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23/03/2018
1
RRT in the critically illJill Vanmassenhove
28-03-2015
Expensive
Care
“ I hate to tell you this, but that
should be INTENSIVE Care”
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
23/03/2018
2
When to
start?General1 Intoxications2 Specific clinical
conditions3
When to
start?General1 Intoxications2 Specific clinical
conditions3
Epidemiology
Wald/AJKD/2015
23/03/2018
3
When to
start?General1 Intoxications2 Specific clinical
conditions3
WHEN TO START= OBVIOUS?
“We’re al little concerned about your
potassium levels”
Factors influencing the decision to start RRT
Clinical symptoms
Solute level
BUN
sCr
Interval between ICU/hospital admission and RRT initiation
Days between biochemical diagnosis of AKI and RRT
Severity of AKI
AKIN/RIFLE classification
Prognostic scores
Number of organ failure
Availability of equipment and personnelMacedo/Seminars in Dialysis/2011
When to
start?General1 Intoxications2 Specific clinical
conditions3
Advantages and shortcomings of earlier RRT initiation in AKI
Advantages ShortcomingsMore effective reversal of volume expansion, particularly in diuretic-resistant patients
Better control of electrolyte and acid base status
Pro active clearance of toxic low andmiddle molecular weight solutes
Avoidance of AKI-related emergencies, (eg cardiac dysrhythmias related tohyperkalemia
Exposure to complications associated withsupplemental vascular access (both at time of insertion and therafter- infections, thrombosis, emboli,…)
Exposure to complications associated withRRT (e.g. intradialytic hypotension, dysrhythmias, clearance of antibiotics-hypokalemia, hypoglycemia…..)
Higher cost, especially if patient was destined to recover kidney function
Adapted from Wald, Bagshaw, Semin Nephrol 36:78-84, 2016
23/03/2018
4
When to
start?General1 Intoxications2 Specific clinical
conditions3
DO WE START TOO LATE?
…BUT HOW DO WE DEFINE
EARLY VS LATE?
When to
start?General1 Intoxications2 Specific clinical
conditions3
Karvellas/CC/2011
Early initiation of RRT may have a
beneficial effect on survival
ELAIN AND AKIKI TRIALS: COMPARISON OF “early” VERSUS
“delayed” RRT
ELAIN AKIKI
Gaudry/NEJM/2016Zarbock/JAMA/2016
23/03/2018
5
Differences in design and methods between ELAIN AND
AKIKI
Bagshaw/Nat Rev Nephrol/2016
Mendu/CJASN/2017
Hemodialysis Hemofiltration Hemoperfusion
Solubility water water Water or lipid
Molecular
weigth
<500 Da <40.000 Da < 40.000 Da
Protein
binding
Low (<80%) low Low or high
Volume of
distribution
<1L/kg <1L/kg <1L/kg
Endogenous
clearance
<4ml/min/kg <4ml/min/kg <4ml/min/kg
Distribution
time
short longer short
When to
start?General1 Intoxications2 Specific clinical
conditions3
23/03/2018
6
De Pont/Curr Opin Crit Care/2007
When to
start?General1 Intoxications2 Specific clinical
conditions3
Mégarbane/Open Access Emergency Medicine/2010
Fomepizole-
CH2OH
AldDH
ADH
HCHO
HCOO-
CO2 + H2O
Methanol
Formaldehyde
Formate
Folate
Metabolic
acidosis
Blindness
Coma
When to
start?General1 Intoxications2 Specific clinical
conditions3
Fomepizole dosing in adult patients
1.Patients not requiring hemodialysis
Initial dose: 15mg/kg IV followed by 4 doses of 10mg/kg every 12 hours
Maintenance dose: 15mg/kg IV every 12 hours thereafter until levels of methanol (or ethylene
glycol) are reduced below 20 mg/dl, and the patient is asymptomatic with normal pH
