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Acute Renal Failure in Intensive

Care Units
* High Mortality
* Mortality relates to severity of underlying condition
* Acute renal failure occurs as part of a complex of
multiple organ failure caused by infection, sepsis,
hypotension, hypovolemia and drug therapy
* Fluid overload causes pulmonary edema
* Increase in interstitial water with "leaky capillary"
leading to impaired tissue perfusion
* Acid-base and electrolyte abnormalities
* Disseminated intravascular coagulation
* Toxic metabolites and drug accumulation
* Frequently hemodynamic unstable
* Required positive pressure ventilation

Proposed Criteria for the Initiation of


Renal Replacement Therapy in Adult
Critically Ill Patients

1. Oliguria (urine output<200 ml/12 hr)

2. Anuria/extreme oliguria (urine output<50 ml/12 hr)

3. Hyperkalemia ([K+]>6.5 mmol/liter)


4. Severe academia (pH<7.1)
5. Azotemia ([urea]>30 mmol/liter)
6. Clinically significant organ (especially lung) edema
7. Uremic encephalopathy
8. Uremic pericarditis
9. Uremic neuropathy/myopathy
10. Severe dysnatremia ([Na]>160 or<115 mmol/liter)
11. Hyperthermia
12. Drug overdose with dialyzable toxin
( KI 1998, R. Belloma and C. Ronco)

Renal Replacement Therapy for


Acute Renal Failure in Intensive
Care Units
* Intermittent therapies: Intermittent
hemodialysis (IHD), extended daily
dialysis (EDD), slow low-efficiency
dialysis (SLED)
* Peritoneal dialysis (PD)
* Continuous renal replacement therapy
(CRRT): SCUF,
CAVH, CAVHD, CAVHDF,
CVVH, CVVHD, CVVHDF

Advantages of CRRT Compared with


IHD
1. CRRT maintains consistent homeostasis through slow,
gradual shifts in volume status and serum osmolality
2. CRRT avoids hypotensive or dysequilibrium episode
3. CRRT permits continuous control of fluid balance and
reduces the need to restrict fluid administration
4. CRRT requires a lower volume of blood to be
circulating outside the body
5. CRRT has less effect on complement or leukocytes
6. CRRT does not require expensive equipment or extensive
training of personnel
7. CRRT has greater clearance of mid-molecular weight
solute

Principles of CRRT

Diffusion: Movement of Diffusion


solute across a
semipermeable membrne
from high concentration
to low concentration
Convection: Water,
affected by hydrostatic
pressure is transferred Convection
across a membrane from
high pressure to low
pressure. Remove fluid
as well as solute

Adsorption: affinity
gradient

Convection vs. Diffusion

Operational Characteristics of CRRT


Continuous Hemofiltration
* Transport of solute is by convection based on a pressure gradient,
Capacity of a solute to press through membrane expressed by sieving
coefficient (S).
S = Cuf/Cp
S: Sieving coefficient
Cuf: solute concentration in ultrafiltration
Cp: Solute concentration in plasma
Molecular weight has a little impact on S as most membranes
used have molecular weight cut offs of 20000-50000 Da.
* Adsorption of solute to membrane and concentration repolarization
can influence sieving coefficient.
* Main determinant of S is extent of protein binding and for most
solutes equals the unbound fraction (a).
* Convective clearance of solute = Ultrafiltration rate
ClHF= Qf x S (a)

Operational Characteristics of
CRRT
Continuous Hemodialysis
* Solute removal based on diffusion driven by concentration
gradient
* Large molecules more restricted and diffusive clearance
decreases with increasing molecular weight
* In CRRT blood flow rates exceed dialysate flow rates thereby
resulting in
complete equilibration between blood and
dialysate
* Capacity of solute to diffuse through membrane and saturation
dialysate is expressed as Sd.
Sd = Cd/Cp
Sd: Dialysate saturation
Cd: Drug concentration in dialysate
Cp: Solute concentration in plasma
* Diffusive clearance = Dialysate flow x Sd
ClHD = Qd X Sd

Types of CRRT for Treating ARF


Physicochemical bases
clearance (cc/min)

CAVH
CVVH
CAVHD
14-16

Convection

Urea

7-10

Convection
Diffusion+small

15-17
Diff.:

amount of convection
Conv: 2-5
CVVHD
14-16

Diffusion+small

Diff.:

amount of convection
Conv: 2-5
CAVHDF
Diffusion+convection

Diff.: 18-20

Anticoagulation During CRRT


*
*
*
*

Efficacy of filter in fluid and solute removal


Overall filter longevity
Optimum patient treatment
Insufficiency: filtration performance deteriorates,
filter clot, blood loss
* Excessive: bleeding complication
* Modalities for anticoagulation
Saline solution
Regional
citrate
Heparin
Prostacyclin
LMW heparin
Nafomostate
mesilate
Regional heparin
No anticoagulant

