blood purification in the icu state of the art

The CRRT Membranes • Nominal Pore size: 20- 30 kD • Highly absorptive capacity • Can bind many mediators in vitro • Can bind mediators in vivo • Can filter some mediators in vitro • Can

Blood Purification in the ICU:

State of the Art

A/Prof Rinaldo Bellomo Austin & Repatriation Medical Centre

Melbourne Australia

Similarities between sepsis and renal failure

• The mediators of “toxemia” are ill-defined

• Continuous removal beneficial ?

• Use Hemofiltration?

The Mediators of Sepsis (the Humoral Theory of Sepsis)

• Others: VIP, vasopressin, endorphin,

myocardial depressant factors (MW<5,000), Phospholipase

The CRRT Membranes

• Nominal Pore size: 20- 30 kD

• Highly absorptive capacity

• Can bind many mediators in vitro

• Can bind mediators in vivo

• Can filter some mediators in vitro

• Can filter some mediators in vivo

Hoffman et al Intensive Care Med 1996

TNF levels: CVVH vs CVVHD

-50 0 50 100 150 200

CVVHD CVVH

High Volume Hemofiltration

• The term was first used by Grootendorst in 1992

• Animal experiments in pigs (weight 36-39 kg)

• Blood flow 300 ml/min

• UF flow 6000 ml/hr

• Replacement fluid given pre-filter

• Polysulfone filters (Amicon, USA)

• IV endotoxin over 30 minutes

HVHF and RVEF

0 10 20 30 40 50 60

p<0.001

Grootendorst et al, Intensive Care Med 1992

HVHF and MAP

0 20 40 60 80 100 120 140

p<0.001

Grootendorst et al, Intensive Care Med 1992

Effect of septic UF on MAP

0 5 10 15 20 25 30 35 40

Effect of HVHF on ischemic gut injury

0 1 2 3 4

Perforation

p < 0.05

Grootendorst et al Shock 1994

• HVHF may be beneficial in human septic shock

• If Hct of 30% and blood flow of 300 ml/min and dilution small solute clearance = approx 60-70

pre-ml/min (110ml/kg/hr)

• In 70 kg patient in pre-dilution need about 11 L/hr

of UF rate less if post-dilution but need big blood flows (>400 ml/min)

• 11L/hr of UF is technically demanding/very difficult in human beings

• Can we achieve similar results at lower UF rates?

• Dog experiment in 20 kg dogs and UF rate of

2000ml/min (blood flow 200 ml and pre-dilution)

• Small solute clearance = approx 80 ml/kg/hr

Change in MAP after IV LPS

-70 -60 -50 -40 -30 -20 -10 0

CVVH Sham

Time after IV LPS (minutes)

MAP

(mmHg)

p < 0.05

Bellomo et al AJRCCM 2000; 161: 1429-1436

HVHF vs CVVH

• 10 patients with septic shock and ARF

• Noradrenaline dependent

• Randomized to 8 hrs of HVHF (6L/hr) or CVVH (1L/hr) in random order

• Physiological outcome: hemodynamic response

• Biological outcome: Complement and cytokines

Technique for HVHF

• Filtral 16 (1.6 m2)- AN 69 membrane

• Blood flow: 300 ml/min

• Catheter: 13.5 Fr double lumen Niagara (Bard)

• Replacement fluid: 2 L/hr pre and 4L/hr post

Norepinephrine Requirements:

HVHF vs CVVH

-30 -25 -20 -15 -10 -5 0 5 10

HVHF CVVH

% change over 8 h.

Cole, Bellomo et al Intensive Care Med 2001 ; 27: 978-986

100 200 300 400 500 600

C5a: HVHF (6 L) vs CVVH (1 L)

0 5 10 15 20 25 30

HFHV CVVH

Cole, Bellomo et al Intensive Care Med 2001

IL-10 during CVVH

0 10 20 30 40 50 60 70

C3a: Serum vs UF concentration

0 50 100 150 200 250 300 350

Maximum C3a Clearance = 3.3 mil/min

Cole, Bellomo et al Intensive Care Med 2001

TNF: HVHF vs CVVH

0 50 100 150 200 250 300

HVHF CVVH

pg / ml

TIME (hrs.)

Cole, Bellomo et al Intensive Care Med 2001

IL-8: HVHF vs CVVH

0 10 20 30 40 50 60 70 80 90 100

HVHF CVVH

• HVHF has beneficial short term effects in human septic shock similar to those in

animals

• With AN69 and molecules >8-9 kD it results

in adsorptive removal, not filtration of

inflammatory mediators

• There is now a rationale for phase II studies

Short Term-Very HVHF

• Patrick Honore et al (Crit Care Med 2000; 28: 3587)

3581-• 20 patients in severe refractory septic shock

• 4 hours of HVHF (blood flow 450 ml/min, 1.6 m2

Fresenius polysulfone filter, bicarbonate buffer, dilution, UF rate 8750 ml/hr)

post-• Approx small solute clearance: 116ml/kg/hr

• 11 responders (rapid increase in CI, MVSO2,

pH>7.3 and 50% reduction in adrenaline dose)

• 9 of 11 responders survived

• Responders weighed less : 66 vs 83 kg

• Responders got more UF: 132 ml/kg/min vs 107 ml/kg/min

• Responders were treated earlier: 6.5 vs 13.8 hrs

• We have no consensus definition for the term “HVHF” but we have several phase I studies suggesting that

“more” UF might be better.

