology
San Bortolo Hospital,
Alessandra Brendolan, MD
Department of Nephrology
St. Bortolo Hospital
Visit us at http://www.nefrologiavicenza.it
AKI – Acute kidney injury
A-V - Arteriovenous
CAVH - Continuous arteriovenous hemofiltration
CAVHD - Continuous arteriovenous hemodialysis
CAVHDF - Continuous arteriovenous hemodiafiltration
CKD – Chronic kidney disease
CPFA Continuous plasmafiltration adsorption
CRRT - Continuous renal replacement therapy
CVVH – Continuous venovenous hemofiltration
CVVHD - Continuous venovenous hemodialysis
CVVHDF – Continuous venovenous hemodiafiltration
EDD – Extended Daily Dialysis
EDHFD – Extended Daily High Flux Hemodialysis
HVHF – High volume hemofiltration
PDIRRT – Prolonged Daily Intermittent Renal
PHVHF – Pulse high volume hemofiltration
RRT – Renal replacement therapy
SCUF – Slow continuous ultrafiltration
SLED – Sustained Low Efficiency Dialysis
SLEDD – Slow Extended Daily Dialysis
V-V - Venovenous
The most serious form of acute kidney injury (AKI) with the highest morbidity and mortality is found in patients in the intensive care unit (ICU). Up to 23% of ICU admissions develop AKI, and mortality is significantly higher in patients who acquire AKI. Both the incidence of and the mortality from AKI are the highest among patients with severe sepsis. In these patients, the kidney is but one of the systems involved in the multi system organ failure (MSOF). The cornerstone of the therapy continues to be early recognition, prompt initiation of antibiotic therapy, and elimination of the underlying infection. Goal-directed hemodynamic, ventilatory and metabolic support is also crucial. In this setting, dialysis or renal replacement therapy is an adjuvant treatment, and its influence on patient outcome may depend less on the dialysis dose per se, but more on the degree to which it is able to support the other organ systems.
It is difficult to provide adequate renal replacement therapy (RRT) to the critically ill patient with AKI. Several factors contribute to this. First, these patients are hemodynamically unstable and tend to become more so when placed on extracorporeal therapy. Secondly, the critically ill patient is highly catabolic, and many factors alter urea generation in these patients on a day-to-day, if not hour-to-hour basis. Therefore, traditional urea kinetic modeling as utilized for end-stage renal disease (Stage 5 CKD/ Chronic Kidney Disease) patients, would not be applicable and would result in under-dialysis in these patients . In addition, volume status is an especially important factor to consider when deciding to initiate RRT in a patient with AKI. Volume excess is an independent risk factor for mortality. Patients dialyzed for solute control had better outcome than those dialyzed for volume control; while patients dialyzed for both volume and solute control had the worst prognosis. Volume status is also an important issue in prescribing and delivering an adequate dialysis regimen. Critically ill patients often have a significant amount of “third spacing”, and patient volume as a factor of patient weight may increase from 60% to as high as 75% in acute renal failure. Therefore a dialysis prescription based on Stage 5 CKD assumptions will again underestimate the dialysis delivery goal. Excessive volume expansion also enhances urea rebound. This rebound is due not only to urea redistribution, but also to disparate blood flow to peripheral urea pools, especially in a patient on vasopressor agents. Hemodynamic instability also severely limits the amount of fluid which can be removed. Other factors which compromise the adequacy of dialysis in the critically ill patient include the use of heparin-free regimens, which may reduce the dialyzer surface area, and temporary catheters, which have higher recirculation rates than the permanent vascular access used in ESRD.
Fortunately, many technological advances in the past 20 years have resulted in the development of more sophisticated dialysis techniques, including continuous therapies (CRRT) that allow us to perform renal replacement therapy more efficiently in these patients.