Substitution or Dialysate
Solution
Lactate Ringer's solution

*
* 1.5% peritoneal dialysate solution
* Bicarbonate with dextrose
* Bicarbonate without dextrose
Bag A:
Bag B:
1 liter 0.9% NaCl
1 liter 0.45% NaCl
80 ml 7% NaHCO3
10 ml 5% CaCl2
4 ml 15% KCl
Bag A : Bag B run 1 : 1
Na 142 mEq/L
K
3.8 mEq/L
Cl
117 mEq/L

4ml 10% MgSO4


Ca 3.2 mEq/L
Mg 1.55 mEq/L
HCO3 31.7 mEq/L

Important Parameter for CRRT


Clinical data
* Skin turgor, humidity of slin folds, body weight
* Determination of total fluid loss:
Estimate of fluid loss in wound secretion and stool; fluid
loss by perspiration, insensiblities in relation to body
temperature, respiration
* Blood pressure, pulse rate, body temperature, respiratory rate
* CVP, Pulmonary capillary pressure
* Chest X-ray, EKG monitoring
Clinical chemistry
Na, K, Ca, Mg, P, Cl, blood gas, urea, creatinine, glucose,
total protein, albumin, GOT, GPT, Alk-P, cholesterol,
triglyceride, hemoglobin, hematocrit, leukocytes, platelets,
PT, APTT

Goals of Continuous Therapy


Electrolyte balance
Na, Cl, Ca, Mg, CO2, K

Fluid balance
Medication, TPN, Colloids

Azotemia control
BUN, Scr, PCR, Phosphorus

Cytokine maniputation
Factor maniputation

Applications for CRRT


Renal Application vs Non-renal
Application
Renal Application ( Renal replacement and Renal support)
* Acute renal failure ( specifically complicated ARF
with multiple organ failure and cardiovascular
failure)
* Oligouric ARF needs large amount of fluid or nutrition
* Acute renal failure with cerebral edema
* Acute renal failure with hypercatabolism
* An alternative to HD in the mass casualty situation
* Electrolytes and acid base disturbance

Applications for CRRT


Renal Application vs Non-renal
Application
Non-renal Application
*
*
*
*
*
*
*
*
*
*

Hepatic failure complicated with hepatic coma


Congestive heart failure refractory to diuretics
Overhydration during & after cardiac surgery ( CPB )
Sepsis
Life-threatening hyperthermia
Lactic acidosis
Cytokine removal: Acute respiratory distress syndrome
Tumor lysis syndrome
Crush injury
Inborn errors of metabolism: maple syrup disease,
urea cycle disorder

Systemic Complications of Fluid Resuscitation


* GI tract
Fluid flux in stomach and intestine
Gut edema and loss of protein
Decreased motility, diarrhea
Tissue hypoxia
* Heart
Myocardial edema
Decreased cardiac function
* Pulmonary edema
* Skin
Edema
Poor wound healing
Decreased tissue O2
* Central nervous system
Cerebral edema
* Increased mortality

CRRT: Fluid Removal vs Fluid


Regulation
Fluid removal

Fluid

Regulation
Ultrafiltration rate
To meet anticipated needs
Greater than
(UFR)
anticipated needs
Fluid management
Adjust UFR
amount of
replacement fluid
Fluid balance
Zero or negative balance
negative,
or zero balance
Volume removed
Based on physician estimate
patient
characteristics
Application
Easy, similar to

Adjust

Positive,

Driven by

Requires

Effects of in vitro hemofiltration (HF)


on levels of inflammatory mediators
Authors
of

Membrane

Barrera et al, 1992 PAN


IL-1
Lonneman et al, 1993 PAN and PS
Nagaki et al, 1992
PAN and PS
Ronco et al, 1995
PS
8, PAF, no TNF
Brown et al, 1994
PAN
Goldfarb et al, 1994 PAN
van Bommel et al, 1995
PAN
IL-6

Adsorption

TNF, IL-1
TNF, IL-1
TNF

Convection

minimal for TNF &

minimal TNF
IL-1, IL-

TNF, IL-1
IL-1
TNF, IL-1,

Effects of in Vivo Hemofiltration


(HF) on Levels of Inflammatory
Mediators
Author

Membrane

Kellum et al. 1998


10

AN69

Hoffmanne et al, 1995


Andreasson et al, 1993
Riegel et al, 1995
C5a, IL-6
Journois et al, 1996
1,6,8,10
Gasche et al, 1996
van Bommel et al, 1995
minimal for TNF
Bellomo et al, 1993
Tonnessen et al, 1993
Millar et al, 1993
Bellomo et al, 1995
Heidemann et al, 1994

