Extracorporeal Therapy in Sepsis

INTRODUCTION

Sepsis is defined as a life-threatening organ dysfunction caused by dysregulated host response to infection. Sepsis continues to be a global health concern, with rising incidence and high mortality, ranging between 20% and 50%, despite advances in diagnosis and management.¹ Apart from adequate source control and appropriate antibiotics, no specific therapy exists for treatment of sepsis. Increasing resistance to antibiotics and high mortality necessitate urgent targeted therapies for improving outcomes, and blood purification by extracorporeal techniques may be proposed for treating sepsis.

IMMUNE RESPONSE AND POTENTIAL ROLE OF BLOOD PURIFICATION in SEPSIS

The first response to any invading pathogen is recognition of the pathogen by the host immune system. Every pathogen (virus, bacteria, fungus, and parasite) expresses certain molecular patterns or endotoxins called as pathogen-associated molecular patterns (PAMPs) and these are recognized by toll-like receptors and other pattern recognition receptors which are predominantly expressed by the neutrophils. This leads to activation of innate immunity and leukocytes, leading to increase in release of cytokines, both proinflammatory and anti-inflammatory, which includes interleukins 1 (IL-1), 6, 8, and 10 and tumor necrosis factor.^2,3 This profound release of cytokines, often referred to as cytokine storm, is responsible for dysregulated host response to infection and contributes to organ failures. The initial response to infection and release of cytokines damages the host cells and the injured host cells express alarmins and other proteins called as damage-associated molecular patterns (DAMPs). Alarmins and DAMPs can be recognized by pattern recognition receptors and cause further activation of leukocytes, aggravating the dysregulated response.⁴ After the initial florid response, follows a phase of immunoparalysis, which contributes to reactivation of viral infections and new onset hospital-acquired infections.

Novel treatment strategies in sepsis and septic shock include early and adequate fluid resuscitation, vasopressors and inotropic support when indicated, early use of broad-spectrum antibiotics with source control, with close monitoring and organ support, if indicated. Other therapies such as immune-modulation and blood purification have been tried to improve outcomes in patients with sepsis and septic shock. Immunomodulation and blood purification techniques aim at restoring the balance of the immune response to infection, by removing the triggers for the response and the cytokines produced and thereby achieve immune homeostasis. Blood purification techniques can potentially disrupt the immune response at various stages, by removing endotoxins, PAMPs, DAMPs, activated leukocytes, cytokines, and direct removal of pathogens from blood.⁵ In this review, we would address the mechanism behind the various therapies and the current evidence pertaining to their use in sepsis and septic shock.

The various hypothesis or theories supporting the role of blood purification include the peak concentration theory, the cytokinetic or threshold immunomodulation concept, the iceberg theory, mediator delivery hypothesis, among others. The iceberg theory was proposed by Cavaillon et al., and it suggests that the cytokines present in blood are because of the saturation at the tissue level, and the presence of mediator does not necessarily parallel the same amount of activity.⁶ The peak concentration theory is cutting or disrupting the peak concentration of soluble inflammatory mediators and was proposed by Ronco et al.⁷ The authors postulated that by disrupting the peaks of soluble inflammatory mediators and by constantly reducing high levels of the mediators, the inflammatory cascade could be curtailed or stopped and thereby preventing organ injury. The cytokinetic theory postulates that removal of inflammatory mediators from the plasma creates a gradient between tissue and plasma and cause the migration of mediators from tissue into blood compartment.⁸ Various blood purification modalities, which have been tried include high-volume hemofiltration (HVHF), polymyxin B hemoperfusion, cytokine hemoadsorption, coupled plasma filtration adsorption (CPFA), plasma exchange, among others (Flowchart 1).

CYTOKINE REMOVAL IN SEPSIS

Inflammatory mediators and cytokines can be removed by HVHF, CytoSorb hemoadsorption cartridge, and CPFA.

