Citrate anticoagulation in CRRT：枸橼酸抗凝CRRT

Citrate anticoagulation in CRRT：枸橼酸抗凝CRRT CITRATE ANTICOAGULATION FOR CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT) IN THE CRITICAL CARE DEPARTMENT (CCD) Rationale To provide a clear and safe protocol for the administration and management of citrate anticoagulation in continuous renal replacement therapy (CRRT) in the critical care department (CCD). Expected outcomes / objectives , To identify patients requiring CRRT in whom citrate anticoagulation could be indicated , To identify patients requiring CRRT in whom citrate anticoagulation is contraindicated To set-up a citrate haemofiltration circuit on the PrismaFlex machine using the , citrate prescription , To monitor citrate therapy and adjust it accordingly to maintain anticoagulation and to avoid patient toxicity Definitions Total calcium In plasma some calcium is bound to proteins (e.g. albumin), another fraction is bound to anions (e.g. citrate and phosphate) whilst the remainder is free or ionized calcium. The amount of bound calcium and free calcium ions in the plasma is the total calcium. Changes in either the levels of free calcium (ionized) or the bound calcium will affect the total calcium. Ionized calcium Ionized calcium is the amount of free calcium (unbound calcium) in the blood (Ca++, Ca+2). Ionized calcium is clinically the most significant and is the metabolically active portion of calcium. Brand names Prismocitrate 10/2 Contains: Tri-sodium citrate (TSC): 10 mmol/L Citric-acid: 2mmol/L Calcium / Magnesium: 0 mmol/L Prism0cal Composition in mmol/L after reconstitution: Sodium 140 Potassium 0 Calcium 0 Magnesium 0.5 Chloride 106 Lactate 3 Glucose 0 Bicarbonate 32 Calcium Chloride 10% injection 1g in 10mL Each 10mL vial contains: Calcium ions 6.8mmols Chloride ions 13.6mmols Pharmocology and pharmacokinetics Ionized calcium forms an integral part of the clotting cascade. Citrate chelates (binds) ionized calcium and the concentration of ionized calcium available to participate in the clotting cascade falls. This leads to inhibition of clotting. Indications To prevent clotting of the extracorporeal circuit during CRRT anticoagulation is often required for prolonged periods of time. All patients receiving CRRT may be considered for citrate anticoagulation unless they have a contraindication. Citrate anticoagulation in CRRT is particularly well suited to patients with: , Heparin induced thrombocytopenia and thrombosis (HITTs) , Active bleeding , Recent bleeding , An increased risk of bleeding (e.g trauma, recent surgery, intracranial lesions, uraemic pericarditis, severe diabetic retinopathy, malignant hypertension) Severe coagulopathy , , Rapid clotting despite use of Heparin Contraindications Citrate is metabolized in the liver and skeletal muscle and is therefore contraindicated in patients with: , Sever liver failure , Acute liver failure , Severely reduced muscle perfusion , Uncorrected hypocalcaemia / hypercalcaemia Lack of properly trained staff (doctors and nurses) in citrate CRRT is also a contraindication as knowledge and close monitoring is required. Strict adherence to protocol is essential in order to prevent metabolic complications Precautions Impaired citrate metabolism may also occur in patients with: , Liver cirrhosis , Septic shock , Lactic acidosis Citrate regional anticoagulation may be used in these patients however more frequent monitoring is highly recommended. Issues to consider In order to administer and monitor citrate anticoagulation safely, the patient MUST also have an arterial line and a dedicated lumen on a separate CVC. The arterial line is necessary in order to perform frequent patient ionized calcium levels, to monitor acid base balance and to monitor for citrate toxicity. The dedicated lumen on a separate CVC is necessary for the administration of calcium chloride without which citrate anticoagulation cannot be commenced. When administered pre-filter, citrate