CRRT Obuka Za Lekare

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Clinical Introduction to AKI
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• Fluid challenges
• I STEP
• In FluidResponsive+ patients, the first
resuscitation step will be to administer a
fluid bolus (FB) of 500 ml of crystalloids
every 30 min until normalizing
CapillaryResponsivenessTime in the
PeriferalPerfusionTestResponders group. In
the LactateTestR group, FB will be stopped if
at 2 h lactate is normalized or has
decreased > 20%, or previously if after any of
the fluid boluses, central venous pressure
(CVP) has increased ≥ 5 mmHg or the
patients have become fluid unresponsive
(FR−).
• II STEP {another FB will be administered}
• Safety measures during fluid challenges
• CVP and FR will be reevaluated after any
fluid challenge. If {CVP increases < 5 mmHg}
and Fluid Response is still +, and so on while
the perfusion (CRT or lactate) goal are not
attained. If {CVP increases ≥ 5 mmHg} or FR
is or become negative, fluids will be stopped
and the patient will be moved to the next
step.
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fluid/vaspressor/inotropic test
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People with CKD are especially susceptible to AKI, and

AKI, in turn, may act as a promoter of CKD progression2
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Potential
causes of AKI
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Potential
causes of AKI
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Potential
causes of AKI
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• Glomerular disease reduces

GFR and increases glomerular
capillary permeability to
proteins; it may be
inflammatory
(glomerulonephritis) or the
result of vascular damage due
to ischaemia or vasculitis.
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Management
options for
AKI
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Introduction to
Continuous Renal
Replacement Therapy
(CRRT)
Baxter Basic Continuous Renal Replacement Therapy (CRRT) Principles
What are the four different clearance mechanisms

used by RRT?
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Basic Continuous Renal Replacement Therapy (CRRT) Principles

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What are the four different clearance mechanisms

used by RRT?
Ultrafiltration
Convection
Diffusion
Adsorption

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Can you remember the definition of CRRT?
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CRRT Definition, Use, and Goals
CRRT can be defined as:
“Any extracorporeal blood purification therapy Intended to substitute for

Impaired renal function over an extended period of time and applied for, or
aimed at being applied for, 24 hours/day”1
In patients with severe acute kidney injury (AKI), CRRT has become a
cornerstone of treatment.15
Image created by Miroslav Indra is reflecting how a CRRT

device can look. This image here is based on Baxter CRRT
systems and does not reflect CRRT devices in general.
HD Requires a Semipermeable Membrane
HD requires a semipermeable membrane. This type of

membrane allows water and molecules of low molecular
weight (MW) to pass through but holds back high MW
molecules.13
O Represents water molecules that are small enough to

pass through the membrane.
• Represents low-MW waste products that are
small enough to pass through the membrane.
^ Represents red blood cells that are too large to pass
through the membrane.
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Overview of CRRT Modalities
CRRT represents a spectrum

of modalities, including: - 8 15
■ Slow continuous ultrafiltration (SCUF)
■ Continuous venovenous hemofiltration (CVVH)

■ Continuous venovenous hemodialysis (CVVHD)
■ Continuous venovenous hemodiafiltration
(CVVHDF)
Âvailable only with select filter membranes
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Overview of CRRT Modalities1’18
SCUF CVVH CVVHD CVVHDF
Ultrafiltration YES YES YES YES
Convection NO YES NO YES
Diffusion NO NO YES YES
Adsorption* * YES** * YES**
(Dialysate) No NO YES YES
* Based on membrane choice and flow rate.

** At high flow rates. Table taken from Prismaflex Tutorial 7.11 Phase 1 Solutions Clinical Presentation.
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Small vs. Large Molecule Clearance

Diffusion Convection
More effective for clearance of small molecules - Effectiveness less dependent on molecular size.28
phosphate, urea, and creatinine.3-28
More effective for middle molecules,3-22 i.e. pro-inflammatory
mediators »
Figures adapted from Zhongping H, et al. Basic Principles of Solute

Transport. In Continuous Renal Replacement Therapy, 2010; pp. 28-29.
Edited by Kellum J, et al. Oxford University Press.28
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Movement of solutes across a semipermeable membrane

Diffusion
■ Solutes move (diffuse) across the membrane because a difference in concentration exists across the membrane (a
concentration gradient). This process occurs in dialysis.1
■ Everyday examples of diffusion include:
Tea particles in a tea bag. Ink particles in a glass of water.
1. Kirk A & Tattersall J. Haemodialysis. 2017. Available at: http://www.renalmed.co.uk/database/haemodialysis# (accessed June 2017).
Baxter Confidential - Do not distribute without prior consent 43
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Movement of solutes across a semipermeable membrane

Filtration
Solutes move (via solvent drag) while dissolved in their solvent as a solution flows under pressure through the membrane. This
process occurs in filtration.1
Everyday examples of filtration include the use of pressure when:
Straining water through a sieve (gravity is the force pulling the water Making coffee in a filter machine
through). (hot water under pressure is the
force pulling the coffee through).
1. Leypoldt JK. Nephrol Dial Transplant. 2000; 15:3-9.
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Solute Removal
Adsorptive therapies are more effective for

Molecular weight, Daltons
removal of larger sized molecules, i.e., some

inflammatory mediators
Convective therapies help remove middle sized

molecules
o Small size molecules removed by diffusion

o All filters can remove small molecules
Note: The performance of the membrane is substantially affected by the number of pores,
their size and distribution15
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Molecular Weights
Molecular weight, daltons1
The MW that can be removed is typically <50,000 Da and is

specific to the membrane used for CRRT.1 2
Animation taken from

UK-ROI MG120 15-0009-1.
1. Lee BS. Neonatal Med. 2013; 20:12-19;

2. Wong A, et al. Drug Dosing in Continuous Renal Replacement Therapy. In Continuous Renal Replacement Therapy, 2010; pp. 149-173. Edited by Kellum J, et al. Oxford University Press.
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How much CRRT do my patients need?
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CRRT Dose
The best way to measure an RRT dose and what constitutes an optimal
dose of RRT for patients with AKI have not been established.3
■ The methods used for RRT dose quantification in AKI have several limitations. Moreover, these
methods have not been fully validated in this population.3
■ The quantity or dose of RRT is traditionally assessed by measuring clearance of urea, which
serves as the prototype low-molecular-weight product of metabolism.14
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CRRT Dose
The best way to measure an RRT dose and what constitutes an optimal
dose of RRT for patients with AKI have not been established.3
Dose = effluent flow rate:

The dose of CRRT is reported as effluent flow rate in ml/h or ml/kg/h.14
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CRRT Dose
The findings of the ATN and RENAL studies provided strong evidence that effluent flow rates above
20-25 mL/kg/h do not improve survival in patients in the ICU.3
In addition, the studies provided strong circumstantial evidence3 to support the observations of Prowle and
colleagues: that CRRT doses of <20 ml/kg/h are likely to be harmful and should be avoided.14
To reach the levels of survival attained in the ATN and RENAL trials with a delivered dose of 20-25 ml/kg/h, the
prescribed dose probably needs to be 25-30 ml/kg/h, and the number of interruptions to CRRT must be
minimized.3
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Benefits of CRRT
The use of CRRT in the treatment of critically ill patients with
AKI is associated with these potential benefits:3’11’19
Hemodynamic tolerability
Solute clearance
Clearance of middle- and large-weight molecules
Control of acid-base balance
Minimal effect on intracranial pressure
Control of intravascular volume
Ability to perform treatment with simple, user-friendly machines
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Benefits of CRRT
The KDIGO Guidelines State
We suggest using CRRT, rather than standard intermittent

RRT, for hemodynamically unstable patients [and] for AKI
patients with acute brain injury or other causes of increased
intracranial pressure or generalized brain edema.3
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Survival in Patients with AKI - CRRT vs. IRRT
At present, the evidence is insufficient to determine whether survival

in patients with AKI differs between those treated with CRRT and
those treated with IRRT.20’21
Systematic reviews have found no difference in the risk of ICU,

hospital, or post-discharge mortality between patients treated with
CRRT and IRRT.22-28
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Long-term Outcomes in Patients with AKI
A 2014 study compared the clinical outcomes in patients who were treated with CRRT or
IHD as their initial form of RRT on hospital admission.29
The main measurement was the prevalence of chronic dialysis in patients who received
CRRT as compared with IHD.29
Study design
This was a retrospective study, comparing matched critically ill patients with AKI, who had
been admitted to an ICU and received either CRRT or IHD and survived.29
In all, 2004 CRRT and 2004 IHD survivors were identified and compared for their need for
subsequent chronic dialysis.29
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Survival in Patients with AKI - CRRT vs. IRRT

Cumulative risk of chronic dialysis for AKI patients treated with CRRT vs IHD
Data from a retrospective cohort study showed that

initiation of CRRT vs. IRRT in critically ill adults with
AKI is associated with a lower risk of chronic
dialysis.29
Figure reprinted from Wald R, et al., The Association Between Renal Replacement Therapy Modality
and Long-Term Outcomes Among Critically Ill Adults With Acute Kidney Injury: A Retrospective Cohort
Study, Crit Care Med., 42(4):868-877; https://iournals.lww.com/ccmiournal/toc/2014/04000.29
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Introduction to
CRRT Filtersets
Introduction to CRRT Filtersets
Which four essential kidney functions can RRT substitute?
Which three (four) basic mechanisms are utilized in RRT?
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CRRT | For the Management of AKI in the ICU
U Itrafi Itrati o n Convection

R R T mimics many of the functions of the
Adsorption’
native kidney and is the cornerstone of
treatment in patients with severe AKI.1
RRT uses four different
clearance mechanisms
*Available only with select filter membranes
Clearance Mechanisms used in CRRT

r
Diffusion
More effective for clearance of
Ultrafiltration
Removal of fluid small molecules - potassium,
urea, and creatinine.2-3
Convection
Effectiveness less dependent on
Adsorption
molecular size.2 More effective for Effective for larger sized molecules,
middle molecules3-4 - e.g., i.e., some inflammatory mediators.5-6
inflammatory mediators.
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Baxter Filterset Components
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Can you identify key components of a CRRT filter set?
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Baxter’s CRRT filtersets are pre-connected disposable, extracorporeal circuits for

use with the Prismaflex or PrisMax system.
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Baxter’s CRRT filtersets are pre-connected disposable, extracorporeal circuits for

Debrief use with the Prismaflex or PrisMax system.
Dialysate line (green) OR

replacement line 2 in CVVH modality
Effluent line (yellow) • Replacement line (purple)
Pre-Blood Pump line (white) Syringe

• Deaeration chamber
• Filter
Return line (blue)
Access line (red)
Acute disposables catalog Job Number: EUMP/MG120/16-0017.

1000013948-IFU PRISMAFLEX ST FINAL
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Fully integrated (no additional components)
Think of advantage statements Have a specific small volume deaeration chamber
DEHP-free blood and fluid pathways
Have an integrated pre-blood pump infusion syringe

driver
Acute disposables catalog Job Number: EUMP/MG120/16-0017. 1000013948-IFU PRISMAFLEX ST FINAL
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What are the PARAMETERS of a prescription?

The patient’s condition guides the details of the prescription and
determines the specific parameters entered by the physician.
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9 Debrief
||f What are the PARAMETERS of a prescription?

Dose, blood flow rate, filter type & size, anti-coagulant,
solutions for dialysate and/or replacement etc.
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Baxter CRRT Filter Membranes
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Can you describe a CRRT filter?
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Debrief
Can you describe a CRRT filter?
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Overview of a CRRT Filter
A CRRT filter houses a semi-permeable membrane that represents the core of the
system. It is this membrane that mimics the nephrons of a native kidney by removing
water, waste products and other molecules as well as exchanging electrolytes.
The filter is designed to bring the patient’s blood in an indirect contact with the
dialyzing solution. This contact is mediated by the membrane shaped in the form of
hollow fibers or capillaries.
Inside the filter, there is an ongoing removal of waste products from the blood as well
as an exchange of electrolytes. Buffer, such as bicarbonate, can be replenished.
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Hemofilter
BLOOD FLOWS INSIDE THE HOLLOW FIBERS
Inside the housing blood flow is split into The membrane structure determines what uremic solutes
◄
thousands of hollow fibers can be removed by dialysis
Blood flows through the hollow fibers, which

Membrane wall
are surrounded by dialysis fluid
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THE SEMI-PERMEABLE MEMBRANE ALLOWS MOLECULES UP TO A

CERTAIN SIZE TO PASS THROUGH
f >
The filter membrane’s chemical and
physical structure determine the size of
the molecules that can pass through it.
For example, if this filter has a 25 kDa
cut-off, the molecules listed below that
are at or below 25 kDa molecular weight
will pass through the filter. Higher
molecular weight molecules, like albumin,
will not.
Electrolytes ✓
Urea & creatinine ✓
IL7 ✓
Myoglobin ✓
Albumin X
V_4
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Baxter Offering | PAES & AN69 Structure

PAES r AN69
The mechanical support and the The AN69 membrane’s selective

selective part have distinct functions part and the mechanical support
in PAES membranes both functions throughout the
membrane
Selective part Selective part

Mechanical support Mechanical support
Selective part the part of the membrane determines the selection of solutes that are able to pass through
Mechanical support: the rest of the membrane is there to give mechanical stability
Size selection and adsorption of solutes occurs throughout the WHOLE AN69 membrane
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AN69 | Surface Charge Attracts Large Middle Molecules

r
■ The whole AN69 membrane is negatively charged

■ Positively charged molecules will bind to the negative
charge in the membrane
■ The sulfonate groups are distributed throughout the
membrane structure of the AN69 membrane
■ Adsorption occurs on the inner membrane surface and
in the whole membrane thickness (AN69)
AN69 membrane performance remains stable over time1
1. Thomas M, Moriyama K, Ledebo I. AN69: Evolution of the World's First High Permeability Membrane. In Saito A, Kawanishi
H, Yamashita AC, Mineshima M, eds. High-Performance Membrane Dialyzers. Contrib Nephrol. Basel, Karger. 2011;173:119-129. PAES membrane AN69 membrane
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Summary | Clearance Mechanisms by Filter Type
PAES AN69 & AN69ST
PAES membrane types have both diffusive and AN69 membranes have diffusive and convective capabilities. In
convective capabilities and
addition, they also have adsorptive capabilities
limited adsorptive capabilities
Adsorption enables the removal of molecules that would not be removed by diffusion & convection
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Filtersets Portfolio
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Baxter Acute CRRT Sets

r
HF20 ST/M60 ST/M100 HF1000 HF1400 ST/M150 oXiris
Filter size 0.2 m2 0.6 m2 0.9 m2 1.1 m2 1.4 m2 1.5 m2 1.5m2
ECBV 60 mL 93 mL 152 mL 165 mL 186 mL 189 mL 193mL
Weight indication 8 kg+ 11 kg+ 30 kg+ 30 kg+ 30 kg+ 30 kg+ 30kg+
Filter type PAES AN 69 AN 69 PAES PAES AN 69 AN69
Membrane Cut-off 20kDa 40kDa 40kDa 40kDa 40kDa 40kDa 40kDa
1. Acute disposables catalog Job Number: EUMP/MG120/16-017. ECBV - ExtraCorporeal Blood Volume
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OXiris is the Latest Evolution in Membrane Innovation
oXiris | a membrane with unique
3-in-1 capabilities for removal of
cytokines, endotoxin and uremic
toxins.
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Clinical Overview:
Homeostasis, Electrolyte
& Fluid Balance, Acid-base Balance
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Logistika CRRT tretmana
Diagram toka CRRT

CRRT CRRT
priprema započinjanje
CRRT Zahtevne
održavanje situacije
CRRT
završetak
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Hronologija koraka Opis koraka Obavlja…

1. CRRT priprema Indikacija za CRRT Lekar
Priprema aparata Medicinska
sestra/tehničar
Pripremiti potrošni Medicinska
materijal sestra/tehničar
Koordinacija uključenja Lekar
2. CRRT započinjanje Montiranje i punjenje Medicinska
START CRRT seta
Uzimanje
sestra/tehničar/lekar
Medicinska
procedure predtretmanske sestra/tehničar/lekar
laboratorije
Provera funkcije katetera Medicinska
sestra/tehničar
Podešavanje preskripcije Medicinska
i uključenje pacijenta sestra/tehničar/lekar
Monitoring pacijenta Medicinska

tokom uključenja sestra/tehničar/lekar

3. CRRT održavanje Monitoring EC Lekar
cirkulacije
Nalog za koagulacioni Lekar
status (ACT,APPT, iCa
pacijenta)
Podešavanje distribucije Lekar
tečnosti (PBP,SUB,DIAL)
ODRŽAVANJE
Podešavanje gubitka Lekar
CRRT tečnosti pacijenta
procedure Korekcija
antikoagulacije prema
Lekar
kontrolonoj tački
(ACT,APPT, iCa
pacijenta)
Promena kesa Medicinska
sestra/tehničar
Promena šprica za Medicinska
antikoagulaciju sestra/tehničar
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4. Zahtevne situacije - Primarni odgovor na Medicinska

alarmi, intervencije alarm sestra/tehničar
Sekundarni odgovor na Medicinska
Zahtevne alarm sestra/tehničar/lekar
situacije Recirkulacija krvi-

razlog: replasman
Medicinska
sestra/tehničar/lekar
CRRT katetera
procedure Recirkulacija Medicinska

fiziološkim rastvorom- sestra/tehničar/lekar
razlozi: snimanja,
reoperacija
Menjanje seta- Ponavljaju se koraci od
ponovno započinjanje tačke 1.
5. CRRT završetak Indikacija za završetak: Medicinska

-Oporavak bubrežne sestra/tehničar/lekar
funkcije
-preteća koagulacija seta:
Završetak TMP,
pad/razlika pritisaka
CRRT -koagulacija seta
procedure -poboljšanje
hemodinamike, prelazak
na IHD
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CRRT Solutions
Introduction to CRRT Solutions
Priming1 Anticoagulation3
Dialysate and replacement2 Return blood to
Removal of unwanted solutes, patient1
restoration of balance in the
Used to fill the blood Prevents clotting of the End of treatment
extracorporeal circuit extracorporeal circuit
(EC*)
*The EC is the path the HD patient's blood takes outside of the body14
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Dialysate and
Replacement Solutions
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Clearance Mechanisms Used in CRRT
Fluid (plasma water) transport across a

ULTRAFILTRATION semipermeable membrane caused by
pressure gradient
Transport of solutes across a

CONVECTION semipermeable membrane caused by the
drag of the solvent (water)
Transport of solutes from an area of higher

DIFFUSION concentration to an area of lower
concentration of these solutes
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Standards and Guidelines
Bacteriological quality of CRRT solutions
■ Replacement solutions must be sterile because of direct

infusion.
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Standards and Guidelines
Warming solution
■ Although reductions of body temperature below 35°C
should probably be avoided (Grade E), available data
do not allow recommendations on whether CRRT
fluids should be warmed.27
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Replacement Solutions
■ Infused in EC blood compartment to replace fluid removed

by ultrafiltration34
— Administered pre-and/or post-filter34 Replacement
■ Components adjusted to meet patient needs5
— Bicarbonate-based or electrolyte solutions5
■ Must be sterile5
■ Prescribed by the physician30
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Dialysate
■ Flows counter-current to blood flow on the other side of the

semipermeable membrane28
■ Drives diffusive transport - depends on the concentration gradient of

solutes and flow rate28
■ Contains electrolytes at physiological levels29
■ Components adjusted to meet patient needs30
■ Prescribed by the physician30
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General Characteristics of
CRRT Solutions
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Citrate Anticoagulation
in CRRT
Citrate Anticoagulation in CRRT
Learning Objectives
By the end of this training, you will be able to:
 Define the term Regional Citrate Anticoagulation (RCA)
 Describe the mechanism of action of citrate in the

clotting cascade
 Identify the advantages/disadvantages of the use of RCA vs.

heparin in CRRT
 Describe the practical management of RCA in CRRT
 Discuss the potential clinical complications associated with

citrate accumulation
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Q&A
What are the impacts of filter clotting?
Role of Anticoagulation in CRRT
To prevent clotting in the EC* and thus: Factors affecting clotting in the EC:
Biological
Preserve filter performance
Technical
Increase circuit survival
 Quality of vascular access (catheter)
 Blood flow rate
Prevent loss of blood in the EC  Haemoconcentration increase in the
filter (ultrafiltration rate/Filtration
fraction)
 Pre/post dilution
*Extracorporeal circuit  Filter/set characteristics
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Q&A How do you think the increase of the parameter on the left will impact the probability of clotting in the circuit?
Probability
INCREASED...
of clotting
...Blood flow rate ↓
...Replacement in pre-dilution ↓
...Haemoconcentrati on ...Replacement in post-dilution ↑

in the fi lter ...Ultrafiltration (fluid removal) ↑
...Filtration fraction ↑
...Biocompatibility ↓
Filter (set) characteristics ...Membrane surface area ↑
...Blood volume in EC ↑
Anticoagulation Strategies in CRRT
Systemic Regional No anticoag.
 Acts in both the EC and  Anticoagulant

the patient‘s body introduced to the EC
 Antidote administered
before returning blood
Example Example Example
 Unfractioned heparin  Citrate - Calcium  Saline flushes