2. Patients requring hemodialysis
-Dose at the beginning of dialysis
<6 hours since last fomepizole dose: do not administer dose, ≥6 hours: administer next scheduled
dose, during dialysis: administer every 4 hours or as a continuous infusion 1 to 1.5 mg/kg/h
-Dose at the time hemodialysis is completed
<1h between last dose and the end of hemodialysis: do not administer dose at the end of
hemodialysis
1-3h between last dose and the end of hemodialysis: administer half of next scheduled dose
>3h between last dose and end of hemodialysis: administer next scheduled dose
Maintenance dose off hemodialysis: give next scheduled dose 12 hours from last dose
administered
When to
start?General1 Intoxications2 Specific clinical
conditions3
23/03/2018
7
Recommendations for hemodialysis in ethylene glycol and
methanol poisoning
Arterial pH<7.10
Drop in arterial pH >0.05 resulting in a pH outside the normal
range despite bicarbonate infusion
Inability to maintain arterial pH > 7.3 despite bicarbonate therapy
Decrease in bicarbonate concentration >5mmol/l, despite
bicarbonate therapy
Renal failure (sCr > 265 µmol/l or rise in the sCr by > 90 µmol/l)
Deteriorating vital signs despite intensive supportive care
Visual or neurological impairment in case of methanol poisoning
Initial plasma methanol concentration > 50 mg/dl
Rate of methanol decline < 10 mg/dl per 24 hours
When to
start?General1 Intoxications2 Specific clinical
conditions3
When to
start?General1 Intoxications2 Specific clinical
conditions3
When to
start?General1 Intoxications2 Specific clinical
conditions3
CRUSH Pathogenesis of ATN in
rhabdomyolysis
Toxic effect of urinary myoglobin
Hypotension (renal ischemia)
Myoglobin and urate crystal
formation at low urine pH
Protease release from injured
muscle
Lipid peroxidation
? Free radical formation
? Release of renal
vasoconstrictor substances
Warren/Muscle and Nerve/2002
23/03/2018
8
When to
start?General1 Intoxications2 Specific clinical
conditions3
Zeng/Cochrane database of systematic reviews/2014
When to
start?General1 Intoxications2 Specific clinical
conditions3
Dialysate circuit
Dialysate circuit
Blood circulation
Albumin circuit
diaFLUX Dialysor
diaMARS® AC250
Adsorber (charcoal)
diaMARS® IE250
Adsorber
(Ion exchanger)
MARS®FLUXDialysor
When to
start?General1 Intoxications2 Specific clinical
conditions3
Albumin
bound
Water soluble
Bilirubin Ammonia
Bile acids Aromatic
amino acids
Indoxylsulfate Creatinine
Middle chain
and short
chain fatty
acids
IL-6
Para cresol Tryptophan
Protoporphyrin GABA
23/03/2018
9
When to
start?General1 Intoxications2 Specific clinical
conditions3
When to
start?General1 Intoxications2 Specific clinical
conditions3
HELIOS
(Prometheus)
and RELIEF
(MARS) trials:
no difference in
outcome
When to
start?General1 Intoxications2 Specific clinical
conditions3
Glycogen
AminoacidsG6P
Pyruvate + H+
NADH + H+
Glucose
Protein
Urea
+
NAD+
Lactate + H+
+LDH
23/03/2018
10
When to
start?General1 Intoxications2 Specific clinical
conditions3
Salpeter/Cochrane database of systematic reviews/2010;Heaf/Clin Diab/2011
When to
start?General1 Intoxications2 Specific clinical
conditions3
De Vriese/JASN/1998
Cytokine Removal during CVVH in sepsis
Inflammatory
cytokines
Anti-
Inflammatory
cytokines
When to
start?General1 Intoxications2 Specific clinical
conditions3
Borthwick/Cochrane Database of Systematic Reviews/2013
