CRRT in Liver Disorders
Akash Deep
Director - PICU
King’s College Hospital
London
Chair
Renal/CRRT Section
European Society of Pediatric and
Neonatal Intensive Care (ESPNIC)
0
Children’s Critical Care Centre
1
Overview
• Case Discussion
• CRRT and AKI in ALF
• CRRT in various Liver Disorders – Why
AKI, When do you intervene, outcome
• Single Pass Albumin Dialysis (SPAD)/
MARS
• Anticoagulation in liver Patients
2
RRT in liver patients
•ALF
•Stable cirrhosis
•AoCLF
•Post Liver Transplant
•Metabolic diseasehyperammonaemia, primary
hyperoxaluria
•CRRT – standard ICU indications in
patients with liver disease
Survival in patients treated by RRT
according to diagnoses: ppCRRT Registry
Symons, Clin J Am Soc Nephrol, 2: 732, 2007
100
90
80
Overall survival
58%
70
60
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40
30
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Case - 1
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9 year old previously well child from Dublin
4 day history of cough, fever
Recovered
2 weeks later – lethargy, jaundice
Readmitted to hospital
Increasing Jaundice, raised INR, fully alert
Diagnosis???
5
KCH
• Admission to King’s Hepatology Ward
• INR > 9, Listed for super-urgent liver
transplantation
• Overnight – going in and out of sleep,
decreased urine output, 3 fluid boluses
• All alarm bells ringing
• It was the weekend!!!!!!
6
Paediatric PICU
•
•
•
•
•
Patient wheeled to ICU
Distinctly looked encephalopathic
INR 7.8 Platelets 13 Hb 7.8
Ammonia – 178 micromol/litre
Waiting for things to get ready – Transcranial
Dopplers done- PI > 2.0
7
Raised ICP results in reduced diastolic flow, PI 2.4
PICU Care
•
•
•
•
Intubated ventilated
Inserted 12.0 F IJV vascath
Right Reversed Internal Jugular Vein
Right Femoral CVL and Left Femoral
Arterial Line
• NIRS started
• Bilateral Pleural effusions – drains
inserted
9
PICU ( 11:00 -13:00)
• Within 60 minutes – HVHF started
• Pump speed – 250 mls/min, Predilution- 2.5
litres, ACT- 200 Started on PGI2 – 4ng/kg/min
• Ph 7.10 CO2-5.5 kpa Lactate 5.6 Base deficit- 14.1 Cl- 110
• Vasopressor support + 60 mls/kg Fluid
• Steroids given
• FFP+ Platelets+ Activated Factor –VII
• Fentanyl + Midazolam started
• Phenytoin loading given, hypertonic saline
10
infusion
Neuro- monitoring
•
•
•
•
•
TCD – PI- 2.4
RIJV – 42%
NIRS correlating with RIJV
Hb -10, CI 4.2 on vasopressor support
DECISION TO INSERT ICP BOLT
11
Neuroprotection ( 13:30)
• Inserted a Camino epidural bolt- scalp
bleeding for > 30 minutes
• Opening pressure – 50 cm H2O
• Immediately started hypothermia ( 32
degrees), full neuro-protection including
thiopentone infusion with continuous EEG
• ICP minimum – 45 cm H20 with good
waveform
12
Case - continued
• At 2 am- when every possible neuroprotection
was thrown at her – Called the surgeon
• Anhepatic – No sign of liver coming up, father
had fatty liver
• CRRT continued in OR for 16 hours
• Increased turnover to 4 litres/hour
13
Temporary anhepatic state
14
Case ( 13:00)
• Within 8 hours – cadaveric liver transplantation
done ( liver not of great quality- but used as a
bridge )
• Patient re-listed for another transplant
• Complete normal neurology
• Re-transplanted in 4 weeks
• Progressive kidney involvement- Urea,
creatinin``e, K rising and fluid overload
• On CRRT from 28/7/12 till 24/01/2013
• Gradually weaned off CRRT
15
Progress
•
•
•
•
•
Progressive BM Suppression and CKD
Listed for BM transplant
Went on to IHD
Developed disseminated aspergillosis
Sadly WG RIP on 28/02/2013
16
Questions
• Why did WG develop AKI in ALF?
