Evaluation of a Simplified Protocol for Regional Citrate Anticoagulation in Continuous Venovenous Hemodiafiltration
Condition: Kidney Failure, Acute
MeSH terms: Renal Insufficiency; Acute Kidney Injury
Study type: Observational

Summary: 
      Dialysis requires thinning of the blood to prevent clotting in the dialysis machine. Thinning
      of the blood is necessary but some forms of blood thinners may cause bleeding. Therefore,
      researchers are seeking ways to minimize bleeding risks and ensure effective dialysis.

      One medication used to thin the blood in the dialysis machine is citrate. Citrate has the
      advantage of having its blood-thinning properties quickly reversed by calcium in the
      patient's blood. As a consequence, only the blood in the machine is thinned, greatly reducing
      the risk of bleeding when dialysis is carried out using other blood thinners. Until now, most
      patients who received citrate for dialysis were administered the citrate in a separate
      infusion through an IV pump into the dialysis machine. This method requires complex
      monitoring and calculations. This study is about Prismocitrate which is a dialysis fluid very
      similar to the regular dialysis fluid that is used in this intensive care unit, except that
      this fluid already contains exactly the correct amount of citrate. Thus, this method does not
      require a separate pump for citrate and calculations to pump the citrate into the blood as it
      goes through the kidney machine. Having the citrate already contained in the dialysis fluid
      simplifies the procedure and reduces the possibility of calculation errors.

      This study seeks to determine if this simplified means of providing blood thinning in the
      kidney machine also results in the correct balance of blood salts.
    

Detailed description: 
      Acute renal failure is common among the critically ill [1-3] , and is an independent
      contributor to morbidity and mortality [4,5]. Continuous renal replacement therapy (CRRT) is
      commonly used for renal replacement in this group. This requires an extracorporeal circuit,
      the maintenance of which requires anticoagulation. Heparin has been the most common
      anticoagulant used with CRRT. However, heparin exposure for CRRT is major risk after surgery
      or trauma. Citrate has been used as a regional anticoagulant for plasmapheresis and chronic
      dialysis for many years [12,13], and is increasingly being used for CRRT. Regional
      anticoagulation refers to the provision of anticoagulation within the extracorporeal circuit
      without any alteration in coagulation in the patient's systemic circulation. Calcium is a
      co-factor in coagulation. Citrate reduces levels of ionized calcium in blood of the
      extracorporeal circuit to levels where coagulation cannot occur. Once the blood is returned
      to the patient's systemic circulation, the calcium levels are restored and coagulation can
      occur again. Renal replacement solutions for CRRT using citrate anticoagulation, should be
      calcium-free. [14-19] Despite a reduced risk of bleeding, widespread adoption of citrate
      regional anticoagulation has been limited by a lack of commercially available calcium-free
      solutions and the complexity of many protocols. Part of this complexity is the requirement
      for a separate citrate infusion into the extracorporeal circuit to achieve regional
      anticoagulation. This simplified protocol provides citrate in the replacement fluid infused
      prefilter as both anticoagulant and as buffer.

      To predict appropriate replacement rates, Hospal Gambro scientific laboratories have
      developed a calculation model to predict the physiological interactions between the
      components of the administered replacement- and hemodialysis fluids and the patient's complex
      metabolic system. These interactions are influenced, in large part, by systemic parameters
      such as blood-flow and ultrafiltration rates, and patient parameters, such as acid
      base-status and liver function. This calculation model needs clinical validation in respect
      to its ability to predict the outcome and narrow the margin of metabolic disturbances caused
      by the administration of citrate anticoagulation. A previous study of a similar replacement
      fluid using citrate 8 mmol/L and citric acid 4 mmol/L resulted in mild metabolic acidosis of
      minimal clinical significance in some subjects and so this study will evaluate a modified
      version of fluid containing citrate 10 mmol/L and citric acid 2 mmol/L which has been
      calculated to provide optimal metabolic balance.

      Subjects:

      Twenty patients in the General Systems ICU at the University of Alberta Hospital treated with
      CVVHDF using a Prisma-CFM machine will be studied.

