CRRT in SEPSIS Benan Bayrakci, 2014 𝜋Q hacettepe

CVVH is not a sepsis drug but an adjuvant! The role of CRRT in sepsis can be seen from two major aspects: Renal replacement therapy - Fluid balance Minor hemodynamic challange Acid-base balance Enhanced nutrition Immunomodulatory tool - Clearance of immune mediators - Adsorption of endotoxins

EU US CRRT in pediatric sepsis has ~40% mortality Largest prospective studies of pediatric CRRT 174 children; Intensive Care Med (2010) 36:843–849 ppCRRT Registry 2007

Predictors of mortality for CVVH patients

Increased FO status at CRRT initiation is associated with mortality, irrespective of severity of illness as measured by PRISM score ppCRRT Registry, 157 patient with 39 % sepsis Kidney International, Vol. 67 (2005), pp. 653–658 Single centre, 21 patient, PEDIATRICS Vol. 107 No. 6 June 2001,

So what is actually threated with CVVH? Sepsis or FO? Of the patients in the ppCRRT Registry over 90% received CRRT to treat fluid abnormalities ppCRRT registry 2007 Indications for CRRT in sepsic AKI are not different from other forms of AKI in the ICU So what is actually threated with CVVH? Sepsis or FO?

R. Renal replacement therapy reccomendations 1. CRRT and intermittant HD are equivalent in severe sepsis and acute renal failure because they achieve similar short-term survival rates (grade 2B). 2. We suggest the use of continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients (grade 2D).

Besides its renal replacement functions in AKI CRRT is often used with the concept of modulating immune response in sepsis, influencing circulating levels of inflammatory mediators like cytokines and chemokines, the complement system, as well as factors of the coagulation system CRRT may not only be supportive but rather therapeutic!

The Peak Concentration Hypothesis Ronco et al. Artif Organs, Vol. 27, No. 9, 2003

Arch Intern Med. 2007;167(15):1655-1663 Nearly 2,000 patients hospitalized for community-acquired pneumonia evaluated the pro- and anti-inflammatory balance by measuring the ratio of IL-6 over IL-10 31% developed severe sepsis. Cytokine levels were highest in fatal severe sepsis The highest risk of death was found to be correlated with a high levels of both pro- and anti-inflammatory cytokine activity together (p < 0.001).

To determine the balance of inflammatory responses, measurement of cytokines’ bioactivity is superior to their absolute concentrations. Plasma from septic patients led to an increased expression of adhesion molecules. Septic plasma permanently suppressed the production of IL-6 and IL-10 Ultrafiltrate from CVVH mirrors the equivalent immune response patterns found for plasma. CVVH withdraws triggering mediators from plasma in equally bioactive proportions

Convection and adsorption Hemofiltration eliminates molecules according to two principles: Convection and adsorption Sepsis mediators are large molecules from 8 kD for IL-8 to 51 kD for trimeric TNF Convantional membrane pores: 5 nm; permits up to 30 kd

High Adsorption Hemofiltration Adsorption depends on the interaction with the membrane and therefore is a size and weight independent process. As binding sites are saturated, there is a decline of removal over time High Adsorption Hemofiltration In a small pilot trial, 12 patients with sepsis were investigated over a 9-hour treatment period every 3 hours changes of filters. A significant reduction of IL-8 and IL-10 levels, and faster reduction in vasopressor requirements were found Int J Artif Organs 30:108–117, 2007

Removal of cytokins and endotoxin has clearly been demostrated for several times IL-1b IL-6 IL-8 TNF-a 20 adult RCS with standart CVVH

What else can be removed? Procalcitonin is a promising biomarker of sepsis; >30% PCT clearance at 48 hours is related with higher survival in septic patients Crit Care Res Pract. 2014

Crit Care. 2003 Dec;7(6):R160-6. Epub 2003 Oct 2. Mass transfer, clearance and plasma concentration of procalcitonin during continuous venovenous hemofiltration in patients with septic shock and acute oliguric renal failure. Level C1, Chauveau P, Guisset O, Cazin MC, Lasseur C, Gabinsky C, Winnock S, Montaudon D,  PCT is removed from the plasma of patients with septic shock during CCVH via convection and adsorption Anaesth Intensive Care. 2002 Jun;30(3):269-74. Procalcitonin and proinflammatory cytokine clearance during cvvhdf in septic patients. Dahaba AA1, Elawady GA, Rehak PH, List WF. The plasma clearance of PCT (13,000 Da) significantly decreased after 12 hours as a result of a decline in the adsorptive elimination due to progressive membrane saturation. 

ISRN Hematology 2012 11 RCS: CVVH eliminated inflammatory mediators in plasma effectively, shorten hospital stays, and better stabilize of hemodynamics. Crit Care Med 2013; 41:2209–2220 16 RCS: Blood purification techniques including hemoperfusion, plasma exchange, and hemofiltration are associated with lower mortality in patients with sepsis.

