U.O. di Nefrologia, Dialisi ed Ipertensione

Policlinico S.Orsola-Malpighi

Azienda Ospedaliero-Universitaria

Bologna

La sepsi

Antonio Santoro

Il circuito extra-corporeo

Blood In

UF

Blood out

&

Incidence of severe clinical complications (non CV) and sepsis in ICU

German and Italian data indicate that 35-45% of patients admitted need mechanical ventilation (Morer, Crit Care 2007, GiViTi report 2010)

German and Dutch studies imply that 11-14% of those admitted to an ICU developed severe sepsis.

(Morer Crit Care 2007)

Nearly 6% of patients admitted to an Italian ICU suffer from septic shock (GiViTi report)

4-9% of ICU patients require renal replacement treatment (Palevsky CJASN, 2006)

In ten western European countries 3.500 liver transplants are performed each year. Average waiting time varies from 30-50 days.

Sepsis is a syndrome

1. type of micro-organism • bacteria (Gram + vs Gram -, virulence, load) • other (viral, fungal)

2. patient co-morbidities 3. age 4. immune “health”

respiratory urinary abdominal blood stream meningitis

≠ ≠ ≠ ≠ ≠

CV system

Sepsis is a syndrome

Common Responses 1. excessive proinflammatory cytokines 2. excessive antiinflammatory cytokines 3. cell activation 4. immunosuppression 5. oxidant stress 6. apoptosis 7. disordered coagulation 8. endothelial dysfunction 9. microcirculatory dysfunction 10. inappropriate cell repair

Lungs Edema Diffuse alveolar damage Acute lung injury ARDS

Liver Steatosis Cholestasis Centriacinar necrosis

Adrenals Hemorrhage Lipid depletion

CNS Confusion Delerium Altered consciousness Cognitive loss

Cardiovascular Ischemia Dilatitative failure

Pancreas Ischemia Decreased insulin production Hyperglycemia

Kidneys Ischemia Decreased insulin production Hyperglycemia

End organ damage in sepsis

respiratory urinary abdominal blood stream meningitis

≠ ≠ ≠ ≠ ≠

CV system

Multi-Organ Failure: incidence of multiple organ disease

AKI 48%

Acute Lung Injury 49%

Liver Failure 15%

Need of integrated and multidisciplinary care

Bertolini G et al, Report GiViTi 2010

Sepsis

Increasing incidence

Sepsis: costly - with few therapeutic choices

Average episode of sepsis in Europe costs €25,000

Healthcare Cost and Utilization Project (HCUP) and the Agency for Healthcare Research and Quality, (U.S. Department of Health and Human Services): National Inpatient Hospital Costs: The Most Expensive Conditions by Payer, 2011

• Aggregate healthcare cost of $20.3 billion in 2011 (U.S. hospital-related costs only)

• Sepsis represented 5.2% of the national costs for all hospitalisations

• Most expensive condition billed to Medicare, accounting for 6.9% of all Medicare costs

Blood purification in sepsis: data from large databases

GiViTi report 2010

• Prevalence of severe sepsis or septic shock 14,2%

• Organ dysfunction in septic shock: – Renal 20,4% – Respiratory 10,4%

• RRT in severe sepsis 27,9%

German national prospective study on sepsis • Prevalence of severe sepsis

or septic shock 12,2% • Organ dysfunction in severe

sepsis: – Renal 42,2% – Respiratory 52,0%

• RRT in severe sepsis 20,2%

Margherita ProSafe report 2010 http://www.giviti.marionegri.it/Download/Rapporto2010.pdf

Engel C et al, Intensive Care Med, 2007, 33, 606-18

Extracoporeal Therapies

Restores physiology

remove toxins decrease fluid overload restore electrolyte balance

IHD

SLED

CRRT

Spectrum extracorpeal therapies

Low volume High volume

Renal replacement therapy options: impact on solute clearances

HDF

Convection

Middle molecules removal

HF

Adsorption

HD Low Flux HD High Flux

Diffusion

Low molecules removal

High Volume HemoFiltration Definition of HVHF:

1. Proc 2° Conference on Crit Care Nephrology (Czhech Repub, 2007) – Continuous HVHF with 50 – 70 mL/Kg/h for 24 h

OR – Intermittent HVHF 100 – 200 mL/Kg/h for 4-8 h followed by conventional

CVVH 1. ADQI – HVHF when > 35 mL/Kg/h

PROs • High KT/V of urea, great removal of middle (beta-2 microglobulin)and

large molecule • New concepts on cytokines compartimentalization

Blood Purification for Systemic Inflammation «...from Cytotoxic Model to Cytokinetic model»

“Improvement of immune dysfunction in patients with severe acute pancreatitis by high-volume hemofiltration”

INF-

ɣ (p

g/L)

TNF-

α (p

g/L)

IL-1

(pg/

L)

IL-2

(pg

/L)

IL-5

(pg

/L)

IL-1

3 (p

g/L)

Gong D. Int J Artif Organs 2010 Medical therapy vs High-Volume HF (4000 ml/h)

High Volume HemoFiltration • Definition of HVHF:

1. Proc 2° Conference on Crit Care Nephrology (Czhech Repub, 2007) – Continuous HVHF with 50 – 70 mL/Kg/h for 24 h

OR – Intermittent HVHF 100 – 200 mL/Kg/h for 4-8 h followed by conventional

CVVH 1. ADQI – HVHF when > 35 mL/Kg/h

Potential drawbacks:

– Hyposphatemia (RENAL, ATN, IVOIRE) – Hypokalemia – Drugs clearances

HVHF: risk of electrolytes dysbalance

Hypophosphatemia Hypokalemia

Relationship between effluent flow intensity during continuous renal replacement therapy and antibiotics’clearance

Meropenem

Piperacillin

Vancomycin

Jamal JA. CCMJ 2014

HVHF: a systematic review and meta-analysis

Clark E et al, Crit Care, 2014, 18, R7

High Cut-Off membrane

Inner surface electronic microscopy of of different membranes

Rimmelé T, Kellum J, Crit Care, 2011, 15, 205

Membrane: nomenclature and classification

00,10,20,30,40,50,60,70,80,9

1

1,0E+03 1,0E+04 1,0E+05

Siev

ing

Coef

ficie

nt

Molecular Weight (Da)

Very High Cut-Off

Superflux

High flux

Low flux

Cytokine clearances by HCO filters

Atan R, Bellomo R, et al, Blood Purif, 2012, 33, 88-100

Amines doses: pilot study comparison betwenn HCO vs standard CVVH

Morgera S et al, Crit Care Med, 2006, 34 (8), 2099-

New paradigm about response to inflammation: genomic storm

Xiao et al , J Exp Med, 2011, 208 (13), 2581-90

Endotoxin Trauma

Kinetics of expression of chemokine and cytokine in Peptidoglycan (PGN), Lipopolysaccharide (LPS) and

Staphylococcus aureus in human monocytes

Wang ZM et al, J Biol Chem, 2000, 275:20260-20267

In vitro study on human blood monocytes cultured with Peptidoglycan (PGN), or Lipopolysaccharide (LPS), or Staphylococcus aureus or interferon-gamma.

Rationale for extracorporeal therapies in sepsis

Lee A O'Brien, Frontiers in Bioscience, 2006, 11, 676-98

1: Renal indication

2: Non Renal indication

New Targets!

Extracoporeal Therapies

Restores physiology

Contributes to resolve

inflammation remove toxins decrease fluid overload restore electrolyte balance

Removal of endotoxins Removal of chemochines Removal of cytochines

Extracorporeal therapies for sepsis

• Hemoadsorption • Plasma Exchange

Endotoxins Bacterial fragments

• HVHF • CPFA • High cut-off / superflux CVVHD

Cytokine removal

IHD

SLED

CRRT

ECMO

CO2 Removal Cytokine

removal Immuno- pheresis

endotoxin removal poisoning

(HP)

SCUF

Spectrum extracorpeal therapies

Endotoxins

• Molecular weight 10 ÷ 20 kDa in acqueous solutions • Molecular weight > 100 kDa in non acqueous solutions (protein

containing solutions) • It complexes with protein forming LPS binding proteins which

makes difficult to remove by ultrafiltration • Highly stable in temperature and pH.