 LMWH  Increased blood flow
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Use of Heparin in CRRT
Clinical considerations for the use of heparin in CRRT

In critically ill patients, heparin is Contraindications to use of Cautions for use:3
associated with: heparin:3
 Increased risk of bleeding1,2  Active bleeding  High risk of bleeding

 Heparin-induced thrombocytopenia  Recent surgery  HIT and thrombosis
(HIT)1,2  Thrombocytopenia
 Anti-thrombin mediated pro-
inflammatory effects2
1. Palsson R & Niles JL. Kidney Int. 1999; 55:1991–1997; 2. Oudemans-van Straaten HM, et al. Crit Care. 2011; 15:202; 3. Summary of
product characteristics. Heparin. 2016. Available at: https://www.medicines.org.uk/emc/medicine/9793#ORIGINAL (accessed March 2018).
Image purchased from pxmedia.de (September 2016).
Citrate in CRRT—Latest Guidelines
Kidney Disease Improving Global Outcomes
Chapter 5.3: Anticoagulation for CRRT:

‘For anticoagulation in CRRT, we suggest using
regional citrate anticoagulation rather than
heparin in patients who do not have
contraindications for citrate’.1
1. KDIGO Acute Kidney Injury Work Group. Kidney Int Suppl. 2012; 2:1–138.
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Citrate Mode of Action and Metabolism
3 Ca++ ions
2 Sodium-Citrate
molecules = 1 Calcium-Citrate
molecule
6 Na+ ions
Calcium-Citrate complex
Citrate is metabolized in the liver,
Citrate chelates
skeletal muscle and kidneys into
ionized calcium
bicarbonate, releasing the chelated
(and also magnesium)
calcium1
1 Citrate = 3 Bicarbonate
~ Bicarbonate Calcium
Figure adapted from information in Kellum J, et al. Regional Citrate Anticoagulation. Continuous Renal Replacement Therapy. 2010; P141–145. Oxford University Press.
Anticoagulation Strategies in CRRT
Heparin action
Citrate action on iCa++
Citrate inhibits the clotting cascade by

chelating ionized calcium (iCa).1
The loss of functional calcium affects a

number of cofactors, preventing the
propagation of the coagulation cascade,
with the ultimate effect being inhibition of
thrombin formation.1
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Circuit
Anticoagulation citrate
Strategies anticoagulation
in CRRT principle
Ca Chloride
Ca++ 0.25-0.5 mmol/l
Ca++ 1.1-
1.3 mmol
Prism0Cal Effluent Dialisan Prism0Citrate

0 Ca++ 1,75 Ca 18 mmol citrate 11
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Citrate Dose to Prevent Clotting
Concentration of citrate required to inhibit extracorporeal

coagulation:
~ 2.5 to 5.0 mmol/l blood1
The target for circuit ionized calcium to prevent or

reduce clotting:
~ 0.25 to 0.40 mmol/l blood2
Scanning electron micrograph (SEM) of red blood cell
1. Pinnick RV, et al. New Engl J Med. 1983; 308:258;

2. Kellum J, et al. Regional Citrate Anticoagulation. In Continuous Renal Replacement Therapy 2010; pp. 141–145.
Image purchased from pxmedia.de (1st September 2016)
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Calcium Distribution
In the blood In the circuit

Ionized Ca (~15%)
~ 0.25–0.40 mmol/l
Ionized Ca (~50%)
~ 1.10–1.30 mmol/l
Protein-bound Ca (~43%)
Total calcium ~ 0.80–1.20 mmol/l
~ 2.2-2.6 mmol/l
Protein-bound Ca (~43%)
~ 0.80–1.20 mmol/l
Complex-bound Ca (~42%)
(including Ca-Citrate)
~ 0.80–1.00 mmol/l
Complex-bound Ca (~7%)
~ 0.15–0.20 mmol/l
Figures adapted from Kellum J, et al. Continuous Renal Replacement Therapy. In Continuous Renal Replacement Therapy 2010; pp. 141–145; Davenport A & Tolwani A. NDT Plus. 2009; 2:439–4472 and
Diem K, Lenter C. Scientific Tables. 565 (7th ed.). Basel: Ciba-Geigy Limited. pp. 653–654
13
13
Poll
How much citrate is required to inhibit extracorporeal

coagulation?
What is the target for circuit ionized calcium to prevent or

reduce clotting?
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Net Loss of Calcium

iCa++
3
monitoring
Ca++ 1.1-
1.3 mmol
2
Calcium
chloride Ca++ 0.25-0.5 mmol/l Calcium-free
dialysate
2
Effluent
1
Citrate
Adapted from: Kellum J, et al. Regional Citrate Anticoagulation. In Continuous Renal Replacement Therapy 2010; pp. 141–145.
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Practical Management of RCA in CRRT1
Frequent
Frequent monitoring
monitoring of
of electrolytes,
electrolytes, patient
patient iCa
iCa++
++
and acid–base status is required.
At least every 6h: At least once daily:
Blood electrolytes, including:

Total blood Calcium
• Sodium, Potassium,
concentration to calculate the
• Chloride, Magnesium
calcium ratio or calcium gap.
• Ionised Calcium,
• Blood gas analysis [...].
The need for monitoring anticoagulation efficacy in the circuit

depends on the method of citrate delivery.
1. Davenport, A. and Tolwani, A. (2009). Citrate anticoagulation for continuous renal replacement therapy (CRRT) in
Image source: Baxter_Renal_Foundations_Media_Asset_Library_v1.0
patients with acute kidney injury admitted to the intensive care unit. Clinical Kidney Journal, 2(6), pp.439–447.
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Practical Management of RCA in CRRT1
1. Measure serum electrolytes before initiation
2. At 0,5 hour, measure post-filter ionized calcium to check circuit calcium

& measure patient ionized calcium to check systemic calcium. 2 ABG’s-
2 results
3. Adjust citrate dose or calcium compensation according to table if required
4. If adjustment has been made, repeat measurement after 0,5 hour
5. Once ideal values/steady state reached, measure 4 hourly for first

24 hours, then 6 hourly
6. Measure total calcium once a day to check calcium ratio
a The
below is a commonly used monitoring plan and is not intended as a definitive guide to management of patients undergoing CRRT with citrate.
Responsibility remains with the clinical team managing the patient
1. Davenport A & Tolwani A. NDT Plus. 2009; 2:439–447; Image source: Baxter_Renal_Foundations_Media_Asset_Library_v1.0
2. Collin, adapted by Gambro, CVVH protocol for regional citrate anticoagulation on Prismaflex system. Protocol 2013; 1-2. HCEN15816_1.
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Daily Monitoring1,2,a
Magnesium
Phosphate
Urea
Hemoglobin
Hematocrit
Creatinine
Sodium
a The above is a commonly used list and is not intended as a definitive guide to
1. Davenport A & Tolwani A. NDT Plus. 2009; 2:439–447; management of patients undergoing CRRT with citrate. Responsibility remains with the
2. Ronco C, et al. Kidney Int Suppl. 1999; 56(Suppl 72):S8–S14. clinical team managing the patient
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Monitoring for Citrate Accumulation
Characteristics of citrate tCa/iCa = 2.4/1.2 = 2.0 In the blood tCa/iCa = 2.4/0.8 = 3.0
accumulation:1
Ionized Ca
 Decreasing iCa in blood ~ 0.80 mmol/l
Ionized Ca
 Increasing calcium ~ 1.20 mmol/l
replacement requirement
Protein-bound Ca
 Increasing tCa/iCa ratio Total calcium ~ 1.00 mmol/l
~ 2.4 mmol/l
(>2.5) and tCa–iCa gap
Protein-bound Ca
~ 1.00 mmol/l
Complex-bound Ca
(including Ca-Citrate)
Complex-bound Ca ~ 0.60 mmol/l
~ 0.20 mmol/l
1. Davenport A & Tolwani A. NDT Plus. 2009; 2:439–447;
Figures adapted from Kellum J, et al. Continuous Renal Replacement Therapy. In Continuous Renal Replacement Therapy 2010; pp. 141–145
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Debrief
What are the advantages & disadvantages of Citrate in CRRT?
Advantages:1,2 Disadvantages:1
 Anticoagulation restricted to the extracorporeal  Initial educational work
circuit  Requires monitoring of calcium level and
 Decreased risk of bleeding vs. systemic heparin pH
 Less circuit downtime vs. heparin – a higher dose  Potential risk of metabolic complications
of therapy  Citrate accumulation if citrate is not
 Can be used in heparin contraindications, e.g., adequately metabolized – see later for
HIT detail
1. Oudemans-van Straaten HM, et al. Crit Care. 2011; 15: 202;

2. Bagshaw SM, et al. Crit Care. 2005; 20:155–161.
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Other Potential Advantages of Citrate: Summary
Less bleeding events
Significantly longer circuit life
Lower rates of blood transfusion
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History: Citrate in CRRT
Composition (mmol/L)
4% Trisodium Low concentration

ACD-A1 Plasma3
citrate1 citrate2
Citrate 136 74.8 18 –
Citric acid – 38 – –
Chloride – – 86 98–106
Sodium 420 224 140 136–145
Dextrose – 124 – 4.2–6.4a

Alternative protocols using dilute citrate solutions with physiological sodium levels have been
developed since 1999.4–7
a Normal fasting glucose level 4. Palsson R & Niles JL. Kidney Int. 1999; 55:1991–1997;
1. Davis TK, et al. Pediatr Crit Care Med. 2014; 15:471–485; 5. Tolwani AJ, et al. Clin J Am Soc Nephrol. 2006; 1:79–87;
2. Baxter. Data on file. Regiocit. SPC. October 2016; 6. Egi T, et al. Int J Artif Organs. 2005; 28:1211–1218;
3. Kratz A, et al. N Engl J Med. 2004; 351:1548–1563; 7. Davenport A & Tolwani A. NDT Plus. 2009; 2:439–447.
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The target range for the patient’s iCa in mmol/l lies within a normal
Treatment Adjustments1,a
range defined by each hospital
Filter Ca2+: <0.25 Filter Ca2+: 0.25–0.5 Filter Ca2+: >0.50
Low ionized Increase citrate dose

plasma Ca2+ Decrease citrate dose Increase calcium compensation by 0.5 mmol/l blood
by 0.5 mmol/l blood by 10% Increase calcium compensation
eg <1.1
Increase calcium by 10%
compensation by
10%
Normal ionized
Decrease citrate dose Normal Increase citrate dose
plasma Ca2+
eg 1.1.-1.3 by 0.5 mmol/l blood ideal values by 0.5 mmol/l blood
High ionized Decrease calcium

plasma Ca2+ compensation by 10% Decrease calcium compensation Decrease calcium compensation
Decrease citrate dose by 10% by 10%
eg >1.3
by 0.5 mmol/l blood
a The table above is taken from UK-ROI/MG14914-0006(1) Prismocitrate 18/0 Kalmar Protocol with adoption based on common clinical practice in the UK.
It is not intended as a definitive guide to management of patients undergoing CRRT with citrate. Responsibility remains with the clinical team managing the patient.1
1. Gambro Prismaflex for CRRT presentation. 2016. UK-ROI/MG120/15-0010(2).
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Activity
How would you respond to the following readings?
Filter Ca2+: <0.25 Filter Ca2+: 0.25–0.5 Filter Ca2+: >0.50
Low ionized Increase citrate dose

plasma Ca2+ Decrease citrate dose Increase calcium compensation by 0.5 mmol/l blood
by 0.5 mmol/l blood by 10% Increase calcium compensation
eg <1.1
by 10%
Normal ionized
Decrease citrate dose Normal Increase citrate dose
plasma Ca2+
eg 1.1.-1.3 by 0.5 mmol/l blood ideal values by 0.5 mmol/l blood
High ionized Decrease calcium

plasma Ca2+ compensation by 10% Decrease calcium compensation Decrease calcium compensation
Decrease citrate dose by 10% by 10%
eg >1.3
by 0.5 mmol/l blood
Filter iCa: 0.32 Filter iCa: 0.52 Filter iCa: 0.19

1 Plasma iCa: 0.94 2 Plasma iCa: 1.15
3 Plasma iCa: 1.45
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Daily Monitoring
Clinical situations in which citrate cannot be metabolized
adequately can cause citrate intolerance/accumulation
These can include:1

 Severe liver failure/cirrhosis
 Reduced hepatic blood flow
 Conditions associated with severely reduced
muscle perfusion e.g. cardiogenic shock
 Muscle injury
1. Davenport A & Tolwani A. NDT Plus. 2009; 2:439–447.
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Citrate Accumulation
Effects include:1,2
When more citrate is being infused
 Metabolic acidosis
than can be cleared by either
 Metabolic alkalosis
metabolic or dialysis pathways, then
 Hypernatremia
calcium–citrate complex remains in
the patient’s circulation.1  Hypocalcemia
 Hypercalcemia
1. Oudemans-van Straaten HM, et al. Crit Care. 2011; 15:202;

2. Davenport A & Tolwani A. NDT Plus. 2009; 2:439–447.
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Example Monitoring Table—Clinical Decision Support1,a
The target range for the patient’s iCa in mmol/l lies within a normal range defined by each hospital
Monitoring of anticoagulation Initially And then
Post-filter ionized calcium

(blood gas from circuit) Hourly until stable 6 Hourly
Target 0.25–0.50 mmol/L
Patient systemic ionized blood calcium

(blood gas from patient) Hourly until stable 6 Hourly
Normal range
Patient total calcium (not corrected calcium)

After 6 hours Daily
Target 2.20–2.50 mmol/L
Calcium ratio
(Total Ca/ patient systemic ionized calcium) After 6 hours Daily
Target ratio <2.5
a The table above is taken from UK-ROI/MG14914-0006(1) Prismocitrate 18/0 Kalmar Protocol with adoption based on common clinical practice in the UK.
It is not intended as a definitive guide to management of patients undergoing CRRT with citrate. Responsibility remains with the clinical team managing the patient.1
1. Gambro Prismaflex for CRRT presentation. 2016. UK-ROI/MG120/15-0010(2).
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Citrate CRRT in Liver

Failure
Ba4x1ter Confidential - Do not distribute without prior consent 38
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Citrate CRRT in Liver Failure
The liver citrate anticoagulation threshold study (L-CAT)1 Regional citrate anticoagulation (RCA) for
continuous renal replacement therapy is widely
 Ratio of total/ionized calcium ≥2.5: n = 3 (2%).1 used in intensive care units (ICUs).1
However, concern exists about the safety of citrate
 Estimated 72-hour filter survival was 96%, after censoring for
in patients with liver failure (LF).1
discontinuation due to non-clotting causes (e.g. renal recovery, death).1
Normal Mild Severe The aim of this study was to evaluate safety and
Liver Impairment Impairment P value efficacy of RCA in 133 ICU patients with varying
(48 pts) (43 pts) (42 pts) degrees of impaired liver function.1
Severe alkalosis 2% 0% 5% 0.41

CONCLUSIONS:
Severe acidosis 13% 16% 14% 0.95 RCA-CVVHD can be safely used in patients with LF.1
The technique yields excellent filter patency and
Severe Hypocalcemia 8% 14% 12% 0.7 thus can be recommended as first-line
anticoagulation for the majority of ICU patients.1
Severe Hypercalcemia 0% 0% 0% n.s.
1. Slowinski T, et al. Crit Care. 2015; 19: 19:349. Doi 10.1186/s13054-015-1066-7
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Pediatric Critical Care
Ba4x3ter Confidential - Do not distribute without prior consent 30
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Citrate anticoagulation during CRRT in pediatric critical care
Pediatric considerations:1
Standardized protocols have been well established for both heparin and
regional citrate anticoagulation in children receiving dialysis.
The ppCRRT Registry Group has shown that heparin- and citrate-based
anticoagulation protocols are able to confer equitable filter survival in
pediatric CRRT, and the use of either is clearly supported over the use of no
anticoagulation schemes.
The main advantage of citrate anticoagulation was the prevention of

systemic pharmacologic anticoagulation of the patient, which can be an
issue in patients with multiorgan failure and sepsis.
1. KDIGO Acute Kidney Injury Work Group. Kidney Int Suppl. 2012; 2:1–138.
31
Citrate anticoagulation during CRRT in pediatric critical care

Citrate
Ca + Citrate
In the past, citrate anticoagulation during CRRT Citrate chelation
in pediatric critical care was a challenge. Citrate
Calcium
replacement
A recent publication states:
 Regional anticoagulation is an ideal option in a critically ill child after recent 20–50% of
surgery or with coagulopathy.1 complexes &
citrate
 Therefore, regional citrate anticoagulation is commonly employed in the removed
pediatric critical care population requiring renal replacement therapy.1
 Complications of citrate anticoagulation can be avoided with a greater
understanding of the properties and clearance of citrate.1
Citrate
Citrate
Ca infusion
Figure reprinted from Davis TK, et al. Citrate Anticoagulation During Continuous Renal Replacement Therapy in
Pediatric Critical Care, Pediatr Crit Care Med. Vol 15 (5), pp. 471–485, Citrate chelation
https://journals.lww.com/pccmjournal/Abstract/2014/06000/Citrate_Anticoagulation_During_Continuous_Renal.10.aspx.
Citrate
1. Davis TK, et al. Pediatr Crit Care Med. 2014; 15:471–485.
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Citrate anticoagulation for continuous renal replacement therapy in

small children
This study was a retrospective review of 30 critically ill children RCA-CRRT HA-CRRT
A recent publication states:
Mean time on 148.73 ± 131.5 110.24 ± 105.3
 (16 on RCA- and 14 on HA-CRRT) therapy in h 8 8
who underwent at least 24 h of CRRT.1
Circuit lifetime
 The mean body weight of the children was 8.69 ± 5.63 kg.1 in h
58.04 ± 51.18 37.64 ± 32.51
 RCA-CRRT was performed with a commercially available pre-dilution citrate

solution.1
Circuit clotting 11.63% 34.15%
Survival at
37.5% 14.3%
discharge
1. Soltysiak J, et al. Pediatr Nephrol. 2014; 29:469–475.
33
Protocol based on Kalmar protocol
Protocol from ICU Kalmar Hospital, Dr Borgström, Sweden.
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Additional Resources
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Heparin Anticoagulation Observations Back
Observed bleeding events with heparin anticoagulation during CRRT

A number of studies have compared bleeding events observed during CRRT using heparin or citrate
anticoagulation, with four studies showing a trend toward less bleeding using citrate.1
Incidence of bleeding events

References2–7 Patients Modality P value
Heparin group Citrate group
Monchi M, et al. Intensive Care Med. n = 12 (heparin) CVVH with heparin

n=1 n=0 –
2004; 30:260–2652 n = 8 (citrate) or citrate
Betjes MG, et al. J Nephrol. n = 27 (heparin) CVVH with heparin

n = 10 n=0 P <0.01
2007; 20:602–6084 n = 21 (citrate) or citrate
Oudemans-van Straaten HM, et al. n = 103 (nadroparin)b CVVH with nadroparin

16% 6% P = 0.08
Crit Care Med. 2009; 37:545–5525 n = 97 (citrate) or citrate
Hetzel GR, et al. Nephrol Dial n = 83 (heparin) CVVH with heparin

14.5%d 5.7%d –
Transplant. 2011; 26:232–2396 n = 87 (citrate) or citratec
a RR; relative risk. Patients randomized to receive citrate trended towards a reduced rate of hemorrhage (relative risk of 0.17; 95% CI 0.03–1.04). 1. Oudemans-van Straaten HM, et al. Crit Care. 2011; 15:202; 2. Monchi M, et al. Intensive Care Med. 2004; 30:260–265;
b Comparing citrate with the low molecular weight heparin, nadroparin. 3. Kutsogiannis DJ, et al. Kidney Int. 2005; 67:2361–2367;
c The median daily heparin dose in the HF-citrate group was 3240 IU (n=62), compared with 12639 IU (n=47) in the HF-bicarbonate group. 4. Betjes MG, et al. J Nephrol. 2007; 20:602–608; 5. Oudemans-van Straaten HM, et al. Crit Care Med. 2009; 37:545–552;
d Values refer to the percentage of patients who presented with bleeding events during the study. 6. Hetzel GR, et al. Nephrol Dial Transplant. 2011; 26:232–239; 7. Stucker F, et al. Crit Care. 2015; 19:91.
e Values refer to the percentage of courses during which a new bleeding event occurred.
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A number of studies have compared circuit life during CRRT using heparin or citrate anticoagulation, with three
studies reporting a significantly longer circuit life using citrate.1
Circuit life (hours)a
References2–6 Patients Modality P value
Heparin group Citrate group
Monchi M, et al. Intensive Care Med. n = 12 (heparin) CVVH with heparin 40 70

P < 0.001
2004; 30:260–2652 n = 8 (citrate) or citrate (17–48) (44–140)
Kutsogiannis DJ, et al. n = 14 (heparin) CRRT with heparin 38 125