High-volume haemofiltration for sepsis
23/03/2018
11
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
General
concepts1 Duration and time
interval2Techniques
23/03/2018
12
General
concepts1 Duration and time
interval2Techniques
General
concepts1 Duration and time
interval2Techniques
General
concepts1 Duration and time
interval2Techniques
23/03/2018
13
General
concepts1 Duration and time
interval2Techniques
General
concepts1 Duration and time
interval2
MW
SC
β2MG
12000
0,5
0,6
Ureum
60
vitB12
1230
1
High FluxLow flux
Techniques
General
concepts1 Duration and time
interval2Techniques
23/03/2018
14
General
concepts1 Duration and time
interval2
SCUF
Qb=100-250 ml/min
Quf=5-15 ml/min
Techniques
Costanzo/JACC/2007
Bart/NEJM/2012
23/03/2018
15
General
concepts1 Duration and time
interval2
CVVH
Qb=100-250 ml/min
Qf=15-60 ml/min
Techniques
Cerebral oedema in
acute (<48 h)
hyponatremia
Osmotic demyelinsation in
chronic (<48 h)
hyponatremia
Osmotic demyelinisation
23/03/2018
16
General
concepts1 Duration and time
interval2
CVVHD
Qb=50-250 ml/min
Qf=1-5 ml/min
Qd=15-30 ml/min
Techniques
General
concepts1 Duration and time
interval2
Qb=50-200
ml/min
Qf=10-30 ml/min
Qd=15-30 ml/min
CVVHDF
Techniques
General
concepts1 Duration and time
interval2Techniques
23/03/2018
17
General
concepts1 Duration and time
interval2Techniques
General
concepts1 Duration and time
interval2
Advantages Disadvantages
No need for anticoagulation Less efficient for treating acute
problems such as hyperK or flash
pulmonary edema
IP administration of drugs Not an option after abdominal and
mostly also not after cardiac surgery
Technically simpler Protein losses
No risk of vascular acces related
problems such as air embolism or
thrombus
Potential leakage
Less hemodynamic instability-
potentially better renal recovery
Not suitable for treating acute
intoxications
Can be an option for patients with
diuretic resistant heart failure
Not a good option for extremely
catabolic patients
Can allow for ascites removal in liver
cirrhosis patients
Can be problematic in case of
underlying respiratory failure
Techniques
Gabriel/KI/2008
23/03/2018
18
General
concepts1 Duration and time
interval2
CONTINUOUS=SUPERIOR?
Techniques
Wald/AJKD/2015
Epidemiology
General
concepts1 Duration and time
interval2
Rabindranath/Cochrane database of systematic reviews/2007
Techniques
23/03/2018
19
General
concepts1 Duration and time
interval2Techniques
General
concepts1 Duration and time
interval2
Schefold/CC/2013
Techniques
General
concepts1 Duration and time
interval2Techniques
23/03/2018
20
Wald/Crit Care Med/2014
Renal recovery in Continuous versus intermittent therapies
Liang/CJASN/2016
Renal recovery in Continuous versus intermittent therapies
General
concepts1 Duration and time
interval2
HYBRID techniques?
EDD
SLED
SLEDDf
IHD CRRT
Techniques
23/03/2018
21
Author Kumar
et al
Marshall
et al
Marshall
et al
Berbece
et al
Treatment name EDD SLED SLEDD-f SLED
Hours/day 7.5 12 8 8
Days/week 6-7 6-7 4-7 6
Qb (ml/min) 200 100 300 200
Qd (ml/min) 300 200 200 350
Replacement fluid
(ml/min)
- - 100 17
General
concepts1 Duration and time
interval2
Berbece/KI/2006
Techniques
EDD versus CRRT
Zhang/AJKD/2015
Ricci/2008/CCM
General
concepts1 Duration and time
interval2Techniques
A B
C D
Increase
frequency!
Increase
duration!
Increase
duration and
increase
clearance!
