【持续性肾脏替代治疗crrt英文精品课件】citrateanticoagulation—stateoftheartandbeyond

CITRATE ANTICOAGULATION STATE OF THE ART AND BEYOND,Prof. Dr. Karl Trger Department of Cardioanaesthesiology, University Hospital Ulm, Germany,14 Sunedrio Entatikh Qerapeia & Epeigousa Iatrikh Aqhna, Ellada 25.-26. Nobembriou 2011,History of CRRT,1913 Dialysator (John Abel, USA) First dialysator with components of a modern system collodium tubes Animal experiments Anticoagulation with hirudin,History of CRRT,1924 Hemodialysis (G. Haas, Germany) First human hemodialysis (Duration 15 minutes) 1927 Anticoagulation with heparin,History of CRRT,1977 First report of a continuous renal replacement therapy (CRRT) by Kramer P et al. Arteriovenous haemofiltration: A new and simple method for treatment of overhydrated patients resistant to diuretics. Klin Wochenschr 1977, 55: 1127 CAVH BF 100 ml/min UF 200-600 ml/h Duration up to 48 h,Activation of coagulation during CRRT,Contact of blood with artificial surfaces Blood-air contact (airtraps) Nonlaminar blood flows Intermittend blood flow stoppage Haemoconcentration in the dialysator,Preterm clotting of extracorporeal circuit leads to.,Decreased efficacy of CRRT Increased blood loss and need for transfusions Workload Costs,Strategies to avoid preterm filter clotting,Optimisation of blood flow, adequate function of dialysis catheter Position of vascular access Material and construction of intravascular catheter Mode and setup of CRRT CVVHD vs. CVVHF vs. CVVHDF Limited UF rate( 20-25%) Predilution vs. Postdilution Biocompatible membranes (Polyacrylonitrile PAN / AN69, Polyamide, Polysulfone) Anticoagulation,Epidemiology of CRRT CRRT: A worldwide practice survey. The Beginning and Ending Supportive Therapy for the Kidney (BEST) Kidney Investgators Uchino S et al., Intensive Care Med 2007: 33: 1563,Renal replacement therapy for acute renal failure: a survey of practice in adult intensive care units in the United Kingdom Gatward JJ et al., Anaesthesia 2008, 63: 959,Anticoagulation during CRRT The ongoing dilemma,Efficacy of anticoagulation with sufficient filter lifetime Safety Feasibility General applicability Risks and adverse effects Sufficient control and reversibility,Characteristics of an ideal“ anticoagulant,Effective anticoagulation Low risk for bleeding Good control Reversibility Safe and easy handling Easy monitoring No/low adverse effects No incompatibility Cost effectiveness,CRRT: A worldwide practice survey. The Beginning and Ending Supportive Therapy for the Kidney (BEST) Kidney Investgators Uchino S et al., Intensive Care Med 2007: 33: 1563,History of citrate anticoagulation,Morita Y et al. Am J Med Sci. 1961, 242: 32-43 Regional anticoagulation during hemodialysis using citrate Pinnick RV et al. N Engl J Med 1983, 308: 258-261 Regional anticoagulation during hemodialysis using citrate,History of citrate anticoagulation,Mehta RL et al. Kidney Int 1990, 38: 976-81 Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients,Why did it take so long for citrate to be widely used?,Manual set-ups require intensive training for the many people working on the ICU Physicians: understand the complexity of anticoagulation, acid-base and calcium control Nurses: learn to deal with the complex device combinations Safety issues resulting from non-integrated citrate and calcium pumps Matching fluids (e.g. citrate solution, adapted CRRT-fluid) not easily available,Complexity reduction by design, one device and one user interface,Integration of both pumps,Legally conform availability,Citrate Anticoagulation: A lot of decisions to be made,Which citrate concentration? Low 11 20 mmol/l = high degree of predilution effect Medium for example 4% citrate / ACD-A with 136 / 113 mmol/l High approx. 