11-14% of each treatment group had sepsis, High volume of exchange (3–5 l) can induce an up to 80-fold increase in lymphatic flow. This can result in a concomitant substantial drag and displacement of mediators and cytokines to the blood compartment where they become available for removal. Prospective Randomised Controled Trial compared doses of 20, 35, and 45 ml ⁄kg⁄hour Ronco et al. Lancet 356:26–30, 2000 11-14% of each treatment group had sepsis, subgroup analysis of the septic patients demonstrated a direct correlation between treatment dose and survival above 35ml/kg/hr

Treatment at 100–120 ml/kg/h for a short period of 4–8 h, followed by conventional CVVH is called ‘pulse HVHF’ Cole et al. used a crossover design in 11 patients with septic shock and MOF. Reduction of complement levels and IL-10, as well as a more rapid decline in vasopressor requirements. This advantage, was lost after 24 hours. Intensive Care Medicine; 27: 978-86, 2001 33 patients with severe sepsis ⁄ septic shock Significant reduction of IL-6 levels. Nephrology (Carlton) 11:386–393, 2006 21 patients HV HF: Mortality rate less then expected mortality No contol groups! Nephrol Dial Transplant 27; 146-152, 2012

Limitations of these data for HVHF: Non-randomized case series, Retrospective cohort studies, No control group, Variability in technique applied (duration of therapy, dose of therapy, filter type) Adverse consequences associated with HVHF: Excessive loss of micronutrients, Antimicrobial clearance

NIH Acute Renal Failure IVOIRE NIH Acute Renal Failure Trial Network 140 participants HVHF at 70 mL/kg/h, SVHF at 35 mL/kg/h, No reduction in 28-day mortality , no improvements in haemodynamic profile or organ function 1,124 critically ill adults with AKI, no difference in 60-day survival groups (35.8±6.4 ml/kg-h) (22.0±6.1 ml/kg-h) 1,508 adult patients, no survival difference at 90 days groups (33.4±12.8 ml/kg/h) (22±17.8 ml/kg/h RENAL Three large multi-center randomized trials comparing the dose of renal replacement failed to show benefit of more aggressive renal replacement dosing

Evidence based medicine says: ‘There is insufficient evidence to recommend the use of high-volume hemofiltration in critically ill patients with severe sepsis/septic shock’ 2013

After the failure of the major randomized studies on dose, attention is now drawn to new membranes that could better in wide spectrum and also could eliminate massive amounts of unbound mediators in great magnitude Membranes directed for inflammation in Sepsis and SIRS are still in the experimental phase! 1- High cutoff (HCO) membranes: 10 nm; permits up to 50 kd 2- Nonselective adsorptive membranes 3- Semiselective membranes (capturing endotoxin) 4- Polymyxin B [PMX] (antibiotic coated ) adsorb endotoxin via hemoperfusion 5- Cytokine-adsorbing columns

1- High cutoff (HCO) membranes: Septex; 60,000 Da 30 patients randomized either a HCO membrane (60 kDa) or classic membrane (35 kDa) In the HCO group, a significant reduction in noradrenaline dose and a 10-fold increase in clearance of interleukin (IL)-6 and IL-Ra were observed PRO Crit Care Med 34: 2099–2104,2006. High Cut-Off Sepsis study (HICOSS) randomized 120 patients with septic shock and AKI to either a conventional membrane or an HCO membrane. The study was stopped prematurely after enrolment of only 81 patients due to a lack of difference in 28-day mortality . No difference was seen in vasopressor need, duration of mechanical ventilation, or duration of ICU stay. CON Blood Purif 33: 44–51, 2012 In an ex vivo study, 11 blood from healthy volunteers was spiked with endotoxin and then exposed to a HCO filter at a dose of 16 ml/kg/h or 80 ml/kg/h. Clearance of cytokines was 10-fold higher in the mixed HCO and HVHF group demonstrating synergy between HVHF and HCO (HYBRİD) Int J Artif Organs 27: 24–28, 2004

2- Nonselective adsorptive membranes: Polyacrylonitrile and AN69 ST (Surface Treated) Effectively adsorb high-mobility group box 1 protein (HMGB-1) which is a very upstream mediator liberated by macrophages and can activate the production of a bunch of cytokines. The molecular weight is around 30 kDa and therefore is not eliminated through filtration Able to remove molecules with molecular weight beyond the membrane cutoff

3- Semiselective Adsorptive CRRT Membranes: Polyacrylonitrile and AN69 Oxiris - Modified membrane surface polarity with a positive charge allowing catching endotoxins with negative charges - No comparable studies on human septic shock Polymethylmethacrylate PMMA - In a recent cohort study, evaluating 43 patients with septic shock exhibiting hypercytokinemia (IL-6), CRRT using PMMA membranes was associated with improvement of hemodynamics and reduction of organ failure. Toraymyxin Endotoxin adsorption (not a CRRT membrane, can be used in hemoperfusion) Prosorba is a kind of sorbent used in apheresis

