EXTRACORPOREAL TECHNIQUES IN MODS: An Update :Techniques For Organ Support Where Are We In 2013? Prof Patrick Honoré,MD, PhD, Intensivist-Nephrologist

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1 EXTRACORPOREAL TECHNIQUES IN MODS: An Update :Techniques For Organ Support Where Are We In 2013? 1.-CRRT : A «Lego» Module? 4.-Antibiotic Adaptation During Low Dose CRRT? 2.- CRRT + ECMO: What to do? 5.- Antifungal Adaptation During Low Dose CRRT :What To 3.- CRRT + Low Flow ECCOR : What on the Shelf? 6.- Conclusions- Perspectives Prof Patrick Honoré,MD, PhD, Intensivist-Nephrologist Head of Clinics,Senior Lecturer,VUB University,Bxl(Bel) 18 th Annual Infection & Sepsis Symposium Porto Palacio Hotel,27 Feb-1st March 2013

2 ECMO + CVVH:How to Couple? Woman, 33 years old, pneumococcal pleuropneumopathy ARDS, 5 Days ventilation, aggravation, NO and PP. PaO2/FiO2 = 50 mmhg Ctp 5 ml/cmh2o. TOE = No cardiac dysfunction NA for PAM > 70 mmhg. Left pneumothorax at D5 Veno-Venous Untreatable ARDS ECMO

3 ECMO + CVVH:How to Couple? Woman, 20 Kg 33 of years hyperhydration old, 80Kg, pneumopathy ARDS, 5 Days ventilation, aggravation, NO and PP. Without AKI PaO2/FiO2 = 50 mmhg Ctp 5 ml/cmh2o. TOE = No cardiac dysfunction NA for PAM > 70 mmhg. Left pneumothorax at D5 Untreatable ARDS Despite normal diuresis Use of diuretics Failed to achieve negative balance after 24h HEMOFILTRATION

4 ECMO + CVVH:How to Couple? 22 liters removed in 3 days, PAPS decreases 50% Extubated at Day 22 Discharge from ICU after 1 month and 1 week Discharge from hospital after 2 months without O 2 4

5 Problems To Overcome When Combining ECMO + CRRT Avoid to insert a new catheter Problems of Positive and Negative Pressures ECMO run with Heparin Coated membrane because of High Flow.. CRRT do need anticoagulation.. High range of pressure tolerated in the software Citrate can be given very efficiently under these conditions..where bleeding should be avoided..

6 Low Flow ECCO²R Technique: DECAP Terragni,Ranieri,Contrib Nephrol 2010;165:

7 Low Flow ECCO²R Technique: DECAP Terragni,Ranieri,Contrib Nephrol 2010;

8 Problems and Potentials When Combining ECCO²R + CRRT Low Blood Flow (250 to 350 ml) Serie: increasing pressure and reducing bubbles Diluting Blood and reducing need of Anticoagulation Recirculating Ultrafitrate & Enhancing Performance Can reduce by 20 % the PCO² & reduce Peak Press Terragni,Ranieri,Contrib Nephrol 2010;165:

9 New Spectrum of Membrane Therapies Proteins with molecular weight 1 M Daltons have a sieving coefficient near 1 Global decrease of proteins Immunoglobulins Lipoproteins about 250,000 kda TNF decrease of about 60% Ag Removal is Feasible (Ag HBs) Dallinga et al :Atherosclerosis 2010

10 Plasmapheresis vs Plasma Exchange Plasma Exchange (PE) centrifugation membrane Plasmapheresis (PP) or Plasmafiltration (PF) PLASMA FILTER PLASMA FILTER Plasma Plasma FFP/colloid/IgG Patient Honore PM et al.ann Intensive Care 2011 Patient ADSORBANT COLUMN

11 «IVOIRE study» 200 Patients with Septic Shock and Acute Kidney Injury 35 ml/kg/h Randomization within 24 hours of ICU admission (! Early septic shock) 70 ml/kg/h Any dose of vasopressors (Noradrenaline) Or > 5µg/kg/m of Dopamine - Oliguria < 0.5 ml/kg/h - creatinine X 2 Mortality RIFLE Injury D28 D90 11