      Inclusion criteria:

        1. Male or female between 17 and 80 years of age.

        2. Intensive care unit patient.

        3. Renal failure requiring CVVHDF.

        4. Likely to survive for at least 72 hours.

      Exclusion criteria

        1. Age > 80 years

        2. Need for systemic anticoagulation, fibrinolytic therapy or activated protein C

        3. Acute or chronic hepatic failure

      Patients are treated by regular CVVHDF setting in pre-dilution mode. The replacement
      flow-rate for the citrate replacement fluid depends on the blood pump speed [fixed ratio, see
      9.3 and table below]. Mean dialysate flow is between 100 ml/hr and 2500ml/hour in accordance
      to the desired base-equivalent intake. Access pressure is kept between -100 and 150mmHg.
      Access and return pressure are monitored. Specially formulated replacement- and dialysate
      fluids are used.

      Citrate anticoagulation Published literature data show that a mean citrate-dosage of 3.5 to
      4mmol/l of undiluted blood is necessary to decrease the level of ionized serum calcium below
      0.4mmol/l which provides sufficient anticoagulation to maintain an extracorporeal circuit. A
      minimum citrate concentration of 3.5 mmol/l blood will be used in this protocol. The infused
      citrate replacement fluid contains trisodium citrate and citric acid in a mixture (10mmol/l
      tri-sodium citrate plus 2 mmol/l citric acid). Preliminary results proved that the
      anticoagulation potency of this mixture is similar to a plain 12 mmol/l tri-sodium citrate
      solution. Therefore a fixed ratio of citrate replacement fluid will be infused in pre-pump
      predilution mode per 1 liter of effective blood flow.

      Calcium replacement:

      The loss of calcium- and magnesium-citrate in the ultra-filtrate via the hemofilter needs to
      be compensated to avoid systemic hypocalcemia and hypomagnesemia. Calcium replacement
      solution is prepared by removing 300 mls from a 1000 mls bag of 0.9% saline and subsequently
      adding 200 mls of 10% calcium gluconate to this bag. This calcium gluconate solution is
      infused via a central line at an initial infusion rate of 60 ml/hr. Ionized calcium levels
      are monitored every 6-8 hours and corrected by changing of flow rate of the infusion.

      Potassium replacement:

      Potassium is added into the replacement and dialysate fluid based on clinical requirement.

      Sodium-bicarbonate adjustment:

      The sodium bicarbonate level is influenced by the flow-rate of the replacement fluid (citrate
      intake) and the dialysate flow (bicarbonate intake). It is monitored every 6 hours and is
      corrected during treatment by altering the dialysate flow. Reducing the flow rate lowers
      bicarbonate intake in case of metabolic alkalosis, raising flow increases the bicarbonate
      intake in case of metabolic acidosis. If these adjustments are not successful, further
      corrections can be done by adding bicarbonate into the next dialysate fluid bag, when it is
      changed:

      Consent procedure Subjects will be identified, recruited and informed consent obtained by the
      principal investigator, co-investigator or research co-ordinators.

      Study benefits The study renal replacement solution includes all elements required for safe
      use. It does not require custom preparation by hospital personnel. This will minimize risk of
      error and increase patient safety. It is hoped this study will eventually enable the general
      use of a simple safe technique for citrate regional anticoagulation during continuous renal
      replacement therapy.

      Adverse effects CVVHDF using citrate regional anticoagulation using any protocol may be
      associated with hypocalcemia, metabolic alkalosis or acidosis, hypernatremia or hyponatremia.
      In anticipation of this, all protocols including this one use extensive metabolic monitoring
      and algorithmic responses to abnormalities. This simplified protocol minimizes the potential
      for complication.

      Adverse effects would be notified to patient or family, investigator, and HREB committee.

      Privacy Patient data will be anonymized to prevent identification. Gambro Canada (study
      sponsor) will have access to anonymized case report forms and aggregate report.
    

Intervention name(s): Regional citrate anticoagulation
Intervention type(s): Drug
Intervention description(s): Continuous venovenous hemodiafiltration with regional anticoagulation using dilute trisodium citrate. This requires the use of a continuous renal replacement therapy (CRRT) machine in venovenous hemodiafiltration mode. Anticoagulation and buffer are provided by the use of a dilute solution of trisodium citrate in the replacement fluid which is infused in a predilution mode. Standard bicarbonate containing dialysate is used.
Other intervention name(s): Prismocitrate - the study fluid; Prismocal - the commercially available dialysate
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        1. Male or female between 17 and 80 years of age.

          2. Critically ill intensive care unit patient.

          3. Renal failure requiring continuous venovenous hemodiafiltration.

          4. Likely to survive for at least 72 hours
      
Keywords: Kidney Failure, Acute; Hemodialysis; Hemofiltration; Anticoagulation; Citrate