4- Polymyxin B [PMX] (antibiotic coated ) adsorbs endotoxin Can run on a hemoperfusion device Cantaluppi et al. investigated in 2007, the effects of PMX therapy on the prevention of AKI during septic shock. 16 patients with gram-negative sepsis were randomly divided into two groups having standard treatment versus standard treatment plus PMX therapy. The plasma was collected and incubated with renal tubular cells and glomerular podocytes. The use of PMX therapy was able to reduce the proapoptotic activity of septic plasma on renal tubular cells and glomerular podocytes. Sepsis can directly induce AKI without the need of hemodynamic instability! The Early Use of Polymyxin B Hemoperfusion in Abdominal Sepsis (EUPHAS) Sixty-four patients with surgical sepsis were randomly assigned to receive either standard treatment or standard treatment plus two sessions of PMX therapy. Beneficial hemodynamic effects, significant improvement in SOFA score and in 28 day mortality JAMA 301: 2445–2452, 2009

5-Cytokine-adsorbing columns: CytoSorb, CYT-860-DHP, Lixelle, CTR-001, and MPCF-X Adsorptive columns and sorbents are not anymore membranes but are seen as cartridges because the surface is extremely huge, They can run with an hemoperfusion device They have enormous surface (8,500 m2) when compared with that of classical CRRT membranes (1.5 m2) CytoSorb seems to be very promising although it is not able to capture endotoxin and IL-10 We still dont know which membrane or which sorbent will be the most useful in adjunctive treatment in patients with sepsis.

Early (< 24h) CRRT in septic AKI has reduced mortality Timing ! 28-day mortality rates (<24 h) (>24 h) Early (< 24h) CRRT in septic AKI has reduced mortality RIFLE is not a good criterion for CRRT timing

No significant difference in organ function and outcome when the timing of CVVH initiation was based on RIFLE criteria Retrospektif cohort on 210 patients; Survivors vasopressör initiation to cvvh start is shorter Early initiation related with lower mortality

Timing Retrospective trials support early initiation of CVVH PRO Intensive Care Med 32:80–86, 2006 Intensive Care Med 25:805–813, 1999 Clin J Am Soc Nephrol 1:915–919,2006 Crit Care 9:R755–R763, 2005 Prospective, only one randomized trial: Early initiation of CRRT did not improve survival (mainly surgical patients with a very few sepsis) Crit Care Med 30:2205–2211, 2002 CON

Timing Retrospective trials support early initiation of CVVH PRO Intensive Care Med 32:80–86, 2006 Intensive Care Med 25:805–813, 1999 Clin J Am Soc Nephrol 1:915–919,2006 Crit Care 9:R755–R763, 2005 Prospective, only one randomized trial: Early initiation of CRRT did not improve survival (mainly surgical patients with a very few sepsis) Crit Care Med 30:2205–2211, 2002 CON Late is worse!

What is the current opinion

Hemophagocytic macrophages constitute a major compartment of heme oxygenase expression in sepsis. Schaer DJ, Schaer CA, Schoedon G, Imhof A, Kurrer MO. Department of Medicine, University Hospital, Zurich, Switzerland Eur J Haematol 2006: 77: 432–436 Hemophagocytosis is a common pathway of systemic inflamation Eritrophagocytosis causes HO-1 expression HO-1 down regulates inflamation in sepsis (CARS triger)

Heme oxygenase expression in sepsis +CVVH is a promising research topic whic has not been studied yet Consider early PE for hemophagocytosis and coagulopathy in sepsis ! Hemoperfusion, adsorption, and plasmafiltration might be integrated into CRRT machines for fully integrated extracorporeal blood purification

CPFA is an hybrid model that incorporates three phases. 1- Plasma filtration. 2- Filtered plasma passes through a sorbent cartridge where a specific resin allows non-specific adsorption inflammatory mediators and endotoxins (purification) 3- Blood and purified plasma are passed through a haemofilter for dialysis CPFA has been shown to be superior to high volume haemofiltration (HVHF) in septic patients with multiple organ dysfunction syndromes (Hu et al., 2012). Hassan et al. very recently (2013) showed that treatment with CPFA + CVVH resulted in earlier and sustained haemodynamic stability and significantly reduced the serum biomarkers of sepsis

As machines and therapies improved, patients become more severely ill MODS need MOST MOST (multipleorgan support therapy): ECMO, CRRT, hemoperfusion, adsorption and plasmafiltration combined in a single device Seminars in Dialysis 24(2), 2011

Biomechanical hybrid model: Renal assist devices using renal tubular cells for implementing renal tubular function into CRRT. The renal tubule assist device (RAD) is composed of a conventional hemofilter lined by monolayers of renal cells. 58 patient randomized, multicenter trial, the addition of renal tubule cell therapy to CVVH treatment showed decreased mortality at 28 d. without statistical significance J Am Soc Nephrol 19: 1034–1040, 2008 What about sepsis ?

Pick up the appropriate Device Method Timing Dose Membrane Drug dose Nutrition Or just pick up a tour ticket to see arround Istanbul