Le terapie sostitutive in corso di sepsiFilippo MARIANO

Dipartimento di Area Medica, SCDO di Nefrologia e DialisiOspedale CTO, Torino

LA TERAPIA SOSTITUTIVA RENALE IN AREA CRITICA

Corso di Aggiornamentoper Personale Infermieristico

Infection

Systemic inflammatory

response

Multi-organ dysfunction

Therapy of SEPSIS

EndothelialDysfunction

Cellactivation

Eliminate infection- Surgery- Antibiotics

- Iv fluids- Vasopressors- Reduce systemic

inflammation

Infectious agent

Other factors

Pro inflammatorymediator

earlyinhibitors

Receptor activation

Pro- inflammatorymediators

Signal pathway activation

Anti- inflammatorymediators

inhibitors Protein synthesis

Coagulation cascade

Inflammatory cascade

ROS

Mediators of sepsis (…..the most are unknown …)

Microcirculatory disturbancesCoagulationHemodynamics

Increased capillarypermeability

Hypotension / Hypoperfusion

EDEMA

… first studies at the end of 80th

Blood purification in sepsis -a concept born more than twenty years ago

Stein et al (1990) Intensive Care Med- Hemodynamic improvement after hemofiltration in the pig after iv endotoxin

Grootendorst et al (1992) Intensive Care Med- UF from endotoxic pigs produced hemodynamic instability in healthy pigs - High volume HF improved endotoxic shock in pigs

Grootendorst et al (1993) J Crit Care - Infusion of ultrafiltrate from endotoxic pigs depresses myocardial performance in normal pigs.

Grootendorst et al (1994) Shock- High volume hemofiltration improves hemodynamics and survival of pigs exposed to gut ischemia and reperfusion.

Gotloib el al, Resuscitation, 1986- ……...…..probably blood could be ‘detoxified’ in patients with sepsis………

Elimination of TNF by conventional membranes: clinical studies

---------------------------------------------------------------------------------------------------------------------------------------------Study Membrane/Method Design Assays Results Comments---------------------------------------------------------------------------------------------------------------------------------------------Hirasawa ? / CVVH 43 pts with MOF ? SC 52.2%; no information Many causative mediators could[Clin Nephrol 1991] no control study about plasma concentrations be effectively removed.

Bellomo PAN / CAVH 16 pts, L 929 12/16 Patients TNF-positive Substantial clearance of cytokines[Crit Care Med sepsis bioassay, SC 30%, constant (TNFa and IL-1b), prevention of further 1993] uncontrolled ELISA study plasma concentration increrases in plasma concentration

Tonnesen PS / CAVH 9 pts / sepsis ELISA 7/9 Patients TNF-positive Release of cytokines by passage[Intensive Care Med 1993 ] uncontrolled TNF SC >1, constant plasma level through the hemofilter.

studyHoffmann PA / CVVH 16 pts with WEHI 13/16 Patients TNF-positive No significant elimination of[Kidney Int 1995] severe sepsis 164 5/5 volunteersTNF-negative mediators by hemofiltration

5 healthy bioassays SC 0%, constant concentration

Wakabayashi? / CVVH 6 pts with ELISA No influence of HF on Validity of unselective mediator[Br J Surg 1996] SIRS; no TNF plasma concentration; removal remains to be clarified.

control study no data on UF concentrations

Sander PAN / CVVH 16 pts with ELISA concentrations constant Despite marked elimination of[Intensive Care SIRS, during 48 hours of CVVH cytokines, plasma levels did notMed 1997] control study TNF clearance 1.7±0.4 g/48 hr decline in the filtration group

Heering PS / CVVH 18 septic/ 15 ELISA SC 1%; no change in plasma There seems to be no argument[Intensive Care non ARF septic during 72 hours of CVVH in favor of establishingMed 1997] 10 healthy HF for elimination of cytokines

Sanchez PAN / CVVH 15 pts with ELISA No change in TNF plasma CVVH is associated with removal of[Am J Kidney incipient MOF concentration (168 hpurs) substantial amounts of TNF….. butDis 1997] 15 controls no difference from controls probably nonclinically relevant

Koperna ? / CVVH 7 pts with ELISA TNF plasma concentration Elimination of cytokines by CVVH[Wordl J Surg MODS, 7 controls increases from 11.1 to may contribute to the CP improvement 1998] 17.9 ng/ml (p , 0.05), SC? in critically ill patients

De Vriese PAN / CVVHDF 15 pts with ELISA TNF, IL-1, IL-6 + IL-10, Transitory decline of cytokine level [J Am Soc Nephrol AKI/Septic shock IL-1ra, sTNFr decrease probably due to a obsorption mechanism 1999] after 1 hour of filter change in critically ill patients---------------------------------------------------------------------------------------------------------------------------------------------