prevents coagulation by chelating ionized calcium and therefore inducing deep hypocalcaemia in the haemofilter. Part of the calcium-citrate complex passes through the filter and is lost in the ultrafiltrate whilst the remainder enters the systemic circulation and is diluted with the patient’s venous blood. With this dilution in the systemic circulation, the addition of the replacement calcium and the liberation of the calcium-citrate complex through hepatic metabolism comes a rise in ionized calcium. This rise in ionized calcium means that systemic anticoagulation does not occur. Therefore patients receiving citrate anticoagulation should receive normal thrombosis prophylaxis (unless contraindicated) Dosage and prescription For optimal anticoagulation, citrate dose is adjusted in accordance with blood flow. When using the Prismocitrate 10/2 solution and the PrismaFlex machine, the PrismaFlex machine will adjust the pre-blood pump (PBP) rate in accordance with the selected citrate dose. The draw back of this simple system is that the buffer solution (PBP solution) and the anticoagulant (citrate) cannot be dosed separately as they are pre-mixed in the one bag. Target concentration of citrate of 3-5mmol/L should be attained pre-filter to reach a filter ionized calcium (ionCa) concentration target of 0.25 - 0.4 mmol/L. Always commence citrate regional anticoagulation with the citrate dose set at 3mmols / L of blood. Always commence citrate regional anticoagulation with the calcium compensation set to 85% (this needs to be changed during set up as it is not the PrismaFlex default) Prescriptions for citrate regional anticoagulation in CRRT must be documented by the medical officer on the citrate haemofiltration plan (MR 412). Blood flow rates When using Prismocitrate 10/2, the blood flow rate is directly related to the citrate dose as the pre blood pump bag contains citrate. Therefore any alteration to the citrate dose will automatically alter the blood flow rate. Because the blood flow rate and the citrate dose cannot be altered independently the priority should be given to targeting the citrate dose. On initiation of CRRT with citrate regional anticoagulation commence blood flow at 80mL/min and gradually increase to a target of 150mL/min. Once a blood flow of 150mL/min has been achieved, commence dialysate flow and adjust up to 1000mL/hr. The replacement flow should now also be commenced and adjusted up to 200mL/hr. Fluids Dialysate Fluid: Prism0cal, 5 litres Flow rate: Target is 1000 mL/hr (however commence at 0 until target blood flow rate is established) Additives: Potassium chloride may be prescribed to prevent or correct hypokalaemia (up to 20 mmols KCl may be added to the 5L Prism0cal bag). This must be documented by the medical officer on the haemofiltration plan MR 412. Replacement Fluid: Prism0cal, 5 litres Flow rate: 200 mL/hr (post replacement – this is a Gambro recommended standard to maintain adequate filter function. However commence at 0 until target blood flow rate is established) Additives: Potassium chloride may be prescribed to prevent or correct hypokalaemia (up to 20 mmols KCl may be added to the 5L Prism0cal bag). This must be documented by the medical officer on the haemofiltration plan MR 412. Pre Blood Pump (PBP) Fluid: Prismocitrate 10/2, 5 litres Flow rate: As set by the PrismaFlex machine when the citrate dose is entered. Set to deliver a citrate dose of 3 mmols/L of blood (the PrismaFlex machine will then determine the required blood flow rate to achieve this citrate target) Additives: Potassium chloride may be prescribed to prevent or correct hypokalaemia (up to 20 mmols KCl may be added to the 5L Prism0cal bag). This must be documented by the medical officer on the haemofiltration plan MR 412. Calcium replacement Due to the loss of approximately 1/3 of the citrate-calcium complex in the ultrafiltrate, additional calcium chloride supplementation above baseline is often necessary. Monitoring