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 Urea clearance (cc/min)
CAVH Convection 7-10
CVVH Convection 15-17
CAVHD Diffusion+small Diff.: 14-16
amount of convection Conv: 2-5
CVVHD Diffusion+small Diff.: 14-16
amount of convection Conv: 2-5
CAVHDF Diffusion+convection Diff.: 18-20
Conv: 10
CVVHDF Diffusion+convection Diff.: 18-20
Conv: 10-13
SCUF Convection 2-5
 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 4ml 10% MgSO4
Bag A : Bag B run 1 : 1
Na 142 mEq/L Ca 3.2 mEq/L
K 3.8 mEq/L Mg 1.55 mEq/L
Cl 117 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 Adjust

amount of
replacement fluid
Fluid balance Zero or negative balance Positive,
negative,
or zero balance
Volume removed Based on physician estimate Driven by
patient
characteristics
Application Easy, similar to Requires
specific intermittent hemodialysis
 Effects of in vitro hemofiltration (HF) on
levels of inflammatory mediators
Authors Membrane Adsorption Convection
of

Barrera et al, 1992 PAN TNF, IL-1 minimal for TNF &
IL-1
Lonneman et al, 1993 PAN and PS TNF, IL-1
Nagaki et al, 1992 PAN and PS TNF minimal TNF
Ronco et al, 1995 PS IL-1, IL-8,
PAF, no TNF
Brown et al, 1994 PAN TNF, IL-1
Goldfarb et al, 1994 PAN IL-1
van Bommel et al, 1995 PAN TNF, IL-1, IL-6
 Effects of in Vivo Hemofiltration (HF) on
Levels of Inflammatory Mediators
Author Membrane Adsorption of Convection of
Kellum et al. 1998 AN69 TNFa, IL6, IL-
10
Hoffmanne et al, 1995 PA C3a, C5a, IL-8
Andreasson et al, 1993 PA C3a, C5a
Riegel et al, 1995 PS and PAN C3a, C5a, IL-6
Journois et al, 1996 PAN C3a, TNF, IL-
1,6,8,10
Gasche et al, 1996 PAN factor D
van Bommel et al, 1995 PS and PAN TNF minimal for TN
Bellomo et al, 1993 PAN TNF, IL-1
Tonnessen et al, 1993 PS IL-1, not IL-6
Millar et al, 1993 PA IL-6
Bellomo et al, 1995 PAN IL-6, IL-8
Heidemann et al, 1994 PS TxB2
Staubach et al, 1989 PA TxB2 and 6-
keto-PGF
 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 Clinical
Vascular access Bleeding
malfunction Hematomas
Circuit clotting Thrombosis
Circuit explosion Infection and
sepsis
Catheter and circuit kinking Allergic reactions
Insufficient blood flow Hypothermia
Line-catheter disconnection Nutrient losses
Fluid balance errors Insufficient blood

purification
Loss of efficiency Hypotension,
arrhythmia
Complications of CRRT recorded in a total of 212
patients
Complication No %
Bleeding 18 8.4
Haematoma 8 3.7
Access Malfunction 1 0.4
Line disconnection 17 8.0
Frequent filter clotting 5 2.3
Treatment-induced hypotension 7 3.3
Cannulation site infection 2 0.9
Hypothermia 4 0.9
Hypophosphatemia 5 2.3
Vein thrombosis 1 0.4
Lactic acidosis 2 0.9
Fluid imbalance 4 1.9
( Ronco C. et al. Nephrol Dial Transplant 1994)
 Recommendation for Initial
Dialysis Modality for ARF
Indication Clinical condition Preferred
Therapy

Uncomplicated ARF Antibiotic nephrotoxicity IHD, PD

Fluid removal Cardiogenic shock CRRT
CP bypass
Uremia Complicated ARF in ICU
CRRT, IHD
Increased
intracranial pressure Subarachnoid hemorrhage, CRRT
hepatorenal syndrome
Shock Sepsis, ARDS CRRT
Nutrition Burns 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:  Against RRT