P < 0.001
Kidney Int. 2005; 67:2361–23673 n = 16 (citrate) or citrate (25–62) (95–157)
Oudemans-van Straaten HM, et al. n = 103 (nadroparin)b CVVH with nadroparin 26 27

n.s.
Crit Care Med. 2009; 37:545–5524 n = 97 (citrate) or citrate (15–43) (13–47)
Hetzel GR et al. Nephrol Dial n = 83 (heparin) CVVH with heparin

26 ± 19 38 ± 23 P < 0.001
Transplant. 2011; 26:232–2395 n = 87 (citrate) or citrate
Stucker F, et al. Crit Care. n = 49 (heparin) CVVHDF with heparin or

28 ± 23 49 ± 29 P = 0.004
2015; 19:916 n = 54 (citrate) citrate
a Median (interquartile range); b Comparing citrate with the low molecular weight heparin, nadroparin.
4. Kutsogiannis DJ, et al. Kidney Int. 2005; 67:2361–2367;
1. Oudemans-van Straaten HM, et al. Crit Care. 2011; 15:202; 5. Hetzel GR, et al. Nephrol Dial Transplant. 2011; 26:232–239;
2. Monchi M, et al. Intensive Care Med. 2004; 30:260–265; 6. Stucker F, et al. Crit Care. 2015; 19:91.
3. Oudemans-van Straaten HM, et al. Crit Care Med. 2009; 37:545–552;
37
37
Citrate coagulation resulted in lower rates of blood transfusion vs. systemic heparin anticoagulation: a
retrospective study of patients with AKI
Filter clotting in RRT can lead to blood loss and the need for blood Blood transfusions during the first treatment episode
transfusions.1 15
A retrospective study found more recorded blood transfusions for
Units of blood
patients given systemic heparin coagulation vs. citrate (10 units vs. 10
10
0 units).1
 More filters were used in the heparin group vs. the citrate group
5
(118 vs. 73).
 A significant correlation was seen between the number of filters 0
used and the number of transfusions required (P ≤ 0.001). 0
Citrate Heparin
Treatment
Figure prepared from data in Borg R, et al. J Intensive Care Soc. 2017; 18:184–1921.
1. Borg R, et al. J Intensive Care Soc. 2017;18:184–192.
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References
 Ahmed I, et al. Postgrad Med J. 2007; 83:575–582.  Davenport A & Tolwani A. NDT Plus. 2009; 2:439–447.
 Akhoundi A, et al. Blood Purif. 2015; 39:333–339.  Davenport A. Home Hemodial Int. 1998; 2:41–59.
 Bagshaw SM, et al. Crit Care. 2005; 20:155–161.  Davenport A. Anticoagulation for continuous renal replacement therapy. 2018. Available at:
https://www.uptodate.com/contents/anticoagulation-for-continuous-renal-replacement-
 Baxter. Data on file. Prismocitrate instructions for use. 2016.
therapy (accessed March 2018).
 Baxter. Data on file. Regiocit. SPC. October 2016.
 Davis TK, et al. Pediatr Crit Care Med. 2014; 15:471–485.
 Beitland S, et al. Crit Care Res Pract. 2012; Article ID: 869237.
 Egi T, et al. Int J Art Organs 2005; 28:1211–1218.
 Betjes MG, et al. J Nephrol. 2007; 20:602–608.
 Gambro Prismaflex for CRRT presentation. 2016. UK-ROI/MG120/15-0010(2).
 Borg R, et al. J Intensive Care Soc. 2017;18:184–192.
 Hetzel GR, et al. Nephrol Dial Transplant. 2011; 26:232–239.
 Claure-Del Granado R, et al. Hemodial Int. 2014; 18:641–649.
 Joannidis M & Oudemans-van Straaten HM. Crit Care. 2007; 11:218.
 Clinical Evaluation of Use of Prismocitrate 18 in Patients Undergoing Acute Continuous Renal
 KDIGO Acute Kidney Injury Work Group. Kidney Int Suppl. 2012; 2:1–138.
Replacement Therapy (CRRT). NCT02860130. Available at:
https://clinicaltrials.gov/ct2/show/study/NCT02860130?term=Prismocitrate&rank=1  Kellum J, et al. Anticoagulation. In Continuous Renal Replacement Therapy 2010; pp. 135–
(accessed March 2018). 139.
 Collin, adapted by Gambro, CVVH protocol for regional citrate anticoagulation on Prismaflex
system. Protocol 2013;
1-2. HCEN15816_1.
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39
References
 Kellum J, et al. Regional Citrate Anticoagulation. In Continuous Renal Replacement Therapy  Palsson R & Niles JL. Kidney Int. 1999; 55:1991–1997.
2010; pp. 141–145.
 Palta S, et al. Indian J Anaesth. 2014; 58:515–523.
 Kratz A, et al. N Engl J Med. 2004; 351:1548–1563.
 Pinnick RV, et al. New Engl J Med. 1983; 308:258–261.
 Kutsogiannis DJ, et al. Kidney Int. 2005; 67:2361–2367.
 Ricci Z, et al. Nephrol Dial Transplant. 2006; 21:690–696.
 Mehta, RL, et al. Kidney Int. 1990; 38:976–981.
 Ronco C, et al. Kidney Int Suppl. 1999; 56(Suppl 72):S8–S14.
 Mehta RL. Crit Care. 2015; 19(Suppl 3):S9.
 Shum HP, et al. Ther Apher Dial. 2012; 16:81–86.
 Mitchell A, et al. Clin Nephrol. 2003; 59:106–114.
 Slowinski T, et al. Crit Care. 2015; 19: 19:349. Doi 10.1186/s13054-015-1066-7.
 Monchi M, et al. Intensive Care Med. 2004; 30:260–265.
 Soltysiak J, et al. Pediatr Nephrol. 2014; 29:469–475.
 Morabito S, et al. BMC Nephrol. 2013;14:232.
 Stucker F, et al. Crit Care. 2015; 19:91.
 Morabito S, et al. Crit Care. 2012; 16:R111.
 Summary of product characteristics. Heparin. 2016. Available at:
 Oudemans-van Straaten HM, et al. Crit Care Med. 2009; 37:545–552. https://www.medicines.org.uk/emc/medicine/9793#ORIGINAL (accessed March 2018).
 Oudemans-van Straaten HM, et al. Crit Care. 2011; 15:202.  The United States Pharmacopeial Convention. Anticoagulant Citrate Dextrose Solution,
2011.
 Oudemans-van Straaten HM, et al. Intensive Care Med. 2006; 32:188–202.
 The United States Pharmacopeial Convention. Anticoagulant Sodium Citrate Solution, 2011.
 Oudemans-van Straaten HM. Anticoagulation in CRRT: Systemic or Regional? In Intensive Care
Medicine 2006; pp. 609–696.
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References
 Thrombosis Adviser. The Coagulation Cascade. Available at: https://www.thrombosisadviser.com/en/understanding-thrombosis/the-coagulation-cascade/ (accessed March 2018).
 Tolwani AJ, et al. Kidney Int. 2001; 60:370–374.
 Tolwani AJ, et al. Clin J Am Soc Nephrol. 2006; 1:79–87.
 Tolwani A & Wille K. Blood Purif. 2012; 34:88–93.
 van der Voort PH, et al. Int J Artif Organs. 2006; 29:559–563.
 Ward DM & Mehta RL. Kidney Int Suppl. 1993; 43(Suppl 41):S237–S244.
“Baxter, Prismaflex, Prismocitrate, and Regiocit are trademarks of Baxter International Inc. or its subsidiaries”.
41
41
Figure
 Stock image purchased September 2016. Image on slide 3

 Photo on this slide by Unknown Author is licensed under CC BY
 Stock animation purchased July 2017. Image on slide 6 and 27
 Figure prepared from data in Borg R, et al. J Intensive Care Soc. 2017; 18:184–1921. Figure on slide 13
 Animation created for Baxter by Colmaint. Animation used on slide 22
 Figure adapted from Thrombosis Adviser. The Coagulation Cascade. Available at: https://www.thrombosisadviser.com/en/understanding-thrombosis/the-coagulation-cascade/ (accessed
March 2018); Davenport A, Home Hemodial. 1998; 2:41–49; Palta S, et al. Indian J Anaesth. 2014; 58:515–523 and KDIGO Acute Kidney Injury Work Group. Kidney Int Suppl. 2012; 2:1–
138. Figure on slide 25
 Figure reprinted from Davis TK, et al. Citrate Anticoagulation During Continuous Renal Replacement Therapy in Pediatric Critical Care, Pediatr Crit Care Med. Vol 15 (5), pp. 471–485,
 Figures adapted from Kellum J, et al. In Continuous Renal Replacement Therapy 2010; pp. 141–145. Figure on slide 28
 Stock image from Baxter_Renal_Foundations_Media_Asset_Library_v1.0. Image on slide 32
 Stock image purchased by Baxter. Image on slide 36
 Figures adapted from Kellum J, et al. In Continuous Renal Replacement Therapy 2010; pp. 141–145. Figure on slide 40
 Figure reprinted from Davis TK, et al. Citrate Anticoagulation During Continuous Renal Replacement Therapy in Pediatric Critical Care, Pediatr Crit Care Med. Vol 15 (5), pp. 471–485,
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Thank You!
Baxter Confidential - Do not distribute without prior consent
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Heparinski protokol
-Kraljevina Katar-
• Preferirana širina korišćenog katetera 12 Frenča i više

• Dodati heparin u prvu kesu za ispiranje (ako pacijent
nema kontraindikacije za Heparin, na primer: HIT tip 1 ili
2). 5000 IU Heparina
• Drugu kesu za ispiranje koristiti bez Heparina.
• Proveriti pacijentov koagulacioni profil (koristeći APTT ili
ACT) – da bismo znali početne parametre.
A – Pre • Podesite kontinuiranu isporuku Heparina tokom CRRT
tretmana: (ml/hr): i bolus doziranje tokom tretmana iili
kontinuirana brzina isporuke Heparina tokom tretmana
se podešava prema telesnoj težini pacijenta. Doziranje:
5 IU/Kg/hr – 20 IU/Kg/hr
• Podesiti samo brzinu krvi. Podešavanje brzine isporuke
tečnosti će uslediti nakon što se stabilizuje protok krvi i
pacijentovi hemodinamski parametri (minimum 3 – 5
minuta)
1
12/04/2022
• Nakon početka CRRT tretmana, dajte trenutni početni

Heparinski Bolus kako bi se započela aktivacija heparina.
Opseg između 20 IU – 40 IU/Kg tel. težine.
• Povećati brzinu krvi nakon što se krv vratila u pacijenta ,
na 150 ml/min (opservirajući parameter pritisaka:
Pristupni & Povratni pritisci).
B – Tokom • Kada su pritisci stabilni, povećati brzinu krvi na 190 do

200 ml/min (zavisno od mogućnosti katetera i
CRRT pacijentove hemodinamike)
• Podestite protoke tečnosti prema preskripciji.
Tretmana: • 30 min od Poetka tretmana ponovo proveriti –APTT ili
ACT. (Pobrinite se da APTT ili ACT dostigne 1.5 do 1.8
puta veću vrednost od početne, npr: aPTT=60-80s;
ACT=180-200s)
• Proveriti aPTT/ACT još jednom nakon 30 min– da bi
ponovo proverili da li je rezultat konzistentan.
C. Ako
rezultat
varira:
2
12/04/2022
CRRT Challenges
Debates and
solutions
Lecturer: Dr Vladimir Novkovic, DOO MEDICON DEČ
Why to talk about CRRT in

ICU?
*Liano F, Junco E, Pascual J, Madero R, Verde E. The spectrum of acute renal failure
in the intensive care unit compared with that seen in other settings.The Madrid
Acute Renal Failure Study Group. Kidney Int Suppl. 1998;66:S16-24.
1
12/04/2022
RRT need during ICU stay
*Piccinni, P.; Cruz, D.N.; Gramaticopolo, S.; Garzotto, F.; Dal Santo, M.; Aneloni, G.; Rocco, M.; Alessandri, E.;
Giunta, F.; Michetti, V.; et al. NEFROINT Investigators. Prospective multicenter study on epidemiology of acute
kidney injury in the ICU: A critical care nephrology Italian collaborative effort (NEFROINT). Minerva Anestesiol.
2011, 77, 1072–1083.
**Oweis, A.O.; Alshelleh, S.A.; Momany, S.M.; Samrah, S.M.; Khassawneh, B.Y.; Al Ali, M.A.K. Incidence, Risk
Factors, and Outcome of Acute Kidney Injury in the Intensive Care Unit: A Single-Center Study from Jordan. Crit.
Care Res. Pract. 2020, 2020, 8753764.
Factors influencing RRT need
*Lohse, R.; Damholt, M.B.;Wiis, J.; Perner, A.; Lange, T.; Ibsen, M. Long term end-stage renal disease and death following acute renal replacement therapy in the
ICU. Acta Anaesthesiol. Scand. 2016, 60, 1092–1101.
*Czempik, P.; Cie´sla, D.; Knapik, P.; Krzych, Ł. Mortality of patients with acute kidney injury requiring renal replacement therapy. Adv. Clin. Exp. Med. 2018, 27,
327–333.
**Fujii, T.; Uchino, S.; Doi, K.; Sato, T.; Kawamura, T. JAKID study group. Diagnosis, management, and prognosis of patients with acute kidney injury in Japanese
intensive care units: The JAKID study. J. Crit. Care 2018, 47, 185–191.
***Gaião, S.M.; Gomes, A.A.; Paiva, J.A. Prognostics factors for mortality and renal recovery in critically ill patients with acute kidney injury and renal replacement
therapy. Rev. Bras. Ter. Intensiva 2016, 28, 70–77.
****Peres, L.A.; Wandeur, V.; Matsuo, T. Predictors of acute kidney injury and mortality in an Intensive Care Unit. J. Bras. Nefrol. 2015,
37, 38–46.
2
12/04/2022
LOS depending on RRT
*Harris, D.G.; McCrone, M.P.; Koo, G.; Weltz, A.S.; Chiu, W.C.; Scalea, T.M.; Diaz, J.J.; Lissauer, M.E. Epidemiology and outcomes
of acute kidney injury in critically ill surgical patients. J. Crit. Care 2015, 30, 102–106.
*Podoll, A.S.; Kozar, R.; Holcomb, J.B.; Finkel, K.W. Incidence and outcome of early acute kidney injury in critically-ill trauma
patients. PLoS ONE 2013, 8, e77376.
**Tiglis, M.; Peride, I.; Florea, I.A.; Niculae, A.; Petcu, L.C.; Neagu, T.P.; Checherita, I.A.; Grintescu, I.M. Overview of Renal
Replacement Therapy Use in a General Intensive Care Unit. Int. J. Environ. Res. Public Health 2022, 19, 2453.
https://doi.org/10.3390/ijerph19042453
Mortality in RRT group in ICU
*Iwagami, M.; Yasunaga, H.; Noiri, E.; Horiguchi, H.; Fushimi, K.; Matsubara, T.; Yahagi, N.; Nangaku, M.; Doi, K. Current state of continuous renal replacement therapy for
acute kidney injury in Japanese intensive care units in 2011: Analysis of a national administrative database. Nephrol. Dial. Transplant. 2015, 30, 988–995.
**Brivet, F.G.; Kleinknecht, D.J.; Loirat, P.; Landais, P.J. Acute renal failure in intensive care units–causes, outcome, and prognostic factors of hospital mortality; A prospective,
multicenter study. French Study Group on Acute Renal Failure. Crit. Care Med. 1996, 24, 192–198.
***Allegretti, A.S.; Steele, D.J.; David-Kasdan, J.A.; Bajwa, E.; Niles, J.L.; Bhan, I. Continuous renal replacement therapy outcomes in acute kidney injury and end-stage renal
disease: A cohort study. Crit. Care 2013, 17, R109.
****Kao, C.C.; Yang, J.Y.; Chen, L.; Chao, C.T.; Peng, Y.S.; Chiang, C.K.; Huang, J.W.; Hung, K.Y. Factors associated with poor outcomes of continuous renal replacement therapy.
PLoS ONE 2017, 12, e0177759.
*****Tiglis, M.; Peride, I.; Florea, I.A.; Niculae, A.; Petcu, L.C.; Neagu, T.P.; Checherita, I.A.; Grintescu, I.M. Overview of Renal Replacement Therapy Use in a General Intensive
Care Unit. Int. J. Environ. Res. Public Health 2022, 19, 2453. https://doi.org/10.3390/ijerph19042453
3
12/04/2022
RRT use significantly influences survival

time
*Tiglis, M.; Peride, I.; Florea, I.A.; Niculae, A.; Petcu, L.C.; Neagu, T.P.; Checherita, I.A.; Grintescu, I.M. Overview of Renal Replacement Therapy Use in a General
Intensive Care Unit. Int. J. Environ. Res. Public Health 2022, 19, 2453. https://doi.org/10.3390/ijerph19042453
Critical care AKI patient possible outcomes
4
12/04/2022
1. CRRT dosing
Issues 2. Initial prescription
3. Possible electrolite/metabolic disbalances
4. Concomitant extracorporeal membrane oxygenation support
5. Net ultrafiltration speed
6. When to start/end CRRT and whom to start CRRT
7. Antibiotic strategy
8. What is more convenient, more promising method of RRT (CRRT, SLED,

IHD)
9. Indications other than AKI (in sepsis, liver disease, acute

neurological injuries and decompensated heart failure)
10. Possible blood loss, Use of regional citrate anticoagulation
11. Practical dilemma and Quality improvement
CRRT dose consensus- increasing

dose intensity above 20–25 ml/kg/h does not improve survival
*Palevsky PM, Zhang JH, Connor TZ, Chertow GM, Crowley ST, Choudhury D, Finkel K, Kellum JA, Paganini E, Schein RM, Smith MW, Swanson KM, Thompson BT, Vijayan A,
Watnick S, Star RA, Peduzzi P. VA/NIH Acute Renal Failure Trial Network: intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359(1):7–
20.
**Bellomo R, Cass A, Cole L, et al. RENAL Replacement Therapy Study Investigators, Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med.
2009;361(17):1627–38.
***Joannes-Boyau O, Honore PM, Perez P, et al. High-volume versus standard- volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a
multicentre randomized controlled trial. Intensive Care Med. 2013;39:1535–46.
****Van Wert R, Friedrich JO, Scales DC, et al. High-dose renal replacement therapy for acute kidney injury: systematic review and meta-analysis. Crit Care Med.
2010;38(5):1360–9.
10
5
12/04/2022
Higher doses concerns
*Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically Ill adult patients receiving continuous renal
replacement therapy or intermittent hemodialysis. Pharmacotherapy. 2009;29(5):562–77. ; Cano NJM, Aparicio M, Brunori G, Carrero JJ, Cianciaruso B, Fiaccadori E,
Lindholm B, Teplan V, Fouque D, Guarnieri G. ESPEN guidelines on parenteral nutrition: adult renal failure. Clin Nutr. 2009;28:401–14.
**Joannes-Boyau O, Honore PM, Perez P, et al. High-volume versus standard- volume haemofiltration for septic shock patients with acute kidney
injury (IVOIRE study): a multicentre randomized controlled trial. Intensive Care Med. 2013;39:1535–46.
11
Prescription and delivery dose
*Neyra JA, Tolwani A. CRRT prescription and delivery of dose. Semin Dial. 2021 Nov;34(6):432-439. doi: 10.1111/sdi.12974. Epub 2021 Apr 28. PMID:
33909931.
**How To Prescribe And Troubleshoot Continuous Renal Replacement Therapy: A Case-Based Review Javier A. Neyra, Lenar Yessayan, Melissa L. Thompson
Bastin, Keith M Wille, Ashita J Tolwani Kidney360 Feb 2021, 2 (2) 371-384; DOI: 10.34067/KID.0004912020
***Bagshaw, S. M. et al. Precision continuous renal replacement therapy and solute control. Blood Purif. 42, 238–247 (2016).
12
6
12/04/2022
Scenario 1**: Patient (68 yrs, 120 kg) is critically ill with multiorgan failure, including
respiratory failure, shock, and anuric AKI. In addition, evolving fluid overload at a level consistently associated
with mortality (.10%) biochemical abnormalities such as metabolic acidosis= PROMPT CRRT INITIATION+ECMO
**How To Prescribe And Troubleshoot Continuous Renal Replacement Therapy: A

Case-Based Review Javier A. Neyra, Lenar Yessayan, Melissa L. Thompson Bastin,
Keith M Wille, Ashita J Tolwani Kidney360 Feb 2021, 2 (2) 371-384; DOI:
10.34067/KID.0004912020
13
Possible electrolite/metabolic disbalances
**How To Prescribe And Troubleshoot Continuous Renal Replacement Therapy: A

Case-Based Review Javier A. Neyra, Lenar Yessayan, Melissa L. Thompson Bastin,
Keith M Wille, Ashita J Tolwani Kidney360 Feb 2021, 2 (2) 371-384; DOI:
10.34067/KID.0004912020
14
7
12/04/2022
Indications, contraindications of CRRT
15
Early intiation, yes or no?
16
8
12/04/2022
When to start/end = or ≠ AKI criteria

Start criteria
*Section 2: AKI Definition. Kidney Int Suppl (2011).