Four major factors requiring monitoring: , Filter anticoagulation , Patient ionized calcium levels , Acid-base balance , Citrate toxicity Filter anticoagulation Adequate circuit anticoagulation occurs when ionized calcium levels within the circuit are reduced to the target range of 0.25 – 0.4 mmol/L. Citrate anticoagulation is ALWAYS commenced at a citrate dose of 3mmol/L and adjusted according to post filter ionized calcium levels. Adjusting citrate dosage will change the patients ultrafiltrate dose as the citrate is pre-mixed in the PBP bag and is therefore administered in direct proportion to the blood flow rate. Normally we would aim for an ultrafiltration rate of 25mLs/kg/hr however with citrate the ultrafiltration dose is dependent on the citrate dose required and is therefore unable to be independently manipulated. Patient ionized calcium levels In order to prevent systemic citrate anticoagulation, patient ionized calcium levels must be maintain at a target ionised calcium levels of between 0.9 – 1.1mmol/L measured from the arterial line. The calcium chloride replacement is ALWAYS commenced at a dose of 85% compensation and is to be run on the PrismaFlex syringe driver. The calcium syringe should be connected to the PrisaFlex CA250 calcium line and attached directly to a dedicated lumen on the patients separate central venous catheter (CVC). The calcium compensation percentage is adjusted in response to the monitored ionized calcium levels. Metabolic monitoring At commencement of citrate CRRT monitor ionized calcium: , 1/24 for 4 hours , 2 hours post any change to flow rates (including citrate dose, calcium compensation) , 4/24 otherwise 6/24 monitoring of: , Na+ , K+ , Cl- , blood gas analysis , calculation of anion gap Twice daily monitoring of: , Creatinine , Urea , Total calcium to calculate Ca ratio (TotCa / ionCa) or Ca gap (TotCa minus ionCa) , Albumin , Magnesium , Phosphate Target levels Serum (patient systemic) ionized calcium of 0.9 – 1.1 mmol/L (measured from the patients arterial line) Post filter ionized calcium of 0.25 – 0.4 mmol/L (measured at the blue port of the filter circuit) Calcium ratio (total calcium ? ionized calcium) of 1.9 – 2.1:1 (total calcium is measured in pathology lab, request MUST say ‘total calcium’). Commence citrate at 3 mmols/L and calcium compensation at 85% Target patient ionized Ca++ 0.9 – 1.1mmols/L Check patient ionized Ca++ 1/24 for 4 hrs 2hrs post any change 4/24 otherwise Patient ionized Patient ionized Patient ionized Patient ionized Patient ionized Ca++ Ca++ Ca++ Ca++ Ca++ 0.8–0.9mmols/L >1.1-<1.4mmols/L >1.4mmols/L <0.8mmols/L 0.9 – 1.1mmols/L Exclude citrate Exclude citrate ? CaCl infusion by ? CaCl infusion by TARGET 5% correction 10% correction toxicity toxicity No change ? CaCl infusion by ? CaCl infusion by required 10% correction 5% correction Recheck patients Recheck patient Recheck patient ionized Ca++ in ionized Ca++ ionized Ca++ 1/24 if within 4 hrs in 1/24 if within 4hrs in 1/24 if within 4hrs of commencing of commencing of commencing citrate OR 4/24 citrate OR 2/24 citrate OR 2/24 otherwise otherwise otherwise Target filter ionized Ca++ 0.25 – 0.4mmols/L Check filter ionized Ca++ 1/24 for 4 hrs 2hrs post any change 4/24 otherwise Filter ionized Filter ionized Filter ionized Ca++ Ca++ Ca++ >0.4mm<0.25mmols/L 0.25-0.4 ols/L mmols/L if patient Patient ionized Patient ionized If patient TARGET Ca++ >0.9mmoCa++ ionized Ca++ ionized ls/L <0.9mmols/L <1.1mmols/L Ca++ >1.1mmoNo change ls/L required ? citrate by ? citrate by ? citrate by ? citrate by 0.5mmols/L 0.5mmols/L 0.5mmols/L 0.5mmols/L AND AND ? CaCl infusion ?CaCl infusion by 5% by 5% correction correction Recheck filter Recheck filter Recheck filter ionized Ca++ ionized Ca++ ionized Ca++ in 1/24 if within in1/24 if within in 1/24 if within 4hrs of 4hrs of 4hrs of commencing commencing commencing citrate OR 2/24 citrate OR 4/24 citrate OR 2/24 otherwise otherwise otherwise Problem solving (see also flow charts above) 1. Patient systemic ionized Ca <0.9mmol/L (target 0.9-1.1mmols/L) , Exclude citrate toxicity (check Ca ratio, pH and base excess) , If ionised Ca 0.8-0.9mmols/L Increase CaCl infusion by 5% correction and recheck ionised Ca 2 hours post change (or in 1 hour if within 4 hours of commencing citrate). , If ionised Ca <0.8mmols/L Increase CaCl infusion by 10% correction and recheck ionised Ca 2 hours post change (or in 1 hour if within 4 hours of commencing citrate). 