1000 mmol/l = risks due to inadvertent bolus application Sodium citrate and/or citric acid? Both achieve anticoagulation and both require metabolism But different net-effect on acid-base status,4% trisodium citrate (established in apheresis),No use of citric acid,Citrate Anticoagulation: A lot of decisions to be made,Which CRRT-modality? CVVHD enables low blood flow and reduces citrate infusion Convective clearance with CVVH as the basis modality Ca2+ in the CRRT-fluid? Ca2+ in the CRRT fluid results in higher citrate demand Mg2+ in the CRRT-fluid? Mg2+ in the CRRT-fluid requires slightly more citrate Without Mg2+ in the CRRT-fluid increases the complexity due to separate Mg2+ infusion,CVVHD, but with large hemofilter,Ca2+-free dialysate,Mg2+ in the dialysate,Anticoagulation with citrate,Ca2+ is a cofactor of coagulation Inactivation of ionised (free) Ca2+ by chelation with citrate With inonised Ca2+ 0.2 to 0.4 mmol/l coagulation blocked by slowing thrombin generation 3 to 4 mmol citrate per l blood decrease ionised Ca2+ below 0.4 mmol/l Thrombin itself is expected to stay active,Physiology of plasma Ca2+ distribution,Physiology Total Ca2+ 2.2 - 2.6 mmol/l Ionised (50%) 1.2 - 1.3 mmol/l Protein bound (40%) 0.9 - 1.2 mmol/l Complex bound (10%) 0.2 mmol/l,Citrate anticoagulation Total Ca2+ 2.2 - 2.6 mmol/l Ionised (25%) 0.3 - 0.4 mmol/l Protein bound (40%) 0.9 - 1.2 mmol/l Complex bound (35%) 0.8 mmol/l,Elimination of Ca2+ citrate complex,Part 1: Transmembranous elimination via hemofilter by diffusion convection Part 2: Appearance in the systemic circulation with consecutive metabolism in the liver, adrenals, muscle resulting in bicarbonate formation 1 mmol citrate 3 mmol HCO3-,Monitoring,ACT or aPTT post filter in the extracorporeal circuit (pre Ca2+ substitution !) But: no linear correlation Analysis of ionized Ca2+ (iCa2+) in the extracorporeal cirucuit (post filter) in the blood gas analysis Interval 3-6 hours,Potential adverse effects of citrate anticoagulation,Metabolic alkalosis Citrate metabolism results in bicarbonate formation Caveat: Use of dialysate fluids with high bicarbonate Metabolic acidosis Hypocalcemia (Ca2+ substitution !) Hypernatremia Trisodium citrate Caveat: Use of dialysate fluid with high Na+ (140 mmol/l) Hypomagnesemia (Mg2+ substitution !),Citrate-CVVHD: Implementation in Berlin Morgera S et al., Nephron Clin Pract 97:c131-c136, 2004,Citrate-CVVHD with buffer-free dialysis fluid (1 l/h) and 100 ml/min blood flow,Frequency of development of metabolic alkalosis,Protocol for citrate based CRRT,trisodium citrate solution (4% resp. 136 mmol/l citrate),Multifiltrate CiCa Fresenius Medical Care,Multifiltrate CiCa (FRESENIUS MEDICAL CARE),Machine Fresenius Multifiltrate with CiCa module Mode CVVHD Solutions 4% trisodium citrate 136 mmol/l Citrate Bags 1000 ml CaCl2 1 N resp. 0,5 M CiCa Dialysate K2 Potassium 2 mmol/l Calcium 0 mmol /l 5 L two-chamber bags Materials Multifiltrate CiCa Kit 1000 10 l filtrate bags,Solutions for citrate based CVVHD FRESENIUS KABI,CiCa Dialysate K2 Fresenius Kabi Na+ 133 mmol/l K+ 2 mmol/l Ca2+ 0 mmol/l Mg2+ 0,75 mmol/l Cl- 116,5 mmol/l Bicarbonate 20 mmol/l Glucose 1 g/l,Solutions for Ca2+ substitution,Calcium gluconate 10% B. Braun Ca2+-gluconate 94 g/l equals Ca2+ 0,23 mmol/ml,Calcium chloride 1 normal (0,5 M) Serag-Wiessner CaCl2 73,5 g/l equals Ca2+ 0,5 mmol/ml Cl- 1 mmol/ml,Fully integrated citrate anticoagulation,Control of the Ci-Ca pumps via the user interface of the multiFiltrate,Calcium pump,Citrate pump,Improvements due to integration of the citrate pump,Control of potential errors No unintended continuation of the citrate pump (e.g. in case of treatment stop) Citrate infusion proportional to blood flow select citrate dose in mmol/l: mmol citrate per liter treated blood easy to understand description of the ratio between citrate solution and blood flow automatic adjustment of the citrate infusion according to the blood flow,Added safety by integration of the calcium pump,Control of potential errors Dismantling of the calcium infusion after therapy stop cannot be forgotten Calcium infusion is stopped during treatment interruptions (e.g. bag changes) Coupling the calcium infusion with the effluent flow Automatic adjustment of the calcium infusion to the Ca2+ removal with the effluent Treatment parameter “Calcium dose” relatively independent from other treatment parameters (such as dialysate flow),Ci-Ca CVVHD: Scheme and typical flows,5 flows selectable = 5 treatment goals achievable,Treatment Goals with Citrate-CVVHD multiFiltrate screen during citrate anticoagulation,Citrate dose regional anticoagulation,Ca2+ Dose Ca2+ balance,Blood and Dialysate flow CVVHD efficacy acid-base status,Ultrafiltration volume removal,multiFiltrate CiCa cassette: Comprehensive set-up instructions,multiFiltrate CiCa cassette,Citrate line guided on the cassette Intuitively correct assignment of pump segments and pumps,to the patient,to the solution bags,multiFiltrate CiCa cassette: Safe connection with the catheter,Citrate and calcium lines