2012;2(1):19-36. doi:10.1038/kisup.2011.32
17
AKIN, RIFLE, KDIGO staging of AKI
References:
Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure-definition, outcome measures, animal models, fluid therapy and
0,3mg/dl Scr=26,5 um/l Scr
4mg/dl Scr=353 um/l Scr
information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI)
Group. Crit Care 2004; 8:B204. Copyright © 2004 BioMed Central Ltd.
Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney
injury. Crit Care 2007; 11:R31. Copyright © 2007 BioMed Central Ltd.
Kidney Disease: Improving Global Outcomes (KDIGO). Acute Kidney Injury Work Group. KDIGO clinical practice guidelines for
acute kidney injury. Kidney Int Suppl 2012; 2:1.
18
9
12/04/2022
Early vs Delayed initiation-AKIKI

Study(2016)*
AKIKI study*: EARLY: 6h after AKI Oliguria or anuria for more than 72 Blood urea nitrogen of more than
DELAYED:
staging 3; DELAYED: hours after randomization 112 md/dl (40 mmol/liter)
Acute pulmonary edema due to fluid

overload responsible for severe
pH below 7.15 in a context of pure
hypoxemia requiring oxygen flow
Serum potassium concentration of metabolic acidosis (PaCO2 below 35
rate of more than 5 l/min to maintain
Serum potassium concentration of more than 5.5 mmol/liter despite mmHg) or in a context of mixed
an SpO2 of more than 95% or
more than 6 mmol/liter medical treatment (bicarbonate acidosis with PaCO2 of 50 mmHg or
requiring an FiO2 greater than 50%
and/or glucose-insulin infusion) more without possibility of increasing
in patients already on invasive or
alveolar ventilation
non-invasive mechanical ventilation
and despite diuretic therapy
*Gaudry S, Hajage D, Schortgen F, et al. Initiation strategies for renal-replacement therapy in the intensive care unit. N Engl J Med. 2016;375:122–33.
19
AKIKI1 Conclusion
20
10
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Delayed vs More-Delayed initiation-

AKIKI2 study (2019)*
Blood urea nitrogen of
Oliguria or anuria (urine
DELAYED, more than 72h more than 112 md/dl (40
output <0·3 mL/kg per h
(Median:72h+3h) mmol/liter) to 140 mg/dL
or
„3 DAYS“ (serum urea concentration
<500 mL/day)
of 50 mmol/L).
Blood urea nitrogen of

Oliguria or anuria (urine
DELAYED, more than 72h more than 112 md/dl (40
output <0·3 mL/kg per h
(Median:72h+33h): mmol/liter) to 140 mg/dL
or
„4DAYS“ (serum urea concentration
<500 mL/day)
of 50 mmol/L).
*Gaudry, S., Hajage, D., Martin-Lefevre, L. et al. The Artificial Kidney Initiation in Kidney Injury 2 (AKIKI2): study protocol for a randomized controlled trial. Trials 20, 726 (2019).
https://doi.org/10.1186/s13063-019-3774-9
21
AKIKI 2 Conclusion
22
11
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Other studies
Cove, M.E., MacLaren, G., Brodie, D. et al. Optimising the timing of renal replacement therapy in acute
kidney injury. Crit Care 25, 184 (2021). https://doi.org/10.1186/s13054-021-03614-5
23
ADQUI AKI/AKD Criteria Hyphotesis

• Persistent acute kidney injury (AKI) is characterized by the continuance of AKI by serum
creatinine or urine output criteria (as defined by KDIGO) beyond 48h from AKI onset.
Complete reversal of AKI by KDIGO criteria within 48h of AKI onset characterizes rapid
reversal of AKI (evidence grade: level 5)
• AKI and acute kidney disease (AKD) are a continuum, and persistent AKI
frequently becomes AKD, defined as a condition wherein criteria for AKI stage
1 or greater persists ≥7 days after an exposure
24
12
12/04/2022
End criteria
25
ADQUI Renal recovery access*
Chawla, L., Bellomo, R., Bihorac, A. et al. Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16
Workgroup. Nat Rev Nephrol 13, 241 257 (2017). https://doi.org/10.1038/nrneph.2017.2
26
13
12/04/2022
Fluid overload and ultrafiltration
*Balakumar, V. et al. Both positive and negative fluid balance may be associated with reduced long- term survival in the critically Ill. Crit. Care Med. 45, e749–e757 (2017).
**Bellomo, R. et al. An observational study fluid balance and patient outcomes in the randomized evaluation of normal vs. augmented level of replacement therapy
trial. Crit. Care Med. 40, 1753–1760 (2012).
***Douvris, A. et al. Mechanisms for hemodynamic instability related to renal replacement therapy: a narrative review. Intensive Care Med. 45, 1333–1346 (2019).
****Tanguay, T. A., Jensen, L. & Johnston, C. Predicting episodes of hypotension by continuous blood volume monitoring among critically ill patients in acute renal
failure on intermittent hemodialysis. Dynamics 18, 19–24 (2007).
27
Net ultrafiltration force:low, high, moderate?
Murugan, R.,
Bellomo, R.,
Palevsky, P.M. et
al. Ultrafiltration
in critically ill
patients treated
with kidney
replacement
therapy. Nat Rev
Nephrol 17, 262
–276 (2021).
https://doi.org/
10.1038/s41581
-020-00358-3
28
14
12/04/2022
Studies based UF dose between 1-1,75

ml/kg/h with better outcomes
Murugan, R.,
Bellomo, R.,
Palevsky, P.M. et
al. Ultrafiltration
in critically ill
patients treated
with kidney
replacement
therapy. Nat Rev
Nephrol 17, 262
–276 (2021).
https://doi.org/
10.1038/s41581
-020-00358-3
29
Reduce adverse reaction to high UF rate
Murugan, R.,
Bellomo, R.,
Palevsky, P.M. et
al. Ultrafiltration
in critically ill
patients treated
with kidney
replacement
therapy. Nat Rev
Nephrol 17, 262
–276 (2021).
https://doi.org/
10.1038/s41581
-020-00358-3
30
15
12/04/2022
Managing haemodynamic instability for UFnet
31
Concomitant ECMO
How To Prescribe And Troubleshoot Continuous Renal

Replacement Therapy: A Case-Based Review Javier
A. Neyra, Lenar Yessayan, Melissa L. Thompson
Bastin, Keith M Wille, Ashita J Tolwani Kidney360 Feb
2021, 2 (2) 371-384; DOI: 10.34067/KID.0004912020
32
16
12/04/2022
Concomitant ECMO
*Kilburn DJ, Shekar K, Fraser JF. The complex relationship of extracorporeal membrane oxygenation and acute kidney injury: Causation or association?
Biomed Res Int. 2016;2016:1094296.
**Antonucci E, Lamanna I, Fagnoul D, et al. The impact of renal failure and renal replacement therapy on outcome during extracorporeal membrane
oxygenation therapy. Artif Organs. 2016;40(8):746-754.
***Chen Y-C, Tsai F-C, Chang C-H, et al. Prognosis of patients on extracorporeal membrane oxygenation: the impact of acute kidney injury on mortality.
Ann Thorac Surg. 2011;91(1):137-142.
****Fleming GM, Askenazi DJ, Bridges BC, et al. A multicenter international survey of renal supportive therapy during ECMO: the Kidney Intervention
During Extracorporeal Membrane Oxygenation (KIDMO) group. ASAIO J. 2012;58(4):407-414.
33
CRRT ECMO
connections
Selewski DT, Wille KM. Continuous renal replacement therapy in patients treated with
extracorporeal membrane oxygenation. Semin Dial. 2021;00:1–13.
https://doi.org/10.1111/sdi.12965
34
17
12/04/2022
ECMO and CRRT complications*
*Selewski DT, Wille KM. Continuous renal replacement therapy in patients treated with extracorporeal membrane oxygenation. Semin Dial.
2021;00:1–13. https://doi.org/10.1111/sdi.12965
35
36
18
12/04/2022
Other than AKI CRRT Indications- septic

patient with multiorgan failure (MOF)
*Ronco C, Kellum JA, Bellomo R, House AA. Potential interventions in sepsis-related acute kidney injury. Clin J Am Soc Nephrol. 2008;3:531-44.
37
Other than AKI CRRT Indications-

patients with liver disease
**Arieff AI, Massry SG, Barrientos A, Kleeman CR. Brain water and electrolyte metabolism in uremia: effects of slow and rapid hemodialysis. Kidney Int. 1973;4:177- 87.
38
19
12/04/2022
Other than AKI CRRT Indications- patients

with decompensated hearth failure
**Arieff AI, Massry SG, Barrientos A, Kleeman CR. Brain water and electrolyte metabolism in uremia: effects of slow and rapid hemodialysis. Kidney Int. 1973;4:177- 87.
***Rogers HL, Marshall J, Bock J, Dowling TC, Feller E, Robinson S, et al. A randomized controlled trial of the renal effects of ultrafi ltration as compared to furosemide in patients
with acute decompensated heart failure. J Card Fal. 2008;14:1-5.
39
CRRT IHD SLED
*Kidney Disease Improving Global Outcome KDIGO. Acute kidney injury work group: KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl.
2012;2:1–138.
** Bell M, Granath F, et al. Continuous renal replacement therapy is associated
with less chronic renal failure than intermittent haemodialysis after
acute renal failure. Intensive Care Med. 2007;33:773–80.; Wald R, Shariff SZ, Adhikari NK, et al. The association between renal replacement therapy modality and
long-term outcomes among critically ill adults with acute kidney injury a retrospective cohort study. Crit Care Med. 2014;42(4):868–77.
40
20
12/04/2022
Antibiotics dosage strategy
41
LiL,LiX,XiaY,ChuY,ZhongH,LiJ,LiangP, BuY,ZhaoR,LiaoY,YangP,LuXandJiangS(2020)RecommendationofAntimicrobial DosingOptimization DuringContinuousRenal

ReplacementTherapy. Front.Pharmacol.11:786.doi:10.3389/fphar.2020.00786
42
21
12/04/2022
Major filter downtime causes
*Joannidis M, Straaten HM. Clinical review: patency of the circuit in continuous renal replacement therapy. Crit Care. 2007;11:218. https ://doi. org/10.1186/cc593 7.
**Karkar, A., Ronco, C. Prescription of CRRT: a pathway to optimize therapy. Ann. Intensive Care 10, 32 (2020). https://doi.org/10.1186/s13613-020-0648-y
***Turani F, Barchetta R, Falco M, Busatti S, Weltert L. Continuous Renal Replacement Therapy with the Adsorbing Filter oXiris in Septic Patients: A Case Series. Blood Purif. 2019;47 Suppl
3:1-5. doi: 10.1159/000499589. Epub 2019 Apr 12. PMID: 30982024.
43
Strategies to prevent clotting*
*Karkar, A., Ronco, C. Prescription of CRRT: a pathway to optimize therapy. Ann. Intensive Care 10, 32 (2020). https://doi.org/10.1186/s13613-020-
0648-y
44
22
12/04/2022
Regional Citrate Anticoagulation
*Kindgen-Milles D, Brandenburger T, Dimski T. Regional citrate anticoagulation for continuous renal replacement therapy. Curr Opin Crit Care. 2018;24(6):450–4.
https ://doi.org/10.1097/MCC.00000 00000 00054 7.
**Bai M, Zhou M, He L, et al. Citrate versus heparin anticoagulation for continuous renal replacement therapy: an updated meta-analysis of RCTs. ICM.
2015;41(12):2098–110.
***Borg R, Ugboma D, Walker DM, Partridge R. Evaluating the safety and efficacy of regional citrate compared to systemic heparin as anticoagulation
for continuous renal replacement therapy in critically ill patients: a service evaluation following a change in practice. J Intensive Care Soc. 2017;18(3):184–92.
****Zhang Z, Hongying N. Efficacy and safety of regional citrate anticoagulation in critically ill patients undergoing continuous renal replacement therapy. ICM.
2012;38(1):20–8.
*****Yu, Y. et al. Regional citrate anticoagulation versus no-anticoagulation for continuous venovenous hemofiltration in patients with liver failure and increased
bleeding risk: A retrospective case-control study. PLoS ONE 15(5), e0232516 (2020).
45
Monitor problems and react constructively
46
23
12/04/2022
Aproach CRRT with Quality improvement*
HOW???
*Ruiz EF, Ortiz-Soriano VM, Talbott M, Klein BA, Thompson Bastin ML, Mayer KP, Price EB, Dorfman R, Adams BN, Fryman L, Neyra JA; University of Kentucky CRRT Quality
Assurance Group. Development, implementation and outcomes of a quality assurance system for the provision of continuous renal replacement therapy in the intensive
care unit. Sci Rep. 2020 Nov 26;10(1):20616. doi: 10.1038/s41598-020-76785-w. PMID: 33244053; PMCID: PMC7692557.
47
Context before and after QI

*Ruiz EF, Ortiz-
Soriano VM, Talbott
M, Klein BA,
Thompson Bastin
ML, Mayer KP, Price
EB, Dorfman R,
Adams BN, Fryman
L, Neyra JA;
University of
Kentucky CRRT
Quality Assurance
Group.
Development,
implementation and
outcomes of a
quality assurance
system for the
provision of
continuous renal
replacement therapy
in the intensive care
unit. Sci Rep. 2020
Nov 26;10(1):20616.
doi:
10.1038/s41598-
020-76785-w. PMID:
33244053; PMCID:
PMC7692557.
48
24
12/04/2022
How to achieve better team and

outcomes? Quality intervention *Ruiz EF, Ortiz-
Soriano VM, Talbott
M, Klein BA,
Thompson Bastin
ML, Mayer KP, Price
EB, Dorfman R,
Adams BN, Fryman
L, Neyra JA;
University of
Kentucky CRRT
Quality Assurance
Group.
Development,
implementation and
outcomes of a
quality assurance
system for the
provision of
continuous renal
replacement therapy
in the intensive care
unit. Sci Rep. 2020
Nov 26;10(1):20616.
doi:
10.1038/s41598-
020-76785-w. PMID:
33244053; PMCID:
PMC7692557.
49
Zlatna sredina: To je sredina

između preterivanja i
zaostajanja za principom mere.
Aristotel
50
25
12/04/2022
OVERVIEW OF SEPSIS
AND ITS MANAGEMENT
Overview of sepsis
and its causes
5
2
1
12/04/2022
Sepsis is a major and growing global

healthcare challenge
Sepsis affects millions of people around the world each year
and is associated with high hospital and ICU mortality rates1–11
Reasons for the increasing impact of sepsis may include:12

• An aging population
• Increased administration of
immunosuppressive medications
• Increased antibiotic resistance
• Increased use of invasive procedures
for medical care
• More people presenting with multiple comorbidities
ICU, intensive care unit.

1. Fleischmann C, et al. Am J Respir Crit Care Med. 2016; 193:259–272; 2. Vincent JL, et al. Crit Care Med. 2006; 34:344–353; 3. Engel C, et al. Intensive Care Med. 2007; 33:606–618;
4. Kaukonen KM, et al. JAMA. 2014; 311:1308–1306; 5. van Vught LA, et al. JAMA. 2016; 315:1469–1479; 6. Harrison DA, et al. Crit Care. 2006; 10:R42; 7. Yebenes JC, et al. Ann Intensive Care. 2017; 7:19;
8. Martin GS, et al. N Engl J Med. 2003; 348:1546–1554; 9. Karlsson S, et al. Intensive Care Med. 2007; 33:435–443; 10. Padkin A, et al. Crit Care Med. 2003; 31:2332–2338;
6
11. SepNet Critical Care Trials Group. Intensive Care Med. 2016; 42:1980–1989; 12. Hall J, et al. NSHS Data Brief. 2011; 62.
Anyone with an infection is potentially at risk of

developing sepsis
Populations at an increased risk may include:
Infants; the elderly; people with a Sepsis is a frequent occurrence among

weakened immune system or a chronic critically ill patients in the ICU3–10
illness; and those recovering from recent
surgery or a serious illness1,2
1. NHS Conditions. Sepsis – Who can get it? 2019. Available at: https://www.nhs.uk/conditions/sepsis/who-can-get-it/ (accessed April 2020); 2. Gauer R, et al. Am Fam Physician. 2013; 88:44–53;
3. Vincent JL, et al. Crit Care Med. 2006; 34:344–353; 4. Engel C, et al. Intensive Care Med. 2007; 33:606–618; 5. Blanco J, et al. Crit Care. 2008; 12:R158; 6. Finfer S, et al. Intensive Care Med.
2004; 30:589–596; 7. Karlsson S, et al. Intensive Care Med. 2007; 33:435−443; 8. Kaukonen KM, et al. JAMA. 2014; 311:1308–1316; 9. Sjoding MW, et al. Crit Care Med. 2016; 44:1353–1360; 8
10. Vincent JL, et al. Intensive Care Med. 2018; 44:337–344.
2
12/04/2022
What is sepsis?
Sepsis is life-threatening organ
dysfunction caused by a dysregulated
host response to infection1
Sepsis is a syndrome caused by an infection that
occurs in any part of the body2,3
• The infection is usually bacterial but can also
be fungal or viral3–5
• Infection can also be introduced directly into

the bloodstream, e.g. catheter infections5
• Pro-inflammatory and anti-inflammatory

mediators are expressed as a response to
infection6
1. Singer M, et al. JAMA. 2016; 315:801–810; 2. Karlsson S, et al. Intensive Care Med. 2007; 33:435–443; 3. Gotts J, et al. BMJ. 2016; 353:i585; 4. Martin GS, et al. N Engl J Med. 2003; 348:1546–1554; 9
5. Vincent JL, et al. Crit Care Med. 2006; 34:344–353; 6. Monard C, et al. Blood Purif. 2019; 47(Suppl. 3):2–15.
Sepsis is caused by a dysregulated

immune response to infection
Normal immune response to infection:
Inflammatory mediators are released into the blood as part of the

normal immune response to the recognition of a pathogen1,2
Dysregulated immune response to infection:
A dysregulated immune response can result in the excessive release of

pro- and anti-inflammatory cytokines, which may trigger a series of
reactions that can lead to cellular and tissue injury1,3
These pathologic effects can result in the failure of one or more organs1,4,5
1. Monard C, et al. Blood Purif. 2019; 47(Suppl. 3):2–15; 2. Gotts JE & Matthay MA. BMJ. 2016; 353:i1585; 3. Singer M, et al. JAMA. 2016; 315:801–810; 10
4. Angus DC & van der Poll T. N Engl J Med. 2013; 369:840–851; 5. Ronco C, et al. Artif Organs. 2003; 27:792–801.
3
12/04/2022
Inflammatory mediators are released into the blood as part of

the normal immune response to the recognition of a pathogen1,2
Injured cell
Pathogen,
e.g. bacterial, fungal,
or viral infection Damage-
associated
molecular
pattern
(DAMP)
Cytokine release
(e.g. interleukin
[IL]-6, IL-8, IL-10,
and tumor necrosis
factor [TNF]-α)
Pathogen-associated
molecular pattern
(PAMP) e.g. endotoxin
exhibited by Gram-
negative bacteria Immune cell
Pattern recognition
receptor (PRR)
7
1. Monard C, et al. Blood Purif. 2019; 47(Suppl. 3):2–15; 2. Gotts JE & Matthay MA. BMJ. 2016; 353:i1585.
Inflammatory mediators are released into the blood as part of

the normal immune response to the recognition of a pathogen1,2
DAMPs
Injured cells can Injured cell
display DAMPs on
their surface, which
Pathogen can also be
recognized by PRRs
on immune cells and
further drive cytokine
release1
PAMPs Cytokine release
PAMPs are conserved
molecules displayed on the
surface of pathogens. They
are recognized by PRRs on
the surface of immune cells,
stimulating the release of
pro- and anti- inflammatory
cytokines into the blood1 Immune cell
Pattern recognition
receptor (PRR)
8
1. Monard C, et al. Blood Purif. 2019; 47(Suppl. 3):2–15; 2. Gotts JE & Matthay MA. BMJ. 2016; 353:i1585.
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12/04/2022
The excessive release of pro- and anti-inflammatory cytokines

can lead to cellular and tissue damage1–4
Injured cell
Excessive cytokine release
Pathogen, (e.g. IL-6, IL-8, IL-10, and TNF-α)
e.g. bacterial, fungal,
Damage-
or viral infection associated
molecular
pattern
(DAMP)
Pathogen-associated
molecular patterns (PAMP) Immune cell
e.g. endotoxin exhibited by
Gram-negative bacteria
Pattern recognition
receptor (PRR)
1. Monard C, et al. Blood Purif. 2019; 47(Suppl. 3):2–15; 2. Gotts JE & Matthay MA. BMJ. 2016; 353:i1585; 14
3. Zarbock A, et al. Curr Opin Crit Care. 2014; 20:588–595; 4. Hotchkiss RS, et al. Lancet Infect Dis. 2013; 13:260–268.
Organ dysfunction in sepsis