The term “conventional” or “standard” intermittent hemodialysis (IHD) refers to hemodialysis treatments between 3 to 4 hours duration performed thrice weekly or on alternate days, as is routinely done in Stage 5 CKD patients. Unfortunately, such standard IHD is profoundly un-physiological when applied to critically ill patients with AKI. These shortcomings relate to hemodynamic instability, the need to remove large volumes of fluid over a short period of time, inadequate small solute control and acid-base balance in these highly catabolic patients, and the limited ability to achieve middle molecular weight solute control. Furthermore, the use of IHD may impose limitations on calorie and protein intake to further posing major disadvantages in these patients. Finally, the rapid solute shifts induced by standard HD induce significant changes in cerebral water, which participate in the pathogenesis of the dysequilibrium syndrome and increased intracranial pressure in patients with, or at risk for, cerebral edema.
There is extensive evidence that the survival of critically ill patients with AKI is influenced by the intensity of RRT. A retrospective study at the Cleveland Clinic showed that a higher dialysis dose, as measured by Kt/V, was associated with improved survival in patients with intermediate severity of critical illness. Increased solute clearance appeared to confer a survival advantage, although this advantage was no longer apparent in patients in either extremely severe or mild MSOF. These retrospective studies suggest that the high mortality rate of AKI may be reduced by maximizing solute clearance.
In a prospective trial, Schiffl and colleagues compared the outcome of critically ill patients treated with daily versus alternate day IHD, at 3.3-3.4 hours per session. As expected, daily dialysis resulted in a higher weekly delivered dialysis dose, as measured by Kt/V. Mortality was significantly lower in the daily dialysis group compared to the alternate day dialysis group (28% vs. 46%, respectively, p =0.01). On a multiple logistic regression analysis, frequency of dialysis remained a significant factor affecting mortality. Time to renal recovery was also significantly shorter in the daily dialysis group (9 2 days vs. 16 6 days in alternate day dialysis group, p=0.001). Fewer hypotensive episodes in the daily dialysis group may be one potential explanation for this finding. The authors concluded that intensive hemodialysis reduces mortality, and further stated that alternate day dialysis should no longer be considered adequate treatment for critically ill patients with ARF.
Nevertheless, IHD remains a widely used treatment in the ICU at present, and will remain an important tool in less developed nations. Appropriate patient selection for IHD and flexibility of the nephrologist to adapt treatment to the clinical needs of the patient is the key. Special attention should be paid to the patient’s weight and total body water when prescribing IHD. Frequent stop-and-start of the treatment due to hypotension also reduces actual effective dialysis time as compared to the “clock time” of the dialysis session, and should also be taken into consideration.
Because of the shortcomings of even daily IHD in the critical care setting, the last 20 years have seen the progressive rise of continuous renal replacement therapy as the prevailing technique of artificial renal support in the intensive care unit, at least in developed countries. CRRT is the acronym used to refer to a group of renal replacement therapies that are applied continuously to critically ill patients with brief interruptions for hemofilter replacement, diagnostic or surgical procedures. There has been no consensus on the superiority of either continuous or intermittent techniques in terms of patient survival. Randomized controlled studies have been either underpowered, or resulted in significant inequalities between IHD and CRRT arms despite the randomization process. Of note are the studies by Mehta and Paganini who both used CRRT doses which would be considered relatively low by current standards. In particular, Paganini’s study used only a diffusive technique (CVVHD, as discussed below). Two meta-analyses have yielded confusing results. However, results from Mehta’s trial suggest that renal recovery is significantly improved by the application of CRRT.
The first CRRT “system” was first described by Peter Kramer in 1977, which he christened with the term continuous arteriovenous hemofiltration (CAVH). This first arteriovenous (A-V) technique originated from an accidental puncture of a femoral artery instead of a femoral vein. A highly permeable filter was connected to the arterial access and the blood returned into a separate venous access, thus creating an A-V circuit without need of a pump. The A-V gradient was adequate to move the blood through the circuit and to create sufficient hydrostatic pressure in the filter to produce a certain amount of ultrafiltration. Since that time, the A-V circulation has been increasingly replaced by venovenous (V-V) techniques thanks to the application of peristaltic pumps. Several techniques are available today. They may differ in terms of vascular access and extracorporeal circuit design, frequency and intensity of treatment, mechanism of transport and type of membrane utilized (Table 1). A brief description of the most commonly used CRRT techniques follows.