Hemoadsorption • Polymxin-B seems to be effective in reducing endotoxins:

– Kojika, 2006 endotoxin reduction from 8.84 to 2.11 pg/mL – Vincent, 2005, no change in endotoxin level from 28 EU to 38.5 EU (LAL test) – Pooled estimation of several studies: decrease by 33% to 80% of pre-

treatment levels (Cruz, 2007) • Mortality:

– In a first meta-analysis PMX-B favourably affects survival (Risk Ratio 0.53, CI 0.49 – 0.65), Cruz, 2007. Most of the study were single center all performed in Japan.

– EUPHAS (Cruz, 2009) adjusted hazard ratio 0.36 (CI 0.16 – 0.80). The study was underpowered.

– The EUPHAS 2 failed to show any significant difference in mortality – The ABDOMIX study failed to show any difference in mortality (

• Hemodynamic response – Pooled estimation of Cruz meta-analysis showed a MAP increase on average

by 26% respect the pre-treatment.

Oxiris®

CH2 CH C

-

CH2

CH2

CH3

CN

SO3 Na - - - - +

Basis structure (polyacrylonitrile)

N

NH

N

NH

NH2

NH NH

Polycation : Polyethyleneimine

Endotoxin adsorption (negatively charged)

Oxiris membrane: adsorption

Cytokine adsorption : adsorption takes place in the membrane bulk mainly on the sulfonic groups (negligible influence of the surface treatment) ; Endotoxin adsorption: adsorption only due

to the surface treatment (interaction between amine groups of high concentrated PEI and phosphate groups of lipid A).

Oxiris®: animal data

Cytokines

[NOME SERIE] [NOME SERIE] [NOME SERIE]

[NOME SERIE]

[NOME SERIE] [NOME SERIE]

[NOME SERIE] [NOME SERIE] [NOME SERIE] [NOME SERIE] [NOME SERIE]

Pro-inflammatory

Anti-inflammatory

Cytokine molecular characteristics

TNF-alfa 17

IL-1beta 17

IL-8 10 IL-12

75

IFN-gamma 25

IL-6 26

IL-4 16

IL-1Ra 17

TGF-beta 12

IL-10 16

IL-13 15

beta2-microG 11,6

Creatinin 0,113

51

25

Pro-inflammatory

Anti-inflammatory

Units kDa Comparison

Cytokine are water soluble compounds

Cytokine molecular size

Pro- and anti-inflammatory simultaneous response to septic shock: in vivo study

Tamayo et al , Eur Cytok Net, 2011, 22 (2), 82-7

N= 31 ICU pts 20 septic shock, 11 SIRS 15 abdominal surgery Blood samples within 24 h from diagnosis

IL-8

(pg/

ml)

IFN

-ϒ(p

g/m

l)

GM

-CSF

(pg/

mL)

IL-6

(pg/

ml)

IL-1

0 (p

g/m

l)

MCP

-1 (p

g/m

l)

MIP

-1b

(pg/

ml)

Coupled Plasma Filtration-Adsorption

• Selective removal of cytokines and inflammatory mediators

Plasma

reinfusion in

UF out

High surface area

1.2 to 2.4 m2 700 m2/g resin 50,000 m2/cartridge

How does the resin work?

From micro

To nano

1. Interphase 2. Intraphase 3. Thin surface film

4. Large molecules bind only at surface

5. Small solutes enter by diffusion

6. Adsorption or elution

Plasmaperfusion Hemoperfusion

Plasma 20-30% of QB

120-200 ml/min

• Slower plasma flow allows more contact time with resin = better adsorption efficiency

• less fouling of resin surface • no interaction of cells with resin • Anticoagulation is sometimes

more difficult

• Faster blood flow allows more blood to be treated.

