Transcript Slide 1

Molecular Adsorbent
Recirculating System:
Practical Issues
Patrick Brophy MD
Director Pediatric Nephrology,
University of Iowa Children’s Hospital
Outline
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Hepatic Dialysis- Liver Support
MARS™
Rationale
Indications
Technical Aspects
Future Directions
Hepatic Failure
• Definition: Loss of functional liver cell mass
below a critical level results in liver failure
(acute or complicating a chronic liver
disease)
• Results in: hepatic encephalopathy & coma,
jaundice, cholestasis, ascites, bleeding, renal
injury, death
Hepatic Failure
• Production of Endogenous Toxins & Drug Metabolic
Failure
• Bile Acids, Bilirubin, Prostacyclins, NO, Toxic
fatty acids, Thiols, Indol-phenol metabolites
• These toxins cause further necrosis/apoptosis
and a vicious cycle
• Detrimental to renal, brain and bone marrow
function; results in poor vascular tone
History
Stadlbauer and Jalan. Acute Liver Failure: liver support Therapies
Current Opin in Crit Care. 2007; 13:215-21
MARS™
MARS™ ADSORPTION
Flux Filter COLUMNS
Patient
Blood
Circuit
DIALYSIS
DiaFlux Filter
20-25% Albumin Dialysis
Circuit
Circuit
MARS Flux Filter
Kapoor D., Journal of Gastroenterology and Hepatology, 2002
Albumin Bound Toxins
Removed During MARS
Therapy
• Aromatic Amino Acids
• Bilirubin
• Bile Acids
• Copper
• Middle and Short Chain
Fatty Acids
• Nitric Oxide (SNitrosothiol)
• Protoporphyrin
Water Soluble Substances
Removed During MARS
Therapy
• Ammonia
• Creatinine
• Tryptophan
• Tumor Necrosis Factor
Alpha
• Urea
• IL-6
Substances Not
Removed During MARS™
• Clotting Factors (Factor VII 50,000
Daltons)
– Improvement in Factor VII levels after
repeated treatments in small studies
• Immunoglobulin G (150,000 Daltons)
• Hormone binding proteins
• Albumin
Rationale
• To provide an environment facilitating
recovery- isolated or as a component of
MOSF Therapy
• To prolong the window of opportunity for
LTx : Bridge to Transplantation
• To allow waiting for the native liver
recovery: Bridge to recovery
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Indications
• Intoxications (US ***)
• Acute Liver Failure (ALF)
– Hepatorenal Syndrome
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Acute on Chronic Liver Failure (AoCLF)
Hepatic Encephalopathy
Refractory Pruritus in Liver Failure
Sepsis / SIRS / MODS
Technical Aspects
• Filters :
– MARS™ flux : 2m2 ECV = 150 ml + lines, 600ml 20% Alb
– MARSMini™: 0.6m2 ECV = 56ml + lines, 500ml 20% Alb *** (not
Available in US)
– PRISMARS™
– 1 kit = $ 2700 (USD)
• Flow Rates :
– Blood flow rate: 4-10 ml/kg/min
– Albumin dialysate Flow Rate = BFR
– UFR : 2000ml/h/1.73m2 in CVVH or in CVVHDF mode
• Anticoagulation:
– No anticoagulation
– Heparin (5 U/kg/h)
– Citrate
pCRRT Rome 2010
Vascular Access and
Anticoagulation for
MARS™
Why Do We Need Vascular
Access?
• Access function is crucial for therapy
• Flows obtained will affect adequacy of
blood flow for dose delivered and can
affect MARS™-circuit life
• Downtime from clotted circuits or access is
time off therapy
Access Considerations
• Low resistance
– Resistance ~ 8lη/2r4
– So, the biggest and shortest catheter should
be best
• Vessel size
– French ~ 3 x diameter of vessel
– Bedside ultrasound nearly universal
– SVC is bigger than femoral vein
Access Considerations
• Internal Jugular
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Very accessible
Large caliber (SVC)
Great flows
Low recirculation rate
Risk for Pneumothorax
Cardiac monitoring
may take precedence
• Femoral
– Usually accessible
– Smaller than SVC
– Flows may be
diminished by:
• Abdominal pressures
• Patient movement
– Risk for retroperitoneal
hemorrhage
– Higher recirculation
rate
Many feel current double lumen vas cath are too stiff to make the
•Subclavian:
turn into the SVC and I don’t personally use them. Although they are used in
some centers.
•Better for bigger kids likely.
•376 Patients
•Femoral 69%
•1574 circuits
•IJ 16%
•Sub-Clavian 8%
•Not Specified 7%
Circuit Survival Curves by French Size of Catheter
5Fr Demise
Hackbarth R et al: IJAIO December 2007
Summary: Vascular Access for
Pediatric MARS™
• Put in the largest and shortest catheter
when possible
– Caveat: short femoral catheters have been
shown to have high rate of recirc in adult
patients. (Little et al. AJKD 2000;36:1135-9)
• The IJ site is preferable (over femoral)
when clinical situation allows
• Avoid 5Fr Catheters
MARS™Anticoagulation
• Another crucial step in delivering the
prescribed dose (reducing downtime)
• Critically ill patients are at risk for both
increased and decreased clot formation
simultaneously
• Especially relevant & controversial in ALF
Calcium is necessary
for each event in the
cascade.
