23/03/2018. Expensive Care. RRT in the critically ill Jill Vanmassenhove I hate to tell you this, but that should be INTENSIVE Care

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1 RRT in the critically ill Jill Vanmassenhove Expensive Care I hate to tell you this, but that should be INTENSIVE Care

2 When to General 2 Intoxications 3 Specific clinical conditions When to General 2 Intoxications 3 Specific clinical conditions Epidemiology Wald/AJKD/205 2

3 When to General 2 Intoxications 3 Specific clinical conditions WHEN TO START= OBVIOUS? We re al little concerned about your potassium levels When to General 2 Intoxications 3 Specific clinical conditions Factors influencing the decision to start RRT Clinical symptoms Solute level BUN scr Interval between ICU/hospital admission and RRT initiation Days between biochemical diagnosis of AKI and RRT Severity of AKI AKIN/RIFLE classification Prognostic scores Number of organ failure Availability of equipment and personnel Macedo/Seminars in Dialysis/20 Advantages and shortcomings of earlier RRT initiation in AKI Advantages More effective reversal of volume expansion, particularly in diureticresistant patients Better control of electrolyte and acid base status Pro active clearance of toxic low and middle molecular weight solutes Avoidance of AKI-related emergencies, (eg cardiac dysrhythmias related to hyperkalemia Shortcomings Exposure to complications associated with supplemental vascular access (both at time of insertion and therafter- infections, thrombosis, emboli, ) Exposure to complications associated with RRT (e.g. intradialytic hypotension, dysrhythmias, clearance of antibioticshypokalemia, hypoglycemia..) Higher cost, especially if patient was destined to recover kidney function Adapted from Wald, Bagshaw, Semin Nephrol 36:78-84, 206 3

4 When to General 2 Intoxications 3 Specific clinical conditions DO WE START TOO LATE? BUT HOW DO WE DEFINE EARLY VS LATE? When to General 2 Intoxications 3 Specific clinical conditions Early initiation of RRT may have a beneficial effect on survival Karvellas/CC/20 ELAIN AND AKIKI TRIALS: COMPARISON OF early VERSUS delayed RRT ELAIN AKIKI Zarbock/JAMA/206 Gaudry/NEJM/206 4

5 Differences in design and methods between ELAIN AND AKIKI Bagshaw/Nat Rev Nephrol/206 Mendu/CJASN/207 When to General 2 Intoxications 3 Specific clinical conditions Hemodialysis Hemofiltration Hemoperfusion Solubility water water Water or lipid Molecular weigth Protein binding Volume of distribution Endogenous clearance Distribution time <500 Da < Da < Da Low (<80%) low Low or high <L/kg <L/kg <L/kg <4ml/min/kg <4ml/min/kg <4ml/min/kg short longer short 5

6 When to General 2 Intoxications 3 Specific clinical conditions De Pont/Curr Opin Crit Care/2007 When to General 2 Intoxications 3 Specific clinical conditions Methanol CH 2 OH ADH - Fomepizole HCHO Formaldehyde AldDH Formate HCOO - Folate Metabolic acidosis Blindness Coma CO 2 + H 2 O Mégarbane/Open Access Emergency Medicine/200 When to General 2 Intoxications 3 Specific clinical conditions Fomepizole in adult patients.patients not requiring hemodialysis Initial dose: 5mg/kg IV followed by 4 doses of 0mg/kg every 2 hours Maintenance dose: 5mg/kg IV every 2 hours thereafter until levels of methanol (or ethylene glycol) are reduced below 20 mg/dl, and the patient is asymptomatic with normal ph 2. Patients requring hemodialysis -Dose at the beginning of dialysis <6 hours since last fomepizole dose: do not administer dose, 6 hours: administer next scheduled dose, during dialysis: administer every 4 hours or as a continuous infusion to.5 mg/kg/h -Dose at the time hemodialysis is completed <h between last dose and the end of hemodialysis: do not administer dose at the end of hemodialysis -3h between last dose and the end of hemodialysis: administer half of next scheduled dose >3h between last dose and end of hemodialysis: administer next scheduled dose Maintenance dose off hemodialysis: give next scheduled dose 2 hours from last dose administered 6

