continuous renal replacement therapy overview · continuous renal replacement therapy overview...
TRANSCRIPT
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Continuous Renal Replacement
Therapy Overview
Bruce A. Mueller, PharmD
Professor of Clinical Pharmacy
University of Michigan College of Pharmacy
Ann Arbor, MI
Thanks to Humaira Nawer, PharmD for citrate slides!
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In your institution, what is the preferred renal replacement therapy in your ICUs?
Intermittent hemodialysis
Continuous Renal Replacement Therapy
Slow Low Efficiency Dialysis
Something else....or I don’t know
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Renal Replacement Therapies (RRT)
Peritoneal
CAPD
CCPD
Intermittent
IHD
Prolonged Intermittent
(PIRRT)
SLED/-f
EDD
SHIFT
Continuous (CRRT)
CVVH
CVVHD
CVVHDF
Ambulatory/ESRD/ Outpatient
Critically Ill/Acute Kidney Injury/Inpatient
Practice #3: Know what are nephrologists / intensivists are doing to your patient and their drug clearance.
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ICU RRT Variability
• First RRT Choice for AKI in Malaysian ICUs • Jamal JA et al. Nephrology 2014;19:507-12.
• Modality: CRRT 79%, IHD 16% PIRRT 5%
• CRRT Type: HF 72%, HDF 56%, HD 28% • Prescribed dose (mL/kg/h) : 30.6 (± 4.6)
• Predilution 33%, Post 11%, Pre + Post 56%
• PIRRT duration 6.2 (± 1.8) hours • Blood flow 263.6 (± 67.4) mL/min
• Dialysate Flow 294.4 (± 80.8) mL/min
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What is CRRT?
• Continuous Renal Replacement Therapy • CVVH – Continuous venovenous hemofiltration
• CVVHD - Continuous venovenous hemodialysis
• CVVHDF - Continuous venovenous hemodiafiltration
• Renal replacement therapy for critically ill patients • 24 hrs/day, 7 days/wk
• Available in most US & Canadian ICUs • Common in Europe, Australia, New Zealand
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Who gets CRRT?
• ICU patients too hemodynamically unstable to tolerate conventional hemodialysis
• Highly catabolic patients who might require hemodialysis 5-7 days/week
• Sepsis the most common co-morbidity
• Multisystem organ failure common
• Mortality rates ~50%
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• Commercial Dialysate is used • In 2018, you should not be making CRRT solutions!
• Good for small solute removal (<500 Da) • diffusion rate inversely proportional to MW
• Less good for larger solutes (Vancomycin?)
Diffusive Therapies: Dialysis (CVVHD)
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Typical CVVHD orders
• Blood Flow – 150-200 mL/minute
• Dialysate Flow – 17-33 mL/min (1-2 L/hr)
• Net volume removal – 2 mL/min (120 mL/hr) • If patient getting net (5 mL/min) 300 mL/hr of meds & TPN
• Suction turned up to remove 300 + 120 = 420 mL/hr
• This 420 mL/hr (7 mL/min) is in addition to the dialysate flow coming out of dialyzer.
Blood in Blood out
150 mL/min
Dialysate in Effluent (Spent Dialysate) out
33 mL/min 40 mL/min
148 mL/min
Drugs/TPN in 5 mL/min
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• No dialysate, removes plasma water as it seeps through membrane
• Removes small and large molecules easily • as long as they can fit through membrane
• Drug removal easy to calculate • based on sieving coefficient
• ultrafiltrate concentration/plasma concentration
Convective Therapies: Hemofiltration (CVVH)
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Typical CVVH orders
• Blood Flow – 150-200 mL/minute
• Ultrafiltrate Flow –33 mL/min (1-2 L/hr)
• Net volume removal – 2 mL/min (120 mL/hr) • If patient getting 5 mL/min (300 mL/hr) of meds & TPN
• UF replacement solution + TPN/Meds infused at to yield 2 mL/min fluid loss
Blood in Blood out
150 mL/min
NOTHING IN Effluent (UF) out
35 mL/min
148 mL/min
TPN/Meds + UF replacement
5 + 28 mL/min
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How CVVH affects waste product removal - convectively • Hematocrit going into hemofilter is 40%
• Coming out of filter is 45%
• Blood in has BUN concentration of 100 mg/dL
• UF out has BUN concentration of 100 mg/dL
• Blood coming out of hemofilter has BUN concentration of 100 mg/dL!