12 Hemodiafe study ATN study Renal study IVOIRE 66 /Mortality 73 % 60 % 52 % 49 %

13 FACTORS POTENTIALLY AFFECTING DRUG CLEARANCE (CRRT) DRUG PROPERTIES DEVICE PROPERTIES MOLECULAR WEIGHT COMPOSITION PLASMA PROTEIN BINDING SURFACE AREA VOLUME OF DISTRIBUTION PORE SIZE PROPORTION OF RENAL CLEARANCE ADSORPTION Honore PM.Oxford Textbook 2013:In Press

14 MOLECULAR WEIGHT Teicoplanin Q/D Vancomycin Colistin Rifampin Ceftriaxone Ceftazidime Piperacillin Cefpirome Cefepime Cefotaxime M oxifloxacin Meropenem Aztreonam Clindamycin Gatifloxacin Levofloxacin Amoxicillin Ampicillin Linezolid Ciprofloxacin Imipenem M etronidazole Pea F et al. Clin Pharmacokinet 2007;12:

15 PLASMA PROTEIN BINDING Clindamycin Teicoplanin Ceftriaxone Aztreonam Vancomycin M oxifloxacin Cefotaxime Linezolid Levofloxacin Ciprofloxacin Piperacillin Ampicillin Gatifloxacin Imipenem Amoxicillin Cefepime Ceftazidime M etronidazole Meropenem Pea F et al. Clin Pharmacokinet 2007;12:

16 SIEVING COEFFICIENT DURING CVVH Sc = C UF C P Cefotaxime Amikacin Netilmicin Tobramycin Imipenem Ceftazidime Metronidazole Piperacillin Gentamicin Vancomycin Ampicillin Penicillin Ciprofloxacin Clindamycin Ceftriaxone Teicoplanin Oxacillin 0 0,2 0,4 0,6 0,8 1 1,2 Golper TA & Marx MA. Kidney Int 1998; Suppl.66:

17 HYDROPHILIC ANTIBIOTICS LIPOPHILIC ANTIBIOTICS BETA-LACTAMS PENICILLINS CEPHALOSPORINS CARBAPENEMS MONOBACTAMS GLYCOPEPTIDES MACROLIDES FLUOROQUINOLONES TETRACYCLINES CHLORAMPHENICOL RIFAMPICIN LINEZOLID AMINOGLYCOSIDES LOW VOLUME OF DISTRIBUTION HIGH VOLUME OF DISTRIBUTION INABILITY OF DIFFUSING THROUGH MEMBRANES ABILITY OF DIFFUSING THROUGH MEMBRANES INACTIVITY AGAINST INTRACELLULAR PATHOGENS ACTIVITY AGAINST INTRACELLULAR PATHOGENS RENAL ELIMINATION AS UNCHANGED DRUG ELIMINATION AFTER LIVER METABOLIZATION Pea F & Viale P. Clin Infect Dis 2006; 42:

18 DRUG PROPERTIES CONDITIONING THE HIGHEST CRRT CLEARANCE LOW MOLECULAR WEIGHT LOW PLASMA PROTEIN BINDING LOW VOLUME OF DISTRIBUTION HIGH RENAL CLEARANCE Honore PM.Oxford Textbook 2013:In Press

19 In the critically ill-pharmacodynamics Pattern of Bactericidal Activity Post-Antibiotic Effect(PAE) Most Abx Aminoglycosides Quinolones Metronidazole Time-dependent No PAE (except Carbapenems) Conc.-Dependent With PAE Continuous Infusions High Doses with prolonged dosing interval

20 How to adapt Antibiotics (Including PK/PD )during CRRT? Honore PM, IJAO 2006;29:649-59/Honore PM Annual Update on IC 2012