2. Patient systemic ionised Ca >1.1mmols/L (target 0.9-1.1mmols/L) , If ionised Ca is >1.1mmols/L and <1.4mmols/L Decrease CaCl infusion by 5% correction and recheck ionised Ca 2 hours post change (or in 1 hour if within 4 hours of commencing citrate). , If ionised Ca is >1.4mmols/L Decrease CaCl infusion by 10% correction and recheck ionised Ca 2 hours post change (or in 1 hour if within 4 hours of commencing citrate). 3. Filter ionised Ca >0.4mmols/L (target 0.25-0.4mmols/L) , Increase citrate dose by 0.5mmols/L if systemic ionised Ca <1.1mmols/L and recheck filter ionized Ca in 2 hours (or in 1 hour if within 4 hours of commencing citrate). , Decrease CaCl infusion by 5% correction if systemic ionised Ca >1.1mmols/L. 4. Filter ionised Ca <0.25mmols/L (target 0.25-0.4mmols/L) , Decrease citrate dose by 0.5mmol/L and recheck filter ionized Ca in 2 hours (or in 1 hour if within 4 hours of commencing citrate). , Increase CaCl infusion by 5% correction if systemic ionised Ca <0.9mmols/L Nursing practice points Key points to remember: , Patients receiving citrate anticoagulation should receive normal thrombosis prophylaxis (unless contraindicated) , During citrate regional anticoagulation the composition of the replacement fluid has to be adjusted (MUST NOT contain calcium) , Metabolic monitoring is essential Adverse effects Metabolic consequences of citrate anticoagulation , The composition of the citrate solution, the citrate infusion rate, the loss of tri- sodium citrate (TSC) by filtration and metabolism of citric acid all influence acid base balance , Tri-sodium citrate acts as a buffer by conversion to citric acid in the liver yielding sodium bicarbonate , Citric acid is readily metabolized to carbon dioxide and bicarbonate by the liver, kidneys and muscle cells , Acid-base balance is subsequently determined by cellular uptake and metabolic degradation of citric acid , If citric acid accumulates then metabolic derangements can occur , Tri-sodium citrate contains a substantial amount of sodium therefore potential for hypernatraemia , Approximately 1/3 of the calcium-citrate complex is lost in the ultrafiltrate therefore potential for hypocalcaemia , The amount of calcium lost in the ultrafiltrate varies with the ultrafiltrate flow (mLs/kg/hr) and consequently the amount of buffer entering the systemic circulation varies if the ultrafiltrate flow is not fixed , If the liver fails to metabolise citric acid, bicarbonate is not produced and citrate may accumulate leading to citrate toxicity Accumulation of citrate Accumulation of citrate may be associated with metabolic acidosis or metabolic alkalosis, depending on metabolism and infusion rate. The patient’s plasma citrate concentration is dependant upon: , The rate of infusion , The loss of citrate in ultrafiltrate , Metabolic degredation Metabolic acidosis Citrate may accumulate if the liver and skeletal muscle fail to metabolise citric acid, and may occur in decompensated liver cirrhosis or severe shock. In this case acid accumulates and metabolic acidosis occurs with a widening anion gap. As citrate binds to calcium, systemic ionized calcium falls and chelated (bound) calcium increases. Total calcium remains constant or rises depending on the amount of calcium infused to correct hypocalaemia. If the replacement calcium infusion is increased to compensate for low ionized calcium, most of this calcium becomes bound to citrate and a disproportionate rise in total calcium