• We have limited understanding of

mechanisms, dose and duration,

however, and no markers like urea

• This is a promising and exciting area

of research We now need a phase II trial.

Why not plasma exchange?

• Fresh frozen plasma (FFP) is available in limited amounts

• If done continuously, after a while one is removing the FFP given

• FFP contains many of the proteins we want to

remove Intermittent therapy is unlikely to be

enough

• No effect in Phase Ib trial (Reeves et al Crit Care Med 1999; 27: 2096-2104)

Why Coupled Plasma Filtration

Adsorption (CPFA)?

• All plasma becomes available for “purification”

• Therapy can be continuous

• No interaction between cells and adsorptive cartridges

CPFA: Ex-vivo testing - cytokine

CPFA in animal models

• Test whether biochemical findings translate into clinical effects

• Assess magnitude of clinical effects

• Assess nature of clinical effects

• Exclude major unexpected adverse events

• Deal with unexpected technical problems

CPFA in the rabbit - TNF

adsorption

0 5000 10000 15000 20000 25000 30000

60 min 90 min 120 min 180 min

TNF bioactivity resin

pre-TNF-bioactivity resin

post-U/mil

Tetta et al Crit Care Med 2000; 28: 1526-1533

CPFA in the rabbit

% survival

p =0.004

Days Tetta et al Crit Care Med 2000; 28:

1526-1533

Phase I trial of CPFA

• 10 patients

• Single ICU

• MODS + ARF + high cardiac output + hypotensive + norepinephrine infusion

• Random allocation to CPFA + CVVHD

or to CVVHD alone each for 10 hours with cross over

Outcome measures

• Primary: decreased need for

norepinephrine and/or increased arterial pressure

• Secondary: a) decreased levels of

TNF and IL-10 b) improved

monocyte response to LPS

Blood In 100-200

CVVHD (Treatment B)

Dialysate In

30 ml/min

Dialysate Out + Uf

Dialysate In

30 ml/min

Blood Out

Plasmafiltrate 30-40 ml/min

Site 2

Site 3 Site 4 Site 5

Site 6

Site 7

Ronco, Brendolan, Lonnemann, Bellomo, et al Crit Care Med 2002; 30: 1250-1255

0 500 1000 1500 2000 2500

Site 1+LPS Site 2+LPS Site 3+LPS

0 100 300 500 700 900

1100

Post alone

Pre + anti-IL-10

*

Pre alone

*

*

Spontaneous TNF production by whole

blood after incubation with PF

Green = t0

Black = t10

Crit Care Med 2002; 30: 1250-1255

• There is a biologic rationale for CPFA

• There is ex-vivo evidence of adsorption

• There is animal evidence of increased survival

• A Phase I trial shows beneficial

hemodynamic effects in humans with septic shock

Problems with CPFA

• Plasmafilter can take limited blood flows

• Limited blood flow = limited PF rate

• Limited PF rate = limited clearance

• Even with 100% adsorption, clearance can only be 30-35 ml/min

• We may need more

Super High Flux Filters (nominal pore size = 100 kD)

• Easier to use

• Do not need complex CPFA circuit

• Cheaper

• Can be used by anyone

• If combined with HVHF may offer “best value”

Clearances (ml/min) of cytokines and albumin in 1L/hr ultrafiltration(ml/min)

0 10 20 30 40 50 60 70 80

IL-1 IL-6 IL-8 IL-10 TNFa Alb

0Hr 2Hr 4Hr

Polyamide super high-flux filter

Note low IL-8 clearance

Uchino, Bellomo et al Intensive Care Med 2002; 28: 651-655

Figure 2B:

Clearances (ml/min) of cytokines and albumin in 6L/hr UF (ml/min)

Polyamide SHF filter + HVHF

Loss of SC with increased UF rate and time

Uchino, Bellomo et al Intensive Care Med 2002; 28: 651-655

Cellulose triacetate SHF filter +

HVHF

Low clearance for MW

Uchino, Bellomo et al Int J Artif Organs 2002; 25: 32

Cellulose triacetate SHF filter + HVHF

Loss of SC

• Time effect small

• Albumin losses sustainable

• Highest cytokine removal ever reported!

Can we dialyze cytokines?

• Hemofiltration requires high blood flows

• Without high blood flows, no high UF flow rates

• High UF flows increase TMP and decrease functional pore size

• Replacement fluid expensive

• How about diffusing cytokines?

Figure 2A:

Clearances of cytokines and albumin in 1L/hr dialysis

(ml/min)

0 10 20 30 40 50 60 70 80 90 100

IL-1 IL-6 IL-8 TNFa Alb

0Hr 2Hr 4Hr

Polyamide filter

Low clearance for MW

Uchino, Morimatsu, Bellomo ASAIO J (2002) (in press)

Clearances of cytokines and albumin in 9L/hr dialysis

Polyamide filter

Citrateeffect

Uchino, Morimatsu, Bellomo ASAIO J (2002) (in press)

• Super high-flux membranes offer new opportunities to explore the usefulness

of blood purification in ICU

• Several technical optimizations may

allow very high cytokine clearances

• Cytokine dialysis is possible

• This is pretty exciting stuff !!!

• New bioreactors with macrophages

• New bioreactors with tubular cells

• The future looks very interesting !!