Table 1: Common continuous renal replacement techniques
|Mode of Solute Removal||Type of Membrane|
|Slow Continuous Ultrafiltration (SCUF)||Slow Continuous Ultrafiltration (SCUF)||Not suitable for blood purification||High-flux; |
small surface area
|Continuous arteriovenous Hemofiltration (CAVH)||Continuous venovenous Hemofiltration (CVVH)||Convection||High-flux|
|Continuous arteriovenous hemodialysis (CAVHD)||Continuous venovenous hemodialysis (CVVHD)||Diffusion||Low-flux or |
|Continuous arteriovenous Hemodiafiltration (CAVHDF)||Continuous venovenous Hemodiafiltration (CVVHDF)||Convection and Diffusion||High-flux|
A-V or V-V SCUF
Slow continuous ultrafiltration (SCUF) is a treatment typically employed for 24 h/day or for only some hours/ day with an A-V or a V-V access using a blood pump. The treatment is carried out with high-flux membranes and the objective is to achieve volume control in fluid-overloaded patients. Since low filtration rates are required, filters with small surface are generally employed. When the system is utilized in the A-V mode, ultrafiltration is somehow self-limited. When a blood pump is utilized, a control system must be used to avoid excessive ultrafiltration. Because of the low filtration rates the treatment is not suitable for solute control, but only volume control.
Continuous hemofiltration is normally applied for an extended period of time up to several weeks. The treatment can be performed in either an A-V or V-V mode. The technique utilizes high-flux membranes and the prevalent mechanism of solute transport is convection. Ultrafiltration in excess of the amount required for volume control is produced and it is partially or totally replaced by fresh substitution fluid. In CAVH, the blood flow is regulated by the A-V pressure gradient and the circuit must be designed to prevent any unnecessary resistance to the circulation; for example, the length of blood tubing should be kept to a minimum. Under these circumstances, the rate of ultrafiltration may vary and it may be increased by lowering the position of the ultrafiltrate collecting bag. In CVVH, the blood flow is regulated by a blood pump and the rate of ultrafiltration can significantly increase. In general, the average ultrafiltration rate should not exceed 20% of the overall blood flow rate. In the presence of high filtration rates, systems for controlling the ultrafiltration and substitution fluid are used. There are several CRRT-dedicated machines currently on the market which utilize integrated volumetric control systems or volumetric pumps regulated by one or multiple scales. The substitution fluid can be infused either before the filter (pre-dilution) or after the filter (post-dilution). If pre-dilution is used, ultrafiltration must be increased slightly to maintain the same efficiency of solute removal observed in the post-dilution mode. Newer CRRT machines are now capable of working in the pre- and post-dilution mode at the same time according to pre-selected ratios.
Since the ultrafiltrate is replaced by the substitution fluid which is urea- and toxin-free, the treatment is used for both blood purification and volume control. Although the optimal rate of ultrafiltration is not yet entirely clear at this time, patient outcome appears to be better at an ultrafiltration rate of 35 ml/kg/hr when compared to a lower dose of 20 ml/kg/hr. At this time, this can be considered as the minimum dose which should be prescribed. There was no additional benefit in using an higher ultrafiltration rate (45 ml/kg/hr) in all-comers. However, a post-hoc analysis looking only at septic patients suggested a potential benefit of the higher dose in this subgroup of patients.
Continuous hemodialysis is a treatment carried out over an extended period of time using either an A-V access or a V-V pump-driven circuit. This treatment was originally described using a low-flux membrane such as cuprophan and a countercurrent flow of dialysate of 15-20 ml/min. Because of the nature of the membrane and the gradient provided by the dialysate, the prevalent mechanism of solute transport is diffusion.