7 When to General 2 Intoxications 3 Specific clinical conditions Recommendations for hemodialysis in ethylene glycol and methanol poisoning Arterial ph<7.0 Drop in arterial ph >0.05 resulting in a ph outside the normal range despite bicarbonate infusion Inability to maintain arterial ph > 7.3 despite bicarbonate therapy Decrease in bicarbonate concentration >5mmol/l, despite bicarbonate therapy Renal failure (scr > 265 µmol/l or rise in the scr by > 90 µmol/l) Deteriorating vital signs despite intensive supportive care Visual or neurological impairment in case of methanol poisoning Initial plasma methanol concentration > 50 mg/dl Rate of methanol decline < 0 mg/dl per 24 hours When to General 2 Intoxications 3 Specific clinical conditions When to General 2 Intoxications 3 Specific clinical conditions CRUSH Pathogenesis of ATN in rhabdomyolysis Toxic effect of urinary myoglobin Hypotension (renal ischemia) Myoglobin and urate crystal formation at low urine ph Protease release from injured muscle Lipid peroxidation? Free radical formation? Release of renal vasoconstrictor substances Warren/Muscle and Nerve/2002 7

8 When to General 2 Intoxications 3 Specific clinical conditions Zeng/Cochrane database of systematic reviews/204 When to General 2 Intoxications 3 Specific clinical conditions Blood circulation Albumin circuit Dialysate circuit Dialysate circuit MARS FLUX Dialysor diamars IE250 Adsorber (Ion exchanger) diaflux Dialysor diamars AC250 Adsorber (charcoal) When to General 2 Intoxications 3 Specific clinical conditions Albumin bound Bilirubin Bile acids Indoxylsulfate Middle chain and short chain fatty acids Para cresol Water soluble Ammonia Aromatic amino acids Creatinine IL-6 Tryptophan Protoporphyrin GABA 8

9 When to General 2 Intoxications 3 Specific clinical conditions When to General 2 Intoxications 3 Specific clinical conditions HELIOS (Prometheus) and RELIEF (MARS) trials: no difference in outcome When to General 2 Intoxications 3 Specific clinical conditions Glycogen Protein Glucose G6P Aminoacids Urea Pyruvate + H + Lactate + H + + LDH + NADH + H + NAD + 9

10 When to General 2 Intoxications 3 Specific clinical conditions Salpeter/Cochrane database of systematic reviews/200;heaf/clin Diab/20 When to General 2 Intoxications 3 Specific clinical conditions Cytokine Removal during CVVH in sepsis Inflammatory cytokines Anti- Inflammatory cytokines De Vriese/JASN/998 When to General 2 Intoxications 3 Specific clinical conditions High-volume haemofiltration for sepsis Borthwick/Cochrane Database of Systematic Reviews/203 0

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13 SC Low flux High Flux 0,6 0,5 Ureum 60 vitb2 230 β2mg 2000 MW 3

14 SCUF Qb= ml/min Quf=5-5 ml/min Costanzo/JACC/2007 Bart/NEJM/202 4

15 CVVH Qb= ml/min Qf=5-60 ml/min Osmotic demyelinsation in chronic (<48 h) hyponatremia Cerebral oedema in acute (<48 h) hyponatremia Osmotic demyelinisation 5

16 CVVHD Qb= ml/min Qf=-5 ml/min Qd=5-30 ml/min CVVHDF Qb= ml/min Qf=0-30 ml/min Qd=5-30 ml/min 6

17 Advantages No need for anticoagulation IP administration of drugs Technically simpler No risk of vascular acces related problems such as air embolism or thrombus Less hemodynamic instabilitypotentially better renal recovery Can be an option for patients with diuretic resistant heart failure Can allow for ascites removal in liver cirrhosis patients Disadvantages Less efficient for treating acute problems such as hyperk or flash pulmonary edema Not an option after abdominal and mostly also not after cardiac surgery Protein losses Potential leakage Not suitable for treating acute intoxications Not a good option for extremely catabolic patients Can be problematic in case of underlying respiratory failure Gabriel/KI/2008 7

18 CONTINUOUS=SUPERIOR? Epidemiology Wald/AJKD/205 Rabindranath/Cochrane database of systematic reviews/2007 8

19 Schefold/CC/203 9

20 Renal recovery in Continuous versus intermittent therapies Wald/Crit Care Med/204 Renal recovery in Continuous versus intermittent therapies Liang/CJASN/206 IHD CRRT HYBRID techniques? EDD SLED SLEDDf 20