occurs whilst ionized calcium remains low. Cause: Accumulation of citrate can occur in patients with liver failure or poor muscle perfusion Signs: , Metabolic acidosis , Increasing anion gap , Falling ionized calcium , Rising calcium ratio (TotCa / ionCa) or calcium gap (TotCa minus ionCa) , Increased lactate Treatment: , Reduce or stop citrate , Continue CRRT without anticoagulation (or with heparin unless contraindicated) , Replace calcium (target ionized calcium = 0.9 -1.1mmol/L) Metabolic alkalosis As the ultrafiltrate rate gradually declines (as occurs with decreased filter performance), larger amounts of citrate may enter the systemic circulation. Providing liver function is normal, citrate is metabolized and yields sodium bicarbonate leading to metabolic alkalosis. Metabolic alkalosis and hypocalcaemia may also occur if accidentally too much citrate is infused, the patient has received a large volume blood transfusion or the ultrafiltrate flow is too low. Cause: Accidental over infusion of citrate OR reduced ultrafiltrate flow Signs: , Metabolic alkalosis , Low ionized calcium , Proportional rise of calcium ratio Treatment: , In case of accidental over infusion - stop citrate , In the case of decreased ultrafiltrate flow - the best treatment is to change the filter. Reducing the citrate dose may lead to filter clotting and is therefore not recommended. Hypocalcaemia If citrate accumulates systemically, hypocalcaemia may occur as the citrate binds to calcium. It may also occur by loss of calcium in the ultrafiltrate as the citrate-calcium complex. Cause: Accumulation of citrate Signs: , Metabolic acidosis OR metabolic alkalosis depending on reason for citrate accumulation , Low ionized calcium , Rise of calcium ratio Treatment: , Depending on cause of citrate accumulation, see above Cause: Increased loss of calcium bound to citrate through ultrafiltration Signs: , Metabolic alkalosis , Low ionized calcium , Proportional rise of calcium ratio Treatment: , Supplemental calcium replacement to target of ionCa 0.9 – 1.1mmol/L Hypernatraemia Cause: Tri-sodium citrate contains a substantial amount of sodium, therefore if the citrate flow is high relative to the ultrafiltration rate, sodium levels will rise Signs: , Hypernatraemia (serum sodium >145mmol/L) Treatment: , Change filter if reduction in ultrafiltration rate is due to reduced filter performance , Replace low sodium, buffer-free solution Hypomagnesemia Cause: Increased loss of magnesium bound to citrate through ultrafiltration Signs: , Hypomagnesemia (serum magnesium <0.75mmol/L) Treatment: , Check magnesium levels twice daily , Supply replacement magnesium as well as calcium replacement Hypophosphataemia Cause: High pre-dilution flow rates or long filter life may result in high dose of haemodialysis Signs: , Hypophosphataemia (serum phosphate <0.7mmol/L) Treatment: , Check phosphate levels twice daily until stable , Supply replacement phosphate as required Citrate toxicity Citrate toxicity occurs when citrate metabolism is insufficient for the citrate load. Cause: Liver impairment Signs: , Increase total calcium , Reduced ionized calcium , Increase in total to ionized calcium ratio , Metabolic acidosis , Persistent worsening anion gap , Persistently low serum ionized calcium despite a calcium infusion , Deranged liver function tests (LFTs) Treatment , Cease citrate anticoagulation Start up procedure Equipment Vascular access device insitu PrismaFlex haemofilter PrismaTherm warmer 1 x 5L Prismocitrate (10/2) pre-prepared bag 2 x 5L Prism0cal pre-prepared bags Potassium chloride ampoules (10mmols in 10mls) 50mL BD syringe Calcium chloride 10% (50mLs neat = 5 x 10mL vials) Calcium line (PrismaFlex CA250) 1000mLs 0.9% sodium chloride bag with 5000 units Heparin added (for prime, unless contraindicated) Haemofilter set (standard is ST100) Sterile effluent bag Wide bore warming extension line 10 mL syringes Sterile gloves Eye protection Sterile dressing