23/03/2018
22
General
concepts1 Duration and time
interval2
CRRT SLED p value
Morning sCr after
day 3 (µmol/l)
136±49 120±55 0.06
Time averaged sCr 136±49 95±49 0.03
Weekly Kt/V 7.1±2.1 8.4±1.8 <0.001
EKRj (ml/min) 31±10 31±7 NS
EKRjc (ml/min) 28±9 29±6 NS
Berbece/KI/2006
Techniques
Kumar/AJKD/2000
General
concepts1 Duration and time
interval2
COMPARISON OF MAP DURING EDD VS. CVVH.
0
10
20
30
40
50
60
70
80
90
100
preMAP midMAP endMAP
CVVH
EDDP=NS P=NS P=NS
Techniques
Kumar/AJKD/2000
General
concepts1 Duration and time
interval2Techniques
PERCENTAGE OF TREATMENT DAYS
REQUIRING INOTROPIC SUPPORT
0
10
20
30
40
50
60
70
80
90
100
1 Inotrope 2 Inotropes 3+ Inotropes
CVVH
EDD
% o
f tr
ea
tme
nt d
ays
23/03/2018
23
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
Clearance21 Dose in acute
RRT 3DialyzerEfficiency
and dose
23/03/2018
24
Clearance21 Dose in acute
RRT 3Dialyzer
Un
mo
dif
ied
ce
llu
los
e
Syn
theti
ca
lly
mo
dif
ied
ce
llu
los
eS
yn
the
tic
Efficiency
and dose
Clearance21 Dose in acute
RRT 3DialyzerEfficiency
and dose
23/03/2018
25
Clearance21 Dose in acute
RRT 3Dialyzer
Classification of clearance and dialysance
Dialyzer clearance
Instantaneous (cross-dialyzer) clearance
Integrated time-averaged clearance, kt/V
Single-pool clearance
Double-pool clearance
Patient clearance and eKt/V
Ionic (conductivity) dialysance
Continuous equivalance of clearance
Efficiency
and dose
Clearance21 Dose in acute
RRT 3Dialyzer
Bi B0
K= (Cbi – Cbo)/Cbi)xQb + (Cbo/Cbi)xQuf
Instantaneous clearance ≠ solute removal
Efficiency
and dose
23/03/2018
26
Clearance21 Dose in acute
RRT 3Dialyzer
Integrated time-averaged clearance=Kt/V
Efficiency
and dose
Clearance21 Dose in acute
RRT 3Dialyzer
V x C
V= total body water
KRC
KDC
G
d(VxC) = G- KxC
dt
SINGLE POOL Kt/V
Efficiency
and dose
URR=1-post SUN/pre SUN= 1-0/80=1
After 2h of diaysis:
Kxt=20L and Kt/V=0,5
URR=1-40/80=0,5
23/03/2018
27
Kt/V=-ln(1-URR)
Clearance21 Dose in acute
RRT 3Dialyzer
V x C
V= total body water
KRC
KDC
G
d(VxC) = G- KxC
dt
SINGLE POOL Kt/V
Efficiency
and dose
Kt/V=-ln(R-0.008.t)+(4-3,5R) (UF/W)
Clearance21 Dose in acute
RRT 3Dialyzer
V1
C1
KR
KD
G
d(C1V1) = G- C1(KD+KR) + KC(C2-C1)
dt
d(C2V2) = -KC(C2-C1)
dt
V2
C2
KC
QF
DOUBLE POOL Kt/V
Efficiency
and dose
23/03/2018
28
Clearance21 Dose in acute
RRT 3Dialyzer
CONTINOUS EQUIVALENT OF CLEARANCE-EKR
G
TAC
COMPARISON OF DIFFERENT MODALITIES
AND SCHEDULES
Efficiency
and dose
Casino/NDT/1996
Casino/NDT/1996
23/03/2018
29
Casino/NDT/1996
Clearance21 Dose in acute
RRT 3Dialyzer
Blood
Dialysate
Membrane
Diffusive force
D = QB x (CBi-CBo)
CBi-CDi
Dialysance (D) (ml/min)
Efficiency
and dose
Clearance21 Dose in acute
RRT 3Dialyzer
Ionic Dialysance (D) (ml/min)
Based on changes in the conductivity of the
dialysate after a step up or a step down in
dialysate sodium concentration
Dialysance of sodium is assumed to equal urea
clearance
Efficiency
and dose
23/03/2018
30
Clearance21 Dose in acute
RRT 3Dialyzer
Characteristics of ideal urea kinetic expression for RRT
dose in AKI
-Kinetic equivalence for irregular/frequent IHD or differing
RRT therapies
-Independent from the assumptions of urea steady state
