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Drug dosing & CRRT - Crit Care · PDF file · 2011-05-05Drug dosing & CRRT Roop...
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Drug dosing & CRRT
Roop Kishen,
Formerly:
Consultant, Intensive Care Medicine & Anaesthesia,
ICU, Salford Royal NHS Foundation Trust.
Hon Lecturer, Translational Medicine & Neurosciences, University of
Manchester, Manchester.
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An Apology!
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Drug dosing in critically ill –
what is the problem?
• Critically ill patients
• Drug dosing extrapolated from ‘ward
patients’
• Critically ill with AKI!
• Drug dosing extrapolated from CRF patients
• Poor understanding of pathophysiology
• Poor understanding of PD and/or PK
• ‘Not very efficient systems of RRT’!
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Back to the basics!
• Under normal physiological conditions
& normal hydration
• Normal glomerular filtrate – 180 l/day
• Or – 7500 ml/hr
• Or – 125 ml/min
• The normal creatinine clearance!
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CC of CRRT systems
Modality Filtrate ml/hr Filtrate ml/min CC – ml/min
CAVH 500-600 8-10 10
CVVH* 2000 33.3 35
CVVH** 1250 20.3 22
CVVH
(35 ml/kg/hr)
2800
(for 80 kg patient)
46 48-50
*Brocklehurst, Thomas, Kishen et al 1996; Anaesthesia 51:551
** Dorval et al 2003 Intensive Care Med 29:1186
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PK and PD in the critically ill
• Altered pathophysiology
• Affects pharmacokinetics
• Which affects pharmacodynamics
• Drug efficacy at target site
• Poor understanding of these principles
• Paucity of literature to date
• Opinions, opinions, opinions!!!!!!
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PK – points to remember
• Volume of distribution – Vd
Total amount of drug in the body
• Vd =
Concentration of drug in plasma
• Vd – determines the loading dose
• Clearance – Cl – renal & non-renal
• Determines half life – t1/2
• Protein binding
• Critically ill – altered Vd & Cl & protein binding
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Drug dosing in
critically ill –
Basic principles
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Drugs in critically ill
• Most drugs given IV - infusions
• Sedatives, narcotics, inotropes
• Little literature
• Effect easily monitored
• Most studies – antibiotics
• Still - inappropriate recommendations
• ‘Nomograms’!
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Drug dosing in critically ill
•Hyperdynamic circulation
• Volume of distribution
•Hypoalbuminaemia
• Increased renal elimination
• Renal & hepatic dysfunction
• Increased acute phase proteins
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Implications!
Antibiotic Usual dose Recommended dose Comments
Ciprofloxacin 400 mg bd 400 mg tds As MIC o.5 mg/l
Vancomycin 1 g bd 1 g tds Continuous
infusions better
Aminoglycosides 5 mg od 7 mg od initial dose Irrespective of CC
Colistin ↑ dose to tds
Linezolid Continuous infusion: 300 mg loading &
900 mg infusion - day 1, then 1200 mg/day
continuous infusion
Varghese et al 2010; Curr Opin Anaesthesiol 23:472-78
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Drug dosing in renal dysfunction
• Can be a difficult area
• Stable chronic renal failure patients
• BNF nomograms for these patients
• The ‘RENAL’ book!
• Extrapolated to critically ill with AKI!
• Critically ill (±AKI; ±CRRT) – different
• No relation to chronic ward patients
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Drug dosing in
patients with AKI
and receiving CRRT
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Chronic stable renal failure VS AKI
Parameter Chronic stable patient Critically ill, Septic, AKI
Body water Contracted Expanded
Serum albumin Normal (may be low) Low
VD Contracted Expanded
Biochemistry ↑ Urea, Creatinine, PO4 Near normal biochemistry
RRT mode IHD CRRT
Cardiac Output Low (may be normal) Usually high (normal – low)
Frequency Dialysis every 2-3 days Continuous
Medications Concomitant long term drugs Usually none
Cumulative CC 35 – 45 ml/min (intermittent) >45-50 ml/min (continuous)
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AKI & drug metabolism
• Anuric AKI – No renal elimination
• Changes in non-renal elimination
• ‘Hidden’ clearance
• Liver most important
• Different in AKI, may be increased
• Paucity of studies
• Poor literature evidence
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Non-renal clearance & AKI
• Altered hepatic elimination
• Altered hepatic blood flow
• Altered protein binding
• Effect on CY P- super family
• Effect on transporters
• Depression of P-glycoprotein activity (Pgp)
• Organic anion transporters (OAT1, OAT3)
• Effect of uraemic toxins – possibly through
effect on CYP3A4
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Fluconazol story!
