Role of CRRT in Sepsis Dr Apoorva Jain Agra

SEPSIS: BACKGROUND Severe Sepsis and Septic Shock are the primary causes of Multiple Organ Dysfunction Syndrome (MODS) [of which Acute Renal Failure-is part of] One of the most common cause of mortality in the ICU setting

SEPSIS: BACKGROUND Variety of Water soluble mediators with Pro & Anti- Inflammatory Activities play a strategic role in Septic Syndrome including (but not limited to): TNF, IL-6,IL-8 and IL-10, Kinins, Thrombins, heat shock proteins

SEPSIS: BACKGROUND Stimulus –Receptor coupling sets off the signal transduction cascade resulting in exacerbated generation of; Platelet activating factor, cytokines, leukotrienes, Arachidonic acid derivatives etc.) and activation of the complement cascade and coagulation pathways.

SEPSIS: Pathophysiology Dysfunctional homeostatic balance results in increased biological activity of sepsis associated mediators and loss of control over these by specific inhibitors-cell hypo-responsiveness This excessive anti-inflammatory counterpart to SIRS has been coined “CARS- Compensated Anti- inflammatory Response Syndrome” Bone et al. Chest 112:235-43, 1997

Goals of Treatment are hemodynamic and relate to outcome Early Goal-Directed Therapy in the treatment of Severe Sepsis and Septic Shock. Rivers E, N Engl J Med 2001;345:1368-1377. RCT 130 adults randomized to aggressive care In First few hours Results: In Hospital Mortality 30.5% vs 46.5% in Controls Early goal directed therapy improves shock outcome (Han Y. 2000 Pediat Res 47:108a. Ceneviva G. Pediatrics 1998;102:e19.)

OUTLINE 1 CRRT for Sepsis - associated AKI 2. CRRT as Immunomodulatory therapy

CRRT for Sepsis-associated AKI

CRRT for Sepsis-associated AKI • Role & Indications • Dosing • Alternative therapies

CRRT for Sepsis-associated AKI Dialysis allows: – Correction of acid-base status – Correction of electrolyte abnormalities – Clearance of toxins – Control of fluid balance

CRRT for Sepsis-associated AKI Advantages of using CRRT Suitable for use in hemodynamically unstable patients Precise, adaptable, volume control Very effective control of uremia, PO4, K Rapid control of metabolic acidosis Improved nutritional support (full protein diet) Available 24 hours a day May have an effect as an adjuvant therapy in sepsis

CRRT for Sepsis-associated AKI Disadvantages of using CRRT Expense – more than IHD, due to fluids Continuous anticoagulation may be required Risk of line disconnection Hypothermia Severe depletion of electrolytes (K and PO4), nutrients

CRRT for Sepsis-associated AKI Dosing of dialysis in AKI 425 patients randomized Post-dilution CVVH mode only 12% had sepsis Ronco et al, Lancet 2000; 355: 26

CRRT for Sepsis-associated AKI Modes of CRRT

CRRT for Sepsis-associated AKI Modes of CRRT

CRRT for Sepsis-associated AKI Modes of CRRT

CRRT for Sepsis-associated AKI Dosing of dialysis in AKI 206 patients randomized 60% sepsis CVVH versus CVVH + added D Saudan et al, Kidney Int 2006; 70:1312

CRRT for Sepsis-associated AKI Negative dosing studies 200 patients CVVHDF 20 v 35 ml/kg/hr No difference Tolwani et al J Am Soc Nephrol 2008; 19:1233 1124 patients, multicentred (NIH ATN study) Intensified (35ml/kg, 6x/wk IHD) versus Standard (20ml/kg, 3x/wk IHD) Palevsky et al N Engl J Med 2008; 359:7.

CRRT for Sepsis-associated AKI Reasons for differences Delayed initiation of RRT in Tolwani and ATN studies: 6 to 8 days No clear separation of dose delivered when combining CRRT and IHD dosing (ATN study) Majority (65%) enrolled after initial dialysis Dosing was not actually achieved in the ATN study

CRRT for Sepsis-associated AKI RENAL study 1508 patients, approx 50% sepsis 48-54 hr in ICU before randomisation Prescribed dose achieved: 84 – 88% CVVHDF, postdilution (1:1 dialysate:filtration) Low intensity: 25 ml/kg/hr High intensity: 40 ml/kg/hr No difference in mortality N Engl J Med Oct 22nd, 2009.

CRRT for Sepsis-associated AKI Alternative therapies IHD mortality higher in many CRRT studies 5 RCT’s: no difference in mortality 7 meta-analyses: no differences

CRRT for Sepsis-associated AKI Alternative therapies Kellum et al. Intensive Care Med 2002; 28:29

CRRT for Sepsis-associated AKI Alternative therapies Bagshaw et al, Crit Care Med 2008; 36:610

CRRT for Sepsis-associated AKI Alternative therapies IHD mortality higher in many CRRT studies 5 RCT’s: no difference in mortality 7 meta-analyses: no differences SLED: sustained low efficiency dialysis safe, effective, cheaper than CRRT limited comparative data Berbece & Richardson, Kidney Int 2006; 70:963

Epidemiology of AKI BEST Kidney study: 23 countries, over 30,000 patients, 2001 1738 developed acute renal failure Dialysis CRRT 80% --- IHD 17% SLED/PD 3% Hospital mortality 60% CVVH 53% CVVHD 13% CVVHDF 34% Uchino et al, JAMA 2005; 294:813 Uchino et al, Intensive Care Med, 2007 33:1563

CRRT as Immunomodulatory therapy

CRRT as Immunomodulatory therapy Background & rationale Studies supporting this hypothesis Clinical studies Variations on standard CRRT

CRRT as Immunomodulatory therapy Rationale – Removal of “Bad Humours”

CRRT as Immunomodulatory therapy Rationale – Removal of “Bad Humours”

CRRT as Immunomodulatory therapy

CRRT as Immunomodulatory therapy Ronco et al. Artif organs 2003; 27:792

CRRT as Immunomodulatory therapy Ronco et al. Artif organs 2003; 27:792

CRRT as Immunomodulatory therapy Mechanism of cytokine removal Convective High flux membranes cut-off 30 – 40 kD Should remove many cytokines (17 – 30 kD) Is removal rate significant given high production? Adsorption Filter dependent: higher with polyacrylonitrile (AN69) than with polysulfone membranes

CRRT as Immunomodulatory therapy Convective therapy can: Remove cytokines In some, but not all studies Adsorption important Frequent filter changes Plasma levels unchanged Improve hemodynamics In animal studies In open clinical studies Heering et al Intensive Care Med. 1997;23:288

CRRT as Immunomodulatory therapy 15 pts, sepsis, AKI first 24 hr hemofiltration AN69 filter De Vriese et al. J Am Soc Nephrol 1999;10:846-853

CRRT as Immunomodulatory therapy Morgera et al. Crit Care Med 2006; 34:2099

CRRT as Immunomodulatory therapy Morgera et al. Crit Care Med 2006; 34:2099

CRRT as Immunomodulatory therapy Outcome studies

CRRT as Immunomodulatory therapy Ronco study Ronco et al, Lancet 2000; 355: 26

CRRT as Immunomodulatory therapy RENAL study

CRRT as Immunomodulatory therapy CRRT without AKI Sepsis, no renal failure CVVH, 2L/hr, AN69 filter No significant reduction in cytokines No clinical benefit Cole et al, Crit Care Med 2002; 30:100

CRRT as Immunomodulatory therapy Outcome studies 80 patients, early CVVH 25ml/kg/hr or control High flux polysulfone filter Payen et al Crit Care Med 2009; 37:803

CRRT as Immunomodulatory therapy Outcome studies 80 patients, early CVVH 25ml/kg/hr or control High flux polysulfone filter No benefit, deleterious? Payen et al Crit Care Med 2009; 37:803

CRRT as Immunomodulatory therapy Outcome studies 80 patients, early CVVH 25ml/kg/hr or control High flux polysulfone filter No benefit, deleterious? Payen et al Crit Care Med 2009; 37:803

CRRT as Immunomodulatory therapy Outcome studies 80 patients, early CVVH 25ml/kg/hr or control High flux polysulfone filter No benefit, deleterious? Can’t expect a mortality benefit with the wrong intervention in the wrong dose Payen et al Crit Care Med 2009; 37:803

Variations on standard CRRT High volume hemofiltration High cutoff hemofiltration Plasmafiltration Cascade filtration Coupled plasma filtration adsorption

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