-Normalization for patient urea distribution volume to allow
dose comparisons between patients of different size
-Easy to calculate without compromise in accuracy
-Possibility to include residual renal urea clearance if present
Efficiency
and dose
Himmelfarb/KI/2002
Clearance21 Dose in acute
RRT 3Dialyzer
Alternate dayhemodialysis (n=80)
Daily hemodialysis(n=80
p value
Mortality(N/%) 37(46) 22(28) 0.01
Resolution of acute renal failure (days)
16 ± 6 9 ± 2 0.001
Efficiency
and dose
23/03/2018
31
Ronco/Lancet/2005
Clearance21 Dose in acute
RRT 3Dialyzer
Group 3: 45 ml/kg/h
Group 2: 35 ml/kg/h
Group 1: 20 ml/kg/h
Efficiency
and dose
Palevsky/NEJM/2008
Clearance21 Dose in acute
RRT 3Dialyzer
CVVHDF 35ml/kg/h versus CVVHDF 20 ml/kg/h
SLED/IHD 6/week vs SLED/IHD 3/week
Efficiency
and dose
Bellomo/NEJM/2009
Clearance21 Dose in acute
RRT 3Dialyzer
CVVHDF 40ml/kg/h versus
CVVHDF 25 ml/kg/h
Efficiency
and dose
23/03/2018
32
Evanson/AJKD/1998
Clearance21 Dose in acute
RRT 3DialyzerEfficiency
and dose
Clearance21 Dose in acute
RRT 3DialyzerEfficiency
and dose
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
23/03/2018
33
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
General1 Citrate2 HIT3Anticoagulation
General1 Citrate2 HIT 3Anticoagulation
KDIGO AKI guidelines/KI/2012
23/03/2018
34
General1 Citrate2 HIT 3Anticoagulation
General1 Citrate2 HIT 3
KDIGO AKI guidelines/KI/2012
Anticoagulation
Liu/Critical Care/2016
23/03/2018
35
Liu/Critical Care/2016
General1 Citrate2 HIT 3Anticoagulation
General1 Citrate2 HIT 3Anticoagulation
23/03/2018
36
General1 Citrate2 HIT 3
“Risk for thrombosis in the days to weeks after stopping
heparin therapy is at least 20% and possibly as high as
50% in HIT patients who present with isolated
thrombocytopenia”Hirsch/Arch of Int Med/2004
Anticoagulation
23/03/2018
37
General1 Citrate2 HIT 3
O’shea/Seminars in dialysis/2003
Anticoagulation
General1 Citrate2 HIT 3
Fischer/Hemodilaysis Int/2007
Anticoagulation
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
23/03/2018
38
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
Patient related factors
Drug-protein complexes and
molecular weight
Volume of distribution
Device related factors
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
23/03/2018
39
Patient related factors
Drug-protein complexes and
molecular weight
Volume of distribution
Device related factors
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
Patient related factors
Drug-protein complexes and
molecular weight
Volume of distribution
Device related factors
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
Patient related factors
Drug-protein complexes and
molecular weight
Volume of distribution
Device related factors
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
23/03/2018
40
Patient related factors
Drug-protein complexes and
molecular weight
Volume of distribution
Device related factors
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
Matuszkiewicz-Rowinska/Pol Archiv Med Wewn/2012
AUC24/MIC
Cmax/MIC
%T>MIC
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
Killer characteristics?