PA

Adsorption of

PA
PS and PAN
PAN

C3a, C5a, ILC3a, C5a


C3a,

C3a, TNF, IL-

PAN
PS and PAN
PAN
PS
PA
PAN
PS

Convection of
TNFa, IL6, IL

factor D
TNF

TNF, IL-1
IL-1, not ILIL-6
IL-6, IL-8
TxB2

Post Cardiac Surgery ARF

Intra-operative support and post-operative problems


a. Oxygenator membranes and cytokine generation
b. Blood tubing and extraction of plasticizers
(DEHP)
c. Prolonged by-pass time and hemodynamic
consequences
Application of aggressive ultrafiltration in the cardiac
support of children and outcome improvement
Dialysis variants added to extracorporeal cardiac
support system
a. VAD and support
b. ECMO and support
c. IABP and support

Advantage of CRRT for Nutritonal


Support
* Fluid restrictions are removed
* Electrolyte overload is avoided
* Hyperosmolar nutrition solutions are safe
* CRRT result in a cumulative Kt/V or small solute removal
rate equivalent or superior to conventional intermittent
4-hr HD
IHD daily X 4 hr: Kt/V weekly 7.5
IHD X three sessions /week: Kt/V weekly 3.2
CAVHD: Kt/V weekly 6.2
CVVHD: Kt/V weekly 8.0
( Leblanc M. et al. Semin Dial 1995)
* CRRT provide adequate clearance of nitrogenous compounds
with the avoidance of repeatedly high peak serum nitrogen
values
( Clark WR et al. J. Am. Soc. Nephrol. 1994)

Reasons for CRRT

Mehta et al. : Am J Nephrol 1999

Potential Complications with CRRT


Technical
Vascular access
malfunction
Circuit clotting
Circuit explosion
sepsis
Catheter and circuit kinking
reactions
Insufficient blood flow
Line-catheter disconnection
Fluid balance errors
blood
purification
Loss of efficiency

Clinical
Bleeding
Hematomas
Thrombosis
Infection and
Allergic
Hypothermia
Nutrient losses
Insufficient

Complications of CRRT recorded in a total


of 212 patients
Complication

No
%

Bleeding

18
8.4

Haematoma
3.7
Access Malfunction
0.4
Line disconnection
8.0
Frequent filter clotting
2.3
Treatment-induced hypotension
3.3
Cannulation site infection
0.9
Hypothermia
0.9

8
1
17
5
7
2
4

Recommendation for Initial


Dialysis Modality for ARF
Indication
Therapy
Uncomplicated ARF
Fluid removal

Clinical condition

Antibiotic nephrotoxicity
Cardiogenic shock
CP bypass
Complicated ARF in ICU

Uremia
IHD
Increased
intracranial pressure

Shock
Nutrition

Subarachnoid hemorrhage,
hepatorenal syndrome
Sepsis, ARDS
Burns

Preferred

IHD, PD
CRRT
CRRT,

CRRT
CRRT
CRRT

Key Players in CRRT Program


Administration
ICU physician
Nephrologist
ICU nurses
Hemodialysis nurses
Pharmacists
Nutritionists
Technicians/store keeper

CRRT and Outcomes in Critical


Illness

RRT vs. no RRT in the ICU


For

RRT:

Hyperkalemia kills
Pulmonary edema
kills
Experience before
RRT available
Visible effects of
uremia

Against

RRT

Costs money
No RCT it makes
any difference
Side effects

PD vs standard IHD
PD:

Standard

Hemodynamic
stability

Continuous therapy

IHD:

Better clearances
No glycemic swings
No abdominal leaks
No splinting of
diaphragm
Decreased risk of
infection

Biocompatible vs.
bioincompatible dialysis

Biocompatible:
Biologic rationale
Two RCTs showing
clinical advantage
Non issue if
convective CRRT
used

Bioincompatible:

Cheaper
Some negative RCTs
(power limitations)

Standard IHD vs. CRRT


Standard

IHD:

cheaper in some parts


of the world (USA)

CRRT:

better volume control


hemodynamic stability
better azotemic control
better nutrition
no cerebral edema
better renal recovery
same cost in Melbourne

Changes in [urea]: CRRT vs. IHD

urea
(mmol/L)

50
45
40
35
30
25
20
15
10
5
0

p<0.05

CRRT
IHD

Days
van Bommel et al. Am J Nephrol 1995

Changes in [creatinine]:
CRRT vs IHD
p<0.05

800
700
600

[creat]
(mcmol/L)

500

CRRT
IHD

400
300
200
100
0
0

Days

van Bommel Am J Nephrol 1995

Achieving fluid goals:


CRRT vs. IHD
30
25
20

p<0.05

15

% of patients

10

CRRT
IHD

5
0

Volume
control

Mehta e al. JASN 1996 (abstract)

Acid-base homeostasis: CRRT vs.