21 Author Kumar et al Marshall et al Marshall et al Berbece et al Treatment name EDD SLED SLEDD-f SLED Hours/day Days/week Qb (ml/min) Qd (ml/min) Replacement fluid (ml/min) Berbece/KI/2006 EDD versus CRRT Zhang/AJKD/205 A B Increase frequency! Increase duration! C D Increase duration and increase clearance! Ricci/2008/CCM 2

22 % of treatment days 23/03/208 Morning scr after day 3 (µmol/l) CRRT SLED p value 36±49 20± Time averaged scr 36±49 95± Weekly Kt/V 7.±2. 8.4±.8 <0.00 EKRj (ml/min) 3±0 3±7 NS EKRjc (ml/min) 28±9 29±6 NS Berbece/KI/2006 COMPARISON OF MAP DURING EDD VS. CVVH. 00 P=NS CVVH P=NS P=NS 90 EDD premap midmap endmap Kumar/AJKD/2000 PERCENTAGE OF TREATMENT DAYS REQUIRING INOTROPIC SUPPORT CVVH EDD Inotrope 2 Inotropes 3+ Inotropes Kumar/AJKD/

23 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT 23

24 Synthetically modified cellulose Unmodified cellulose Synthetic 23/03/208 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT 24

25 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT Classification of clearance and dialysance Dialyzer clearance Instantaneous (cross-dialyzer) clearance Integrated time-averaged clearance, kt/v Single-pool clearance Double-pool clearance Patient clearance and ekt/v Ionic (conductivity) dialysance Continuous equivalance of clearance Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT Instantaneous clearance solute removal Bi B0 K= (Cbi Cbo)/Cbi)xQb + (Cbo/Cbi)xQuf 25

26 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT Integrated time-averaged clearance=kt/v Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT SINGLE POOL Kt/V d(vxc) = G- KxC dt K R C G V x C V= total body water K D C After 2h of diaysis: Kxt=20L and Kt/V=0,5 URR=-40/80=0,5 URR=-post SUN/pre SUN= -0/80= 26

27 Kt/V=-ln(-URR) Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT SINGLE POOL Kt/V d(vxc) = G- KxC dt K R C G V x C V= total body water Kt/V=-ln(R t)+(4-3,5R) (UF/W) K D C Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT DOUBLE POOL Kt/V d(c V ) = G- C (K D +K R ) + K C (C 2 -C ) dt K R G V C K C V 2 C 2 K D Q F d(c 2 V 2 ) = -K C (C 2 -C ) dt 27

28 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT CONTINOUS EQUIVALENT OF CLEARANCE-EKR G TAC COMPARISON OF DIFFERENT MODALITIES AND SCHEDULES Casino/NDT/996 Casino/NDT/996 28

29 Casino/NDT/996 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT Dialysance (D) (ml/min) Diffusive force Blood Membrane Dialysate D = QB x (CBi-CBo) CBi-CDi Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT Ionic Dialysance (D) (ml/min) Based on changes in the conductivity of the dialysate after a step up or a step down in dialysate sodium concentration Dialysance of sodium is assumed to equal urea clearance 29

30 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT Characteristics of ideal urea kinetic expression for RRT dose in AKI -Kinetic equivalence for irregular/frequent IHD or differing RRT therapies -Independent from the assumptions of urea steady state -Normalization for patient urea distribution volume to allow dose comparisons between patients of different size -Easy to calculate without compromise in accuracy -Possibility to include residual renal urea clearance if present Himmelfarb/KI/2002 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT Alternate day hemodialysis (n=80) Daily hemodialysis (n=80 p value Mortality(N/%) 37(46) 22(28) 0.0 Resolution of acute renal failure (days) 6 ± 6 9 ±

31 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT Group 3: 45 ml/kg/h Group 2: 35 ml/kg/h Group : 20 ml/kg/h Ronco/Lancet/2005 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT CVVHDF 35ml/kg/h versus CVVHDF 20 ml/kg/h SLED/IHD 6/week vs SLED/IHD 3/week Palevsky/NEJM/2008 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT CVVHDF 40ml/kg/h versus CVVHDF 25 ml/kg/h Bellomo/NEJM/2009 3

32 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT Evanson/AJKD/998 Efficiency and dose Dialyzer 2 Clearance 3 Dose in acute RRT 32

33 Anticoagulation General 2 Citrate 3 HIT Anticoagulation General 2 Citrate 3 HIT KDIGO AKI guidelines/ki/202 33

34 Anticoagulation General 2 Citrate 3 HIT Anticoagulation General 2 Citrate 3 HIT KDIGO AKI guidelines/ki/202 Liu/Critical Care/206 34