• How does patient’s BUN ever go down?
Blood in Blood out
BUN 100 mg/dL
UF out BUN 100 mg/dL
BUN 100 mg/dL
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Coffee maker analogy for convective RRT
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Combination therapies (CVVHDF) • Most complicated because has convective
and diffusive drug removal
• CVVHDF example when I want net 2 mL/min fluid loss in patient
Blood out
150 mL/min
Dialysate in Effluent out
20 mL/min
43 mL/min
148 mL/min
Blood in
TPN/Meds + UF replacement
5 + 16 mL/min
(2 + 5 + 16 + 20 mL/min)
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What CRRT Effluent Rate is Best?
• Most large trials show no difference in survival between higher vs. lower effluent rates
• DoReMi Trial. Vesconi et al. Crit Care. 2009;13(2):R57.
• ATN Trial. Palevsky et al N Engl J Med. 2008;359:7–20
• Renal Trial. Bellomo et al. NEJM 2009 22;361:1627-38.
• KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guidelines:
• Aim to deliver an effluent volume of 20-25 mL/kg/h
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Patient
Pump
Replacement solution Dialysate
1-2 L/h
Effluent
Blood flow 150-300 mL/min
Continuous Renal Replacement Therapy (CRRT)1,3
Diagram adapted from: goo.gl/8p2fuQ goo.gl/4x98j3
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Anticoagulation for CRRT
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Activation of platelets, inflammatory mediators, coagulation cascade
Blood flows through CRRT circuit ● Contact with
tubing ● Turbulence ● No endothelium
Fibrin deposition and clotting of the circuit/filter
CRRT Circuit Clotting2,5
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Hofbauer et al. (1999)
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Issues Associated with Clotting2,6
• Reduced RRT treatment time and dose
• Increased expense, time, and workload
• Potential blood loss and increased transfusion needs
• Increased risk of infections • Complicated drug
pharmacokinetics
18 https://goo.gl/jqB6
RS
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Here are the CRRT anticoagulation options…
• No anticoagulation • Saline flushes • Heparin • Regional heparinization • Regional citrate • Low-molecular weight heparin • Thrombin inhibitors • Nafamostat • Prostacyclin • Heparinoids
19 https://goo.gl/WuhYpr
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Here are the CRRT anticoagulation options…
• No anticoagulation • Saline flushes • Heparin • Regional heparinization • Regional citrate • Low-molecular weight heparin • Thrombin inhibitors • Nafamostat • Prostacyclin • Heparinoids
20 https://goo.gl/WuhYpr
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What anticoagulation do you use?
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Citrate3,6,10
• Not approved by the FDA for CRRT anticoagulation
• Approved as an anticoagulant for preparation of blood products
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Citrate for Anticoagulation
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Calcium citrate complex
35-50% removed by dialysis across hemofilter (depending on flow rates of blood, citrate)
Liver, kidney, skeletal muscle
Bicarbonate
https://goo.gl/TMB5Vw https://goo.gl/3VK4b3 https://goo.gl/dJbjYN
https://goo.gl/fYQhNs
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Patient
Pump
Calcium-containing replacement solution Calcium-free
dialysate
Effluent
Blood flow 150-300 mL/min
Citrate
Diagram adapted from: goo.gl/8p2fuQ goo.gl/4x98j3
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Citrate for Anticoagulation
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General Protocol Considerations
• Citrate introduced at earliest point possible in the circuit before filter
• Replace calcium at the end of the extracorporeal circuit or through a separate line to replace calcium that is chelated and lost
• Must ensure that dialysis, citrate infusion, and calcium infusion are started and stopped simultaneously
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Citrate for Anticoagulation
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Adverse effects:
• Hypernatremia
• Metabolic alkalosis
• Hyperglycemia
• Hypocalcemia or hypercalcemia
• Hypomagnesemia
• Increased ion gap
https://goo.gl/W3At47
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Citrate for Anticoagulation
