CRRT and Drug dosing. Karlee Johnston Lead Pharmacist Division of Critical Care ICU Education June 2017

Transcription

1 CRRT and Drug dosing Karlee Johnston Lead Pharmacist Division of Critical Care ICU Education June 2017

2 This talk In scope CRRT modalities with regard to medicine Principles of drugs with regard to dialysis Dosing considerations for CRRT Out of scope CRRT modalities for dialysis indications Dosing in IHD Dosing considerations for renal failure

3 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

4 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

5 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 ( Daltons) Drugs CVVHDF combination of both concentration and pressure modalities

6 Dialysate Solution to waste CVVHDF Blood In (from patient) Pre- Dilution Replacement Fluid Blood Out (to patient) Post- Dilution LOW PRESSURE LOW CONCENTRATION HIGH PRESSURE HIGH CONCENTRATION (Convection) (Diffusion)

7 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

8 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

9 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)

10 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

11 Renal failure dosing Use TG

12 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

13 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 % 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

14 Pharmacodynamics (PD) of antimicrobials Concentration-dependent (C max /MIC) Concentration-dependent with time-dependence (AUC/MIC) Time-dependent (f T >MIC )

15 PK/PD of antibiotic classes

16 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

17 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!

18 QUESTIONS??