• Results depend strongly on adsorption efficiency under high linear velocity - and eventual decrease of resin efficiency after fouling.

• More likely to have “channeling”

120-200 ml/min

24-60 ml/min 120-200 ml/min

Tetta C. Nephrol Dial Transplant 1998

Author Target population

Study Design Major Results of CPFA trials P

Tetta et al, 2000 Animal model Prospective RCT w. out CPFA - CPFA

- Survival @ 2 days 85% in CPFA - Survival @ 2 days 25% w.out CPFA

0.041

Ronco et al, 2000 Septic pts N=?

Prospective RCT CPFA – CVVH CVVH - CPFA

- ↑ Hemodynamic response - ↓ Norepinephrine dose

Formica et al, 2003

Septic shock pts N= 12

Prospective Longitudinal CPFA

- ↑MAP - ↓Cardiac Index - ↑ Syst Vasc Res Index - PaO2/FiO2 - No change extracvasc lung water - intra-thoracic blood index - Survival @ 28 days 90% - Survival at 90 days 70%

<0.001 <0.001 <0.001 <0.001 Ns Ns

Ronco et al, 2002 Septic shock pts N= 10

Prospective pilot CPFA (10h) – CVVHDF

(10h) CVVHDF (10h) – CPFA

(10h)

- ↑ MAP 11.8 vs 5.5 mmHg - ↓ Norepinephrine 0.08 vs 0.0049

ug/Kg/min

0.001 0.003

Mariano et al, 2004

Septic shock, ARF N=13

Parallel group CPFA + Hep

CPFA + Citrate

- Kit survival Hep: 8.40±0.39 h - Kit survival Cit: 7.79±0.19 h

ns

Lentini et al, 2009 Septic shock, AKI N=8

Prospective RCT HVHF-CVVH-CPFA-CVVH CPFA-CVVH-HVHF-CVVH

- No change MAP - No change Norepinephrine - No change Vasopressor - No change PaO2/FiO2

0.29 0.18 0.22 0.08

CPFA: main results

Author Target population

Study Design Major Results of CPFA trials P

Caroleo et al, 2010 Case report Liver Failure

CPFA -Bilirubin levels (RR 47.8%, 53.8%, 59.3%)

Lucisano et al, 2011

Case Report ARDS

Case Report -↑ IL-6 vs baseline -↑ TNF vs baseline -↑ PCT vs baseline -↑ PC-R vs baseline

Mao et al, 2011 Septic shock, MOF N=7

RCT CPFA (10h) – HVHF (10h) HVHF (10h) – CPFA (10h)

-↑ MAP 120.75±20 vs 115.3±18.5 mmHg -paO2/FiO2 297.3±204 vs 265.45±173.7 -↑ Citokines

<0.05 <0.05

Berlot et al, 2011 Case report Septic shock

CPFA -↑ Vessels perfusions in the microcirculation

Moretti et al, 2011 Case report Weil’s syndrome

CPFA -Patient’s survival

CPFA: main results

CPFA: largest RCT, COMPACT

Mortality in H Mortality in ICU

Chi-square p 0.2 0.07

Trend tests p 0.05 0.02

Mortality in Internal Medicine / Nephrology Unit

CPFA 44.0 %

Stadard care 47.3 %

Mortality rate in ICU per CPFA dose in 5 days

56,7

35,526,7

0

10

20

30

40

50

60

70

80

0 - 0,55 (30) 0,55 - 0,90 (31) > 0,90 (30)

Tertiles CPFA Dose (L of plasma/Kg Body weigth)

Mor

talit

y ra

te (%

)

Intensive Care Unit

Mortality rate in ward per CPFA dose in 5 days

56,7

45,5

33,3

01020304050607080

0 - 0,55 (30) 0,55 - 0,90 (31) > 0,90 (30)