• Fluconazol cleared at first pass in kidneys
• 85% clearance by kidneys; no hepatic clearance
• Reabsorbed in renal tubules
• Thus a long half life
• Twice daily dosing sufficient
• Usual dose – 200 mg bd
• Patients on IHD – 100-200 mg after dialysis
• Till next dialysis
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Fluconazol story!
• Now consider a patient on CVVH
• Drug filtered like normal nephron
• But filter is a ‘stupid’ nephron
• No reabsorption
• Fluconazol cleared but not reabsorbed
• Need higher doses – i.e., 400 mg bd
• New recommendation – 800 mg bd!
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Factors affecting drug kinetics in CRRT
• Patient related factors
• Drug related factors
• CRRT related factors
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Patient Related Factors
• Dose
• Absorption – most drugs in ICU are IV
• Protein binding
• Low albumin
• Acidosis
• Uraemic toxins, bilirubin, free fatty acids
• Vd
• ↑ Vd in sepsis
• Water retention in AKI
• Clearance (renal & non-renal); residual renal function
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Drug related factors
• Molecular weight
• Most antibiotics <1kD
• Convective transport ↑ as MW ↑
• Protein binding
• Most antibiotics minimally protein bound
• ↓ Alb, ↓pH , uraemia, acute phase proteins
• Tubular secretion & tubular reabsorption
• CRRT clearance VS total clearance
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CRRT related factors
• Sieving coefficient
• Ability to pass though filter membrane (0-1)
• From 0.02 (oxacillin) – 0.9 (ceftazidime)
• Volume of ultrafilrate produced
• Membrane factors
• Concentration polarisation
• Porosity
• Membrane material
• Adsorption
• Pre or post-dilution
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What suggestions
for drug dosing in
AKI and RRT?
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Suggestions?
• Problematic
• Variability in RRT/CRRT
• Variable Qf
• Down times etc
• Local MIC, AUC & AUC24:MIC
• AKI is not a homogeneous entity!
• Paucity of literature
• CAVH, CVVH, CVVHD, CVVHDF???????
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Some guidance re antibiotics
Loading Dose Maintenance Dose
Pip-Tazo 4,500 mg 4,500 mg q 8 h – Tazobactam may accumulate
Meropenum 1,000 mg 1,000 mg q 12 h – q 8 h
Vancomicin 15 mg/kg 1,000 – 1,500 mg daily – Monitor levels (15 – 25 mg trough)
Aminoglycosides Once daily dose regimens – monitor drug levels
Erythromycin No dose adjustment required
Metronidazole No dose adjustment required
Cefpriome 2,000 mg 1,000 mg q 12 h
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Basic principles of drug dosing in CRRT
• Forget BNF, Renal book, data from CKD patients
• AKI & RRT reduction in antibiotic dosing
• Antibiotics in RRT require adjustments based on
mode of RRT & Qf (in CRRT)
• ↑protein binding & low Vd = ↓ elimination by CRRT
• Water solubility = ↑ elimination by CRRT
• Drugs with narrow therapeutic index = monitor levels
• Broad therapeutic index = err on higher dose
• Use basic principles and common sense!!!
• Ethambutol
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More suggestions
• AKI is a dynamic process
• AKI may affect non-renal clearance
• Metabolites may accumulate
• RTT/CRRT affect drug elimination
• Depends upon mode of RRT
• CRRT is not same as IRRT
• RRT may modify non-renal elimination
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Drugs in CRRT
• Avoid a drug if it is not needed!
• Avoid nephrotoxins if you can
• Drug dosing – extrapolated from ESRD
patients on IHD
• Inappropriate for patients on CRRT
• Monitor drug levels
• Watch out under-dosing!
• Be wary of ‘books’ on renal drug doses!
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Some important references
• Glossop J, Seidel J Intensive Care Soc 2008; 9:160
http://journal.ics.ac.uk/pdf/0902160.pdf
• Vilay AM et al Crit Care 2008; 12:235
• Choi G et al Crit Care Med 2009; 37:2268
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Be careful with
drug dosing in
AKI and in
patients on CRRT
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For those who were listening,
Questions?