Multiple organ dysfunction has been Brain
reported in approximately 20–25% of
patients hospitalized with sepsis1,2
In patients with sepsis, a greater degree of
organ dysfunction is associated with an
increased risk of mortality3–6 Heart
Lungs
Liver
Kidneys
Intestines
1. Mayr FB, et al. JAMA. 2010; 303:2495–2503; 2. Angus DC, et al. Crit Care Med. 2001; 29:1303–1310; 3. Vincent JL, et al. Crit Care Med. 2006; 34:344–353;
16
4. Brun-Buisson C, et al. Intensive Care Med. 2004; 30:580–588; 5. Quenot JP, et al. Crit Care. 2013; 17:R65; 6. Pavon A, et al. Crit Care Med. 2013; 41:2600–2609.
10
5
12/04/2022
Organ dysfunction in sepsis REPORTED INCIDENCE AND POTENTIAL

CLINICAL MANIFESTATIONS
1. Neurologic dysfunction: 1
Reported to occur in 23–70% of patients.1–4
Characterized by compromise of the blood–brain barrier,
delirium, and encephalopathy.5
2. Cardiovascular (CV) dysfunction
Reported to occur in 23–77% of patients.2–4,6,7
Characterized by changes in cardiac output, peripheral
vascular resistance, and peripheral perfusion.5
3. Respiratory dysfunction
Reported to occur in 16–92% of patients.1–3,6,8–12 2
Characterized by acute respiratory distress syndrome (ARDS): 3
pulmonary edema, and impaired oxygenation of the blood.5,13
4. Hepatic dysfunction 4
Reported to occur in 34–46% of patients.3,4,7 5
Characterized by jaundice, cholestasis, and coagulopathy.5,13
5. Renal dysfunction
Reported to occur in 22–69% of patients.1–3,6,8–12
Characterized by acute kidney injury (AKI).14,15
ARDS, acute respiratory distress syndrome; AKI, acute kidney injury; CV, cardiovascular.
1. Vincent JL, et al. Crit Care Med. 2006; 34:344–353; 2. van Gestel A, et al. Crit Care. 2004; 8:R153–R162; 3. Brun-Buisson C, et al. Intensive Care Med. 2004; 30:580–588; 4. Cheng B, et al. Crit Care Med. 2007;
35:2538–2546; 5. Gotts JE & Matthay MA. BMJ. 2016; 353:i1585; 6. Karlsson S, et al. Intensive Care Med. 2007; 33:435–443; 7. Vincent JL, et al. Crit Care Med. 2003; 31:834–840; 8. Yebenes JC, et al. Ann Intensive
Care. 2017; 7:19; 9. Blanco J, et al. Crit Care. 2008; 12:R158; 10. Engel C, et al. Intensive Care Med. 2007; 33:606–618; 11. SepNet Critical Care Trials Group. Intensive Care Med. 2016; 42:1980–1989; 12. Mayr FB, et al. 17
JAMA. 2010; 303:2495–2503; 13. Fujishima S. Inflamm Regen. 2016; 36:24; 14. Poston JT & Koyner JL. BMJ. 2019; 364:k4891; 15. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group.
Kidney Int Suppl. 2012; 2:1–138.
11
Prevalence and
potential outcomes
of sepsis
18
12
6
12/04/2022
Sepsis occurs frequently among ICU patients

As different definitions and criteria are used for diagnosis, it is difficult
to accurately describe the number of patients impacted by sepsis
• Analysis of data from the Global Burden of Diseases Study

estimated the total annual number of cases to be 48.9 million, with up to
11 million deaths, representing ~20% of all deaths worldwide1
• Approximately
• 10–40% of ICU patients have been reported to have sepsis2–9,a
• 10–50% of patients have been reported to have sepsis on ICU admission

2,7–13,a
• 25–30% of patients have been reported to develop sepsis

within 24 hours of ICU admission14–16,a
aThe wide range of values for sepsis incidence and prevalence reported in published studies is due to a number of factors, including variations in the demographic and clinical characteristics of the patient
populations and the criteria used to define sepsis.
1. Rudd KE, et al. Lancet. 2020; 395:200–211; 2. Vincent JL, et al. Crit Care Med. 2006; 34:344–353; 3. Engel C, et al. Intensive Care Med. 2007; 33:606–618; 4. Blanco J, et al. Crit Care. 2008; 12:R158;
5. Finfer S, et al. Intensive Care Med. 2004; 30:589–596; 6. Karlsson S, et al. Intensive Care Med. 2007; 33:435−443; 7. Kaukonen KM, et al. JAMA. 2014; 311:1308–1316; 8. Sjoding MW, et al. Crit Care
Med. 2016; 44:1353–1360; 9. Vincent JL, et al. Intensive Care Med. 2018; 44:337–344; 10. van Vught LA, et al. JAMA. 2016; 315:1469–1479; 11. Vincent JL, et al. Lancet Respir Med. 2014; 2:380–386; 19
12. Lee J, et al. J Korean Med Sci. 2017; 32:528–533; 13. Sakr Y, et al. Crit Care Med. 2017; 45:386–394; 14. Padkin A, et al. Crit Care Med. 2003; 31:2332–2338; 15. van Gestel A, et al. Crit Care. 2004;
8:R153–R162; 16. Harrison DA, et al. Crit Care. 2006; 10:R42.
13
14
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12/04/2022
Sepsis and septic shock are associated with

high rates of mortality and morbidity
Morbidities: Even survivors can be
Reported Reported left with long-term damage and
hospital mortalitya ICU mortalitya disability
• Survivors of sepsis may experience long-term
Patients with functional, cognitive, and psychological
20–45%1–10 15–35%1,3,5,6,8
sepsis: complications13–16
• Approximately 23–32% are re-admitted to
Patients with hospital within 30 days of being discharged17−21
50–60%2,11,12 40%11
septic shock: • Patients with sepsis may have an increased
risk of prolonged CV complications or stroke22,23
Mortality
Mortalit
y
a Values are approximate estimates based on study data. The wide range of sepsis mortality rates reported in published studies is due to a number of factors, including variations in the demographic and clinical
characteristics of the patient populations, the criteria used to define sepsis, and protocols used to manage sepsis.
1. Vincent JL, et al. Crit Care Med. 2006; 34:344–353; 2. Engel C, et al. Intensive Care Med. 2007; 33:606–618; 3. Karlsson S, et al. Intensive Care Med. 2007; 33:435–443; 4. Kaukonen KM, et al. JAMA. 2014;
311:1308–1316; 5. van Vught LA, et al. JAMA. 2016; 315:1469–1479; 6. Padkin A, et al. Crit Care Med. 2003; 31:2332–2338; 7. Harrison DA, et al. Crit Care. 2006; 10:R42; 8. SepNet Critical Care Trials Group.
Intensive Care Med. 2016; 42:1980–1989; 9. Yébenes JC, et al. Ann Intensive Care. 2017; 7:19;10. Martin GS, et al. N Engl J Med. 2003; 348:1546–1554; 11. Pavon A, et al. Crit Care Med. 2013; 41:2600–2609;
12. Kadri SS, et al. Chest. 2017; 151:278–285; 13. Jones C & Griffiths RD. Minerva Anestesiol. 2013; 79:1306–1312; 14. Iwashyna T, et al. JAMA. 2010; 304:1787–1794; 15. Boer KR, et al. Intensive Care Med. 2008;
34:664–674; 16. Davydow DS, et al. Gen Hosp Psychiatry. 2008; 30:421–434; 17. Norman B, et al. Crit Care Med. 2017; 45:1130–1137; 18. Jones T, et al. Ann Am Thorac Soc. 2015; 12:904–913; 20
19. Goodwin A, et al. Crit Care Med. 2015; 43:738–746; 20. Sun A, et al. Crit Care Med. 2016; 44:478–487; 21. Zilberberg MD, et al. J Hosp Med. 2015; 10:678–685; 22. Ou SM, et al. Am J Respir Crit Care Med. 2016;
194:209–217; 23. Boehme AK, et al. Stroke. 2017; 48:574–580.
15
Definition and
diagnosis of sepsis
21
16
8
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Previous definition: SIRS in the presence of an

infection (1991)
Systemic inflammatory response syndrome (SIRS) in the presence of an
infection was introduced as the definition of sepsis in 19911
The focus was on

• the clinical inflammatory response to an
infection, including
• respiration rate, heart rate, white blood
cell count, and body temperature1
22
SIRS, systemic inflammatory response syndrome.
1. Bone RC, et al. Chest. 1992; 101:1644–1655.
17
Recent definition: Sepsis-3 criteria (2016)

The 3rd International Consensus Definitions for Sepsis Sepsis-3 defines
and Septic Shock:1–3 sepsis as
“life-threatening organ
• Reflect a greater understanding of the pathophysiology dysfunction caused by a
of sepsis dysregulated host response
to infection”1
• Recognize the presence of organ dysfunction as part of
the definition of sepsis Sepsis-3 defines septi
• Highlight the critical role of a dysregulated immune shock as c
response during sepsis “a subset of sepsis in
which underlying circ
• Consider the term severe sepsis “redundant” as sepsis and cellular/metaboliulatory
does not necessarily follow a continuum through severe abnormalities are pro c
enough to substantially
sepsis to shock increase mortality”1
23
1. Singer M, et al. JAMA. 2016; 315:801–810; 2. Monard C, et al. Blood Purif. 2019; 47(Suppl. 3):2–15; 3. Ronco C. Blood Purif. 2019; 47(Suppl. 3):1.
18
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12/04/2022
Sequential Organ Failure Assessment score (SOFA)

SOFA score is typically used to track a patient’s organ function
status during their stay in the ICU1
Sepsis-3 defines
The overall score is calculated from six different scores (0–4),
one each for the respiratory, coagulation, hepatic, organ dysfunction as:
cardiovascular, central nervous, and renal systems2,3 An increase in total SOFA score of
According to the Sepsis-3 criteria, organ dysfunction is ≥2 points4

defined as an acute change in total SOFA score by
≥2 points, consequent to the infection4
For a general hospital population with presumed infection, a

SOFA score of ≥2 points has been reported to be associated
with an in-hospital mortality risk of approximately 10%4,5
SOFA, Sequential Organ Failure Assessment. 24

1. Jones A, et al. Crit Care Med. 2009; 37:1649–1654; 2. Vincent JL, et al. Intensive Care Med. 1996; 22:707–710; 3. Lambden S, et al. Crit Care. 2019; 23:374;
4. Singer A, et al. JAMA. 2016; 315:801–810; 5. Seymour CW, et al. JAMA. 2016: 315; 762–774.
19
SOFA scoring system1

System1 0 1 2 3 4
Respiration ≥400 <400 <300 <200 <100
PaO2/FiO2, mmHg (kPa) (53.3) (53.3) (40) (26.7)a (13.3)a
Coagulation ≥150 <150 <100 <50 <20

Platelets, ×103/µL
Liver <20 20–32 33–101 102–204 >204

Bilirubin, µmol/L (mg/dL) (1.2) (1.2–1.9) (2.0–5.9) (6.0–11.9) (12.0)
Dopamine 5.1–15 Dopamine >15

Dopamine <5
Cardiovascular MAP MAP or
or or
MAP or catecholamine doses in epinephrine ≤0.1 epinephrine >0.1
≥70 mmHg <70 mmHg dobutamine or or
µg/kg/min for ≥1 hour
(any dose)
norepinephrine ≤0.1 norepinephrine >0.1
Central nervous system 15 13–14 10–12 6–9 <6

Glasgow Coma Scale (GCS) score
Renal
Creatinine, µmol/L (mg/dL) <110 110–170 171–299 300–440 >440
(1.2) (1.2–1.9) (2.0–3.4) (3.5–4.9) (5.0)
Urine output, mL/day <500 <200
aWith respiratory support.
FiO2, fraction of inspired oxygen; MAP, mean arterial pressure; PaO2, partial pressure of oxygen. 25
1. Singer A, et al. JAMA. 2016; 315:801–810.
20
10
12/04/2022
Glasgow Coma Score Otvaranje očiju

Nikad 1
Na bolnu nadražaj 2
Najbolji očni odgovor (Eye- E)
1 (najgori) do 4 (najbolji/normalni) Na verbalnu stimulaciju 3
poena Spontano 4
Najbolji verbalni odgovor (Verbal- V) Najbolji verbalni odgovor
1 (najgori) do 5 (najbolji/normalni) Nema odgovora 1
poena Nerazumljivi zvuci 2
Najbolji motorni odgovor (Motor- M)
Neprikladne reči 3
1 (najgori) do 6 (najbolji/normalni)
poena Razgovara, dezorijentisan 4
Razgovara, orijentisan 5
Najbolji motorni odgovor
*TOTAL = E + V+ M Nema odgovora 1
Decerebraciona rigidnost 2
Dekortikalna rigidnost 3
*Rezultat 3 ili 4 je loš prognostički znak
izuzev ako se radi o trovanjima. Fleksiono povlačenje 4
Lokalizacija bola 5
Izvršava naloge 6
UKUPNO 3-15
21
qSOFA (quick SOFA)

The SOFA score requires multiple laboratory tests and therefore may delay diagnosis,
which is suboptimal in a time-sensitive setting
Sepsis-3 therefore suggests the use of “quick SOFA” (qSOFA) to screen patients likely to have sepsis1
qSOFA is a simple score that assesses for the presence of two or more of the following:1
Altered mental status: Tachypnea: Hypotension:

Glasgow Coma Respiratory rate Systolic blood
Scale <15 ≥22 breaths per minute pressure ≤100 mmHg
26
qSOFA, quick Sequential Organ Failure Assessment.
1. Singer A, et al. JAMA. 2016; 315:801–810.
22
11
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Uses of qSOFA (quick SOFA)

Altered mental status:
• As a bedside assessment, qSOFA is used to promptly identify patients Glasgow Coma
with suspected infection who are likely to have a prolonged ICU stay or to Scale <15
die in the hospital1
• Results can prompt1
• further investigation for organ dysfunction
Tachypnea:
• initiation/escalation of therapy as appropriate Respiratory rate
≥22 breaths per minute
• consideration of referral to critical care
• more frequent monitoring
• However, studies have raised concerns about the sensitivity and
predictive accuracy of qSOFA2,3 Hypotension:
Systolic blood
pressure ≤100 mmHg
27
qSOFA, quick Sequential Organ Failure Assessment.
1. Singer A, et al. JAMA. 2016; 315:801–810; 2. Askim A, et al. Scand J Trauma Resusc Emerg Med. 2017; 25:56; 3. Amland RC & Sutariya BB. Am J Med Qual. 2018; 33:50–57.
23
Overview of biomarkers and other tests

used to identify inflammation associated with sepsis
C-reactive protein (CRP) Procalcitonin (PCT) Interleukin-6 (IL-6) Endotoxin
• Levels of the acute • In response to infection, • IL-6 is an interleukin • Endotoxins are cell surface
inflammatory protein CRP PCT is released from almost that acts as a compounds shed by Gram-
are increased during all tissues3 pro-inflammatory cytokine in negative bacteria that induce
inflammatory conditions such • PCT has been reported as a response to infection7 cytokine production13
as infection1 useful biomarker for early • Increased levels of IL-6 • Endotoxin levels
• CRP plasma levels diagnosis of sepsis in circulate during sepsis7–10 have been reported to
have been reported to critically ill patients4 • Elevated IL-6 levels correlate with
correlate with sepsis severity2 • PCT has been used to support are linked to infection severity sepsis severity and patient
• Commonly used in the ICU decisions about initiating or and outcomes, making it a outcomes14–16
to evaluate patients with discontinuing antibiotic useful predictor of the extent
presumed sepsis therapy, to reduce the of sepsis8,9,11,12
unnecessary use of antibiotics + PRESEPSIN:
in critically ill patients5,6
• Commonly used in the ICU to
evaluate patients with
presumed sepsis
CRP, C-reactive protein; IL, interleukin; PCT, procalcitonin.

1. Sproston NR & Ashworth JJ. Front. Immunol. 2018. 9:754; 2. Póvoa P, et al. Clin Microbiol Infect. 2005; 11:101–108; 3. Cho S-T, et al. Infect Chemother. 2014; 46:1−12; 4. Wacker C, et al. Lancet Infect Dis. 2013; 13:426–435; 5. de Jong E,
et al. Lancet Infect Dis. 2016; 16:819–827; 6. Iankova I, et al. Crit Care Med. 2018; 46:691–698; 7. Hack CE, et al. Blood. 1989; 74:1704−1710; 8. Gogos CA, et al. J Infect Dis. 2000; 181:176–180; 9. Bozza FA, et al. Crit Care. 2007; 11:R49; 28
10. Damas P, et al. Ann Surg. 1992; 215:356–362; 11. Barre M, et al. J Crit Care. 2018; 43:21–28; 12. Frencken JF, et al. Crit Care Med. 2017; 45:e493–e499; 13. Cavaillon JM. Toxicon. 2018; 149:45–53; 14. Yaroustovsky M, et al. J Inflamm
(Lond). 2013; 10:8; 15. Bottiroli M, et al. J Crit Care. 2017; 41:124–129; 16. Marshall JC, et al. J Infect Dis. 2004; 190:527–534.
24
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Limitations of biomarkers and other tests

used to identify inflammation associated with sepsis
C-reactive protein (CRP) Procalcitonin (PCT) Interleukin-6 (IL-6) Endotoxin
Limitation: Limitation: Limitation: Limitation:

Lacks the ability to Elevated PCT levels can Lacks the ability to Endotoxemia was shown
distinguish between occur in conditions other distinguish infection from to be common in a
infectious and non-infectious than sepsis1,2 inflammation2 heterogeneous population of
causes of inflammation1 critically ill patients in
the ICU3
29
CRP, C-reactive protein; IL, interleukin; PCT, procalcitonin.
1. Cho S-T, et al. Infect Chemother. 2014; 46:1−12; 2. Reinhart K, et al. Clin Microbiol Rev. 2012; 25:609−634; 3. Marshall JC, et al. J Infect Dis. 2004; 190:527–534.
25
Early diagnosis and management of sepsis may

positively impact patient outcomes
Sepsis and septic shock are medical emergencies; treatment and
resuscitation should begin immediately1
However, diagnosis of sepsis in critically ill patients can be challenging:2

• Clinical manifestations can be complicated by comorbidities in the critically ill population.
This may be the result of inflammation caused by other underlying disease processes2
• Prior use of antibiotics in critically ill patients is common and can result in negative
microbial blood cultures2,3
30
1. Rhodes A, et al. Intensive Care Med. 2017; 43:304–377; 2. Vincent JL. PLoS Med. 2016; 13:e1002022; 3. Vincent JL, et al. JAMA. 2009; 302:2323–2329.
26
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Management of sepsis
31
27
Categories of focus for sepsis management

If a physician suspects sepsis, there are several parameters that
can be measured to tailor treatment appropriately:1
Presence of infection
General variables (e.g. fever or hypothermia)
Inflammatory variables (e.g. elevated procalcitonin, leukopenia or leukocytosis)
Hemodynamic variables (e.g. hypotension, elevated cardiac index)
Organ dysfunction (e.g. hypoxemia, acute oliguria)
Tissue perfusion (e.g. hyperlactatemia)
32
1. Angus DC, et al. N Engl J Med. 2013; 369:840–851.
28
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Elements of sepsis management

The approach to management will vary
depending on the clinical manifestations of sepsis, the underlying health of the patient,
and the pattern of organ dysfunction observed in the patient1
According to the Surviving Sepsis Campaign (SSC) guidelines,

aspects of sepsis management include:2,3
Fluid resuscitation Management

and hemodynamic Infection control of organ dysfunction
support (e.g. kidneys, lungs)
The SSC guidelines recommend that treatment and fluid resuscitation begin immediately.2,3
33
SSC, Surviving Sepsis Campaign.
1. Angus DC, et al. N Engl J Med. 2013; 369:840–851; 2. Levy M, et al. Crit Care Med. 2018; 44:925–928; 3. Rhodes A, et al. Intensive Care Med. 2017; 43:304–377.
29
Fluid resuscitation and hemodynamic support

The Hour-1 Surviving Sepsis Campaign Bundle recommend s1
• Measure lactate level1,2
(Weak recommendation, low quality of evidence)
• If initial lactate is >2 mmol/L, remeasure within 2–4 hours to guide
resuscitation to normalize lactate levels1,2
• Begin rapid administration of ≥30 mL/kg intravenous (IV) crystalloid
fluid for sepsis-induced hypoperfusion or lactate levels ≥4 mmol/L1, 2
(Strong recommendation, low quality of evidence)
• Should begin immediately and be completed within 3 hours of sepsis
recognition1,2
• Use norepinephrine as the first choice vasopressor1,2
(Strong recommendation, moderate quality of evidence)
• If the patient is hypotensive during or after fluid resuscitation, with a me
arterial pressure target of ≥65 mmHg1,2 an
34
IV, intravenous.
1. Levy MM, et al. Intensive Care Med. 2018; 44:925–928; 2. Rhodes A, et al. Intensive Care Med. 2017; 43:304–377.
30
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Infection control
The Hour-1 Surviving Sepsis Campaign Bundle recommends:1
• Obtain blood cultures prior to the administration of antibiotics1,2
(Best practice statement)
• Appropriate routine microbiologic cultures should include

at least two sets of blood cultures1,2
• Administration of antibiotics should not be delayed in order
to obtain blood cultures1,2
• Administer broad-spectrum antibiotics1,2

(Strong recommendation, moderate quality of evidence)
• IV administration of empiric broad-spectrum antimicrobials

should be initiated within 1 hour of recognition of sepsis or
septic shock1,2
35
1. Levy MM, et al. Intensive Care Med. 2018; 44:925–928; 2. Rhodes A, et al. Intensive Care Med. 2017; 43:304–377.
31
Management of organ dysfunction: Kidneys

The Surviving Sepsis Campaign guidelines provide recommendations on
management of organ dysfunction, including:1
Renal replacement therapy (RRT)
“We suggest that either continuous or
intermittent renal replacement therapy (RRT) be
used in patients with sepsis and AKI”1
(Weak recommendation, moderate quality of evidence)
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RRT, renal replacement therapy.
1. Rhodes A, et al. Intensive Care Med. 2017; 43:304–377.
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Management of organ dysfunction: Lungs

The Surviving Sepsis Campaign guidelines provide recommendations on
management of organ dysfunction, including:1
Mechanical ventilation
“We recommend using a target tidal volume
of 6 mL/kg predicted body weight compared
with 12 mL/kg in adult patients with sepsis-
induced acute respiratory distress syndrome
(ARDS)”1
(Strong recommendation, high quality of evidence)
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RRT, renal replacement therapy.
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General supportive care

The Surviving Sepsis Campaign guidelines
provide recommendations on general
supportive care for critically ill patients,
including:1
1. Prevention of stress ulcers
2. Prevention of venous thromboembolism
3. Nutritional support
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Extracorporeal removal of inflammatory mediators

Blood purification (BP) therapies are designed to address the effects of an unbalanced immune
system during sepsis by the removal of endotoxins and/or cytokines1
BP therapies are adjunctive therapy options for sepsis management and their use may be
associated with improvements in certain patient-related outcomes such as organ function and
hemodynamic stability2–5
However, results of clinical studies evaluating efficacy have been inconsistent, perhaps due to variations in:
• Device(s) used
• Limitations in study design
• Heterogeneity of patients’ clinical status6
The Surviving Sepsis Guidelines make no recommendations regarding the use of blood purification
techniques due to the limitations of available evidence6
BP, blood purification.