Heparin acts in conjunction
with ATIII on thrombin and F
IX, FX, FXII
Anticoagulation
• Systemic Heparin
– Goal ACT 180-240 sec
– Patient anticoagulated
• Risk of bleeding
– Risk for HIT
• Regional Citrate
– Goal Circuit iCal 0.30.4mmol/L
– Goal Patient iCal 1.11.4 mmol/L
– Risk for
• Hypocalcemia
• Alkalosis
• Hypernatremia
•138 Patients in multicenter registry study
•442 circuits
•Circuit survival time evaluated for three anticoagulation
strategies
•Heparin (52% of circuits)
•Regional citrate (36% of circuits)
•No anticoagulation (12% of circuits)
Brophy PD et al. Nephrol Dial Transplant. 2005;20:1416-21
•Mean circuit survival (42 and 44 hr) were not different for Hep vs Citrate, but
both longer than no anticoagulation (27 hr)
•At 60 hr, 69% of Hep and Citrate circuits were functional, but only 28% of the
no-anticoagulation circuits
•In this analysis circuit survival was not affected by the access size
•Citrate group had no bleeding complications, 9 Heparin patients with bleeding
Citrate Specific Issues
• Alkalosis
– 1 mmol Citrate to 3 mmol HCO3
– High-bicarbonate solutions may exacerbate (35
mEq/L)
• Hypernatremia
– Tri-Sodium Citrate infusion
• Hypocalcemic Citrate Toxicity
– Incomplete clearance of citrate, usually due to liver
dysfunction
– Rising total calcium, decreasing iCal
Summary: Anticoagulation for Pediatric
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MARS™
Heparin or citrate is better than no
anticoagulation (even in liver failure, DIC,
etc)
Citrate has fewer bleeding complications
Circuit survival means less downtime
hence more delivered therapy
Pick institutional strategy and learn to use
it well
Prescribing Pediatric MARS™
Choosing QB for Pediatric MARS™
Choose blood flow rate (QB) of 3-5ml/kg/min, or:
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0-10 kg:
11-20kg:
21-50kg:
>50kg:
25-50ml/min
80-100ml/min
100-150ml/min
150-180ml/min
Albumin Dialysate flow rate must equal
QB (minimum of 100 ml/min for US presently)
Solutions for Pediatric MARS™:
Dialysis Fluids and Replacement Fluids
Characteristics of the Ideal
MARS™ Solution
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Physiological
Reliable
Inexpensive
Easy to prepare
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Simple to store
Quick to the bedside
Widely available
Fully compatible
Purpose of MARS™ solutions
• Provide safe and consistent metabolic
control
• To be adaptive to the choice of therapy –
convection vs. diffusion vs. combined
modality- this is relevant on the dialysis
side
Summary: MARS™ Solutions
• Solutions needed to maximize clearance
• Pharmacy made solutions give greatest
flexibility but have increased risks/costs
• Several industry-made solutions
Benefits of MARS
• Improvement in Hemodynamic Stability
– Increased systemic vascular resistance
– Increased mean arterial pressure
– Decreased portal venous pressure in AoCLF
– Improvement in renal blood flow (RBF)
– Laleman W., Critical Care 10:R108, 2006
– Schmidt LE., Liver Transpl 9: 290-297, 2003
– Kapoor D., Journal of Gastroenterology and Hepatology
2002, 17: S280 – 86, 2002
– Mitzner SR., J Am Soc Nephrol 12: S75-82, 2006
Combined CRRT/MARS
MTX Intoxication
• 17 year-old Hispanic male with high-risk
pre-B ALL
• Chemotherapeutic treatment was modified
due to previous delayed Methotrexate
(MTX) clearance
• Admitting serum creatinine 0.64 mg/dl
• 24 hours post MTX infusion:
– Serum creatinine: 2 mg/dl
– MTX level: 226 mol/L (Normal<5 mol/L )
Combined CRRT/MARS
MTX Intoxication
Start CRRT
76.6 mol/L
MARS Started
STOP MARS
0.39 mol/L
Risks
• Hemodynamic
Instability
– Has been seen
primarily in children
weighing < 10kg
also undergoing
hemodialysis
– Overall
improvement with
continued therapy
• Thrombocytopenia
• Bleeding
Complications
• Transfusion of Blood
Products
• DRUG Clearance**
Cost Benefit
• Positive benefit in terms of health cost
reductions using MARS
• Kantola et.al. Cost-utility of MARS treatment in ALF.
World Journal of Gastroenter 2010; 16; 2227-34
• Hessel et.al. Cost-effectiveness of MARS in patients
with acute-on-chronic liver failure. Gastroenterol
Hepatol 2010; 22: 213-20
• Positive impact on reduction of Pharmacy
utilization (albumin)- compared to SPAD
– Drexler et. al. Albumin dialysis MARS: impact of albumin
dialysate concentration on detoxification efficacy. Ther
Apher Dial 2009; 13; 393-8
Non-Biological
artificial support
• Issues:
– Still don’t understand the complexity of the liver
and the causes of hepatic encephalopathy/coma
– May be removing both good (growth factors-for
liver regeneration) and bad substances
– Need to standardize end points in these studies
– Multicenter RCTs are desperately required in
Pediatrics
Future Horizons
Huge potential Impact on critical care & Transplantation
Potential for managing patients chronically as an
outpatient with intractable pruritus- High impact on
quality of life:
Leckie et.al. Outpatient albumin dialysis for Cholestatic patients with
intractable pruritus Aliment Pharmacol Ther 2012; 35: 696-714
Schaefer et.al. MARS dialysis in children with cholestatic pruritus.
Pediatr Nephrol 2012; 27: 829-34
Thank You
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Pediatric Dialysis Staff
Mary Lee Neuberger
Critical Care physicians/Nursing
Pharmacy