The ultrafiltration rate is regulated to remove only enough fluid to keep the patient in a normovolemic state without the need for substitution fluid. Recently, with the availability of blood pumps, both the blood flow and dialysate flow could be increased, allowing the use of modified-cellulosic membranes and dialyzers with larger surface area. When dialysate is run at low flow rates, the fluid saturation is almost complete. When dialysate flow is increased in spite of a progressive desaturation of the spent dialysate, there is an increase in the small molecular weight solute clearances. Dedicated CRRT machines are able to control dialysate inlet and outlet dialysate flows. A further modification of these techniques is called continuous high-flux dialysis. In this technique high-flux dialyzers are utilized in a continuous hemodialysis circuit with continuous ultrafiltration control. Since the spontaneous ultrafiltration occurring in the hollow-fiber dialyzer would be much greater than the desired fluid loss, a positive pressure is automatically applied to the dialysate compartment and the transmembrane pressure is reduced significantly. This results in a very specific pressure profile inside the dialyzer. Large amounts of filtration and, therefore, convective transport, are maintained in the proximal part of the hemodialyzer in spite of a moderate net ultrafiltration. The net fluid balance is achieved by virtue of a significant amount of backfiltration of fresh dialysate in the distal (outlet) portion of the dialyzer. In this mechanism, diffusion and convection are combined. Clearance of middle to high-molecular weight solutes can reach values as high as 60% of that seen for low-molecular weight solutes such as urea. The system can be run in either a single-pass mode or recirculation mode.
Continuous hemodiafiltration is a treatment carried out over an extended period of time in A-V or V-V mode. This technique combines the principles of both hemodialysis and hemofiltration, using a high-flux hemodiafilter. Similar to CVVHD, dialysate is pumped in a countercurrent direction to blood. Simultaneously, ultrafiltration in excess of desired fluid loss is performed, and this is totally or partially replaced by substitution fluid in either the pre-dilution or post-dilution mode. Since this technique utilizes both principles of diffusion and convection for solute removal, optimal clearances are expected for both small and middle-molecular weight solutes.
CRRT and IHD both have features which are advantageous in the management of critically ill patients with AKI. CRRT provides relatively lower rates of ultrafiltration and solute clearances per unit time which are maintained for long periods. This results in improved hemodynamic stability, superior solute control without rapid solute shifts, even in severely catabolic patients. However, its continuous nature renders it labor-intensive and limits patient mobility for diagnostic, therapeutic or rehabilitative procedures. The need for dedicated machinery and sterile substitution fluid also add to the cost of therapy. Conversely, IHD allows convenient periods of unrestricted access to the patient, utilizes equipment already available in almost all tertiary care centers, and is generally thought to be more cost-effective with respect to the cost of the RRT alone. Therapeutic components of both modalities have been combined in the development of several “hybrid” therapies. Several different acronyms have been used in the literature for this genre of therapy, including EDD (Extended Daily Dialysis), EDHFD (Extended Daily High Flux Hemodialysis), SLED (Sustained Low Efficiency Dialysis), SLEDD (Slow Extended Daily Dialysis), and PDIRRT (Prolonged Daily Intermittent Renal Replacement Therapy). These terms clearly illustrate the fact that the stereotyped approach to IHD for AKI has been broken, and flexibility of therapy is crucial. The key principles of these hybrid therapies include the following: (1) standard or modified dialysis equipment is used; (2) Since dialysis is performed, the main mode of solute removal is by diffusion; (3) a lower than “standard” intensity of dialysis is used, and achieved by reducing blood flow and dialysis fluid rates; (4) the therapy is intermittent; and (5) the duration of therapy is longer than 4 hours to allow lower rates of fluid removal, intended to improve hemodynamic tolerance of the procedure and to compensate for the lower intensity of dialysis. In the literature, this has been performed usually, but not always, on a daily schedule.
A few centers have described their experience with hybrid techniques, the most extensive being that of the group at the University of Arkansas Medical Sciences Center. A general comparison of technical considerations among standard IHD, “standard” CRRT and hybrid therapy is presented in Table 2.