• Could we have acted more swiftly and
started CRRT overnight – i.e, what is the
exact time of initiation of CRRT?
• What was our aim of starting CRRT?
• The fact that she was neurologically
completely intact – Did CRRT help or was
it the aggressive neuro-protection?
17
CRRT in ALF
18
Liver can Regenerate!!!
Pierre Paul Rubens
Chained Prometheus
The Philadelphia Museum of Art
Ultimate Aim of RRT in ALF
Conducive Environment for Either Liver
Regeneration /Liver Transplant – Stable
haemodynamics, removal of toxins, CPP
•The potential for recovery of native organ function
•Too little donor organ pool
•To prolong the window of opportunity for LT : “Bridge to LT”
• Risk of death awaiting liver transplant ( MODS) – Fluid
manipulation, acid-base, ammonia, nutrition
Liver Support Devices until recovery from ALF or bridging
to transplant.
Hepatology 1998:27:1050-5
King’s College Hospital PICU Admissions
Jan 2003- Dec 2013
EXCLUDED:
Acute on chronic (5%)
Liver n=1289
(18%)
ALF n=165
(13%)
EXCLUDED:
Post-transplant (18%)
Primary HSV sepsis (5%)
HDU (13%)
Managed prior to
transplant/recovery
n=106 (64%)
with CRRT
n=45 (42%)
25
Distribution by
Age and
Aetiology
20
Ischaemic
15
Autoimmune
Wilson's disease
Haematological malignancy
Neonatal haemochromatosis
10
Infectious
Metabolic
Drug induced
Indeterminate
5
Mean PIM2 score = 54
0
<28days
28days-1yr
1-2yrs
2-5yrs
5-10yrs
10-18yrs
Use of CRRT in Paediatric ALF at KCH
• Average time to start
CRRT 29 hrs (1 in 3
<8hrs)
• Commonest indication
hepatic encephalopathy
• 100% required
mechanical ventilation
• 93% required
ionotropes
• Mean duration of CRRT
was 54 hours.
Mean Ammonia (umol/L) in Relation to CRRT in ALF
PICU Patients by Outcome on Discharge
n=45
Mean Lactate (umol/L) in Relation to CRRT in ALF
PICU Patients by Outcome on Discharge
n=45
Mean Fluid Overload (%) in Relation to CRRT in ALF
PICU Patients by Outcome on Discharge
H24
H48
H48
40
40
40
20
20
40
20
0
0
-20
-20
-40
-40
-60
-60
-80
-60
-80
-60
-40
-40
-20
0
-20
0
20
-80
Variation in serum creatinine, %
H24
P= 0.0002
-80
Variation in Creat, %
Variation in Creat, %
p=0.002
H48
80
80
60
60
60
40
40
20
20
0
0
20
0
0
20
40
40
60
80
80
H24
-20
-20
-20
-20
-40
-40
-40
-40
Variation in mean arterial pressure , %
p=0.0002
P=0.0002
P=0.0005
p=0.0002
p=0.0005
Variation in PAM, %
Variation in PAM, %
Variation in hepatic encephalopathy grade
P= 0.002
At 24 hours:
Increase MAP (p=0.0002)
Decrease serum creatinine
(p=0.0002)
H24
H48
8
8
6
6
4
4
2
2
0
0
2
-
2
-
4
-
4
-
P= 0.90
p=0.90
Variation in Encephalopathy grade
P= 0.04
p=0.04
Variation in Encephalopathy grade
At 48 hours:
Increase MAP (p=0.0002)
Decrease serum creatinine
(p=0.0002)
HE grade improvement (p=0.04)
Effect on outcome of CVVH
Cumulative Survival
1
,8
,6
,4
< 1 year
,2
> 1 year
HV- CVVH era
2002-2008
HV- CVVH era
2002-2008
0
0
10
20
30
40
Days
50
60
70
80
No effect on long term survival, but
significant prolonged initial delay
Cumulative Survival
1
,8
,6
,4
< 1 year
,2
> 1 year
HV- CVVH era
2002-2008
HV- CVVH era
2002-2008
0
0
10
20
30
40
Days
50
60
70
80
Conclusion CVVH in Paediatric ALF
• Improved hemodynamic, renal and neurological
function
• Allows a prolonged period of stability to ELT
Renal Support in Liver Failure
• Why do patients with Liver failure develop
AKI?