1. Monard C, et al. Blood Purif. 2019; 47(Suppl. 3):2–15; 2. Shum HP, et al. Hong Kong Med J. 2013; 19:491–497;
3. Cruz DN, et al. JAMA. 2009; 301:2445–2452; 4. Turani F, et al. Blood Purif. 2019; 47(Suppl. 3):54–58; 39
5. Hawchar F, et al. J Crit Care. 2019; 49:172–178; 6. Rhodes A, et al. Intensive Care Med. 2017; 43:304–377.
35
Selected studies showing an improvement in clinical status

with BP therapies
from
baseline after 48 hours (P = 0.011)1,a from baseline by the end of treatment
(74 ± 36 hours, P < 0.01)3,c
from
baseline after 72 hours (P < 0.001)2,b
from baseline after 48 hours (P < 0.05)4,d
from
baseline after 24 hours (P < 0.001)3,c from baseline after
72 hours (P < 0.001)2,b
Further research is needed to clarify the role of the mechanisms of action of BP therapies in improving clinical
outcomes, identifying patients that may benefit, and determining the appropriate timing of initiation
aSmall, prospective case study series (2011–2012) of 6 patients with septic shock and sepsis-induced AKI treated with continuous veno-venous hemofiltration (CVVH) with an adsorptive membrane. Compared with a 3% increase in SOFA score in the
historical control group; b Prospective randomized controlled trial (RCT) conducted between 2004 and 2007 in 64 patients with severe sepsis or septic shock who underwent emergency surgery for abdominal infection and were treated with either
conventional therapy or conventional therapy plus 2 sessions of hemoperfusion with a polymyxin B-immobilized column. Significant difference compared with conventional therapy (P < 0.001). Note: vasopressor dependency index is calculated as the
ratio of inotropic score to mean arterial pressure; a higher score indicates a greater vasopressor requirement; c Retrospective, baseline-controlled, observational study conducted between 2011 and 2018 of 60 patients with sepsis/septic shock treated
with CVVH with an adsorptive membrane; d Prospective RCT conducted between 2015 and 2017 of 20 septic shock patients after treatment with an adsorptive copolymer bead cartridge. Compared with a control group (no treatment) in which the
reduction in norepinephrine dose was non-significant. 40
1. Shum HP, et al. Hong Kong Med J. 2013; 19:491–497; 2. Cruz DN, et al. JAMA. 2009; 301:2445–2452; 3. Turani F, et al. Blood Purif. 2019; 47(Suppl. 3):54–58; 4. Hawchar F, et al. J Crit Care. 2019; 49:172–178.
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Conclusions &
Summary
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Conclusions
Sepsis is a major and growing healthcare challenge that affects millions of people around the world
each year and is associated with high hospital and ICU mortality rates
The dysregulated immune response to infection in sepsis can result in the excessive release of
pro- and anti-inflammatory cytokines into the blood, which may trigger a series of reactions leading
to cellular and tissue injury
Immune dysregulation in sepsis can result in damage to organs and tissues and can lead to multiple
organ dysfunction (including respiratory and renal failure)
The SSC guidelines include fluid resuscitation/ hemodynamic support, infection control, general
supportive care, and management of organ dysfunction
BP therapies are designed to help address the effects of an unbalanced immune system through the
removal of endotoxins and/or cytokines as adjunctive therapy options for sepsis management. Their
use may be associated with an improvement in certain patient-related outcomes.
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References
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• Angus DC, et al. N Engl J Med. 2013; 369:840–851. • Damas P, et al. Ann Surg. 1992; 215:356–362.
• Askim A, et al. Scand J Trauma Resusc Emerg Med. 2017; • Davydow DS, et al. Gen Hosp Psychiatry. 2008; 30:421–434.
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• Barre M, et al. J Crit Care. 2018; 43:21–28. • Engel C, et al. Intensive Care Med. 2007; 33:606–618.
• Blanco J, et al. Crit Care. 2008; 12:R158. • Finfer S, et al. Intensive Care Med. 2004; 30:589–596.
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• Bone RC, et al. Chest. 1992; 101:1644–1655. • Frencken JF, et al. Crit Care Med. 2017; 45:e493–e499.
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• Bozza FA, et al. Crit Care. 2007; 11:R49. • Gauer R, et al. Am Fam Physician. 2013; 88:44–53.
• Broman ME, et al. PLOS One. 2019; 14:e0220444. • Gogos CA, et al. J Infect Dis. 2000; 181:176–180.
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• Cavaillon JM. Toxicon. 2018; 149:45–53. • Gotts J, et al. BMJ. 2016; 353:i585.
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• Hotchkiss RS, et al. Lancet Inf Dis. 2013; 13:260–268. • NHS Conditions. Sepsis – Who can get it? 2019. Available at:
• Iankova I, et al. Crit Care Med. 2018; 46:691–698; https://www.nhs.uk/conditions/sepsis/who-can-get-it/ (accessed
April 2020)
• Iwashyna T, et al. JAMA. 2010; 304:1787–1794.
• NHS England. Improving outcomes for patients with sepsis. 2015.
• Jones A, et al. Crit Care Med. 2009; 37:1649–1654. Available at: https://www.england.nhs.uk/wp-
• Jones C & Griffiths RD. Minerva Anestesiol. 2013; 79:1306– content/uploads/2015/08/Sepsis-Action-Plan-23.12.15-v1.pdf
1312. (accessed July 2019).
• Jones T, et al. Ann Am Thorac Soc. 2015; 12:904–913. • NHS England. Second sepsis action plan. 2017. Available at:
https://www.england.nhs.uk/wp-
• Karlsson S, et al. Intensive Care Med. 2007; 33:435−443.
content/uploads/2017/09/second-sepsis-action-plan.pdf
• Kaukonen KM, et al. JAMA. 2014; 311:1308–1316. (accessed July 2019).
• Knaup H, et al. Crit Care. 2018; 22:205. • Norman B, et al. Crit Care Med. 2017; 45:1130–1137.
• Lambden S, et al. Crit Care. 2019; 23:374. • Opal SM, et al. J Infect Dis. 1999; 180:1584–1589.
• Lee J, et al. J Korean Med Sci. 2017; 32:528–533. • Ou SM, et al. Am J Respir Crit Care Med. 2016; 194:209–217.
• Levy M, et al. Crit Care Med. 2018; 44:925–928. • Padkin A, et al. Crit Care Med. 2003; 31:2332–2338.
• Marshall JC, et al. J Infect Dis. 2004; 190:527–534. • Pavon A, et al. Crit Care Med. 2013; 41:2600–2609.
• Martin GS, et al. N Engl J Med. 2003; 348:1546–1554. • Poston JT & Koyner JL. BMJ. 2019; 364:k4891.
• Mayr FB, et al. JAMA. 2010; 303:2495–2503. • Póvoa P, et al. Clin Microbiol Infect. 2005; 11:101–108.
• Monard C, et al. Blood Purif. 2019; 47(Suppl. 3):2–15. • Quenot JP, et al. Crit Care. 2013; 17:R65.
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• Reinhart K, et al. Clin Microbiol Rev. 2012; 25:609–634. • Sun A, et al. Crit Care Med. 2016; 44:478–487.
• Rhodes A, et al. Intensive Care Med. 2017; 43:304–377. • Terragni PP, et al. Anesthesiology. 2009; 111:826–835.
• Ronco C, et al. Artif Organs. 2003; 27:792–801. • van Gestel A, et al. Crit Care. 2004; 8:R153–R162.
• Ronco C. Blood Purif. 2019; 47(Suppl. 3):1. • van Vught LA, et al. JAMA. 2016; 315:1469–1479.
• Rudd KE, et al. Lancet. 2020; 395:200–211. • Vincent JL, et al. Crit Care Med. 2003; 31:834–840.
• Sakr Y, et al. Crit Care Med. 2017; 45:386–394. • Vincent JL, et al. Crit Care Med. 2006; 34:344–353.
• SepNet Critical Care Trials Group. Intensive Care Med. 2016; • Vincent JL, et al. Intensive Care Med. 1996; 22:707–710
42:1980–1989. • Vincent JL, et al. Intensive Care Med. 2018; 44:337–344.
• Sepsis Alliance. Sepsis and Kidney Failure. 2019. Available at: • Vincent JL, et al. JAMA. 2009; 302:2323–2329.
http://www.sepsis.org/sepsis-and/kidney-failure/ (accessed
May 2020). • Vincent JL, et al. Lancet Respir Med. 2014; 2:380–386.
• Singer A, et al. JAMA. 2016; 315:801–810. • Vincent JL. PLoS Med. 2016; 13:e1002022.
• Sjoding MW, et al. Crit Care Med. 2016; 44:1353–1360. • Wacker C, et al. Lancet Infect Dis. 2013; 13:426–435.
• Society of Critical Care Medicine (SCCM) and the European • Yaroustovsky M, et al. J Inflamm (Lond). 2013; 10:8.
Society of Intensive Care Medicine (ESICM). Surviving Sepsis • Yebenes JC, et al. Ann Intensive Care. 2017; 7:19.
Campaign. 2018. Available at:
• Zarbock A, et al. Curr Opin Crit Care. 2014; 20:588–595.
http://www.survivingsepsis.org/Pages/default.aspx (accessed
July 2019). • Zilberberg MD, et al. J Hosp Med. 2015; 10:678–685.
• Sproston NR & Ashworth JJ. Front. Immunol. 2018. 9:754.
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- J. Kellum presentation from San Diego CRRT

Conference 2021 (intensivist perspective)
- Serbian experience: One centre study (nephrology

perspective)
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COVID-AKI vs Sepsis-associated AKI

Mechanism Bacterial sepsis COVID-19 sepsis
Systemic inflammation +++ ++
DAMPs released from injured +++ +++

tissue
PAMPs e.g. endotoxin
released from +++ +
microorganisms
TMA/Coagulopathy + ++
Nephrotoxic drugs +++ +++
Direct viral infection of N/A ±

tubular epithelial cells
Cardiac dysfunction and/or + ++
reduced preload
Macrophage activation + +
syndrome
Kellum JA, Nadim M, Forni LG. Kidney Int 2020
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Stage-based management of COVID-19 AKI

High risk AKI stage 1 AKI stage 2 AKI stage 3
Standard of care to prevent and manage multiorgan failure

Individualize fluid management, avoid saline unless specific indication
Consider dynamic haemodynamic monitoring

Monitor serum creatinine and urine output
Correct hypoglycemia
Consider alternatives to radiocontrast if possible without delaying urgent

imaging
Avoid nephrotoxic agents when possible
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COVID-19 specific interventions

Antivirals (remdesivir, favipiravir)
Immunomodulatory agents (e.g. corticosteroids, hydroxychloroquine,

tocilizumab, sarilumab, anakinra, imatinib, dasatinib, immunoglobulins,
baricitinib, plasma exchange)
Systemic anticoagulation
Antiplatelets
Recombinant ACE2, Serine inhibitors, NSAIDs, Statin, RAAS inhibitors
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12/04/2022

Antivirals (remdesivir, favipiravir)
Remdesivir
• Predominantly (74%) renally eliminated.
• Potential accumulation of its sulfobutylether-β-cyclodextrin
(SBECD) carrier.
• Approved in patients with eGFR > 30 ml/min/1.73m2
Tocilizumab (anti IL6-Antibody) is not dialyzable
47

Consider AKI risk in selecting ventilator strategies
• Lung-protective mechanical ventilation strategies similar to

other forms of ARDS.
• Individualization of PEEP
• Prone positioning in respiratory failure does not impact the
risk of AKI.
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Consider altered pharmacokinetics
• Consider dose adjustment in patients with impaired kidney

function or during RRT.
• Special considerations for antibiotics and anticoagulants
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RRT DURING COVID 19 EPIDEMIC. EXPIRIENCE OF ONE

CENTER
Gordana Strazmester Majstorovic1,2, Violeta Knezevic1,2, Tijana Azasevac1,2,

Mira Markovic1, Vladimir Veselinov1, Igor Mitic1,2
1. Clinical center of Vojvodina, Clinic for nephrology and clinical immunology, Novi
Sad, Serbia and
2. University of Novi Sad, Medical faculty Novi Sad, Novi Sad, Serbia
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DURING COVID 19 EPIDEMIC. EXPIRIENCE OF ONE

CENTER
BACKGROUND AND AIMS: The incidence of Acute kidney injury AKI during Covid 19 infection is 3–
15%, up to 50% for patients (pts) with Acute respiratory distress syndrome ARDS.
METHOD: From March till December 2020. Department for haemodialysis in Novi Sad did 184
renal replacement therapy (RRT) procedures (proc) on 65 Covid19 positive pts.
CONCLUSION: Comparing group of pts who survived with group of those who died, greater
number of pts with ESRD was in the first group. In survivor group, RRT was started earlier with
greater number and shorter duration of proc. In the group of pts who died, there were more
ARDS and vasoactive support need. They had a higher levels of CRP, leukocyte count and the
neutrophil to lymphocyte ratio.
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RRT DURING COVID 19 EPIDEMIC.

EXPIRIENCE OF ONE
CENTER
Non-survival group:
Greater hemodinamic disturbances
99% of anuria
86% ARDS
Greater leucocytosis, CRP and PCT (inflammation markers)
Short dilaysis- RRT less of equal to 12 h
Number of sets use aprox. 2
Late aproach (Los 10 days)
All (100%) of AKI pts died
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Oxiris Membrane Technology
53
Introduction to Oxiris
Membrane Technology
Learning Objectives
By the end of this training, you will be able to:
 Articulate how the membrane structure can

influence the clearance of solutes
 Describe different clearance mechanisms
 List the different components of the unique Oxiris
membrane
 Demonstrate the heritage of the AN 69 membrane
and how it has evolved into the Oxiris membrane
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Membrane Technology
Membrane Structure
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Membrane Technology
Membrane Structure
CRRT synthetic membranes can consist of a wide range of chemical structures and co-polymers
PS AN69 PAES
Polysulfone Acrylonitrile sodium methallyl sulfonate copolymer PolyAryl Ether Sulfone
CH3
C O SO2 O CH2 CH CH2 C O
SO2
CH3
CN
CH2 SO3Na
Asymmetrical Symmetrical Asymmetrical

Microporous Dense 3 Layers
Popular CRRT membranes in use today are AN 69 and Polysulfone-based

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Membrane Technology
Membrane Structure
The membrane microstructure dictates its selective capabilities
AN 69
SELECTIVE PART
Size selection and adsorption of solutes occurs
throughout the WHOLE membrane
 Gelification determines the characteristics of the AN 69 membrane (the isotropic* dense microstructure).
* Equal physical properties in all directions of the material
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Membrane Technology
Clearance Mechanisms
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Membrane Technology
Conventional Clearance Mechanisms
Diffusion & convection are governed by non-

selective purification methods, solute concentration
for diffusion and solute size for convection.
These processes do not take into account solute-

membrane interactions, such as the adsorption
of substances to the membrane material.
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Introduction to Oxiris Membrane Technology

Click the icon to know more.
Impact of the Microstructure | Polysulfone vs. AN 69
Hydrogel membrane: AN 69
Porous membrane: e.g., PS
 Very hydrated structure – dilution and space
 Mircroporous structure with polymer chains between polymer chains. No porous network
building a network of pores  Interactions of ionic nature
 Adsorption is limited to the inner membrane  Toxin accessibility (adsorption) is considerably
surface and possibly to the pores surface increased
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Membrane Technology
PAES membrane vs. AN 69
The whole AN69 membrane is negatively

charged
Positively charged molecules will bind to the

negative charge in the membrane
Adsorption occurs on the inner membrane

surface and in the whole membrane thickness
(AN69)4
PAES AN69
membrane membrane
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Introduction to Oxiris Membrane Technology
Estimation of the whole surface area of pores in hollow fibre
Case of AN 69 (1.5m2)
• Ƞ = 0.69 x 10-2 λ= 4.5 x 10-3

• H= 0.69 LP# 9 x 10-10
Ratio S Adsorption / S membrane:

Sa/Sm= 1.1 x 104
Internal documentation based on calculations performed by Baxter R&D
This calculation results in an accessible theoretical membrane surface of 17,500 m2
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Membrane Technology
Oxiris Unique Membrane

Technology
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Membrane Technology
Oxiris Membrane Technology Overview
3-in-1 membrane technology
Pre-coating with heparin Surface treatment provides AN 69 core membrane

helps reduce membrane ability to adsorb endotoxins provides efficient renal
thrombogenicity support by diffusion &
convection, as well as
cytokine & toxin adsorption
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Membrane Technology
Debrief
Can you label the layers of the Oxiris

membrane?
Heparin
C
coating
*PEI surface
B
treatment
AN
A 69 base
membrane
*PEI: PolyEthyleneimine
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Membrane Technology
oXiris: Membrane Structure
oXiris | The only set for 3-in-1 CRRT-Sepsis management
Heparin coating reduces membrane thrombogenicity5
PEI* surface treatment adsorbs endotoxin**
AN 69 base membrane adsorbs cytokines and toxins

whilst providing continuous renal support. Cytokine
adsorption occurs throughout the entire membrane
thickness
*PEI: PolyEthyleneimine
**Endotoxin: lipopolysaccharide complex associated with outer membrane of Gram-negative bacteria
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Membrane Technology
Adsorption of Inflammatory Mediators
67
Malard B, et al. Intensive Care Medicine Experimental. 2018;6:12.
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Membrane Technology
Section B: oXiris Membrane
Adsorption of Inflammatory Mediators
Removal of cytokines by adsorption

with the oXiris set is similar to that
achieved with CytoSorb1
Malard B, et al. Intensive Care Medicine Experimental. 2018;6:12.
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Membrane Technology
oXiris | PEI surface treatment
PE surface treatment adsorbs endotoxin

I
Adsorbed on PEI: the molecules that are negatively

charged like Lipopolysaccharide (LPS) and heparin
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69
Membrane Technology
Endotoxin (LPS) removal capabilities in vitro
Adapted from Malard B, et al. Intensive Care Medicine Experimental. 2018;6:12.
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Membrane Technology
Endotoxin (LPS) removal capabilities in vitro
oXiris can remove both

cytokines AND endotoxins and
is designed to perform more
than one function
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In vitro comparison of the adsorption of inflammatory

mediators by blood purification devices
Malard B., Lambert C., Kellum J. A.
Study Blue Print
June 2018
GLBL/MG146/18-0011
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Open Access Publication:

https://rd.springer.com/article/10.1186/s40635-018-0177-2
This is the first study to compare the solute removal capacity of three blood purification
devices across a large spectrum of inflammatory mediators.
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Agenda
1. Study Overview
2. Comparison oXiris, CytoSorb, Toraymyixin
3. Methods short and long term experiment
4. Results endotoxin removal (short term)
5. Results endotoxin removal (long term)
6. Results cytokine removal (long term)
7. Adsorption of other inflammatory mediators
8. Conclusion
9. Appendix: FAQ, in vitro model, etc.
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1. Study Overview
Rationale:
 Septic shock, a leading cause of acute kidney injury,
induces the release of pro-/anti-inflammatory
mediators in response to infection. This may be
associated with increased mortality and poor renal
recovery
Objective:
 Compare 3 single-use blood purification devices in
terms of their removal of a large panel of sepsis-
associated inflammatory mediators from blood
Toraymyxin CytoSorb oXiris
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2. Comparison Toraymyxin, CytoSorb, oXiris: Membrane Structure,