Table 2: Comparison of technical considerations in IHD, hybrid therapies and CRRT
|Frequency||3-4 days/week||5-7 days/week||Daily|
|Principle of solute removal||Diffusion||Diffusion1||Convection and diffusion|
|Machine||Standard HD equipment||Standard or modified HD equipment2||Usually dedicated machines|
|Blood flow (cc/min)||200-350||70-2003||80-200|
|Dialysate flow (cc/min)||500-600||70-3003||16-42|
|Substitution fluid||None||100 cc/min in SLEDD-f||16-754 |
|Dialyzer||Low or high-flux||Low or high-flux||Usually high-flux|
1Some convection in SLEDD-f
2The Fresenius 2008H requires activation of the ‘slow dialysis’ option in service mode with recalibration of dialysate temperature control to 37C at this flow rate. This task is automated by the use of newly available acute renal replacement therapy software.
3The Fresenius Genius machine operates at equal blood and dialysate flow, as low as 70 cc/min.
4Some CRRT machines are capable of higher substitution fluid rates.
Most reports deal with treatments of 12 hours, although both shorter and longer duration of dialysis have been published. The dialysis nurses are responsible for provision and initiation of SLEDD, while troubleshooting and discontinuation responsibilities are shared with ICU nursing personnel. Recently, two centers have published their experience in which the treatments were run entirely by ICU staff. Some centers perform their treatments nocturnally to allow unrestricted patient access for daytime procedures and tests, and to make the dialysis machines available for routine patients during the day. Other centers perform them during the day to avoid nighttime troubleshooting and to ensure constant review and readjustment of treatment goals. In terms of hemodynamic tolerance, in one study, up to 17% of treatments were associated with concurrent transient hypotension requiring modification of ultrafiltration goals, and approximately 50% of treatments were associated with concurrent transient increases in inotropic support, with a median dose increase of 66%. However, only 7.6% of treatments were prematurely terminated because of intractable hypotension. Other authors have reported hemodynamic stability comparable to CVVH. Small solute clearance is reported to be generally good, with some degree of urea rebound after discontinuation of therapy; however, vitamin B12 clearance was approximately half of that observed with CVVH.
A more recent development in hybrid therapies is SLEDD-f (Sustained Low Efficiency Daily Diafiltration). The availability of machines which are able to produce substitution fluid online has given the hybrid therapies the additional facet of convective solute removal. Initial experience with this technique in Australia and New Zealand using a dialysate flow of 200 cc/min and online hemofiltration at 100 cc/min for a targeted duration of 8 hours/day have been promising. The treatment appeared to be well-tolerated hemodynamically, and nursing acceptance in their ICUs was good. The addition of hemofiltration provided a considerable degree of convective clearance. It has been reported that SLEDD-f can provide small solute clearance comparable to CRRT doses of 35 ml/kg/hr, but is still less effective than CRRT for the removal of larger molecular weight solutes, as represented by vitamin B12. Further studies on this technique are anticipated in the near future.
Sepsis and other Extracorporeal Techniques
The pathogenesis of sepsis is complex, and involves a redundant, synergistic inflammatory network that acts like a cascade. Pro-inflammatory mediators including tumor necrosis factor- (TNF), interleukins (IL-1, IL-6, IL-8 and IL-10), interleukin 1 receptor antagonist, soluble TNF receptors types I and II and lipid mediators such as platelet activating factor (PAF) are produced and are considered to be of pathogenetic relevance. Almost paralleling the surge in pro-inflammatory mediators is a rise in anti-inflammatory substances, resulting in the induction of a state of immunoparalysis or monocyte hyporesponsiveness or deactivation. Both pro-inflammatory and anti-inflammatory factors become upregulated and interact with each other, leading to various peaks in mediator levels which change over time. The general picture of the clinical disorder is therefore better characterized as an immunodysregulation rather than as a simple pro- or anti-inflammatory disorder. Due to the short half-life of cytokines and other mediators, it is extremely difficult to approach the problem at the right moment with a targeted pharmacologic agent. And indeed, in intensive care, blocking any one mediator has not led to a measurable outcome improvement in patients with sepsis. With this in mind, one of the major criticisms attributed to continuous blood purification techniques in sepsis – its lack of specificity – could turn out to be a major point of strength. Non-specific removal of soluble mediators, be they pro- or anti-inflammatory, without completely eliminating their effect may be the most logical and adequate approach to a complex and long-running process like sepsis. The concept of cutting peaks of soluble mediators, e.g. through continuous hemofiltration, is a paradigm that has been called the “peak concentration hypothesis”. However, removal rates and clearances of pro-inflammatory cytokines are hindered by limited diffusive or convective rates in standard CVVH or CVVHDF. Other extracorporeal techniques such as high volume hemofiltration, coupled plasma filtration adsorption, and use of high cut-off membranes show promise in this regard.