connected with the blood lines Mixing-up of citrate and calcium lines at the catheter excluded,Double-lumen tubings to the patient Clearly laid-out course of the tubings between the device and the patient,citrate,calcium,Safety features enabled by full integration,Comprehensive set-up instructions,Pre-fixed connections avoid mistakes,How much citrate is needed for regional anticoagulation?,Gabutti et al. Intensive Care Med 28:14191425, 2002,Time since start of a new hemofilter h,Citrate dose about 2.6 mmol/l (mmol citrate per liter treated blood),Ci-Ca Treatment: Prescription of the citrate dose,General approach,Prescription of the citrate dose,*: if clinically indicated, additional measurements should be done,Ci-Ca Treatment: Prescription of the citrate dose,General approach,Prescription of the citrate dose,*: if clinically indicated, additional measurements should be done,Initial choice and adjustment of the citrate dose,Initial citrate dose 4.0 mmol/l Monitoring post-filter ionised Ca (venous/blue sampling side) after start of the treatment (about 5 min) to ensure that citrate and calcium solutions have not been mixed up regular measurements (e.g. every 6 h) adjust the citrate dose according to the table,Ci-Ca Treatment: Prescription of the calcium dose,Prescription of the Ca-dose,General approach,*: if clinically indicated, additional measurements should be done,Ci-Ca Treatment: Prescription of the calcium dose,Prescription of the Ca2+ dose,General approach,*: if clinically indicated, additional measurements should be done,Initial choice and adjustment of the calcium dose,Initial Ca2+ dose 1.7 mmol/l Monitoring systemic ionised Ca2+ sample from arterial catheter sample from the “arterial”/red sampling side while the blood pump is running regular measurements each 6 h in stable patients adjust the calcium dose according to the table,Why calcium needs to be substituted?,Compensation of the citrate effect in case of citrate-induced hypocalcemia Citrate effect on systemic ionised calcium only transient, due to fast metabolism Neutral calcium balance (Key reason) Removal of calcium with the effluent, as with citrate anticoagulation mostly calcium-free fluids are used negative calcium balance in case of missing calcium substitution,Ci-Ca Treatment: Control of the acid-base-status,Prescription of the ratio between dialysate and blood flow (D/B ratio),General approach,*: if clinically indicated, additional measurements should be done,Ci-Ca Treatment: Control of the acid-base-status,Prescription of the ratio between dialysate and blood flow (D/B ratio),General approach,*: if clinically indicated, additional measurements should be done,Dialysate flow influences efficacy and acid-base status,Blood and Dialysate flow Adjustment of the acid- base status,CiCa CVVHD: Effect of blood and dialysate flow on the acid-base status,Management of the acid-base status,Possible interventions in case of metabolic acidosis,More blood flow,Less dialysate flow,or,Possible interventions in case of metabolic alkalosis,Less blood flow,More dialysate flow,or,Increasing the efficacy of Ci-Ca CVVHD,More dialysate flow,and,More blood flow,What about the efficacy of middle molecule elimination with CiCa CVVHD?,Ci-Ca CVVHD with Ultraflux EMiC2,Enhanced Middle Molecule Clearance comparable to CVVH Substantially stable albumin levels Reliable citrate anticoagulation High efficacy with low blood flows,Citrate metabolism requires availability of oxygen,Recognition of citrate accumulation due to effects on Ca2+,Effects on calcium: clinically clear sign for reduced citrate metabolism,Effects on the acid-base status: clinically more rare, frequently other causes,Metabolic acidosis due to reduced systemic citrate infusion?,Correct with bicarbonate,Possible reactions to a citrate accumulation,Clinically relevant citrate accumulation? Criteria: Heavy drop of ionised calcium concentration Total calcium 3 mmol/l Ratio total calcium/ionis. calcium 2.5,Continue Ci-Ca treatment,1. Reduction of citrate dose combined with that of the systemic citrate infusion, accept higher value for the post-filter-Ca for instance 0.4-0.5 mmol/l,2. Reduction of blood flow and systemic citrate infusion, blood flow should not be below 60 ml/min in relation to 1500ml/h dialysate,Continue Ci-Ca treatment, monitor closely,End Ci-Ca treatment,Check for citrate accumulation routinely or in the situation of