• Why do patients with AKI in liver failure
require RRT /detoxification modalities?
• What is the best time to initiate RRT in
patients with ALF?
• Elective versus standard CRRT
• What dose of RRT is the best dose – role of
HVHF?
• Anticoagulation in CRRT for ALF
31
Pathogenesis of AKI in ALF
Arterial vasodilatation (‘’VASOPLEGIA’’)
Decreased SVR
High Cardiac Output
Renal Auto-regulation becomes Pressure
Dependent - Intra-renal Vasoconstriction
32
Aetiology of Kidney Involvement in ALF
• Multifactorial
• Pre-renal AKI
• Acute tubular necrosis due to profound hypovolemia
and hypotension
• Direct drug nephrotoxicity (paracetamol, NSAIDs)
• Hepatorenal syndrome
• Intra-abdominal hypertension (IAH) and development
of abdominal compartment syndrome - USCOM
34
Renal
• Renal replacement therapy in ALF
– Continuous filtration not intermittent dialysis
• Improved metabolic stability
• Improved cardiovascular stability
Davenport et al Crit Care Med 1993;21:328-338
– Additional benefits from high filtration rates ?
• 35 ml/kg/h as standard.
• 90ml/kg/h severe lactic acidosis ++ vasopressors.
• We use minimum of 60 mls/kg /hour and increase if
lactate/ammonia not getting better
NH4 cut off 124 : pH, cerebral
oedema + NH4 predict outcome
Bhatia V Gut 2005
Patients who develop ICH tend to have
persistently high ammonia levels.
Bernal W Hepatology 2007
Evidence for Ammonia
Comparison of arterial ammonia
levels at admission between
survivors and non‐ survivors
among acute liver failure patients
Gut. 2006 January; 55(1): 98–104
Mortality, advanced encephalopathy, and complications
in acute liver failure patients as a function of plasma
ammonia levels
Parameter
Ammonia
Ammonia
<124 μmol/l (n=38) 124 μmol/l (n=42)
p Value
Mortality
9 (23.7)
33 (78.6)
<0.001
Renal failure
1 (2.7)
10 (23.3)
0.009
Ventilation
10 (27.0)
30 (69.8)
<0.001
Infection
19 (51.4)
28 (65.1)
0.212
Cerebral oedema
8 (21.6)
20 (46.5)
0.020
Encephalopathy
grade (3/4)
23 (62.2)
35 (81.4)
0.055
Seizures
3 (8)
15 (35)
0.006
Higher percentages of cerebral oedema (71% vs 37%; P < .001)
Gut. 2006 January; 55(1): 98–104
Clin Gastroenterol Hepatol. 2012 Aug;10(8):925-31
Timing of Initiation of RRT
• Do NOT wait for frank signs of renal failure
• Metabolic complications - metabolic
acidosis, lactate, hyponatraemia and NH3
>150 µmol/litre
• If child intubated for grade ¾
encephalopathy – insert vascath
• Challenges – High INR, potential for
bleeding and vascath complications
42
43
Authors – Akash Deep, Anil Dhawan
RRT – Indications in ALF
• Hepatic encephalopathy grade 3-4
• NH3 >150 µmol/litre and not getting controlled or an
absolute value >200 µmol/litre
• Renal dysfunction (Oligo-anuria, Hyperkalemia, fluid
overload)
• Metabolic abnormalities ( hyponatremia Na <125
meq/litre, High lactate and increasing despite optimising
fluid therapy, Metabolic acidosis)
No one indication is an absolute one for
initiation of RRT
45
If Early HVHF looks promising, what are
the potential drawbacks?