IHD
0.7
0.6

Change in pH
after 24 h of treatment

0.5
0.4

p<0.05

0.3

CRRT
IHD

0.2
0.1
0

pH

Bellomo et al. Blood Purif 1994

Metabolic acidosis during RRT

p<0.001
40
35
30
25
20
15
10

Days of Treatment

HCO-13

HCO-12

HCO-11

HCO-10

HCO-9

HCO-8

HCO-7

HCO-6

HCO-5

HCO-4

HCO-3

HCO-2

HCO-1

HCO-0

[HCO3-]
mmol/L

Normalization of serum potassium during RRT


8

p<0.001

7
6
5
4

Days of Treatment

K-13

K-12

K-11

K-10

K-9

K-8

K-7

K-6

K-5

K-4

K-3

K-2

K-1

K-0

[K+]
mmol/L

Normalization of serum sodium during RRT


160

p<0.001

155
150
145
140
135
130
125

Days of Treatment

Na-13

Na-12

Na-11

Na-10

Na-9

Na-8

Na-7

Na-6

Na-5

Na-4

Na-3

Na-2

115

Na-1

120

Na-0

[Na+]
mmol/L

Correction of hyperphosphatemia during RRT

p<0.001

5
4
3
2

Days of Treatment

P13

P12

P11

P10

P9

P8

P7

P6

P5

P4

P3

P2

P1

P0

[Phos.]
mmol/L

Cardiovascular Side Effects of CRRT and


IHD

Total %

VT/SVT/VF

CRRT
IHD
> 20% fall
in MAP

Events

10
9
8
7
6
5
4
3
2
1
0

p<0.05

Renal recovery: CRRT vs. IHD


% of
total patients

100
90
80
70
60
50
40
30
20
10
0

p<
0.01

CRRT
IHD

Recovery

San Diego Trial (unpublished)

Early vs. Late CRRT in Trauma


Late CRRT = BUN >60 mg/dl

Late
Early

10

20

30

% survival
Gettings et al. Intensive Care Med 1999

40

50

Approach to RRT in ICU


Start early
Use CRRT
Use convection
Good azotemic control (at least 2L/hr UF)
Change if new evidence becomes
available
Work hard to create better evidence

Outcomes of RRT in Victoria


(Australia)

Data from 90 day prospective study (Am J Respir


Crit Care Med, 2000)

RRT cases/year: 464


CRRT used: 444
Nephrologists consulted: 120
Predicted mortality: 59.6%; actual: 49.2%
Dialysis dependence: 9.4%

Severe ARF in ICU:The Other Option

Three series this decade:


Chertow: 70% mortality (IHD); (DD at discharge: 33%)
Douma: 76% mortality (IHD)
Brivet 64% mortality (mostly IHD)
Liano 79% mortality (mostly IHD)

Only two other series besides Victoria this decade


with mortality below 50% (Barton, 1993, Alarabi 1993)
both in closed units both with CRRT only! No
dialysis dependence below 30% for IHD series!

2003-4
Issues of dose become important
High volume hemofiltration
Multicentre work more common
ADQI defines research goals
New membranes being developed
New circuit modifications for sepsis

RCT of UF Dose in ARF


Pre-intervention values
350
300
250
200

BUN (mg/dl)
Creatinine (mcmol/L)

150
100
50
0

Group I Group II Group III


Ronco C, Bellomo R et al. Lancet 2000; 355: 26-30

RCT of UF dose
80

**

70

*p<0.05
**p<0.001

60
50

APACHE II
UF (l/day)

40
30

20
10
0

Group I

Group II

Group III
Ronco C, Bellomo R et al. Lancet 2000; 355: 2630

UF dose and outcome

p=0.0013
45ml/kg/hr
Survivors
Total

35ml/kg/hr
20 ml/kg/hr
0

50

100

150

CRRT and outcomes

We have limited evidence, however lots of


data in favour of CRRT, none against
No RCT is not = two therapies are equivalent.
Returning to the bad old days of standard
IHD is not feasible.
Based on all outcomes available so far in
2001, higher dose convective CRRT is the
standard of care in ICU until proven otherwise

Best Kidney:

Survey of ARF in
Asia,Australia,USA,Canada,Europe,South
America ( 29.269 pts)
ARF : 1758 pts.
1260 pts in 24 hours ( BUN > 80 mg/dl).
151 pts > 24 hours. 498 did not receive RRT.
Incidence of ARF : 6,3 % Asia, 6,4% Aus 5,5%
Europe, 5,4% S . America.
No diff in SAPS II score, striking difference in
timing , morbidity , mortality . LOS.