High Volume Hemofiltration (HVHF) and Pulse High Volume Hemofiltration (PHVHF)
In vitro studies have shown that hemofiltration is capable of removing to some degree several substances known to be involved with sepsis and the systemic inflammatory response syndrome. Animal studies have shown a beneficial effect of HVHF on survival, hemodynamics and improvement in immune cell hyporesponsiveness in endotoxemic models. In addition, infusion of the ultrafiltrate from septic animals into healthy animals induced the development of septic shock. Conversely, when ultrafiltrate from healthy animals were infused, there was a moderate blood pressure rise. These results suggest that the improvement in hemodynamics and immune responsiveness seen in the animals after HVHF was likely due to the removal of mediators through ultrafiltration. During HVHF, adsorption is also increased due to the effects of an increased hemofiltration rate on transmembrane pressure. Human studies have demonstrated that HVHF improves hemodynamics, decreasing vasopressor requirement in septic patients. Results of a subgroup analysis in our own study suggested that ultrafiltration rates of at least 45 ml/kg/hr may be beneficial in the subset of septic patients.
HVHF can be performed in one of 2 ways. First, continuous hemofiltration can be performed with a fluid exchange rate >3 L/hr. In this case, if the therapy is performed for 24 hours, clearances in excess of 80 L/day can be obtained. However, the need for very close nursing surveillance places great demand on ICU nursing expertise. Also, solute kinetics may render the high volumes useless after a few hours because of reduction in plasma concentration and saturation of membrane adsorption. An alternate method is pulse high volume hemofiltration (PHVHF). In this case, a daily schedule of very HVHF (85 ml/kg/hr) for 6-8 hours is followed by CVVH at 35 ml/kg/hr for the remaining 16-18 hours. This leads to a cumulative dose of approximately 50 ml/kg/hr. The standard CVVH may help to maintain the effect of PHVHF and prevent post-treatment rebound. In terms of nurse workload, the 6-8 hours of PHVHF during the daytime was widely accepted by the ICU nursing staff because it reduced the labor intensity of the protocol during the night shift. We studied the effect of HVHF on 15 critically ill patients with severe sepsis. Hemodynamics were improved by PHVHF, allowing a significant reduction in noradrenaline dose during and at the end of the PHVHF. This positive effect was maintained up to 12 hours after the end of the treatment. In this study, there was no control group for comparison. However, the observed mortality rate of 47% was lower than the predicted mortality rates of 72% (based on APACHE II score) and 68% (based on SAPS II score).
Coupled Plasma Filtration Adsorption (CPFA)
Coupled plasma filtration adsorption is an extracorporeal technique that utilizes a plasma filter to separate plasma from blood and then allows passage of the separated plasma through a sorbent cartridge for the non-specific removal of various mediators. After purification, the plasma is returned to the blood. The reconstituted blood can then pass through a hemodialyzer/ hemofilter for additional blood purification by conventional hemodialysis, hemofiltration or hemodiafiltration. The treatment goal of CPFA is to target the excess of circulating pro- and anti-inflammatory mediators in order to restore normal immune function. Early trials with sorbents were associated with severe side effects which included hemolysis, electrolyte disturbances, pyrogenic reactions and thrombocytopenia. Today, there is a wide range of commercial adsorption therapies raging from specific ones such as polymixin B to more generalized or combination systems for artificial liver support devices. The resin used in the CPFA sorbent cartridge is a synthetic cross-linked styrenic divinylbenzene resin. It is well suited for extracorporeal applications because of its high homogeneity, good pressure-flow performance, excellent mechanical and chemical stability, and its capacity to adsorb a wide variety of inflammatory mediators.
