CRRT and Drug dosing

Karlee Johnston

Lead Pharmacist – Division of Critical Care

ICU Education June 2017

This talk

In scope Out of scope

CRRT modalities with regard to medicine

CRRT modalities for dialysis indications

Principles of drugs with regard to dialysis

Dosing in IHD

Dosing considerations for CRRT Dosing considerations for renal failure

Which dialysis modality?• CRRT

• Continuous Renal Replacement Therapy• Umbrella term for all modes of continuous dialysis• Significant differences in terms of dialysis method and solute (drug!)

clearance• Frequently encountered modes of CRRT:

• CVVHDF

• Continuous Venovenous Haemodiafiltration• Most commonly used modality in this unit

• CVVH(F)

• Continuous Venovenous Haemofiltration• CVVHD

• Continuous Venovenous Haemodialysis• IHD

• Intermittent haemodialysis• Not commonly used in critical illness due to haemodynamic

instability

Principles of CRRT• Dialysis : CVVHD

• Removal of small molecules up to 500 daltons

• Achieved by DIFFUSION: the transfer of a molecule through a membrane from an area of high concentration to an area of low concentration

• Filtration: CVVH (F)• Removal of larger molecules 30,000 – 50,000 daltons (eg

medicines!)

• Achieved by CONVECTION which is the forcing of a molecule across a membrane by the use of hydrostatic pressure

Diffusion vs convection

• Diffusion: primary modality for dialysis• Concentration gradient• Clearance of small molecules (less than 500 Daltons)• Not many drugs

• Convection: primary modality in filtration• Pressure gradient• Clearance of larger molecules (30000-50000 Daltons)• Drugs

• CVVHDF – combination of both concentration and pressure modalities

CVVHDF

Replacement

Fluid

Dialysate

Solution

Blood In

Blood Out

to waste

(from patient)

(to patient)

HIGH PRESSURELOW PRESSURE

HIGH CONCENTRATIONLOW CONCENTRATION (Diffusion)

(Convection)

Pre-

Dilution

Post-

Dilution

Replacement fluid

• Pre-dilution

– Dilutes the blood before reaching the filter

– Reduces the solute clearance rate (including drugs)

BUT

– Lowers the risk of the filter clotting

• Post-dilution

– More concentrate blood passes through the filter

– Maximises the rate of solute clearance

BUT

– Higher risk of filter clotting

– A higher blood flow rate is required to reduce clotting risk

Theories of drug clearance

• Drugs with predominantly renal clearance will most likely require dose adjustment for RRT

• Drugs with high Vd are poorly cleared by RRT• Drug with high protein binding are poorly cleared by

RRT• Unbound fraction is active and cleared• Patients in ICU often have low albumin

• CRRT is less effective than normal kidneys at clearing drugs

• Molecular weight matters depending on dialysis modality

Other things that complicate clearance

• Residual renal function• Varied and unpredictable• How much does that influence overall clearance

• Time on and off RRT• Inconsistent• Filter clotting• Transport

• Dose• Effluent rate might matter but unclear to what extent is

unknown and in what drugs is also unknown• Most studies done on doses no longer used (40ml/kg/hr)

Dosing considerations

• Studies are varied, different CRRT modalities, doses and pre-post dilution • Very heterogeneous population• Often specifics are not reported• Not generalisable• Most do not consider other critical illness PK issues such as

increased Vd• CVVHDF is probably approx. a GFR of ~25-50mL/min

• Standard references are a reasonable start• TG• Renal Drug Handbook• Renal drug database• Consider limitations to critical care patients

Renal failure dosing – Use TG

Dosing in CRRT

• Many drugs in ICU are titrate to effect so easy to manage• Also many have large Vd and therefore not cleared by CRRT

• For others (silent PD) consider• TDM (Vanc, gent, beta lactams)• Therapeutic window

• Most antibiotics have safe toxicity profiles so ‘overdose’ is preferred to ‘underdose’

• There may be upregulation of the non-renal clearance pathways

• Remember PK/PD principals and what you’re trying to achieve

PK considerations

• Vd is important for loading doses• Patients in ICU have increased Vd for hydrophilic drugs

• “Fill the tank”

• CRRT patients may require a large loading dose• Probably 100-150% of usual dose

• Clearance is important for maintenance dosing• Is the drug renally cleared (and if so what proportion)

• Consider therapeutic window of the agent and the relative risk of under and overdosing of the agent

Pharmacodynamics (PD) of antimicrobials

– Concentration-dependent (Cmax/MIC)

– Concentration-dependent with time-dependence (AUC/MIC)

– Time-dependent (f T>MIC)

PK/PD of antibiotic classes

Pharmacodynamic considerations for CRRT

• What is the best way to achieve PD targets• Time-dependent – continuous (or extended) infusions• Concentration dependent – Large loading dose and long dosing

interval

• Consider that ICU organisms have higher MIC than non-ICU organisms• Optimising doses is critical

• Risk of under-dosing v over-dosing of antimicrobials• TDM

• Useful• Time-frames of results• Interpretation of results (Need an MIC usually)• Purpose

Take home messages

• Drug dosing in CRRT is complex• Modality• Dose• Drug characteristics• Patient characteristics

• Vd• Residual renal function• Drug regimen and indications (empiric v directed antimicrobial therapy)C

• Clearance is related to maintanence dosing not loading dose• Give a big first dose regardless of renal function and CRRT

• Heterogeneous patient population• Inter and intra patient variability

• Standard texts are useful but understand limitations and consider patient specific information in context (individualisation of dosing is essential)

• Pharmacists are handy to help!

QUESTIONS??

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