pack Chlorhexidine 2% with alcohol Priming procedure – regional citrate anticoagulation 1. Plug the Prismaflex and Prismatherm into the UPS power point 2. Turn on the Prismaflex machine 3. Follow the on screen instructions, press "CONTINUE" and choose "NEW PATIENT" 4. Input the patient's ID (UR number), weight and haematocrit 5. Choose the treatment mode (usually CVVHDF) 6. Check that the time and date displayed on the Prismaflex screen are correct (to change, press "CUSTOM MODE", "CONTINUE" then "DATE AND TIME" 7. Choose anticoagulation method select "CITRATE VIA PRISMAFLEX SYRINGE DRIVER" (please note: if you select "CITRATE VIA EXTERNAL SYRINGE" you will disable the PrismaFlex syringe driver and will be unable to administer the calcium infusion via the PrismaFlex machine) 8. Check the prescription (MR 412) against the default settings on the Prismaflex 9. Press "CONTINUE" 10. Load set as instructed on the screen 11. Prepare BD 50mL calcium chloride 10% syringe and prime dedicated calcium line (Prismaflex CA 250) 12. Place calcium chloride syringe in PrismaFlex syringe driver (to be connected directly to the patient NOT the filter) 13. Use the "AUTO UP / DOWN" button on the screen to secure the calcium syringe 14. Clamp the unused syringe to filter line (green filter) and leave this line unattached 15. Once the set is loaded, the blood warming extension tubing needs to be added to the blue return line 16. Locate the luer lock connection between the filter and the de-aeration chamber at the beginning of the blue line 17. Connect the blood warming tubing aseptically 18. Place the blood warming line in the PrismaTherm heater winding in a counter current direction from back to front ensuring that the length of tubing returning to the de-aeration chamber is as short as possible to reduce heat loss 19. Connect 5L bag of Prismocitrate 10/2 to pre blood pump (PBP) line (white) 20. Connect 5L bags of Prism0cal to dialysate line (green) and replacement fluid line (purple) (Please note: the Prism0cal solution MUST be mixed prior to use see instructions in 'fluids' section of CRRT CPG) 21. Connect 1000mL 0.9% sodium chloride bag with 5000 units Heparin (unless contraindicatedc e.g. HITs) to the access line (as per instructions on the Prismaflex screen) and return line to the sterile effluent bag (ensure aseptic technique is maintained at all times) 22. Press "CONTINUE" 23. Ensure that all appropriate lines are unclamped (and that the anticoagulation line that normally runs from syringe to filter IS clamped) 24. Press "PRIME" 25. Once the set is primed, inspect the entire length for any air. Press "REPRIME" if air is evident, otherwise if satisfactory, press "PRIME TEST" 26. In the 'prime test passed' screen, you have the option to reprime, manual prime or adjust chamber. Press "ADJUST CHAMBER" 27. The de-aeration chamber is designed to minimize the risk of air bubbles entering the patient, therefore adjust the chamber to the appropriate level using the arrow keys on screen 28. Select "CONTINUE" 29. Select "ANTICOAGULATION" 30. Change calcium compensation to commence at 85% 31. Select citrate dose commencing at 3mmols 32. Connect calcium chloride 10% line directly to dedicated patient CVC line 33. Connect patient as per instructions in continuous renal replacement guideline References Frankston Hospital (2010). Intensive Care Unit – Citrate protocol uses PrismaFlex & regional citrate anticoagulation. Frankston Hospital (2010). Intensive Care Unit – CRRT – Citrate – Setup Procedure. Frankston Hospital (2010). Intensive Care Unit – Prescribing guideline for citrate protocol. Oudemans-van Straaten, H.M. (2007). Review and guidelines for regional anticoagulation with citrate in continuous haemofiltration. Anticoagulation in continuous veneovenous hemofiltration (CVVH) – Nephrology and Intensive Care Committee of the NVIC, Amsterdam St Vincents Hospital (2012). Citrate anticoagulation for haemofiltration. Intensive Care Unit.