In an animal model of endotoxic shock, cumulative survival was significantly better in the animals treated with CPFA. In humans, two small studies have demonstrated an improvement in hemodynamics and a decrease in vasopressor requirement in patients with septic shock. In our cross-over study comparing CPFA with hemodiafiltration, we also observed a significant increase in leukocyte responsiveness after CPFA treatment. Interestingly, we did not observe significant changes in circulating plasma levels of IL-10 or TNF- even though there was almost complete adsorption of these cytokines by the resin cartridge. This suggests that there may still be other factors that are adsorbed by the cartridge that play a role in immunosuppression. This is particularly relevant since the end point of the study was restoration of immune responsiveness rather than a net decrease or increase in any one specific inflammatory mediator. Although sample sizes for both studies were small, the technique shows promise and merits further investigation in human sepsis.
Polymixin B fiber column
Recently a new device for extracorporeal removal of circulating endotoxin was released into the market Toraymixin (Toray Industries, Osaka, Japan). This device uses polystyrene fibers coated with polymyxin B which adsorbs endotoxin and other products, and intended to be used as adjuvant therapy to improve the deranged homeostasis characteristic of Gram-negative sepsis. It has been used routinely in Japan since 1995; however the published literature gives conflicting results. A recent study evaluating 36 septic patients showed that mean blood levels of plasminogen activator inhibitor-1, norepinephrine and IL-8 were significantly decreased up to 48 hours after hemoperfusion with an immobilized polymixin B fiber column, with an associated improvement in PaO2/FiO2 ratio. This device represents a potential therapy for patients with early Gram negative sepsis, but further work needs to be done to identify the appropriate patient group and the optimal timing for this therapy.
High Cut-Off Membranes (HCOM)
Conventional hemofilters usually have a pore size of about 5 nm, allowing the elimination of molecules with a molecular weight of up to 30 kD. High permeability or high cut-off membranes (HCOM) have larger pore sizes allowing the elimination of molecules with higher molecular weights. They represent a potential method for removing cytokines without the use of large amounts of sterile substitution fluid used to facilitate convective clearance in HVHF. These HCOM were developed in order to increase the clearance rate for septic mediators, having a pore size of 10 nm, theoretically allowing the elimination of molecules up to 60-70 kD in size. Protein adsorption occurs more easily with larger pore sizes, and in turn this adsorbed protein results in narrowing of the effective pore size. As a consequence, the cut-off point of the hemofilter is high in the initial phase of hemofiltration but declines rapidly over time. Also the high cut-off may also allow the exit of other important plasma proteins such as albumin.
Clearance studies show that HCOM are able to achieve high clearance rates for a variety of septic mediators. IL-6 is an important pro-inflammatory mediator with a molecular weight of 28 kD, and cannot be eliminated in substantial amounts by conventional CVVH. The sieving coefficient for IL-6 during hemofiltration with HCOM was 0.92, decreasing to 0.65 after 24 hours. In animal models of sepsis, hemofiltration with HCOM significantly improved survival. In human studies, continuous RRT with these HCOM allow good clearance rates for IL-1receptor antagonisy, IL-1, and IL-6. However, an important side effect of high-cutoff hemofilters is the loss of plasma proteins. Of note, using diffusion instead of convection appears to significantly reduce the loss of proteins while maintaining good cytokine clearance rates. The clinical significance of removal of these cytokines, as well as any potential ill effects of protein loss, remains to be investigated.
Several techniques are available for the therapy of AKI in the critical ill setting. Continuous therapies seem to display important advantages in terms of hemodynamic tolerance. New approaches are under evaluation in prospective randomized trials to prove their efficiency in the septic patients.
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Sepsis and other Extracorporeal Techniques
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