HIGH-VOLUME HEMOFILTRATION

Standard renal dose hemofiltration is defined as effluent rates up to 25 mL/kg/hour and any dose above 35 mL/kg/hour is considered as HVHF. The consensus conference defined HVHF as continuous hemofiltration with effluent volumes between 50 and 70 mL/kg/hour for 24 hours or 100 to 120 mL/kg/hour for 4 to 8 hours intermittently followed by renal dose hemofiltration,⁹ using a high-flux dialyzer. Most of the inflammatory mediators in the plasma are water soluble and has a molecular weight of less than 60 kDa and, thus, can be easily cleared from plasma by convection. Also, many currently used membranes such as AN69 membranes, have adsorptive properties and improve solute and middle molecular clearance. With hemofiltration dosing higher than conventional volumes, a significant amount of mediators can be cleared from the plasma.¹⁰

Initial animal and human studies, predominantly observational or case series, showed significant improvement in hemodynamic variables after HVHF, though data on mortality were lacking. The initial human studies were of small patient numbers and heterogeneous, using different doses of hemofiltration. The only large randomized trial, IVOIRE study, compared filtration doses of 35 mL/kg/hour with 70 mL/kg/hour.¹¹ In a total of 137 patients, who were analyzed, no difference was observed in mortality and any of the secondary end points such as hemodynamic variables, duration of mechanical ventilation or organ function scores. The study was prematurely terminated because of slow recruitment and the necessitated number of patients to achieve a power of 85% could not be achieved. A Cochrane review of four randomized trails, involving 200 patients, showed a pooled risk ratio of mortality at 0.89 with HVHF.¹² The Cochrane review and similar meta-analysis in the past have failed to show any mortality benefit with HVHF.

The main demerits with HVHF is the large volume exchanges. Along with inflammatory mediators, antibiotics, vitamins, and essential elements, nutrients and albumin are also lost in the effluent. Also HVHF is likely to cause massive electrolyte shifts, thus offsetting the potential benefits. These drawbacks can be overcome by use of cascade hemofiltration, though not popularly used.

CYTOSORB® HEMOADSORPTION

CytoSorb® hemoadsorption device (CytoSorbents, New Jersey, USA) is a cytokine adsorption cartridge made of polystyrene divinylbenzene copolymer beads. The device has a surface area of 45000 m² with a molecular cutoff size of 60 kDa, thereby adsorbing both pro- and anti-inflammatory mediators, but not endotoxins. Apart from inflammatory mediators, it has also been shown to adsorb myoglobin, bilirubin, bile acids, PAMPs, and DAMPs.⁵ It can be used as a stand-alone therapy with standard blood pumps or can be connected in series with hemodialysis or continuous renal replacement therapy (CRRT).

Multiple case series have shown improved hemodynamics, reduction in vasopressor dose, and reduced observed mortality in patients with sepsis, when compared to predicted mortality, without significant adverse effects.^13,14 Two randomized control trials using CytoSorb® have been conducted by the same group of investigators. In the initial trial involving 43 patients with septic shock and acute lung injury, the use of Cytosorb® for 6 hours a day for 7 days was associated with significant reductions in cytokines IL-6, IL-8, and monocyte chemotactic proteins. The intervention did not translate into any survival benefit.¹⁵ The same group of investigators followed up with larger intervention involving 97 patients of septic shock with acute respiratory distress syndrome and used CytoSorb® for similar duration with or without renal replacement therapy. Primary outcome of the intervention was to analyze reduction in plasma IL-6 concentrations. The study showed a significant elimination of IL-6 per pass of blood through the cartridge (5 to 18% per pass), but IL-6 levels were comparable in both groups at the end of therapy. No improvement was observed in other secondary parameters such as ventilation days, vasopressor index, and oxygenation and a higher 60-day mortality was observed in the intervention group.¹⁶ Albeit, the study was not powered to assess mortality, and the number of patients requiring renal replacement therapy was higher in the intervention group (31.9 vs 16.3%), suggesting sicker patients in the study arm.