 Hyperkalemia kills  Costs money
 Pulmonary edema  No RCT it makes
kills any difference
 Experience before  Side effects
RRT available
 Visible effects of
uremia
 PD vs standard IHD

 PD:  Standard IHD:

 Hemodynamic  Better clearances
stability  No glycemic swings
 Continuous therapy  No abdominal leaks
 No splinting of
diaphragm
 Decreased risk of
infection
 Biocompatible vs.
bioincompatible dialysis
 Biocompatible:
 Bioincompatible:
 Biologic rationale
 Cheaper
 Two RCTs showing
clinical advantage  Some negative RCTs
(power limitations)
 Non issue if
convective CRRT
used
 Standard IHD vs. CRRT

 Standard IHD:  CRRT:

 cheaper in some parts  better volume control
of the world (USA)  hemodynamic stability
 better azotemic control
 better nutrition
 no cerebral edema
 better renal recovery
 same cost in Melbourne
 Changes in [urea]: CRRT vs. IHD
50
p<0.05
45
40
35
30
urea CRRT
25
(mmol/L) IHD
20
15
10
5
0
0 1 2 3 4 5 6

Days
van Bommel et al. Am J Nephrol 1995
Changes in [creatinine]:
CRRT vs IHD
p<0.05
800
700
600
500
[creat] CRRT
(mcmol/L) 400
IHD
300
200
100
0
0 1 2 3 4 5 6
Days
van Bommel Am J Nephrol 1995
Achieving fluid goals:
CRRT vs. IHD

30

25

20

15 p<0.05 CRRT
% of patients 10 IHD

0
Volume
control

Mehta e al. JASN 1996 (abstract)

 Acid-base homeostasis: CRRT vs.
IHD
0.7
0.6
0.5
Change in pH
after 24 h of treatment 0.4 p<0.05
CRRT
0.3 IHD
0.2
0.1
0
pH

Bellomo et al. Blood Purif 1994

Metabolic acidosis during RRT
p<0.001
40

35

30

25

[HCO3-] 20
mmol/L 15

10

HCO-10

HCO-11

HCO-12

HCO-13
HCO-0

HCO-1

HCO-2

HCO-3

HCO-4

HCO-5

HCO-6

HCO-7

HCO-8

Days of Treatment HCO-9

Normalization of serum potassium during RRT

8
p<0.001
7

[K+] 5
mmol/L
4

2
K-0

K-1

K-2

K-3

K-4

K-5

K-6

K-7

K-8

K-9

K-10

K-11

K-12

K-13
Days of Treatment
Normalization of serum sodium during RRT

160

155 p<0.001
150

145

140
[Na+]
mmol/L 135

130

125

120

115

Na-10

Na-11

Na-12

Na-13
Na-0

Na-1

Na-2

Na-3

Na-4

Na-5

Na-6

Na-7

Na-8

Days of Treatment Na-9

Correction of hyperphosphatemia during RRT

6
p<0.001
5

4
[Phos.]
mmol/L 3

0
P0
P1
P2
P3
P4
P5
P6
P7
P8
P9
P10
P11
P12
P13
Days of Treatment
 Cardiovascular Side Effects of CRRT and
IHD
p<0.05
10
9
8
7
6
5
Events 4
3 CRRT
2 IHD
1
0
VT/SVT/VF
> 20% fall

Total %
in MAP
Renal recovery: CRRT vs. IHD
p<
100 0.01
90
80
% of 70
total patients 60
50 CRRT
40 IHD
30
20
10
0
Recovery

San Diego Trial (unpublished)

Early vs. Late CRRT in Trauma

Late CRRT = BUN >60 mg/dl

Late
Early

0 10 20 30 40 50

% survival
Gettings et al. Intensive Care Med 1999
 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)
150 Creatinine (mcmol/L)
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
60 **p<0.001

50
40 APACHE II
30 UF (l/day)

20 *
10
0
Group I Group II Group III

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

UF dose and outcome

p=0.0013

45ml/kg/hr
Survivors
35ml/kg/hr Total

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.