• Invasive procedure
• Haemodynamic instability, decreased
cerebral perfusion
• Clearance of medications
• Side effects
Acute kidney injury in patients admitted to a
liver intensive therapy unit. O’Riordan A
• 2000-2007 : 302 ALF managed without OLT
• 21% did not develop AKI : all survived
• 239 with AKI of whom 164 survived(68%) – LOS increased
by 5 -7 days
• 51% return of normal renal function
• eGFR > 60 at time of discharge
Nephrol Dial Transplant. 2011
Nov;26(11):3501-8.
48
49
SUMMARY
No Evidence for RRT in Liver patients
Should we undertake CRRT in ALF
• Yes - and review : population data vs individual care
Why ? –Neuro-protection, metabolic disarray, bridge for recovery or transplant
When
• Earlier - need new markers
Mode
• CRRT - unstable
Access sites
• Internal Jugular
Dose
• No evidence in Paediatrics
•High /Low - No Adequate - yes
Anticoagulation - YES
•PGI2 and /or low dose heparin
AKI in Chronic Liver Disease
51
Progress of cirrhosis
52
Kidney dysfunction in cirrhosis
Natural Progression of disease
complications
Renal dysfunction
HRS
V/s
Stable patient with cirrhosis, PHT
precipitating event
HRS-1
53
AKI in Liver disease
• Is every AKI in liver disease HRS ?
• What are the different causes of AKI in
liver disease?
• Can we reliably differentiate between the
various causes of AKI?
55
Frequent causes of AKI in CLD
• Hypovolaemia: GI bleeding – (don’t forget the
ulcer ) GI fluid losses (Lactulose, Terlipressin,
PPI, GI infection) Diuretics abuse/over use
• Parenchymal disease: GN, Cryoglobulinaemia,
IgA nephropathy – Biopsy? ATN/HRS
• Drugs: CIN, NSAIDS, Abx, CNI post Tx
• Intra Abdominal Hypertension
• Hepato-renal Syndrome
Epidemiology
• 50% of patients with cirrhosis with ascites will develop
AKI
• HRS constitutes a very small proportion of AKI in cirrhosis
• ONLY 7.6% of all 129 cirrhotics with AKI had HRS as the
cause of deterioration
(Montoliu S, Ballesté B, Planas R, et al )
• Multicentre trial – 423 patients with cirrhosis and AKI
(ATN -35%, Pre-renal failure-32%, HRS-1- 20%, HRS-2 6.6%
(Moreau R, Durand F, Poynard T, et al)
Creatinine >1 .5 mg/dl
463 patients over 6 years
Single centre
3 month
mortality
Renal Replacement therapy
• Mainstay of supportive therapy for patients who
deteriorate despite aggressive resuscitation
• Volume overload, intractable metabolic acidosis, and
hyperkalemia
• Delay in RRT – MORTALITY > 90%
• High risk in hepatic encephalopathy, hypotension,
and coagulopathy
• Serves as bridge to transplant
• If RRT > 8 weeks before LT - ???? Combined LiverKidney Transplantation
Kidney Dysfunction post Transplant
• AoCLD or ALF with raised ICP pretransplant
• Pre-transplant - Renal Dysfunction
• Intra-operative factors – Haemorrhage,
hypotension after graft reperfusion,
requirement for blood transfusion, IVC
clamping
• Post operative : Hypotension, nephrotoxic
drugs ( immuno suppression, antibiotics) 60
61
Metabolic Disease
• Hyperammonaemia of the newborn – UCD,
citrullinaemia, Propionic acidaemia
• Primary Hyperoxaluria
• Collapsed newborn – postnatal diagnosis (
prognosis, ethical issues)
• Antenatal UCD diagnosis – Hepatocyte
transplantation and more controlled lowering of
NH3
• Modality – CVVH versus CVVHD versus
CVVHDF
62
1. Time critical (get patient to your PICU)
• Time to make diagnosis
• Time to transfer to PICU
• Time to start medical detox
2. Secure IV access for dialysis
• Largest vascath possible
• Best site (least recirculation)
• Peritoneal dialysis may by time
3. Time of effective dialysis
• Mode dialysis you are familiar with
• Circuit downtime
Dialysis for inborn errors
– Technically challenging
– Time critical
– No room for error
– Make sure you have right diagnosis
– Does not always work if production toxins
extreme
65
Sauer et al 2004: SPAD In Vitro
In vitro samples: 6 pts with MARS, 6 SPAD, 6 CVVHDF
Ammonia - No difference between MARS, SPAD, CVVHDF
Bile Acids - MARS = SPAD
Total Bilirubin - SPAD > MARS
66
MARS
68
Anticoagulation
Anticoagulation in RRT in liver patients
– is it different ?