Although initial duration of therapy was recommended as 24 hours per session, potential concern exists over saturation of adsorption beyond 8 hours of therapy as noted by rebound increase in vasopressor levels after 8 hours of therapy, which reversed after the cartridge was changed.⁸ Multiple theories exist for the failure of therapy. Most appropriate is the cytokinetic theory, as discussed previously.⁸ Cytokine release is a continuous process and thereby a continuous therapy could prove beneficial when compared to intermittent treatment, especially when initiated early in the treatment of septic shock. This was recently evaluated in a pilot study and showed significant reduction in norepinephrine levels and in procalcitonin and big-endothelin 1 concentrations in the treatment group.¹⁷

With limited evidence and heterogeneous trial interventions, routine use of CytoSorb® cannot be recommended, and further studies are needed, taking into consideration the pitfalls of previous studies like desired dose and duration of therapy.

COUPLED PLASMA FILTRATION ADSORPTION

The circuit of CPFA contains a plasma filter, a resin sorbent cartridge, and a high-flux dialyzer for convection (Fig. 1). The CPFA technique separates plasma from blood. The cytokines in the plasma component is then adsorbed through a sorbent cartridge and the plasma free of cytokines is redirected to the dialyzer for renal replacement therapy. The potential advantages of CPFA include improved biocompatibility and less hemolysis, as there is no direct contact between blood cells and sorbent, improved cytokine clearance as lower plasma flow allows longer duration of contact with the resin cartridge, and combined cytokine removal with renal replacement therapy by convection.¹⁸ The suggested duration of therapy is a 10-hour session, for 5 consecutive days, with a plasma filtration fraction ranging between 10 and 18%.¹⁹ Beyond 10 hours, the sorbent cartridge shows signs of saturation.

Multiple small observational studies showed improved hemodynamics without survival benefits. In a large multicenter trial involving 192 patients, the use of CPFA did not result in any survival benefit. No difference was observed in any of the secondary outcome parameters such as new organ function scores and intensive care unit length of stay.²⁰ Although the study was adequately powered for assessing mortality, it had multiple limitations. Close to 48.4% of the patients in the intervention group did not receive the desired dose of CPFA, and clotting of the circuit was the single most common factor for treatment interruption. This is despite the fact that heparin was used for anticoagulation. The study was also stopped prematurely due to futility.²⁰ The perceived benefits of CPFA are offset by multiple factors, complexity of the circuit needing trained staff, increased need for anticoagulation, and filter cost. A large randomized control trial, COMPACT 2, is ongoing (Clinicaltrials.gov NCT01639664) and would bring new insights in the role of CPFA for cytokine removal in sepsis.

ENDOTOXIN REMOVAL IN SEPSIS

COMBINED ENDOTOXIN AND CYTOKINE REMOVAL

MULTIMODAL APPROACH

NEWER THERAPEUTIC APPROACH

Treatment strategies directly targeting the pathogen and activated leukocytes have been tested in experimental studies and in animal population. Selective cytopheretic device (SCD) is a cartridge, which sequesters activated leukocytes connected to the CRRT device. Interestingly, SCD with regional citrate anticoagulation has been shown to change the activity of the bound leukocytes, probably due to the inhibition of neutrophils by ionized hypocalcemia in the filter. The SCD has been evaluated in clinical trials of patients with sepsis and acute kidney injury and a randomized trial of 134 patients, wherein the use of SCD was not found to be superior to CRRT alone. But the subset of patients in whom post filter ionized hypocalcemia of 0.4 mmol/L was maintained, a significant reduction was observed in the 60-day mortality.³²

Adsorption and removal of various pathogens is a potential treatment strategy to improve outcomes in sepsis patients. Multiple cartridges are under various stages of trials. The Seraph® 100 Microbind® Affinity Blood Filter (ExThera Medical, California, USA) can bind both bacteria and viruses. The Hemopurifier® (Aethlon Medical, California, USA) and FcMBL (Opsonix, USA) are predominantly virus-binding cartridges and opens a new horizon in the management of sepsis.

CONCLUSION

Significant progress has been made in the arena of sepsis treatment and blood purification, but till date no conclusive evidence has emerged to support a routine use of any of these modalities as an adjunct to standard sepsis care. With limited evidence, the therapy should be individualized to patient-specific needs and resources available, and further research should be directed at unanswered questions of previous trials.

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