Extracorporeal Blood Purification Techniques Beyond Dialysis: Coupled Plasmafiltration-Adsorption

Sepsis is one of the main causes of morbidity and mortality in intensive care units worldwide and the tenth leading cause of death in the United States. Mortality of sepsis has been estimated to range from 20% to 80%—depending to a large extent on the severity of the clinical picture, the involvement of one or more organs (the so-called multiple organ dysfunction syndrome [MODS]), the study design (and reporting methods), and the timing of treatment initiation. MODS and renal failure often result from the exaggerated host response to infection. Although several attempts have targeted specific components of the inflammatory cascade, no improvements in outcome have been reported in clinical trials.

Sepsis is the leading cause of acute kidney injury (AKI), the prevalence of which ranges from 19% in sepsis, to 23% in severe sepsis, to 51% in septic shock.

Sepsis involves two important pathways, the proinflammatory response and an immunosuppressive (or immunodysfunctional) response. The first is aimed at the delivery of mediators with a proinflammatory action, such as tumor necrosis factor-alpha (TNF-α), interleukin-1, interleukin-6, and the other releases cytokines with a predominant antiinflammatory activity, such as interleukin-10 and interleukin-4. Both responses may take place at the same time and not in sequence, as previously considered.

It is hypothesized that inflammatory molecules are responsible for diffuse endothelial injury, inducing vasoparalysis and driving selective permeability with important ramifications on systemic hemodynamics and MODS. On the other hand, monocytes lose their ability to synthesize and deliver cytokines as a consequence of inflammatory stimuli, leading to an “immunoparalytic” state characterized by monocyte deactivation. The substantial failure of the first interventional trials targeting specific components of the proinflammatory cascade, such as TNF-α, moved attention to different targets, for example, to blood purification techniques, which may remove several mediators simultaneously, positively affecting the outcome in septic shock.

Of the extracorporeal treatments as a whole, “classic” continuous renal replacement therapies show intrinsic limitations tied to constrained exchange volumes and a low sieving coefficient of the molecules affected (with an approximate molecular weight ranging from 5 to 50 kDa), which leads to low removal rates and clearances. In vitro and in vivo studies have shown that employing a large-pore membrane may enhance the convective transfer of soluble proinflammatory and antiinflammatory mediators, leading to increased clearance of nonselective cytokines.

To overcome some of these problems, a new extracorporeal blood purification system was developed, coupled plasmafiltration adsorption (CPFA), which uses a resin cartridge along with a second hemofiltration system that allows convective exchange. The system exploits the nonselective removal of inflammatory mediators by means of a hydrophobic styrenic resin. The resin has high affinity and a large capacity for many cytokines and mediators. The rationale for sorbent adsorption is to reinfuse the endogenous plasma after nonselective, simultaneous removal of different sepsis-associated mediators by means of processing it through a specific cartridge.

CPFA currently is performed with the use of a four-pump modular treatment (Amplya, Bellco, Mirandola, Italy) consisting of a plasma filter—0.45 m ² polyethersulfone with approximate cutoff of 800 kDa and absorption on a unselective hydrophobic resin cartridge (140 mL)—with a surface of about 700 m ² /g, and a final passage of the reconstituted blood through a synthetic, high-permeability, 1.4-m ² polyethersulfone hemofilter in which convective exchanges may be applied in a postdilutional mode ( Fig. 191.1 ).

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Schematic diagram of coupled plasmafiltration-adsorption.

The advantage in processing the plasma and not the blood through the sorbent cartridge is related to the fact that the plasma flow is lower than blood flow, allowing for a longer contact time with the sorbent. Other advantages of using plasma are that there are no bioincompatibility issues and the problem of having to “coat” the resin with a biocompatible matrix, which often decreases efficacy, is avoided.

The postdilution reinfusion rate can be set for up to 4 L/hr. The blood flow is usually 150 to 180 mL/min, and the plasma filtration rate is maintained at a fractional filtration of the blood flow (approximately 15%–20%). The treatment usually is run for approximately 10 hours, after which the cartridge begins to show saturation by the mediators.