.. not significantremoval ofcytokine…

Table 1: Pre- and postfilter IL-8 concentrations at T0 and at T4 in Groups Control HF and ARF/HF. * = p < 0.05

---------------------------------------------------------------------------------------------------------------------------------TIME T0 (pg/ml) TIME T4 (pg/ml)

IL-8 PreFilter Il-8PostFilter IL-8 PreFilter IL-8 PostFilter Il-8 UF (ng/4 hours)---------------------------------------------------------------------------------------------------------------------------------

Control/HF 9.0 (9-26) 9.0 (9-15) 9.0 (4.5-19) 9.0 (4.5-19) 26.0 (0-53)

ARF/HF 1260 (905-1945)* 820 (450-1560)a 908 (540-1345) * 700 (395-1055)* 6930 (4242-9282) *---------------------------------------------------------------------------------------------------------------------------

Fig. 3: Chemiluminescencepriming activity on PMNs of Serum Prefilter,

0

200

400

800

1000

To T4 To T4Group ARF/HF Group Control/HF

Chem

ilumines

cenc

e%

Serup Prefilter + FMLP

Serum Postfilter + FMLP

Ultrafiltrate + FMLP

1200

600

*

* *

Mariano F et al, Kidney Int 60(4):1598-605, 2001

Table 1: Pre- and postfilter IL-8 concentrations at T0 and at T4 in Groups Control HF and ARF/HF. * = p < 0.05

---------------------------------------------------------------------------------------------------------------------------------TIME T0 (pg/ml) TIME T4 (pg/ml)

IL-8 PreFilter Il-8PostFilter IL-8 PreFilter IL-8 PostFilter Il-8 UF (ng/4 hours)---------------------------------------------------------------------------------------------------------------------------------

Control/HF 9.0 (9-26) 9.0 (9-15) 9.0 (4.5-19) 9.0 (4.5-19) 26.0 (0-53)

ARF/HF 1260 (905-1945)* 820 (450-1560)a 908 (540-1345) * 700 (395-1055)* 6930 (4242-9282) *---------------------------------------------------------------------------------------------------------------------------

Fig. 3: Chemiluminescencepriming activity on PMNs of Serum Prefilter,

0

200

400

800

1000

To T4 To T4Group ARF/HF Group Control/HF

Chem

ilumines

cenc

e%

Serup Prefilter + FMLP

Serum Postfilter + FMLP

Ultrafiltrate + FMLP

1200

600

*

* *

Mariano F et al, Kidney Int 60(4):1598-605, 2001

….. during CVVHF: ……. elimination of IL-8 and immunomodulatorysubstances by ultrafiltrate ……..

… in September, 2011 …..

Blood purification in sepsis

.. sorbents didn’t modify bloodcytokine levels …

.. but animals treated with sorbents livedsignificantly longer …

UREMIASmall solutesFluid and electrolyte (acid-base) managementLarger solutes?

SEPSISLarge solutes (cytokines, chemokines)Other high molecular weight factors ?

Nefro-Dial, DAM CTO

BLOOD PURIFICATION: differentgoals in uremia and sepsis

As removal rates and clearances of pro-anti inflammatory substancesof middle/high molecular weight by conventional hemodialysis,hemodiafiltration or hemofiltration are hindered by limited diffusiveor convective rates, alternative approaches to increasing mediatorremoval could be based on:

Nefro-Dial, DAM CTO

Increased exchange volume ----- > High volume HDF/HFAdsorption mechanisms ------------> HemoperfusionProximal tubular cell culture ------ > Bioartificial kidney

Increased membrane permeability -> “Open“ membranes 1) with substitution fluid (plasmapheresis, other)2) coupled with sorbent technology (CPFA,other)3) without regeneration of ultrafiltrate (high-cutoff

membrane HF/HDF/HD)

As removal rates and clearances of pro-anti inflammatory substancesof middle/high molecular weight by conventional hemodialysis,hemodiafiltration or hemofiltration are hindered by limited diffusiveor convective rates, alternative approaches to increasing mediatorremoval could be based on:

Nefro-Dial, DAM CTO

Increased exchange volume ----- > High volume HDF/HFAdsorption mechanisms ------------> HemoperfusionProximal tubular cell culture ------ > Bioartificial kidney

Increased membrane permeability -> “Open“ membranes 1) with substitution fluid (plasmapheresis, other)2) coupled with sorbent technology (CPFA,other)3) without regeneration of ultrafiltrate (high-cutoff

membrane HF/HDF/HD)

…. in 2000…….. .raccomandation wasat least 35 ml/kg/hr… and 45 ml/Kg/hrin septic patients …