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Monitoring
• Electrolytes (Na, K, Cl, Ca, Mg)
• Ionized calcium both in the circuit post-filter and in the patient → measure of anticoagulation
• Total calcium to ionized calcium ratio (T/I)
• Blood sugar
• Blood gas
• Anion gap
• EKG
https://goo.gl/ccvYu7
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Patient
Pump
Calcium-containing replacement solution Calcium-free
dialysate
Effluent
Blood flow 150-300 mL/min
Citrate
Diagram adapted from: goo.gl/8p2fuQ goo.gl/4x98j3
CRRT Drug Dosing
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CRRT Drug Removal Mechanisms • Adsorption to the membrane (usually ignored)
• Transmembrane drug clearance dependent on: • Small volume of distribution
• Not protein bound – only free drug can cross CRRT membrane
• Drug molecular weight <2000 Daltons • Even “large” drugs (daptomycin, vancomycin, telavancin)
will cross membrane
• All CRRT membranes are “high-flux” dialyzers
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30
30
Deep/Central
Compartment
Pool 2
???Liters
Dialysate
UF Soln
Qb
Qb
UF Soln
Spent
Dialysate
&/or
UF
Dialysate
Pool 1
6L?
k12
k21
k32
k23
Deeper
compartment(s)?
Pool 3
???Liters
Kinetics in ARF and RRT
Peripheral
compartment
PatientRRT
Mueller BA, Pasko DA. Artif Organs 2003;27:808-14.
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Drug Dosing Recommendations Based on Sieving Coefficient (SC)
• CRRT Drug clearance a function of • Rate of effluent flow
• Ability of drug to cross membrane (sieving coefficient)
• For drugs <2000 Daltons: • Sieving Coefficient ≈ % Free Fraction
• Protein binding important determinant of CRRT clearance
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CRRT Drug Removal • CRRT Clearance = SC X Effluent Rate
• Mg lost/time =
• (Serum Concentration)(SC)(effluent rate)
• Vancomycin example: • SC = 0.8,
• CRRT Effluent rate= 2L/hr
• Vancomycin Serum Concentration = 20mg/L
• Amount lost by CRRT=
• 20 mg/L (0.8) (2L/hr) = 32 mg/hr • Remember... Patient also lost drug via liver, residual
renal clearance, etc.
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Effects of CRRT Effluent Rates on Antibiotics
CRRT at 40 mL/min
CRRT at 20 mL/min
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Of last 10 CRRT patients at your institution… How many of them perished from infection-related issues (sepsis, etc)?
0-1 patient
2-3 patients
3-4 patients
4 or more patients
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Of last 10 CRRT patients at your institution… How many experienced symptoms of too high antibiotic concentrations?
0-1 patient
2-3 patients
3-4 patients
4 or more patients
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Difficult Balance in Antibiotic Dosing Clinicians’ Dilemma
Lewis SJ, Mueller BA. J Intensive Care Med. 2014 36
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Pharmacokinetic Changes in the ICU
PK Change Ability to Reach Pharmacodynamic Target
Fluid Overload Reduced Ability
↓ Serum Albumin / ↓ Protein Binding
Mixed Effects
Retained Non-renal Clearance Reduced Ability
Aggressive CRRT Reduced Ability
Augmented Renal Clearance Reduced Ability
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• Must increase loading dose for many drugs
• As volume overload is corrected, doses must change again
Fluid Overload
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Antibiotic volume of distribution in the critically ill
Drug Critically ill Healthy volunteers
Author
Aminoglycosides 0.41 L/kg 0.25 L/kg Marik 93
Ceftriaxone 20 L 10.1 L Joynt 01
Ceftazidime 0.32 L/kg 0.21 L/kg Hanes 00
Ceftazidime 56.9 L 13.6 L Gomez 99
Vancomycin 1.69 L/kg 0.72 L/kg Del Mar Fernandez 07
Ertapenem 0.38 L/kg 0.08 L/kg Brink 09
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Patient Size Matters
• You should use an antibiotic loading dose
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Non-renal clearance rates of selected drugs in patients with normal renal function and ESRD
DRUG NORMAL RENAL FX
(ML/MIN/70 KG) ESRD % DECLINE IN CL
Acyclovir 65 29 55
Aztreonam 40 27 33
Cefotaxime 217 130 40
Imipenem 128 54 56
Procainamide 257 102 60
Vancomycin 40 6 85
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• 53 CRRT patients receiving meropenem, pip-tazo, cefepime or ceftazidime had serum assayed.