Early studies of CPFA used a prototype machine and cartridge with less resin that needed to be changed more often. Ronco et al., who tested the first clinical treatments of CPFA using the prototype machine, reported that a single CPFA treatment lasting 10 hours showed better hemodynamic improvement than continuous venovenous hemodiafiltration (referring to an improvement in mean arterial pressure and a decrease in norepinephrine requirement). Furthermore, this study provided very interesting biologic data: Monocytes in plasma drawn after passage through the sorbent cartridge were again able to respond to the lipopolysaccharide challenge with TNF-α production at a magnitude significantly greater than with continuous venovenous hemodiafiltration ( Fig. 191.2 ). According to these preliminary data, CPFA was suggested to have a potential role for blood purification in septic shock treatment, modulating the immune response and resetting the balance between proinflammatory and antiinflammatory mediators. This concept was novel in that it suggested a role for extracorporeal therapies in actual purification of blood to remove inflammatory mediators, reaching beyond the traditional role of support for patients with renal failure.

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A, In vitro production of tumor necrosis factor-alpha (TNF-α) after lipopolysaccharide challenge at different times during coupled plasmafiltration-adsorption (CPFA). Top, Plasma TNF-α level; bottom, in vitro production. Dark green bar indicates white blood cells plus lipopolysaccharide; light green bar indicates white blood cells plus RPMI medium only. B, Effect of septic plasma on normal white blood cell production of TNF-α during CPFA treatment. Top, Precartridge plasma; bottom, postcartridge plasma. Dark green bar indicates plasma plus normal white blood cells plus lipopolysaccharides; light green bar indicates plasma plus normal white blood cells.

(Data from Ronco C, Brendolan A, Lonnemann G, et al. A pilot study of coupled plasma filtration with adsorption in septic shock. Crit Care Med. 2002;30:1250–1255.)

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Still employing the prototype machine, Formica et al. evaluated the hemodynamic performance of CPFA. Their study had two unique features: (1) repeated application of the technique during the course of the septic shock (a mean of ten 10-hour sessions were applied) and (2) use in patients without concomitant AKI. Improvements have been reported in the main hemodynamic and respiratory parameters, such as mean arterial pressure, cardiac index, peripheral vascular resistance, and ratio of oxygen arterial pressure to inspired oxygen fraction ratio, as well as in levels of some mediators and severity of illness scores ( Fig. 191.3 ). Norepinephrine was tapered progressively and stopped with different timings in the patient's population. Therefore it may have been stopped in one patient after three sessions and in another after eight sessions. The mean among the patients was five sessions.

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A, Interleukin-6 (IL-6) blood concentration before (Pre) and after (Post) a session of coupled plasmafiltration-adsorption (CPFA). B, Precartridge and postcartridge plasma IL-6 concentrations. C, Sequential Organ Failure Assessment (SOFA) scores before (Pre) and after (Post) CPFA treatment in survivors and nonsurvivors.

(Data from Formica M, Olivieri C, Livigni S, et al. Hemodynamic response to coupled plasmafiltration-adsorption in human septic shock. Intensive Care Med. 2003;29:703–708.)

No untoward clinical effects were recorded during the procedures, thus underlying the safety of the technique, which may be applied irrespective of the presence of AKI. The sessions had been planned originally for a duration of 10 hours, but the mean delivery time was about 8 hours, 45 minutes. Reasons for shorter sessions related to clinical requirements (radiologic procedures, emergency surgery) and to technical problems (circuit coagulation, plasma filter malfunction). The issue of coagulation with CPFA has been addressed further in a study performed in a particular AKI population.

These technical problems have delayed significantly the introduction of a new machine that contained seven pressure transducers to monitor the transmembrane pressure and pressure drops of the plasma filter, hemofilter, and adsorptive cartridge in real time. Several pilot studies evaluated the role of mediator removal during barotraumas induced by mechanical ventilation and the role of CPFA versus pulsed high-volume hemofiltration in sepsis-induced apoptosis (C. Ronco, personal communication, 2006).