ATN ATN studystudy

InstableInstable stablestable(CV SOFA 3(CV SOFA 3--44)) (CV SOFA 0(CV SOFA 0--2)2)

CVVHDF CVVHDF II--HDFHDFat 35 ml/ at 35 ml/ at 6 at 6 timestimesKg/Kg/hourhour //weeklyweekly

((KtKt/V 1.2/V 1.2--1.4)1.4)

•• ThereforeTherefore, in , in eacheach groupgroup a) or b) a) or b) patientspatients werewere randomizedrandomized forfor less-intensive orintensive therapytherapy strategystrategy..PrimaryPrimary end end pointpoint: : death within 60 days after randomization

InstableInstable stablestable(CV SOFA 3(CV SOFA 3--44)) (CV SOFA 0(CV SOFA 0--2)2)

CVVHDF CVVHDF II--HDFHDFat 20 ml/ at 20 ml/ at 3 at 3 timestimes//Kg/Kg/hourhour weeklyweekly

((KtKt/V 1.2/V 1.2--1.4)1.4)

IntensiveIntensive LessLess intensiveintensive

1124 patients with AKI in 27 ICUs (USA) 1124 patients with AKI in 27 ICUs (USA) ffrom November 01, 2003 to July 31, 2007rom November 01, 2003 to July 31, 2007 …. in 2008

ATN Study…….

p=0.10p=0.10

The VA/NIH Acute Renal failure Trial Network. Palevski et al N Eng J Med 2008

The VA/NIH Acute Renal failure Trial Network. Palevski et al N Eng J Med 2008

RENAL RENAL studystudy

CVVHDF CVVHDF at 40 ml/Kg/at 40 ml/Kg/hourhour

•• ThereforeTherefore, in , in eacheach groupgroup a) or b) a) or b) patientspatients werewere randomizedrandomized forfor CVVHDF loweror or CVVHDF higher therapytherapy strategystrategy..PrimaryPrimary end end pointpoint: : death within 60 days after randomization

CVVHDF CVVHDF at 20 ml/Kg/at 20 ml/Kg/hourhour

CVVHDF CVVHDF higherhigher CVVHDF CVVHDF lowerlower

1124 patients with AKI in 27 ICUs (USA) 1124 patients with AKI in 27 ICUs (USA) from November 01, 2003 to July 31, 2007from November 01, 2003 to July 31, 2007 …. in 2009

RENAL Study…….

RENAL STUDY

The RENAL Replacement Therapy Study Investigators. N Eng J Med 361:1627, 2009

RENAL STUDY

The RENAL Replacement Therapy Study Investigators. N Eng J Med 361:1627, 2009

risk of death RR 0.89, 95% CI 0.76 to 1.04, P = 0.143

recovery of renal function RR 1.12, 95% CI 0.95 to 1.31, P = 0.181

High intensity (35 to 48 ml/kg/h or equivalent)

vs lower intensity (20 to 25 ml/kg/h or equivalent)

Jun M, et al. Intensities of renal replacement therapy in acute kidney injury: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2010;5:956-63

ATN delivered 95% of the prescribed dose of CVVHDFPrescribed = 20 ml/kg/h / Delivered = 19 ml/kg/hPredilution

RENAL delivered 88% of the prescribed dose of CVVHDFPrescribed = 25 ml/kg/h / Delivered = 22 ml/kg/hPostdilution (~25 ml in pre-dilution mode)

DOREMI delivered 79% of the prescribed dose of CRRTPrescribed = 34.3 ml/kg/h / Delivered = 24.1 ml/kg/h

,,,,, delivered dose is not prescribed dose in multicenter trials

Standard clinical practice delivers 68% of prescribed dosePrescribed = 24.5 ml/kg/h / Delivered = 16.6 ml/kg/h

Venkataraman et al. J Crit Care, 17; 2002: 246-250

.. some unanswered remarks ……..

Table 2: Dialysis flow rates in 70 severe burn patients underwent HDF (31 patients with citrate or 39 with heparin). Dialysis flow rate were given according to dialysis duration (CVVHDF or SLED-HDF)

-----------------------------------------------------------------------------------------------------------------------------------------------with citrate with heparinCVVHDF SLED-HDF CVVHDF SLED-HDF