Time-dependent killing
(e.g. Beta lactams)
Concentration-dependent
killing (e.g. Gentamycin)
%T>MIC Cmax>MIC
23/03/2018
41
1990s 2015
Low-permeability dialyzers High-permeability dialyzers
Dialysis dose not quantified Kt/Vurea target≥1,2
Dialyzer membranes less
compatible
Dialyzer membranes more
compatible
Smaller surface area dialyzers Larger surface area dialyzers
CAPD CCPD
Lower effluent volumes CRRT Higher effluent volumes CRRT
Mueller/Clin Pharmacol Ther/2009
INCREASE IN DRUG
CLEARANCE
1990s 2015
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
Böhler/KI/1999
Hemofiltration:
Postdilution mode
Hemofiltration:
Predilution mode Hemodialysis
Drug Clearance=
ultrafiltration rate
Drug Clearance=
UF rate x (blood flow/
Blood flow + SF flow rate)
Drug Clearance depends
on molecular weight
Pharmacokinetic principles during continuous treatments
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
Other factors to
consider
-Protein binding
-Blood Flow
-Larger membrane
surface area
-Different membrane
charge
-Thinner membrane
material
-Adsorption
Böhler/KI/1999
23/03/2018
42
Choi/2010/Blood Purification
Choi/2010/Blood Purification
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
23/03/2018
43
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
Complications Technical1 Clinical2
23/03/2018
44
Complications Technical1 Clinical2
Technical complications
of RRT in the ICU
Vascular access problems
Air embolism
Hemolysis
Electrolyte and Acid-Base
Disorders
Complications Technical1 Clinical2
Insertion site Complications of insertion Disadvantage
Internal jugular Punction carotid artery
Pneumothorax(PT),
Hemothorax(HT)
Rupture superior VC
Trendelenburg required
More prone to infectious
complications, especially in
patients with trachetomy
Femoral Punction femoral artery
Retroperitoneal hematoma
Infection
Highest infectious rate?
Highest recirculation rate
Only for bed-bound patients
Subclavian Punction subclavian artery
Risk of PT, HT
Rupture superior VC
Technically difficult
High rate of central venous
stenosis
Trendelenburg required
Complications Technical1 Clinical2
Hoste/JASN/2004
Bloodstream
infection
No Bloodstream
infection
p=0.53
23/03/2018
45
Complications Technical1 Clinical2
BMI<28: femoral
BMI>28: jugular
Complications Technical1 Clinical2
Complications Technical1 Clinical2
23/03/2018
46
Complications Technical1 Clinical2
Complications Technical1 Clinical2
Complications Technical1 Clinical2
Clinical complications of RRT
in the ICU
Bleeding and thrombosis
Hypoxemia
Hypotension
Biocompatibility
Hypersensitivity reactions
Dialysis Dyequilibrium Syndrome
Prolongation of renal recovery
Nutritional and metabolic
problems
Cardiac arrhythmias
Febrile reactions
23/03/2018
47
Complications Technical1 Clinical2
Clinical complications of RRT
in the ICU
RCA metabolic complications
Hypophosphataemia
Hypocalcemia
Hyper- or Hypomagnesemia
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
When to
start?Techniques Efficiency
and doseAnticoagulation Drug
dosingComplications Conclusion
• No strict criteria for RRT start but a too precocious start of RRT is not helpful and might cause further damage to an already injured kidney.
• No clear benefit for continous over intermittent therapies. SLED probably a good alternative
• Treshold dose is important but beyond that no additional benefit when increasing dose
• Acute PD can be considered, especially in case of heart failure and liver cirrhosis with ascites
• RRT is not a harmless technique
• Think about adapting drug dosage