In 2007 a randomized multicenter clinical trial was performed in 18 adult intensive care units (ICUs) that regularly used CPFA in the treatment of septic shock to assess the efficacy of CPFA in reducing mortality of critically ill patients with septic shock (COMPACT study). Patients more than 18 years of age with septic shock either at or during their admission to the ICU were eligible for study entry, provided that CPFA could be started within 6 hours from the occurrence of hypotension refractory to fluid resuscitation. Between January 2007 and November 2010, a total of 192 patients had been randomized. Recruitment in each ICU lasted a median of 22 months (IQR 13–26). Unfortunately, issues of circuit coagulation constrain the volume of treated plasma leading to numerous protocol violations. No statistical difference was found in hospital mortality with 47.3% dying in the control group (44/93) versus 45.1% dying in the CPFA group (41/91, p = .76), with an absolute risk difference of 2.2% (95% CI −12.2% to 16.6%). The 90-day survival curves of the two groups substantially overlapped (LOG-RANK test, p = .48; Fig. 191.4 ). Secondary end points did not differ statistically; the occurrence of new organ failure was 55.9% in the control versus 56% for CPFA patients ( p = .99); the free ICU days during the first 30 days postrandomization were 6.8 in the control group versus 7.5 in the CPFA group ( p = .35). Hospital mortality in patients with septic shock on ICU admission was comparable (16/39 [41%] for control vs. 19/43 [44.2%] for CPFA; p = .77). The same was observed for the subgroup of patients who developed septic shock during their ICU stay (27/53 [50.9%] control vs. 21/47 [44.7%] CPFA; p = .53).

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90-day survival curves of the two groups of the COMPACT study. CPFA, Coupled Plasmafiltration-Adsorption; COMPACT, COMbined Plasmafiltration and Adsorption Clinical Trial.

The per-protocol analysis revealed a nonsignificant trend in hospital mortality according to the tertiles of volume of plasma treated per kilogram per day over the first 5 days. The logistic regression model, aimed at adjusting for possible confounders, verified that hospital mortality in patients falling within the third tertile (≥0.18 L/kg/day of plasma treated over the first 5 days) was statistically lower than in the control group (OR 0.36, 95% CI 0.13 to 0.99; Fig. 191.5 ). Two sensitivity analyses were performed, namely limiting the evaluation of the volume of plasma treated to the first 3 days and excluding from the control and treated groups patients who died in the first 24 hours postrandomization. The first analysis was aimed at assessing whether any possible benefit of CPFA was obtained before 5 days; the second was intended to minimize any possible selection bias as patients who died early could not have entered the highest tertile of treated plasma because of insufficient time. Both sensitivity analyses confirmed the same estimates, even though statistical significance was lost for lack of power.

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Hospital mortality according to the quantity of treated plasma volume.

The subgroup analysis was suggestive of efficacy, provided that a high volume of plasma was treated. Given the new availability of citrate regional anticoagulation, it has been designed a confirmatory, adaptive trial whose first step will be to prove this new technique easily allows high volume of plasma treated with CPFA, identified by the acronym COMPACT-2 (COMbined Plasmafiltration and Adsorption Clinical Trial)—registered on ClinicalTrials.gov with the identifier NCT01639664. The study objective is to clarify whether the application of high doses CPFA in addition to the current clinical practice is able to reduce hospital mortality in septic shock patients in ICU. Secondary objectives are the resolution of septic shock and the reduction of ICU length of stay. According to the rationale of the study, a lower mortality is expected in patients treated with CPFA to higher doses than patients treated according to current medical practice. The study will then be conducted according to the adaptive scheme, in which two intermediate evaluations of the results are foreseen, which will determine the continuation or not of randomization. If the study will exceed both of these interim evaluations, enrollment will continue until the size expected for the analysis of mortality.