21 Antimicrobial Agent Elimination Mechanism Proportion Dose Adsorbed First 24 H Current Dosages CRRT Class Effect Recommended Dosages H-A-M CRRT Amikacin Amino-glycosides Convection with Sieving of 0.9 remains the Main Mechanism but with H-A-M CRRT, Adsorption could reach perhaps 50 % (To be Confirmed ) As high as 1000 mg but no Saturation Yet Seen- Irreversible Binding- 30 mg/kg/d as first dose during Classical CRRT Yes, Class Effect and Occuring also for Tobramycin, Nethylmycin, Arbekacin Hypothetical Dose of 40 to 45 mg/kg/d as first dose during H-A- M CRRT but needs to be confirmed Colistin Adsorption by Far the Main Mechanism up to 90 % As High as between 5 MI & 10 MI No Saturation Yet Seen 9 MI as loading Dose 4.5 MI BD No 9 MI as Loading Dose Hypothetical Dose during H-A-M CRRT 4.5 MI TDS Need to be confirmed Vancomycin Convection Remains the Main Mechanism with S of Adsorption could reach perhaps 20 % Could Reach 1/3 of the loading dose and so About mg with No Saturation Yet Seen- 20 mg/kg as Loading Dose 30 mg/kg as Maintenance Dose See Levels. No Hypothetical Doses during H-A-M CRRT : Loading of 25 mg/kg and maintenance of 40 mg/kg Needs to Be Confirmed. See Levels. Teicoplanin Adsorption could be the Main Mechanism Convection is Very Poor with S of 0.15 Adsoption could explain % of Elimination Could Reach 25 % of the loading Dose and so About 200 to 250 mg. Saturation Remains Unknown 10 mg/kg as Loading Dose Every 12 hours Three Times Maintenance dose of 10 mg/kg/d See Levels. No Hypothetical Doses during H-A-M CRRT Loading Dose of 12 mg/kg per 12 Hours (3 times). Maintenance of 12 mg/kg/d Needs to be confirmed See Levels Levofloxacin Conection remains the main mechanism with S of 0.8 (about 85 % of Elimination) Satuation occurs. Saturation Coeffiecient is about 0.75 Could reach 30 % of the Loading Dose and so About 250 to 300 mg.saturation Occurs. Loading Dose of 750 mg first day.maintenance Dose of 500mg/day. Highly Suspected but Needs to be Shown. Hypothetical Doses during H-A-M CRRT Loading Dose of 1000 mg. Maintenance of 750 mg Needs to be confirmed. Honore PM, Spapen HS Chapter Annual Update ISICEM 2013

22 Azoles: Fluconazole Drug that exhibits time-dependent activity Plasma levels above the minimal inhibitory concentration (MIC) Target fluconazole plasma trough concentrations above 10 µg/ml (Surely if MIC > 8 Mg/dL) Administering a dose of either 400 mg every 12 h or 800 mg /24 H Elimination half-life below 10 hours in ICU patients under CRRT (normally 30 H) 2/3 of Fluconazole are eliminated by CRRT Dose of Fluconazole of mg every 12 h Yagasaki K et al.icm 2003;29: Trotman R CID 2005/Bergner NDT 2006

23 Fluconazole Tolerability and Safety Generally very well tolerated: no adverse events Side effects only occur in high doses (>400 mg/day) Common: headache, nausea, abdominal pain Elevated AST/ALT levels: generally mild Reported in 20% of ICU patients with fluco prophylaxis Rare: case reports of Fulminant Hepatitis Dosage (TDM ) is still very difficult Very rare: Neurotoxicity (high doses > 1200 mg/day), Prolongation of the QT interval Charlier C. JAC 2006; 57:

24 Honore PM, Jacobs R, Spapen HDAnnual Update 2012:

25 Conclusions & Perspectives CRRT should evolve towards a Module Approach (All in One System..) CRRT can be connected to an ECMO following some rules. Low Flow ECCOR will be soon available as a New Set for CRRT Liver Support.BUT Plasmafiltration could revolutionate this area During Low Dose CRRT, Antibiotics are frequently underdosed During Low Dose CRRT, Antifungals can be underdosed, especially Fluconazole Adsorption of Antibiotics by any type of Membrane including oxygenators is becoming a major issue