• Serum concentrations remained >4X MIC of Pseudomonas spp. for the recommended time
• 81% patients treated with Meropenem 1000mg Q 12h
• 71% with Piperacillin/Tazobactam 4.0/0.5 g Q 6h
• 53% with Ceftazidime 2000 mg Q 12h
• 0% with Cefepime 2000 mg Q 12h
• Seyler L et al: Recommended b-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy. Crit Care 2011;15:R137
Do We Meet Pharmacodynamic Targets in CRRT?
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Dosing antibiotics in septic critically ill patients receiving Renal Replacement Therapies…
Mortality rate of critically ill patients receiving renal replacement therapy (RRT) is ~60% (Uchino et al 2005) In the USA, severe sepsis & septic shock account for ~10% of all mortality
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How do you adjust all doses?
• For example: • Vasopressors
• Pain Meds
• Sedation Meds
• Paralytics
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How should a clinician decide on antibiotic dosing in ICU RRT patients??
• Should I give everyone a “normal renal” dose?
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Give “normal” dose to all?
- 90% patients met or exceeded pharmacodynamic goals - 53% had dangerously high antibiotic levels
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Key Takeaways • Key Takeaway #1
• Learn how to read the machine to determine how much effluent (dialysate + ultrafiltrate) is coming out of patient. Effluent = mechanical GFR!
• Key Takeaway #2 • Use doses on high end of range vs. low end of
range for AKI patients receiving CRRT.
• Key Takeaway #3 • Although the “C” in CRRT is Continuous,
sometimes CRRT is interrupted. Be ready to reduce doses if CRRT stops
• Key Takeaway #4 • Anticoagulation very important. Know which type
you use and monitor accordingly
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If there are no published RRT antibiotic dosing recommendations...
• Consider the effluent rate as the “mechanical GFR”.
• If there is residual renal function as measured by urine output, add that to the effluent rate to figure out an empiric dose.
Be aggressive early – Loading Dose
Therapeutic drug monitoring if possible.
DO DO NOT
DO NOT use MDRD, E-GFR, Cockcroft-Gault, etc to calculate a creatinine clearance on CRRT patients!
DO NOT use the
usual hemodialysis dose – Use more!
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My “Best Practices” for Antibiotic Dosing in ICU and RRT
• They can be summed up easily…
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Be Aggressive in your CRRT Antibiotic Dosing!
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• The main advantage of CRRT over other types of renal replacement therapies is which one of the following?
A. Faster electrolyte normalization
B. Superior fluid control
C. Faster recovery from acute kidney injury
D. Lower mortality rates
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• Which of the following statements is true regarding CRRT modalities?
A. CRRT should be performed with a peripheral blood access
B. CVVH uses a dialysate
C. IV fluids can be only be given after the filter in CVVH or CVVHDF
D. CVVH, CVVHD, CVVHDF all use the same types of filters
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• Which of the following statements is true regarding CRRT modalities?
A. Faster effluent rates are associated with improved outcomes
B. Effluent rates should be adjusted based on patient size
C. CVVHDF is associated with better patient outcomes than CVVHD or CVVH
D. Drug dosing in CVVH differs from dosing in CVVHD and CVVHDF
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• Which one of the following statements is true regarding CRRT anticoagulation?
A. Heparin yields longer filter life than citrate
B. Oral citrate (Shohl’s solution) is as effective as parenteral citrate
C. Cirate use is unaffected by liver disease
D. Citrate anticoagulation requires concomitant calcium administration
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• Drug dosing in CRRT is most affected by which of the following CRRT conditions?
A. Effluent rate
B. Blood flow rate
C. Net fluid loss
D. Hemofilter type