------------------------------------------------------------------- ---------------------------------------------------------------Patients 23 8 7 32Duration of RRT (days/patient) 7 (4-17) 6 (5-7.5) 10 (6-22) 12 (9-16)Blood flow rate (ml/min) 120 (110-130)b 130 (120-140)e 120 (110-120)c 130 (120-130)Dialysate flow rate (L/hour) 1.20 (0.70-1.80)bd 2.00 (1.50-2.50)e 1.40 (1.30-1.50)c 2.50 (2.50-2.50)Infusion flow rate (L/hour) 0.70 (0.65-0.75)bd 1.35 (0.80-1.50)e 0.90 (0.90-1.00)c 1.00 (1.00-1.10)Calcium chloride (mmol/hour) 3.1 (2.7-3.4)b 5.1 (4.0-5.4) ----- -----Delivered dialysis dose (ml/Kg/day)a 578.9 (461.5-769.2)bd 322.6 (268.4-453.2) 493.1 (362.9-651.5)c 370.3 (308.6-464.1)Fluid removal (ml/Kg/day) a 34.6 (15.0-55.4)b 12.8 (0.0-25.9) 29.1 (11.1-48.0)c 14.2 (2.1-28.3)Filtration fraction (% of blood inflow) 1.92 (1.03-2.78) 1.32 (0.0-2.90) 1.81 (0.72-3.29) 1.81 (0.29-3.64)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Data are expressed as median (quartile 1, quartile 3)aDelivered dialysis dose and fluid removal are expressed in ml/kg/day using the first measured weight. bStudent t-test between CVVHDF and SLED-HDF in group with citrate: p <0.05cStudent t-test between CVVHDF and SLED-HDF in group with heparin: p <0.05dStudent t-test between citrate and heparin in CVVHDF: p <0.05eStudent t-test between citrate and heparin in SLED-HDF: p <0.05

Mariano F et al, Intensive Care Med 36:1735-43, 2010

Delivered dose in severe burned patients trated by RRT at CTO Hospital

Kt/V ≈ 1per day

As removal rates and clearances of pro-anti inflammatory substancesof middle/high molecular weight by conventional hemodialysis,hemodiafiltration or hemofiltration are hindered by limited diffusiveor convective rates, alternative approaches to increasing mediatorremoval could be based on:

Nefro-Dial, DAM CTO

Increased exchange volume ----- > High volume HDF/HFAdsorption mechanisms ------------> HemoperfusionProximal tubular cell culture ------ > Bioartificial kidney

Increased membrane permeability -> “Open“ membranes 1) with substitution fluid (plasmapheresis, other)2) coupled with sorbent technology (CPFA,other)3) without regeneration of ultrafiltrate (high-cutoff

membrane HF/HDF/HD)

Adsorbents developed for use in sepsis can bind toxins

nonselective (charcoal)selective (polymyxin B- immobilized

polystyrene-derivative fiber)specific (antibody-coated microsphere-based

detoxification system)

Sorbents in Sepsis

Sorbents act retaining some molecules for hydrophobic binding of affinity

External “interphase”Transfer solute from bulkThin film on outer surface of resin

Internal “intraphase”Solute enters pore by diffusion

Surface DiffusionSurface Adsorption by hydrophobic binding

or by affinity binding (if specific resin)

Possible Advantages of Sorbents

Sorbent technology

Access to substances bound to proteinSorbents can remove larger MW toxins

exceeding cut-off of dialysis membranesIn future many advances in resin sorbent

technology

700 m2/g resin

HemoperfusionRadial flow system

PMX20R

PMX-DHP CPFA

Plasma filtration and adsorption

Plasma

reinfusate in

UF out

“good molecules”

Prospective, multicenter, randomized controlled trial

64 patients randomized

Fig. 3: Estimation of survival rate according to treatment group

700 m2/g resin

HemoperfusionRadial flow system

PMX20R

CPFA

Plasma filtration and adsorption

PMX-DHP

Plasma

reinfusate in

UF out

“good molecules”

As the authors point out, this conclusion does not mean that dose does not matter, since the targeted standard dialysis goal was greater than what is often achieved in intermittent hemodialysis. Neither does it mean that higher doses of continuous therapies are not beneficial.Given the results of the ATN study, the renal and intensive care communities must now focus on other strategies to help this population of patients. ...........Current approaches to dialysis are probably inadequate to replace critical functions of the kidney other than regulation of volume and electrolyte and acid–base homeostasis.………. We still have a long way to go in treating acute kidney injury.

....dialytic target for AKI (with or without sepsis)......

20-25 ml/Kg/hour(500-600 ml/Kg/day)

Conclusions

Standard “renal dose” of dialysis is relatively ineffective in affecting cytokine levels, or organ failure and patient survival

Sorbent technology are a promising and potential tool for blood purification in sepsis. Preliminary data showed that;

In severe sepsis/septic shock patients polymyxin B hemoperfusion added to conventional therapy significantly improved hemodynamics, organ dysfunction and mortality

A large randomized trial on CPFA in early septic shock patientsindicated that CPFA treated group had a global survival similar to control group. However, in dose-dependent subgroup analysis patients treated with an exchanged plasma dose of 0.22 L/Kg/die for 3 days had a significant decrease of mortality rate.

Conclusions....blood purification in sepsis without AKI......

.....underway....