Practical issues - dosing on extracorporeal circuits

Transcription

1 Practical issues - dosing on extracorporeal circuits Jason A Roberts B Pharm (Hons), PhD, FSHP Professor of Medicine and Pharmacy The University of Queensland, Australia Royal Brisbane and Women s Hospital, Australia

2 Disclosures (previous 24 months) Grants NHMRC, ANZ ICF, ANZCA, RBWH Foundation, Queensland Health, MSD, The Medicines Company, Cardeas Pharma Consultancies MSD, Bayer, Astellas, biomerieux, Accelerate Diagnostics

3 Sources of PK variability in ICU If dosing does not account for these changes sub-optimal therapy! Sub-optimal patient outcomes

4 Contents 1. RRT 2. ECMO 3. Plasmapheresis 4. Conclusions

5 Definitions CRRT Continuous Renal Replacement Therapy SCUF Slow Continuous Ultra Filtration CVVHD (3%) Continuous Venovenous Haemodialysis CVVH(F) (35%) Continuous Venovenous Haemofiltration CVVHDF (62%) Continuous Venovenous Haemodiafiltration HVHF High Volume Haemofiltration HPHF High Permeability Haemofiltration PIRRT Prolonged Intermittent RRT Is Continuous Really Continuous?????

6 Definition of Terms (Continued) SLED(D) Sustained Low Efficiency (Daily) Dialysis EDD Extended Daily Dialysis IHD Intermittent Haemodialysis SLED(D), EDD, IHD are hybrids of conventional 3x per week haemodialysis (Cheaper, â filter clotting, â anticoagulation requirements than CRRT)

7 Principles of CRRT Dialysis Removal of small molecules up to 500 daltons DIFFUSION : the transfer of a molecule through a membrane from an area of high concentration to an area of low concentration Filtration Removal of larger molecules up to 30,000 50,000 daltons CONVECTION : which is the forcing of a molecule across a membrane by the use of pressure

8 CVVH(F) Continuous VV HaemoFiltration Primary therapeutic goal: Convective solute removal Management of intravascular volume Blood Flow rate = ml/min (max 450ml/min) UF rate ranges l/hr (max 6 L/hr) Convection is controlled by pump rate No dialysate Inflammatory components may be removed Replacement fluid require to balance the loss from the ultrafiltrate

9 CVVH(F) Pre- Dilution to waste Blood In (from patient) Replacement Fluid Blood Out (to patient) Post- Dilution LOW PRESS HIGH PRESS Transmembrane Pressure (TMP) (Convection)

10 CVVHDF Continuous VV HaemoDiaFiltration Primary therapeutic goal: Solute removal by diffusion and convection Management of intravascular volume Blood Flow rate = ml/min (max 250ml/ min) Combines CVVH and CVVHD therapies UF rate ranges 1-2 L/h Dialysate Flow rate = ml/min (~1-3 L/h) Most places use 1:1 (dialysis/replacement fluid flow rate)

11 CVVHDF to waste Blood In Pre- Dilution Dialysate Solution (from patient) Replacement Fluid Blood Out (to patient) Post- Dilution LOW PRESS LOW CONC HIGH PRESS HIGH CONC (Convection) (Diffusion)

12 Factors Affecting RRT clearance Systemic Variables Blood flow to filter Site of vascular access Protein - filter interactions Membrane polarity Ultra filtrate rate Drug Variables Protein Binding Volume of Distribution Drug concentration Drug polarity Molecular Weight??

13 Molecular Weight HF using modern membranes have a molecular weight cut-off between Da Therefore HF is independent of drug size as they are generally < Da This enables the removal of large amounts of inflammatory cytokines. HD is more dependant on molecular weight (can not effectively remove molecules > 500Da)

14 Volume of Distribution Drugs with V D < 1 L/kg is more likely to be clear by CRRT than V D > 2 L/kg. Note: Vd is increased in sepsis

15 Protein Binding Only the unbound fraction is available for extracorporeal elimination Free fraction often higher in patients with renal failure and / or sepsis

16 Determinants of Sieving Coefficient (CVVHF) Protein binding Only unbound drug passes through the filter Protein binding changes in critical illness Drug membrane interactions? clinically relevant (except aminoglycosides and ACE inhibitors) Adsorption of proteins and blood products onto filter Related to filter age Decreased efficiency of filter Sc = 1 Solute freely passes through the filter Sc = 0 Solute does not pass through the filter C UF = Concentration in ultrafiltrate C P = Concentration in plasma Sc = C UF / C P

17 Sieving Coefficient

18 HF vs HDF Convection + diffusion Combined CL not additive Piperacillin CL (L/hr) Meropenem CL (L/hr) Fluconazole CL (L/hr) CVVH CVVHDF - 1 L/hr (dialysate flow rate) CVVHDF (2 L/hr) (dialysate flow rate) J Antimicrob Chemother 2000; 45: 701-4; J Antimicrob Chemother 2001; 48: 881-5

19 Equidoses of HF vs HDF: linezolid - N = 9 HDF (15 ml/kg/h + 15 ml/kg/h) and N = 8 HF (30 ml/ kg/h) - Linezolid 600mg IV q12h - Mean CL in HDF group was 20% higher than HF; not significant - Profound PK variability of linezolid described best by differences in patient weight and sickness severity

20 SLED/EDD (-f) Gentamicin Gentamicin MCS 6mg/kg q48h administered pre EDD-f

21 RRT Studies SMARRT >450 dosing PK profiles Data & analyses expected early 2018

22 Contents 1. RRT 2. ECMO 3. Plasmapheresis 4. Conclusions

23 Interplay of critical illness and ECMO

24 Clinical neonatal PK studies Vd CL Antibiotics, sedatives, analgesics most studied Drug metabolites affected as well Heparin, vasoactive drugs, diuretics, micro/macro nutrients also affected However, the PK of neonates is not the same as adults Amaker et al.antimicrob Agents Chemother 1996, 40(5): ; Shekar et al. J Crit Care Dec;27(6): 741 :Ahsman et al. Clin Pharmacokinet 2010, 49(6):

25 Meropenem and Pip/tazo case control study

26

27

28 Meropenem in ECMO and RRT PK study 11 patients with ECMO (5 RRT) 10 patients without ECMO (5 RRT)

29

30

31 Vancomycin in ECMO +/- RRT

32 Ovine caspofungin data C a s p o fu n g in C o n c e n t r a t io n ( m g /m L ) m e a n ± S E M H e a lth y S h e e p H e a lth y S h e e p o n E C M O S -A L I o n E C M O T im e ( h )

33 Population PK studies in critically ill adult patients on ECMO ACTRN , Recruiting now 5 study sites, 300 pts, 19 study drugs patients per drug Study sites Australia & New Zealand + others?

34 ASAP ECMO RECRUITING >100 drug profiles to date Recruitment continues until Dec 2018

35 Contents 1. RRT 2. ECMO 3. Plasmapheresis 4. Conclusions

36 Plasmapheresis Plasma exchange Technique to separate (remove) proteins/cells from plasma Drugs affected High protein binding Low Vd E.g. ceftriaxone, teicoplanin May require supplemental doses for timedependent drugs

37 Contents 1. RRT 2. ECMO 3. Plasmapheresis 4. Conclusions

38 Conclusion Antibiotic dosing in extracorporeal therapies is challenging Dosing principles and data from in vitro and other models are helpful! For RRT hydrophilic drugs with low protein binding most commonly need dose adjustment For ECMO - lipophilic drugs with high protein binding most commonly need dose adjustment Use TDM where possible Results from current studies will be valuable!

39 @jasonroberts_pk