Tertiles CPFA Dose (L of plasma/Kg Body weight)

Mor

talit

y ra

te (%

)

In Ward (General Medicine / Nephrology Unit)

Livigni S et al, 2014, BMJ Open

Other extracorporeal therapies

Fresenius

High permeability polysulfone membrane

Targeting large middle molecule removal (with low albumin loss)

Cut-off 40 kDa

High efficiency with “low blood flows”

Captive for Multifiltrate

Marketed with CiCa (citrate anticoagulation)

24 hr treatment

Cytosorbents: Cytosorb

Divinylbenzene styrenic beads, beads and cartridge manufactured by Cytosorbents Hemoperfusion, works with standard RRT equipment Marketed towards

Sepsis Cytokine storm Cardiac surgery

Technical / clinical aspects

Removal main action

Duration (h)

Blood flow mL/min

Anticoagulation

Hemoadsorption Endotoxins (gram negative)

2 100 Heparin

Plasma exchange Endotoxins / Cytokines

3 100 Heparin

HVHF Cytokines 4 – 24 ≥200 Heparin / Citrate in predil.

CPFA Cytokines 12 150 Heparin / Citrate

HCO CVVHD Cytokines Up to 72 100 Heparin / Citrate

Pros and Cons Pro Cons

Hemoadsorption • Specific to gram-negative endotoxins • Easy to deliver • No need of specific equipments • Non vascular access issues

• Poorly efficient on gram positive • Need of extra hemodialysis in case of

concomitant AKI • Only Heparin as anticoagulant. No

indicated in high bleeding risk pts

Plasma exchange • Removal of both endogenous and exogenous source of sepsis

• No vascular access issues

• Only Heparin as anticoagulant. No indicated in high bleeding risk pts

• Need of albumin or fresh frozen plasma • Need of extra hemodialysis in case of

concomitant AKI

HVHF • Effective on cytokine removal • No need of extradialysis in case of AKI

• Need good vascular access (large size catheters)

• Huge nursing workload • It may yeld to hypophosphatemia if not

well compensated • Albumin loos can be an issue

CPFA • Removal in a wide range of molecular size

• Expert personnel

HCO CVVHD • Cytokines •Cost and non selective removal

Extracoporeal Therapies

Restores inflammation

Contributes pathophysiology

remove endotoxins remove cytochines remove chemochines

loss of physiologic compounds activation of inflammation activation coagulation

Elements for the realization of a low-inflammatory-impact dialysis treatment. Because of the multifactorial nature of inflammation in the chronic hemodialysis patient, an approach on several fronts should be implemented: on the one hand, the elimination of the factors inducing an inflammatory response, and on the other, the direct removal of the inflammatory mediators. Among the former, a high-quality water treatment system, the exclusive use of ultrapure dialysis fluids, and the avoidance of acetate in dialysate, as well as the use of highly biocompatible materials, are the main steps. Among the latter, apart from the mandatory use of high-flux membranes, adsorptive membrane, as well as the direct adsorption of inflammatory mediators on the sorbent cartridge, to arrive at the high-volume convection associated or not to diffusion are

the different possible options.

Kidney International (2014) 86, 235–237; doi:10.1038/ki.2014.81 Is hemodiafiltration the technical solution to chronic inflammation

affecting hemodialysis patients? Antonio Santoro and Elena Mancini

Conclusions 1. In the lack of effective agents against SIRS and sepsis, the use of devices to remove

the product of bacterials infection is advocated

2. The response of infective attack is triggered very fast and pro- and anti-imflmmatories mediators pathways plays concomitantly.

3. Several device has been developed over the years eventhough no results on main outcome (survival) has been proven

4. The several devices present several pro and cons according to patients status (vascular access, AKI presence, etc)

5. Sinergic and holistic approach seems to be the only ways to recover from sepsis so far

6. Several aspects must be defined:

Time and accuracy of diagnosis

Time and type to intervention according to diagnosis

Treatments discontinuation