35 Liu/Critical Care/206 Anticoagulation General 2 Citrate 3 HIT Anticoagulation General 2 Citrate 3 HIT 35

36 Anticoagulation General 2 Citrate 3 HIT Risk for thrombosis in the days to weeks after stopping heparin therapy is at least 20% and possibly as high as 50% in HIT patients who present with isolated thrombocytopenia Hirsch/Arch of Int Med/

37 Anticoagulation General 2 Citrate 3 HIT O shea/seminars in dialysis/2003 Anticoagulation General 2 Citrate 3 HIT Fischer/Hemodilaysis Int/

38 Patient related factors Drug-protein complexes and molecular weight Volume of distribution Device related factors 38

39 Patient related factors Drug-protein complexes and molecular weight Volume of distribution Device related factors Patient related factors Drug-protein complexes and molecular weight Volume of distribution Device related factors Patient related factors Drug-protein complexes and molecular weight Volume of distribution Device related factors 39

40 Patient related factors Drug-protein complexes and molecular weight Volume of distribution Device related factors AUC 24 /MIC Cmax/MIC %T>MIC Matuszkiewicz-Rowinska/Pol Archiv Med Wewn/202 Killer characteristics? Time-dependent killing (e.g. Beta lactams) %T>MIC Concentration-dependent killing (e.g. Gentamycin) Cmax>MIC 40

41 990s 205 Low-permeability dialyzers Dialysis dose not quantified Dialyzer membranes less compatible Smaller surface area dialyzers CAPD Lower effluent volumes CRRT High-permeability dialyzers Kt/V urea target,2 Dialyzer membranes more compatible Larger surface area dialyzers CCPD Higher effluent volumes CRRT 990s INCREASE IN DRUG 205 CLEARANCE Mueller/Clin Pharmacol Ther/2009 Pharmacokinetic principles during continuous treatments Hemofiltration: Postdilution mode Hemofiltration: Predilution mode Hemodialysis Drug Clearance= ultrafiltration rate Drug Clearance= UF rate x (blood flow/ Blood flow + SF flow rate) Drug Clearance depends on molecular weight Böhler/KI/999 Other factors to consider -Protein binding -Blood Flow -Larger membrane surface area -Different membrane charge -Thinner membrane material -Adsorption Böhler/KI/999 4

42 Choi/200/Blood Purification Choi/200/Blood Purification 42

43 Complications Technical 2 Clinical 43

44 Complications Technical 2 Clinical Technical complications of RRT in the ICU Vascular access problems Air embolism Hemolysis Electrolyte and Acid-Base Disorders Complications Technical 2 Clinical Insertion site Complications of insertion Disadvantage Internal jugular Femoral Subclavian Punction carotid artery Pneumothorax(PT), Hemothorax(HT) Rupture superior VC Punction femoral artery Retroperitoneal hematoma Infection Punction subclavian artery Risk of PT, HT Rupture superior VC Trendelenburg required More prone to infectious complications, especially in patients with trachetomy Highest infectious rate? Highest recirculation rate Only for bed-bound patients Technically difficult High rate of central venous stenosis Trendelenburg required Complications Technical 2 Clinical p=0.53 No Bloodstream infection Bloodstream infection Hoste/JASN/

45 Complications Technical 2 Clinical BMI<28: femoral BMI>28: jugular Complications Technical 2 Clinical Complications Technical 2 Clinical 45

46 Complications Technical 2 Clinical Complications Technical 2 Clinical Complications Technical 2 Clinical Clinical complications of RRT in the ICU Bleeding and thrombosis Hypoxemia Hypotension Biocompatibility Hypersensitivity reactions Dialysis Dyequilibrium Syndrome Prolongation of renal recovery Nutritional and metabolic problems Cardiac arrhythmias Febrile reactions 46

47 Complications Technical 2 Clinical Clinical complications of RRT in the ICU RCA metabolic complications Hypophosphataemia Hypocalcemia Hyper- or Hypomagnesemia No strict criteria for RRT start but a too precocious start of RRT is not helpful and might cause further damage to an already injured kidney. No clear benefit for continous over intermittent therapies. SLED probably a good alternative Treshold dose is important but beyond that no additional benefit when increasing dose Acute PD can be considered, especially in case of heart failure and liver cirrhosis with ascites RRT is not a harmless technique Think about adapting drug dosage 47