Indication & Target
Membrane Structure: Membrane Structure: Membrane Structure:

Polystyrene woven fibers coated with Cartridge filled with adsorptive 3-layer structure: AN 69 base
PMX-B (antibiotic) microspheres membrane, PEI surface treatment,
Heparin coating
Indication:
Indication: Indication: • For patients in need of blood
Sepsis/Septic shock cause by gram- Conditions where excessive cytokine purification, including continuous renal
negative infection level exists replacement therapy
• And in conditions where excessive
endotoxin and inflammatory mediator
levels exist
Target:
Target: endotoxin by Target: cytokines by • endotoxin adsorption
adsorption1 adsorption2 • cytokine adsorption
• fluid and uremic toxin
removal
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3. Methods
In vitro study: experimental HP was performed using oXiris, CytoSorb and Toraymyxin
• Heparinized fresh frozen human plasma was pre-incubated with pathologic quantities of
inflammatory mediators (endotoxin (LPS), pro-inflammatory cytokines, anti-inflammatory cytokines,
and other inflammatory mediators)
• Pool was divided into 4 x 500ml and filtered in a closed-loop circulation model
Part 1: short term experimental set up: all inflammatory mediators

• Measured and compared removal capabilities of 27 different inflammatory mediators for each
device over 2h.
• Samples were taken at times (t): t0, t5, t30, t60, t120
Part 2: long term experimental set up (same closed-circuit loop): endotoxin

• Hemoperfusion* procedure was performed on oXiris, Toraymyxin, and a control tubing over 6h
(3 x 2h) to document the removal of endotoxin over time
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In vitro model
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4. Short Term Results Over 2h: Endotoxin Removal I
• Adsorption of
endotoxin (LPS*) was
observed with oXiris
and Toraymyxin, but
not with CytoSorb
* lipopolysaccharide
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4. Short Term Results Over 2h: Endotoxin Removal II
• The rate of endotoxin removal was most rapid with Toraymyxin: Mean absorptive clearance over the
first 30 minutes was ~20 ml/min versus ~8 ml/min with oXiris (p < 0.05)
• However, LPS removal rates (RRs) at 120 min were not significantly different between oXiris and
Toraymyxin
• Removal of LPS by oXiris and Toraymyxin were significantly greater than with CytoSorb
Please note: the figure does not

show clearance (ml/min) but the
amount remaining in circulation
at various timepoints.
Key Takeaway:
oXiris showed similar
endotoxin adsorption
to Toraymyxin
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5. Long Term Results Over 6h: Endotoxin Removal
• High endotoxin (LPS) removal capacities were confirmed with oXiris and Toraymyxin over 6h
• The total quantity removed over 6h with oXiris was 6.9 μg vs 9.7 μg for Toraymyxin (total LPS
quantity: ca 15.8 μg)
Key Takeaway:
The amount of endotoxin
removed was not significantly
different between oXiris and
Toraymyxin
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6. Short Term Results over 2h: Adsorption of Pro- and Anti-Inflammatory

Cytokines I
• For both oXiris and CytoSorb, removal rates (RRs) were similar for 18 of the 20 cytokines studied
• The RRs of > 70% for oXiris and > 80% for CytoSorb were observed for most cytokines
• RRs were significantly lower with Toraymyxin compared to both oXiris and CytoSorb
• In general, adsorption kinetics were faster with CytoSorb than with oXiris
Please note: the figure does not

show clearance (ml/min) but the
amount remaining in circulation
at various timepoints.
Key Takeaway:
Levels of most
cytokines measured at
t120 min were not
significantly different
between CytoSorb and
oXiris
(Source: Appendix 3)
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6. Short Term results over 2h: Adsorption of Pro- and Anti-Inflammatory

Cytokines II
• For a number of cytokines, removal was above 90% with both of the oXiris and CytoSorb devices
Key takeaway: The removal of cytokines by adsorption with the oXiris set is similar to that
achieved with the CytoSorb device
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7. Adsorption of other Inflammatory Mediators
• Removal rates of complement factors, serine proteases, fibroblast growth factors and glycoproteins
were higher with CytoSorb and oXiris versus Toraymyxin
Key takeaway:
oXiris and CytoSorb
adsorption rates were
generally comparable
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8. Conclusion: Three of the most widely available sorbent devices have

very different spectrums of in vitro inflammatory mediator removal
Toraymyxin is efficient in removing endotoxin, it does not effectively remove
cytokines in comparison to oXiris and CytoSorb
CytoSorb removes cytokines and other inflammatory mediators, it does not remove
endotoxin
oXiris
• Removes similar amounts of endotoxin compared to Toraymyxin
• Removes similar amounts of most cytokines and other inflammatory
mediators compared to CytoSorb
• Was shown to have the broadest adsorption capacity of the devices tested
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Slide from oXiris Sales ppt
oXiris 3-in-1 | The only set for 3-in-1 CRRT-Sepsis Management
Summary of removal capabilities of investigated blood purification device per mediator*

Removal Rates (RR%) at 120 min
Mediators oXiris CytoSorb Toraymyxin
HMGB-1 89.5 (± 0.4) 91.8 (± 0.9) 61.5 (± 1.4)
IL-6 93.5 (± 1.4) 99.6 (± 0.4) 41.8 (± 14.6)
MCP-1 100 (± 0.0) 100 (± 0.0) 11.3 (± 4.4)
TNF-ɑ 90.1 (± 2.2) 98.4 (± 0.2) 17.9 (± 9.2)
Fluid Removal Yes No No
Adsorption of cytokines was similar for CytoSorb and oXiris but not for
Toraymyxin. In addition, oXiris is able to remove fluid and uremic toxins.
Means expressed ±SD
Adapted from: Malard B, et al. Intensive Care Medicine Experimental. 2018;6:12
Baxter, oXiris, and AN 69 are trademarks of Baxter International Inc. or its subsidiaries. 86
Other trademarks appearing herein are the property of their respective owners.
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oXiris | The only set for 3-in-1 CRRT-Sepsis Management
ENDOTOXIN
1 REMOVAL
The only filter that achieves
significant removal of both
endotoxin and cytokines while
also having the capacity to
3
FLUID & UREMIC deliver CRRT
TOXIN REMOVAL
CYTOKINE
2
REMOVAL
87
87
Membrane Technology
oXiris | Heparin co ating
Hearin coating helps reduce membrane

pmbogenicity
thro
Heparin at surface active for Inhibition of thrombin by

formation of thrombin – antithrombin (TAT) complex
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Membrane Technology
oXiris Membrane
Designed to help reduce membrane thrombogenicity by adsorbing ATIII and facilitating formation of
ATIII-thrombin complex
Adapted from: Baxter (Gambro Industries.) oXiris preclinical data and clinical evaluation. Data on file, 2007.
89
89
Membrane Technology
oXiris Membrane
Designed to help reduce membrane thrombogenicity by adsorbing ATIII and facilitating formation of
ATIII-thrombin complex
The oXiris membrane adsorbs the ATIII

and this helps reduce surface
thrombogenicity
Adapted from: Baxter (Gambro Industries.) oXiris preclinical data and clinical evaluation. Data on file, 2007.
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Membrane Technology Section C: AN 69ST compared to Oxiris
Debrief
Tick whether the statement applies to the AN 69ST and/or Oxiris membrane
AN 69ST Oxiris
AN 69 hollow fibre with high ionic adsorptive capacity in the bulk

Membrane 
thickness 
Surface treatment PEI15,16  
Surface treatment Heparin15 
Sterilization Ethylene oxide15,16  
Initial heparin grafting
~ 4500 IU/m2 (15)
during manufacturing 
Heparin solution (w/5000 IU per liter) to minimize residual
Priming recommendation adsorption capacities16,17  
High affinity and rapid removal of endotoxin. Fast removal of a

Endotoxin adsorption 
pathological concentration shown in vitro (> 50 EU/ml)15
91
91
Membrane Technology
AN 69ST and Oxiris Are Not the Same
AN 69ST Oxiris
Membrane AN 69 hollow fibre with high ionic adsorptive capacity in the bulk thickness
PEI: ~ 1.7 mg/m2 (18) PEI: ~ 17 mg/m2 (19)

Surface treatment
Heparin: none Heparin: 4500 ±1500 IU/m2 (17)
Sterilization Ethylene oxide16,17
Priming recommendation Heparin solution (w/5000 IU per liter) to minimize residual adsorption capacities16,17
Heparin adsorption during

< 500 IU/m2 (20) ~ 1500 IU/m2 (20)
priming
High affinity and rapid removal of endotoxin. Fast
Endotoxin adsorption Low affinity for endotoxin removal removal of a pathological concentration shown in vitro
(> 50 EU/ml)17
In contrast to the AN 69ST membrane, the Oxiris membrane has: - Heparin coating
- More PEI surface treatment
- High affinity and rapid removal of endotoxin
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Membrane Technology
Oxiris: The Only Set for 3-in-1

CRRT-Sepsis Management
Blood purification and beyond CRRT by targeting

cytokine and endotoxin removal
93
93
ZhangL, CoveM, NguyenBG, LumlertgulN, GaneshK, ChanA, BuiGTH, GuoC, LiJ,LiuS, PengM, FoongKW, ZhangJ,
WangM, GoldsteinJ, HarenskiK. ChinMedJ2021; 00:00–00.doi:10.1097/CM9.0000000000001671
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Adsorptive hemofiltration for sepsis management: expert

recommendations based on the Asia Pacific experience
• 14 critical care experts from APAC developed a list of consensus recommendations for Oxiris
use in sepsis using a standardized,three-step, modified Delphi-based process
Observations and conclusions:
• Both endotoxins and cytokines have been implicated in the development of
organ dysfunction ,including acute kidney injury
• AIMS: Removing circulating endotoxins and excess cytokines from the
circulation restores chemotactic gradients, localizing the immune response to
the principal site of infection and reestablishing a regulated immune response
• Therefore, using hemofilters with enhanced endotoxin and cytokine adsorptive
properties may bring about additional therapeutic benefits compared with
conventional continuous renal replacement therapy (CRRT) filters.
• Oxiris is the only CRRT filter capable of simultaneously adsorbing endotoxins
and inflammatory mediators while providing renal support
ZhangL,CoveM,NguyenBG,LumlertgulN,GaneshK,ChanA,BuiGTH,GuoC,LiJ,LiuS,PengM,FoongKW,ZhangJ,WangM,GoldsteinJ,HarenskiK.ChinMedJ2021;00:00–00.doi:10.1097/CM9.0000000000001671
95

ZhangL,CoveM,NguyenBG,LumlertgulN,GaneshK,ChanA,BuiGTH,GuoC,LiJ,LiuS,PengM,FoongKW,ZhangJ,WangM,GoldsteinJ,HarenskiK.ChinMedJ2021;00:00–
00.doi:10.1097/CM9.0000000000001671
How long and how to access results:

• The Oxiris filter should be changed at 12 to 24h if:
• {high cytokine levels persist},
• {high filter transmembrane pressures are observed}, or
• {imminent circuit clotting is anticipated}.
• However, filter change may be extended up to 72h if:
• {the patient’s overall condition and biomarkers continue to improve}.
• Treatment success should be evaluated based on a combination of clinical
observations and improvements in laboratory markers within the first 24h of
Oxiris initiation:
• {improvements in hemodynamic stability},
• {organ function},
• {immune response}, as well as evidence of
• {microbial clearance} and
• {stabilization of metabolic function},
• indicate treatment success and can direct discontinuation of Oxiris.
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ZhangL,CoveM,NguyenBG,LumlertgulN,GaneshK,ChanA,BuiGTH,GuoC,LiJ,LiuS,PengM,FoongKW,ZhangJ,WangM,GoldsteinJ,HarenskiK.ChinMedJ2021;00:00–
00.doi:10.1097/CM9.0000000000001671
How long and how to access results:

• In terms of measuring treatment success,the relative improvement in each of
these parameters is more important than specifically defined values or cut-
offs.
Caution and contraindications: CRRT TH Parameters:
• CAUTION: • Regional citrate or systemic heparin should
• compromised/exhausted vascular access be used as an anticoagulant for CRRT with
points, Oxiris
• patients with disseminated intravascular • Effluent dose of 20 to 35mL/kg/h/ with a
coagulation or low platelet counts, blood flow rate of 150 to 200 mL/min,
• pediatric patients with body weight<30kg, depending on the patient’s hemodynamic
• those receiving palliative care stability
• CONTRAINICATIONS:
• HIT (heparin-induced thrombocytopenia)
97
Patient population/syndromes: Primarily for patients in critical condition with both septic
shock and AKI requiring CRRT:
• CRRT with Oxiris may also be considered in patients
with sepsis or septic shock before KDIGO stage 2 AKI
criteria are met, based on clinical indicators that
include marked disturbances in hemodynamic stability,
microcirculatory function,and organ function
• Clinical judgment based on a combination of clinical
and laboratory parameters should ultimately drive the
decision of whether CRRT with Oxiris is necessary
Clinical criteria for initiation: Marked disturbances in:
• Hemodynamic stability (eg.fluid balance, MAP,
vasopressor dose);
• Micro circulatory function (eg.PCO2 gap); and/or
• Organ function (eg.high SOFA score)
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Laboratory criteria for initiation: Indicators of:

• Infection severity (eg.elevated levels of PCT, IL-6);
• Sepsis severity (eg.lactate levels);
• Kidney function (eg.urine output); and/or
• Metabolic function (eg,life threatening electrolyte
imbalances)
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Immunito
modulation
during CRRT
In CRRT procedures Lecturer: Dr Vladimir Novkovic, DOO MEDICON DEČ
Studies overviewed
• 30 studies
• Key words: Oxiris, Cytosorb, Torray,
Immunomodulation, Sepsis,AKI
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Sepsis, septic shock, causes, AKI included

• (Sepsis-3 criteria, 2016) Sepsis is defined: as a life-threatening organ dysfunction associated with
a dysregulated host response to an infection*
• Organ dysfunction: clinical deterioration reflected by an increase of >2 points in the Sequential
Organ Failure Assessment (SOFA) score in response to infection*
• Mortality: hospital mortality rate of 15–30% and a one-year mortality of 35% in patients with
sepsis**
• (Sepsis-3 criteria, 2016) Septic shock:
• persistent hypotension necessitating vasopressor medication to maintain a target mean arterial
pressure of >65 mmHg and a serum lactate level of >2 mmol/l in spite of volume
resuscitation*
• Mortality: ICU, hospital, and one-year mortality rates ranging between 37–47%, 39–56%, and
60%, respectively**
• Sepsis causes: most commonly Gram-positive bacteria followed by Gram-negative
• bacteria and fungi***
• AKI included in 40% sepsis patients, and to 64% septic shock patients, with mortality high to
70%****
*Singer, M.; Deutschman, C.S.; Seymour, C.C.; Shankar-Hari, M.; Annane, D.; Bauer, M.; Bellomo, R.; Bernard, G.R.; Chiche, J.-D.; Coopersmith, C.C.M.; et al. The third international
consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016, 315, 801–810. [CrossRef] [PubMed]
**Shankar-Hari, M.; Harrison, D.; Rubenfeld, G.; Rowan, K. Epidemiology of sepsis and septic shock in critical care units: Comparison between sepsis-2 and sepsis-3 populations
using a national critical care database. Br. J. Anaesth. 2017, 119, 626–636. [CrossRef] [PubMed]
***Vincent, J.-L.; Sakr, Y.; Sprung, C.L.; Ranieri, V.M.; Reinhart, K.; Gerlach, H.; Moreno, R.; Carlet, J.; Le Gall, J.-R.; Payen, D. Sepsis in European intensive care units: Results of the
SOAP study. Crit. Care Med. 2006, 34, 344–353. [CrossRef]
**** Bagshaw,S.M.;George,C.;Bellomo,R.Earlyacutekidneyinjuryandsepsis:Amulticentreevaluation.Crit.Care2008,12,R47.[CrossRef]
Consequences of citokine storm

• Early simptoms: fever, fatigue, myalgia, arthralgia, headache, rash, diarrhea, anorexia, and
neuropsychiatric disorders.
• Later effects:hypoxemia, dyspnea, hypotension, vasodilatory shock, disseminated intravascular

coagulation with vascular thromboses, and/or catastrophic hemorrhages, renal failure, acute
liver injury*
• Laboratory findings:
• increased levels of CRP, procalcitonin, leukocytosis or leukopenia, thrombocytopenia,
anemia, as well as elevated ferritin and D-dimer levels**
• The concentrations of interferon-gamma , IL-6, and IL-10 are typically raised during a
cytokine storm. However, precise measurement of circulating cytokine levels can be difficult
due to the short half-lives of these molecules*
*Fajgenbaum, D.C.; June, C.H. Cytokine storm. N. Engl. J. Med. 2020, 383, 2255–2273. [CrossRef]
**Lee, D.W.; Gardner, R.A.; Porter, D.L.; Louis, C.U.; Ahmed, N.; Jensen, M.C.; Grupp, S.A.; Mackall, C.L. Current
concepts in the diagnosis and management of cytokine release syndrome. Blood 2014, 124, 188–195. [CrossRef]
[PubMed]
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How to predict
outcomes
• 2nd version of the Acute
Physiologic Assessment
and Chronic Health
Evaluation II (APACHE II)
score introduced in 1985.
• It generates a point score
ranging from 0 to 71
based on 12 physiologic
variables, age, and
underlying health
Citokine release
syndrome
clinical findings
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CRS differential diagnosis
Current
immuno-
modulatory
technics
Hellman,T.;Uusalo,P.;Järvisalo,M.J.RenalRepl
acement
TechniquesinSepticShock.Int.J.Mol.Sci.2021,
22,10238.https://
doi.org/10.3390/ijms221910238
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12/04/2022
RRT in sepsis
• Septic dose: 35ml/kg/h vs 70ml/kg/h*

• HVHF, as applied in this trial, cannot be recommended
for treatment of septic shock complicated by AKI*
• There is no convincing evidence that increasing the
effective dose of dialysis to over 25mL/kg/ in CRRT
confers any benefit in terms of mortality, duration of
hospitalization,or renal recovery**
*Joannes-Boyau O, Honoré PM, Perez P, Bagshaw SM, Grand H, Canivet JL, Dewitte A, Flamens C, Pujol W, Grandoulier AS, Fleureau C,
Jacobs R, Broux C, Floch H, Branchard O, Franck S, Rozé H, Collin V, Boer W, Calderon J, Gauche B, Spapen HD, Janvier G, Ouattara A. High-
volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized
controlled trial. Intensive Care Med. 2013 Sep;39(9):1535-46. doi: 10.1007/s00134-013-2967-z. Epub 2013 Jun 6. PMID: 23740278.
**Hellman,T.;Uusalo,P.;Järvisalo,M.J.RenalReplacement TechniquesinSepticShock.Int.J.Mol.Sci.2021,22,10238.https://
doi.org/10.3390/ijms221910238
HCO membranes vs standard

membranes
• In an Australian single-center randomized double-blind study comparing HCO and
standard CVVHF in 76 (36 vs. 36) patients with vasopressor dependent AKI, no
differences between the groups were observed in terms of the duration of
vasopressor requirement or hospital and ICU mortality*
• In an analysis of cytokine clearance in the same study cohort, the sieving coefficient
values and clearances were higher for IL-6 and IL-8 with an HCO membrane, as was
combined cytokine mass removal. However, there were no significant differences in
the reduction of cytokine plasma levels between the HCO and standard groups**
• Endogenous cytokine metabolism may be a more important determinant of plasma
levels than the CRRT-associated clearance***
*Atan, R.; Peck, L.; Prowle, J.; Licari, E.; Eastwood, G.M.; Storr, M.; Goehl, H.; Bellomo, R. A double-blind randomized controlled trial of high cutoff versus standard hemofiltration
in critically ill patients with acute kidney injury. Crit. Care Med. 2018, 46, e988–e994. [CrossRef]
**Atari, R.; Peck, L.; Visvanathan, K.; Skinner, N.; Eastwood, G.; Bellomo, R.; Storr, M.; Goehl, H. High Cut-off hemofiltration versus standard hemofiltration: Effect on plasma
cytokines. Int. J. Artif. Organs 2016, 39, 479–486. [CrossRef]
***Lumlertgul, N.; Hall, A.; Camporota, L.; Crichton, S.; Ostermann, M. Clearance of inflammatory cytokines in patients with septic acute kidney injury during renal replacement
therapy using the EMiC2 filter (Clic-AKI study). Crit. Care 2021, 25, 1–11. [CrossRef] [PubMed]
10
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Medium cut-off membranes for sepsis