69
Liver Failure
• Bleeding in ALF – defective synthesis of both pro
and anti- coagulation factors
• Conventional forms of anticoagulation contraindicated
in patients with a high risk of bleeding (Coagulopathic,
decreased metabolic clearance of citrate, enhanced
bleeding risk)
• Monitoring of heparin liver failure – tricky( Factor-8
and vwF increased)
• Should CRRT circuits in patients with hepatic failure be
anti-coagulated?
endogenous thrombin
potential ratio (ETP) suggesting
hypercoagulability.
71
• Retrospective analysis of 50 patients
– Acute liver failure
– Acute on chronic liver disease
– Post-elective liver transplantation
• Comparison groups
– Sepsis
– Hematological malignancies
• No ACG initially
• Outcomes
– Mean circuit life
– # circuits per 48 hours
 On starting ACG in patients with liver failure filter life increased from 5.6 to 19 hours.
There was no increased bleeding or requirement for blood transfusions
 Patients with liver disease contrary to common belief do require anticoagulation to keep
CRRT going continuously
Treatment options
• Low dose Heparin
• Prostacyclin
• Citrate ???
74
Anticoagulation in CRRT for ALF
• Depending on ACT
• No Anticoagulation: If ACT >220 sec.
• Prostacycline : If ACT between 180-220 Sec
• Low Dose Heparin: If ACT < 180 sec.
If ACT persistently low, patient is septic –
combination of low dose heparin and prostacycline
75
Heparin and Prostacyclin combined
HEPARIN
PROSTACYCLIN
76
Safety and Efficacy of Prostacyclin as an
anticoagulant in CRRT in patients with ALF
• First ever Paediatric data (King’s PICU)
• 3 year period ( 2011-2013)
• All children with ALF on CRRT ( n=76)
• Efficacy
 Filter life
 Mortality
• Safety
 Bleeding episodes during CVVH
 Hypotension ( requirement for fluids/vasopressors)
 Platelet consumption
Epoprostenol ( n= 45)versus Heparin ( n=26)
77
Dialysed children 76
Total filters used 210 (Prostacyclin 127, Heparin 45, None- 38)
Target event – clotted filter
Censored – filter removed due to other reasons
CRRT in Liver Disease
• Different from non-liver ICU patients
Indications
Timing
?Dose – Role of HVHF
Anticoagulation
79
Liver pCRRT Registry at KCH
• PICU ALF registry at KCH
Every patient gets a standard
documentation of all parameters
• Liver pCRRT Registry – All patients with
liver disease on CRRT(mode, indication,
dose, filter size, biochemical markers,
pre/post dilution, ACG, outcome etc etc)
• Protocol Development – CRRT,
hyperammonaemia, ACG
464 variables measured per patient
Treat the kidneys early
Large blood volume - all
in the wrong space !
Large volume of distribution
Reversal of neurological
dysfunction
Need more studies