a clinical suspicion (e.g. hypoxia),Yes,No,Yes,No,No,Yes,No,Check-up still shows clinically relevant citrate accumulation?,Check-up still shows clinically relevant citrate accumulation?,Yes,Case Report: Citrate Accumulation,Ratio Ca2+ges/iCa2+ = 3,2,Quit citrate anticoagulation Switch to use bicarbonate buffered dialysate (e.g. MultiBic),Labaratory parameters monitoring during CiCa CVVHD,Post filter ionised calcium iCa2+ 5 min after start 8 h intervals goal: 0,25 - 0,34 mmol/l Systemic ionised calcium iCa2+ 4-6 h intervals goal: 1,12 - 1,20 mmol/l Acid-base status parameters 4-6 h intervals Bicarbonate / BE / pH Total calcium 1x per day Ratio Ca2+tot / iCa2+ 2,5 Magnesium 1x per day Phosphate 1x per day,Citrate anticoagulation,Filter and system change after 72 h (manufacturers warranty for pump segments) No precaution interval preoperatively or preinterventional Additional systemic anticoagulantion as necessary with e.g. Heparin (UFH, LMWH) Orgaran Lepirudin Argatroban Prostaglandins,Citrate anticoagulation: Clinical results,Is regional citrate superior to systemic heparin anticoagulation for continuous renal replacement therapy? A prospective observational study in an adult regional critical care system Bagshaw SM et al., J Crit Care 2005, 20: 155 161,N = 87 Citrate n= 54 Heparin n= 29 Saline n=4,Citrate anticoagulation: Clinical results,N= 20 Patienten The median lifetime of hemofilters was 70 h (interquartile range 44-140) with citrate anticoagulation and 40 h (17-48) with heparin (p=0.0007). One major bleeding occurred during heparin anticoagulation and one metabolic alkalosis (pH=7.60) was noted with citrate.,Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: a prospective randomized study. Monchi M et al., Intensive Care Med 2004, 30: 260,Citrate anticoagulation: What is the evidence?,Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Oudemans-van Straaten HM et al., Intensive Care Med, 2006: 32 :188 If facilities are adequate, regional anticoagulation with citrate may be preferred (grade C) If bleeding risk is increased, anticoagulation with citrate is recommended (grade D),Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Oudemans-van Straaten HM et al., Intensive Care Med, 2006: 32 :188,Risk of bleeding not increased Use UFH (APTT 11.4 times normal) or LMWH (anti-Xa 0.250.35) When systemic anticoagulation is not indicated regional anticoagulation with citrate may be preferred (grade C),Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Oudemans-van Straaten HM et al., Intensive Care Med, 2006: 32 :188,Heparin-induced thrombocytopenia Stop UFH or LMWH (grade C) Use citrate for anticoagulation of the circuit and provide systemic thromboprophylaxis (grade E) For systemic therapy use (grade E) danaparoid (anti-Xa 0.250.35 U/ml) fondaparinux argatroban,Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Oudemans-van Straaten HM et al., Intensive Care Med, 2006: 32 :188,Risk of bleeding increased Use regional anticoagulation with citrate (grade C) CRRT without anticoagulation can be considered, especially with coagulopathy (grade E) Prostaglandins might be considered (grade E),Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Oudemans-van Straaten HM et al., Intensive Care Med, 2006: 32 :188,Increased tendency to clotting addition of prostaglandins to UFH or LMWH (grade C) application of predilution (grade C) combined systemic anticoagulation with regional citrate can be considered (grade E),Safety of citrate anticoagulation Continuous venovenous hemofiltration with citrate-based replacement fluid: efficacy, safety, and impact on nutrition Bihorac A et al., Am J Kidney Dis 2005, 46: 908-918,Good safety with use of citrate based predilution during CVVH with volumes up to 72 l/d Diffusive clearance of citrate via filter avoids potential citrate accumulation and citrate toxicity High convective elimination of citrate (sieving coefficient 0,9) No clinically relevant adverse effects even in patients with hepatic disease,Regional citrate anticoagulation in patients with liver failure supported by a molecular adsorbent recirculating system Faybik P et al. Crit Care Med 2011, 39 : 273,Conclusions: Our results suggest that regional citrate anticoagulation is a SAFETY safe and feasible method to maintain adequate circuit lifespan RISK OF BLLEDING without increasing the risk of hemorrhagic complications ACID-BASE STATUS AND