• FMC EMic2 and AV-1000 in a randomized cross-over setting. They showed that
plasma levels of neither the proinflammatory cytokines TNF-alpha, IL-1alpha, IL-
1beta, IL2, IL-6, and IL-8, nor the anti-inflammatory cytokines IL-4 or IL-10, were
lowered during 24 h of CRRT, irrespective of which hemofilter was employed*
• Baxter developed oXiris® haemofilter (Baxter, Deerfield, IL, USA) is a medium
cut-off (35–40 kDa) polyacrylonitrile methalylsulfonate (AN69)-based membrane,
coated with positively charged polyethyleneimine (PEI) and pre-grafted with 4500
IU of heparin per m2. The positively charged PEI coating enables the adsorption
of negatively charged endotoxins in addition to the cytokine adsorption and
clearance in addition to renal replacement properties attributable to the AN69
hemofilter membrane
*Balgobin, S.; Morena, M.; Brunot, V.; Besnard, N.; Daubin, D.; Platon, L.; Larcher, R.; Amigues, L.; Landreau, L.; Bargnoux, A.-S.; et al. Continuous veno-venous high cut-off
hemodialysis compared to continuous veno-venous hemodiafiltration in intensive care unit acute kidney injury patients. Blood Purif. 2018, 46, 248–256. [CrossRef]
[PubMed]
11
Oxiris membrane
• Adsorption as need: the large scale of pro- and anti-inflammatory mediators’
molecular weights, ranging from 0.5 to 60 kDa
• Also very effectively adsorb (in vitro) high-mobility group box 1 protein (HMGB-
1) as shown by recent studies in Japan*
• HMGB 1 protein is a very upstream mediator stimulated by endotoxin and liberated by
macrophages. It can then activate the production of a bunch of cytokines
• AN69 membrane adsorbs not only antibiotics such as aminoglycosides,
vancomycin, and several others but also lactate*
*Yumoto M, Nishida O, Moriyama K, et al: In vitro evaluation of high mobility group box 1 protein removal with various membranes for
continuous hemofiltration. Ther Apher Dial 15: 385– 393, 2011.
12
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Open Access Publication:

https://rd.springer.com/article/10.1186/s40635-018-0177-
2
This is the first study to compare the solute removal capacity of three
blood purification devices across a large spectrum of inflammatory
mediators.
Baxter Confidential – For Internal Use Only |
13
Agenda
1. Study Overview
2. Comparison oXiris, CytoSorb, Toraymyixin
3. Methods short and long term experiment
4. Results endotoxin removal (short term)
5. Results endotoxin removal (long term)
6. Results cytokine removal (long term)
7. Adsorption of other inflammatory mediators
8. Conclusion
9. Appendix: FAQ, in vitro model, etc.
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1. Study Overview
Rationale:
 Septic shock, a leading cause of acute kidney injury,
induces the release of pro-/anti-inflammatory
mediators in response to infection. This may be
associated with increased mortality and poor renal
recovery
Objective:
 Compare 3 single-use blood purification devices in
terms of their removal of a large panel of sepsis-
associated inflammatory mediators from blood
Toraymy CytoSor oXiris

xin b
15
2. Comparison Toraymyxin, CytoSorb, oXiris: Membrane Structure,

Indication & Target
Membrane Structure: Membrane Structure: Membrane Structure:

Polystyrene woven fibers Cartridge filled with adsorptive 3-layer structure: AN 69 base
coated with PMX-B (antibiotic) microspheres membrane, PEI surface
treatment, Heparin coating
Indication:
Indication: Indication: • For patients in need of blood
Sepsis/Septic shock cause by Conditions where excessive purification, including
gram-negative infection cytokine level exists continuous renal replacement
therapy
• And in conditions where
excessive endotoxin and
inflammatory mediator levels
Target:
exist
• endotoxin
Target: endotoxin by Target: cytokines by
adsorption
adsorption1 adsorption2
• cytokine adsorption
• fluid and uremic
toxin removal
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3. Methods
In vitro study: experimental HP was performed using oXiris, CytoSorb and Toraymyxin
• Heparinized fresh frozen human plasma was pre-incubated with pathologic quantities of
inflammatory mediators (endotoxin (LPS), pro-inflammatory cytokines, anti-inflammatory cytokines,
and other inflammatory mediators)
• Pool was divided into 4 x 500ml and filtered in a closed-loop circulation model
Part 1: short term experimental set up: all inflammatory mediators

• Measured and compared removal capabilities of 27 different inflammatory mediators for each
device over 2h.
• Samples were taken at times (t): t0, t5, t30, t60, t120
Part 2: long term experimental set up (same closed-circuit loop): endotoxin

• Hemoperfusion* procedure was performed on oXiris, Toraymyxin, and a control tubing over 6h
(3 x 2h) to document the removal of endotoxin over time
*see
more information in FAQ section in Appendix
17
4. Short Term Results Over 2h: Endotoxin Removal I
• Adsorption of
endotoxin (LPS*) was
observed with oXiris
and Toraymyxin, but
not with CytoSorb
* lipopolysaccharide
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4. Short Term Results Over 2h: Endotoxin Removal II
• The rate of endotoxin removal was most rapid with Toraymyxin: Mean absorptive clearance over the
first 30 minutes was ~20 ml/min versus ~8 ml/min with oXiris (p < 0.05)
• However, LPS removal rates (RRs) at 120 min were not significantly different between oXiris and
Toraymyxin
• Removal of LPS by oXiris and Toraymyxin were significantly greater than with CytoSorb
Please note: the figure

does not show clearance
(ml/min) but the amount
remaining in circulation at
various timepoints.
Key Takeaway:
oXiris showed
similar endotoxin
adsorption to
Toraymyxin
19
5. Long Term Results Over 6h: Endotoxin Removal
• High endotoxin (LPS) removal capacities were confirmed with oXiris and Toraymyxin over 6h
• The total quantity removed over 6h with oXiris was 6.9 μg vs 9.7 μg for Toraymyxin (total LPS
quantity: ca 15.8 μg)
Key Takeaway:
The amount of endotoxin
removed was not
significantly different
between oXiris and
Toraymyxin
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6. Short Term Results over 2h: Adsorption of Pro- and Anti-Inflammatory

Cytokines I
• For both oXiris and CytoSorb, removal rates (RRs) were similar for 18 of the 20 cytokines studied
• The RRs of > 70% for oXiris and > 80% for CytoSorb were observed for most cytokines
• RRs were significantly lower with Toraymyxin compared to both oXiris and CytoSorb
• In general, adsorption kinetics were faster with CytoSorb than with oXiris Please note: the figure
does not show clearance
(ml/min) but the amount
remaining in circulation at
various timepoints.
Key Takeaway:
Levels of most
cytokines
measured at t120
min were not
significantly
different between
CytoSorb and
oXiris
(Source: Appendix 3)
21
6. Short Term results over 2h: Adsorption of Pro- and Anti-Inflammatory

Cytokines II
• For a number of cytokines, removal was above 90% with both of the oXiris and CytoSorb devices
Key takeaway: The removal of cytokines by adsorption with the oXiris set
is similar to that achieved with the CytoSorb device
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7. Adsorption of other Inflammatory Mediators
• Removal rates of complement factors, serine proteases, fibroblast growth factors and glycoproteins
were higher with CytoSorb and oXiris versus Toraymyxin
Key takeaway:
oXiris and
CytoSorb
adsorption rates
were generally
comparable
2
23
8. Conclusion: Three of the most widely available sorbent devices have

very different spectrums of in vitro inflammatory mediator removal
Toraymyxin is efficient in removing endotoxin, it does not effectively remove
cytokines in comparison to oXiris and CytoSorb
CytoSorb removes cytokines and other inflammatory mediators, it does not remove
endotoxin
oXiris
• Removes similar amounts of endotoxin compared to Toraymyxin
• Removes similar amounts of most cytokines and other inflammatory
mediators compared to CytoSorb
• Was shown to have the broadest adsorption capacity of the devices tested
24
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oXiris | The only set for 3-in-1 CRRT-Sepsis

Management
ENDOTOXI
1
N
REMOVAL The only filter that achieves
significant removal of both
endotoxin and cytokines while
also having the capacity to
3 FLUID & deliver CRRT
UREMIC
TOXIN
REMOVAL
2 CYTOKINE
REMOVAL
25
Cytosorb other factors

• Price initial and instruction for use:
• Day 1: Change device every 12 hours;
• Day 2: Change device at 24 hours;
• Day 3: Change device at 24 hours.*
• Volume: 150/300 ml (Cytosorb) +189ml (ST set)*
• Contraindications: very low platelet counts (< 20,000/μL)
• Removes bilirubin, and myoglobin.**
*Instruction for use, safety information

**Chen G, Zhou Y, Ma J, Xia P, Qin Y, Li X. Is there a role for blood purification therapies targeting cytokine storm syndrome in critically severe COVID-19 patients? Ren Fail. 2020 Nov;42(1):483-488. doi:
10.1080/0886022X.2020.1764369. PMID: 32438839; PMCID: PMC7946020.
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Oxiris vs standard hemofilter

• Broman et al. compared the endotoxin and cytokine reducing properties of Oxiris and a standard
medium cut-off hemofilter (M150ST, Baxter, USA) for CRRT in a randomized cross-over double-blind
study including 16 patients with septic shock. They reported that {endotoxin levels} decreased with
Oxiris, whereas they remained stable with the standard hemofilter. Levels of {TNF-alpha}, {IL-6},
{IL-8}, and {interferon y}, decreased more with the Oxiris filter*
• Shum and coworkers examined the development of SOFA scores during CVVHF with the
Oxiris filter compared to a matched historical cohort treated with standard CVVHF. They
reported a reduction of 37% in {SOFA} scores at 48 h post-initiation of Oxiris–CVVHF
versus an increment of 3% in the historical controls but no differences were observed in
mortality between the two cohorts**
• In a retrospective cohort of 60 patients with sepsis or septic shock and CVVHD using the
Oxiris membrane, there were improvements in {hemodynamics} and {vasoactive}
requirements and SOFA scores became reduced during the first 48 h of CVVHD. At the
same time, reductions were observed in the levels of IL-6, {IL-10}, {procalcitonin}, and
endotoxin activity.***
*Broman, M.E.; Hansson, F.; Vincent, J.-L.; Bodelsson, M. Endotoxin and cytokine reducing properties of the oXiris membrane inpatients with septic shock: A randomized crossover double-blind study. PLoS ONE 2019,
14, e0220444. [CrossRef] [PubMed]
**Shum, H.; Chan, K.; Kwan, M.; Yan, W. Application of endotoxin and cytokine adsorption haemofilter in septic acute kidney injury due to gram-negative bacterial infection. Hong Kong Med. J. 2013, 19, 491–497.
[CrossRef]
***Turani, F.; Barchetta, R.; Falco, M.; Busatti, S.; Weltert, L. Continuous renal replacement therapy with the adsorbing filter oXiris inseptic patients: A case series. Blood Purif. 2019, 47, 54–58. [CrossRef] [PubMed]
27
Oxiris vs standard hemofilter

• The {lactic acid}, {PCT}, {urine volume} and sofa scores in observation group after
treatment were notably lower than those in control group (P<0.05)*
• The lactic acid, procalcitonin (PCT), urine volume and systemic infection related organ failure assessment
(sofa) scores were recorded before and 3 days after treatment.
• The changes of serum inflammatory factors interleukin-6 (IL-6), interleukin-10 (IL-10) and endotoxin degree
prior-treatment and 3 d after treatment were compared between the two groups of patients
• The {ICU stay}, {organ support duration}, and {incidence of cardiovascular events} in
the observation group were notably lower than those in the control group (P<0.05)*
*Zhai Y, Pan J, Zhang C. The application value of oXiris-endotoxin adsorption in sepsis. Am J Transl Res. 2021 Apr 15;13(4):3839-3844. PMID: 34017574; PMCID: PMC8129347.
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Oxiris vs HA380 (Jafron Biomedical Co.,

Ltd., Zhuhai, China)
• HA380 contains hemocompatible, porous polymeric beads that adsorb
cytokines and mid-molecular-weight toxins onto the surface of the beads*
• clinical trial examining the use of the HA380 hemoadsorption in tandem
with CVVHDF using the Oxiris membrane compared to mere Oxiris CVVHDF
(ClinicalTrials.gov identifier: NCT04997421) still PENDING
*Montin, D.P.; Ankawi, G.; Lorenzin, A.; Neri, M.; Caprara, C.; Ronco, C. Biocompatibility and cytotoxic evaluation of new sorbent cartridges for blood hemoperfusion. Blood
Purif. 2018, 46, 187–195. [CrossRef]
29
Plasmapheresis in sepsis
• Only one randomized controlled trial on the efficacy of PE in adult patients with sepsis or
septic shock has been performed by Busund et al., demonstrating a lower 28-day all-
cause mortality in the PE arm*
• case report on the use of a new technique, i.e., continuous PE in combination with
dialysis in the management of sepsis, was published; this may represent a new
approach for investigating the feasibility of PE in the treatment of sepsis**
• Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and
Septic Shock: 2016 does not recommend the use of PE in the management of sepsis
due to insufficient evidence***
*Busund, R.; Kuklin, V.; Utrobin, U.; Nedashkovsky, E. Plasmapheresis in severe sepsis and septic shock: A prospective, randomised, controlled trial. Intensive Care Med. 2002,
28, 1434–1439. [CrossRef]
**Satoh, K.; Okuyama, M.; Irie, Y.; Kitamura, T.; Nakae, H. Continuous plasma exchange with dialysis for severe sepsis: Case series of a novel blood purification method. Cureus
2021, 13, e12495. [CrossRef]
***Rhodes, A.A.; Evans, L.E.; Alhazzani,W.; Levy, M.M.; Antonelli, M.; Ferrer, R.; Kumar, A.; Sevransky, J.E.; Sprung, C.L.; Nunnally, M.E.; et al. Surviving sepsis campaign:
International guidelines for management of sepsis and septic shock: 2016. Crit. Care Med. 2017, 43, 304–377. [CrossRef] [PubMed]
30
15
12/04/2022
CPFA- Coupled plasma filtration and

adsorption
• plasma filter diverts the plasma of the patient through a hydrophobic styrenic polymer
resin adsorbent cartridge with a high affinity for inflammatory mediators (such as IL-1,
TNF-, IL-6, IL-8, C3a desArg, and IL-10) and endotoxins. Then, the filtered plasma is
returned to the patient through a dialysis hemofilter for further solute and fluid
removal*
• In a pilot study conducted by Ronco et al. in 2002, CPFA was demonstrated to improve
hemodynamics, decrease vasopressor requirement and TNF- levels in a small sample of
patients with septic shock as compared to CVVHDF**
• meta-analysis on the effects of CPFA on patients with severe sepsis including 17 eligible
studies concluded that further evidence is required before one can draw definite
conclusions. However, fewer deaths were observed in patients who received CPFA
compared to other treatments***
*Tetta, C.; Cavaillon, J.M.; Schulze, M.; Ronco, C.; Ghezzi, P.M.; Camussi, G.; Serra, A.M.; Curti, F.; Lonnemann, G. Removal of cytokines and activated
complement components in an experimental model of continuous plasma filtration coupled with sorbent adsorption. Nephrol. Dial. Transplant. 1998, 13,
1458–1464. [CrossRef]
**Ronco, C.; Brendolan, A.; Lonnemann, G.; Bellomo, R.; Piccinni, P.; Digito, A.; Dan, M.; Irone, M.; La Greca, G.; Inguaggiato, P.; et al. A pilot study of coupled
plasma filtration with adsorption in septic shock. Crit. Care Med. 2002, 30, 1250–1255. [CrossRef]
***Hazzard, I.; Jones, S.; Quinn, T. Coupled plasma haemofiltration filtration in severe sepsis: Systematic review and meta-analysis. J. R. Army Med. Corps 2015,
161, i17–i22. [CrossRef]
31
Oxiris experience
in septic
patients,Rome*
• Aurelia Hospital and European
Hospital, Rome, Italy
• from April 2011 to December 2018
• 60 septic patients
• basal time (T0), at 24 h (T1), and
at the end of the treatment (T2)
• Analyzed: clinical data, the
cytokines, and the time course of
endotoxin.
*Turani F, Barchetta R, Falco M, Busatti S, Weltert L. Continuous Renal Replacement Therapy with the Adsorbing Filter oXiris in Septic Patients: A Case Series. Blood Purif. 2019;47 Suppl
3:1-5. doi: 10.1159/000499589. Epub 2019 Apr 12. PMID: 30982024.
32
16
12/04/2022
Oxiris experience
• During the treatment, there was an improvement of the MAP and a decrease
of the noradrenaline support. This was accompanied by an increase‚of the
oxygenation index.
in septic
• The treatment had an effect on the creatinine, on the urinary OFA
• The improvement of the cardiorenal function is associated with a decrease of
IL-6, IL-10, and procalcitonin, as shown in Table 4. Also endotoxin decreased,
patients,Rome*
when analyzed patients are with basal level of EAA > 0.6
*Turani F, Barchetta R, Falco M, Busatti S, Weltert L. Continuous Renal Replacement Therapy with the Adsorbing Filter oXiris in Septic Patients: A Case Series. Blood Purif. 2019;47 Suppl
3:1-5. doi: 10.1159/000499589. Epub 2019 Apr 12. PMID: 30982024.
33
Sepsis- RRT initiation time*

• 158 septic shock patients with AKI in the medical intensive care unit (ICU)
• From July 2016 to April 2018
• At the time of ICU discharge, the mortality rate was 50.6%
• It took longer to initiate CRRT in non-survivors than in survivors (hazard ratio
1.009; 95% confidence interval [CI] 1.003–1.014; P = 0.002).
• The cumulative mortality rate was significantly higher in patients in whom
CRRT was initiated beyond 16.5 hours after AKI onset than in those in whom
CCRT was initiated within 16.5 hours (log-rank test, P < 0.001).
*Yoon, B.R., Leem, A.Y., Park, M.S. et al. Optimal timing of initiating continuous renal replacement therapy in septic shock patients with acute kidney injury. Sci Rep 9, 11981
(2019). https://doi.org/10.1038/s41598-019-48418-4
34
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12/04/2022
Thank you
35
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12/04/2022

Clinical Introduction to AKI

People with CKD are especially susceptible to AKI, and

• Glomerular disease reduces

Baxter Basic Continuous Renal Replacement Therapy (CRRT) Principles

What are the four different clearance mechanisms

Basic Continuous Renal Replacement Therapy (CRRT) Principles

What are the four different clearance mechanisms

Basic Continuous Renal Replacement Therapy (CRRT) Principles

Can you remember the definition of CRRT?

Basic Continuous Renal Replacement Therapy (CRRT) Principles

CRRT Definition, Use, and Goals

CRRT can be defined as:

“Any extracorporeal blood purification therapy Intended to substitute for

Image created by Miroslav Indra is reflecting how a CRRT

Basic Continuous Renal Replacement Therapy (CRRT) Principles

HD Requires a Semipermeable Membrane

HD requires a semipermeable membrane. This type of

O Represents water molecules that are small enough to

Baxter Basic Continuous Renal Replacement Therapy (CRRT) Principles

Basic Continuous Renal Replacement Therapy (CRRT) Principles

Basic Continuous Renal Replacement Therapy (CRRT) Principles

Baxter Basic Continuous Renal Replacement Therapy (CRRT) Principles

Overview of CRRT Modalities

CRRT represents a spectrum

■ Slow continuous ultrafiltration (SCUF)

■ Continuous venovenous hemofiltration (CVVH)

^Available only with select filter membranes

Basic Continuous Renal Replacement Therapy (CRRT) Principles

Overview of CRRT Modalities1’18

SCUF CVVH CVVHD CVVHDF

Ultrafiltration YES YES YES YES

Convection NO YES NO YES

Diffusion NO NO YES YES

Adsorption* * YES** * YES**

(Dialysate) No NO YES YES

* Based on membrane choice and flow rate.

Basic Continuous Renal Replacement Therapy (CRRT) Principles

Small vs. Large Molecule Clearance

Figures adapted from Zhongping H, et al. Basic Principles of Solute

Basic Continuous Renal Replacement Therapy (CRRT) Principles

Movement of solutes across a semipermeable membrane

Tea particles in a tea bag. Ink particles in a glass of water.

Baxter Confidential - Do not distribute without prior consent 43

Basic Continuous Renal Replacement Therapy (CRRT) Principles

Movement of solutes across a semipermeable membrane

Basic Continuous Renal Replacement Therapy (CRRT) Principles

Adsorptive therapies are more effective for

removal of larger sized molecules, i.e., some

Convective therapies help remove middle sized

o Small size molecules removed by diffusion

Basic Continuous Renal Replacement Therapy (CRRT) Principles

The MW that can be removed is typically <50,000 Da and is

Animation taken from

1. Lee BS. Neonatal Med. 2013; 20:12-19;

Basic Continuous Renal Replacement Therapy (CRRT) Principles

Baxter Basic Continuous Renal Replacement Therapy (CRRT) Principles

How much CRRT do my patients need?

Baxter Confidential - Do not distribute without prior consent 22

Basic Continuous Renal Replacement Therapy (CRRT) Principles

Baxter Confidential - Do not distribute without prior consent 23

Baxter Basic Continuous Renal Replacement Therapy (CRRT) Principles

Dose = effluent flow rate: