Haemofiltration for sepsis: burial or resurrection? Andrew Durward London 2015 Haemofiltration for sepsis: burial or resurrection?

Is haemofiltration beneficial in sepsis? Mortality benefit in sepsis ? With or with kidney injury ? What mechanism ? Dialysis dose benefit ? Disease Sepsis Disease Modification OUTCOME Apoptosis Cell death AKI Severity of illness Haemofiltration Target /Goal Indication CVVH Efficiency Timing CVVH Complications

Haemofiltration in sepsis Obtain fluid balance Acid base balance Electrolyte normalisation Cyotkine and toxin removal Oliguria is not good Titratable fluid loss Haemodynamic stability Temperature control Antibiotic dosing may be modified Risk anticoagulation / vascular access Macedo Nephrol Dial Transplant 2010

Plasma exchange in meningococcal sepsis Plasma exchange (3-4 volumes) Followed by CVVH n=85 children Of 23 with CVVH 6 died (26%)

Cytokine Peak Concentration Hypothesis Just need to Balance the Cytokine scales Annu. Rev. Pathol. Mech. Dis. 2006. 1:467–96

Endotoxin adsorption on haemofilter Kellum CCM 2004

Cytokine removal in sepsis n=24 adults with sepsis, no AKI No reduction in cytokines, no clinical benefit Cole CCM 2002:30,100-106 De Vriese Am Soc Nephrol 1999;10:846

CVVH may be harmful in sepsis n=76 adults sepsis . CVVH (35ml/kg/hr) vs standard care No change cytokines worse organ failure scores with CVVH Longer ventilation and inotrope need Worsening SOFA Score Time to death Payen Crit Care Med 2009; 37:803–810

Genetic and inflammatory markers of Sepsis n=1886 adults pneumonia in 28 US centres Systemic cytokine activation common, not universal Cytokines had peaked by ICU admission No rise in cytokine with the onset of organ dysfunction Differences between groups with different outcomes were modest Cytokines remained high even with clinical recovery in some Mortlaity highest when both pro and anti-inflammatory cytokines are high Arch Intern Med. 2007;167(15):1655-1663

JAMA. 2011;306(23):2594-2605

Dose dialysis in sepsis: No effect RENAL study (n=1508) NEJM 2009 CVVHDF 25ml/kg vs 40ml/kg/hr No difference mortality Tolwani (n=200) J Am Soc Neph 2008 CVVHDF 20ml/kg vs 35ml/kg/hr No difference mortality NIH ATN (n=1124) NEJM 2008 CVVHDF 35ml/kg vs 20ml/kg/hr

Mode dialysis in sepsis: CVVH vs CVVHD Acute Kidney Injury (OMAKI) Canadian Trial group CVVH vs CVVHD n=78 adults (80% sepsis) Same dialysis dose of 35ml/kg/hr effluent rate No difference mortality CVVH 12/35 35% CVVHD 10/38 27% Wald et al. Critical Care 2012, 16:R205

CVVH 70ml/kg/hr vs 35ml/kg/hr No difference 28 day mortality 15 % absolute reduction in 28-day mortality (460 patients) Stopped early before power obtained n=144 Adults (96 hrs dialysis) CVVH 70ml/kg/hr vs 35ml/kg/hr No difference 28 day mortality Intensive Care Med (2013) 39:1535–1546

Falling annual mortality with sepsis Over 1 million patients (171 ICU’s Australia / NZ) Absolute mortality in severe sepsis decreased from 35% to 18% in 2012 (1.3% reduction per year) Surviving sepsis 5.4% fall in mortality in participating centres over 3 yrs Giving antibiotics quicker 8% increase death / hour delay. CCM 2006;34:1589-1596 10% severe sepsis ARF mortality 55 % (2000) 35% (2012)

Paediatric sepsis 2002 – 2012 (Australia / NZ) 97127 children 2.9% sepsis 2.1% septic shock Mortality severe sepsis unchanged 19% 2002-2007 15% 2008-20012 Lancet Infect Dis 2015;15: 46–54

Untreated AKI without dialysis is not good 29 vs 43% sepsis Schneider A G et al. Nephrol. Dial. Transplant. 2012;27:947-952

Adults vs Children: BFR vs UFR

CVVH for fluid overload N=297 children Multicentre 3% mortality per 1% increase fluid overload GET THE FLUID OFF Sepsis 25% 37% 40%

Hyperchloraemia: Survival advantage in children

Summary AKI increases mortality in sepsis CVVH benefit for fluid overload No evidence immune modulating Get basic care right first (eg. surviving sepsis campaign)