Citrate Versus Heparin Anticoagulation in Continuous Venovenous Hemofiltration
Condition: Acute Kidney Injury
MeSH terms: Acute Kidney Injury
Study type: Interventional

Summary: 
      The purpose of this study is to compare citrate regional anticoagulation with systemic
      heparinization in continuous venovenous hemofiltration. The investigators' hypothesis is,
      that regional citrate anticoagulation with replacement solution containing trisodium citrate,
      will be associated with lower mortality and less bleeding complications compared to heparin,
      with also a better filter survival.
    

Detailed description: 
      Acute renal failure occurs in about 20% of critically ill patients and is associated with
      increased morbidity and mortality, in spite of modern renal replacement techniques. The
      latter include continuous venovenous hemofiltration (CVVH) techniques, necessitating
      anticoagulation of blood entering the extracorporeal circuit to prevent premature clot
      formation and hemofilter dysfunction. Heparin is commonly used for that purpose, but carries
      a serious risk of bleeding complications and heparin induced thrombocytopenia. In a subgroup
      of critically ill patients systemic anticoagulation is absolutely contraindicated.
      Citrate-anticoagulant CVVH carries the potential advantage of less bleeding complications and
      prolonged filter survival, but carries the risk of hypocalcaemia, when citrate is
      inappropriately or insufficiently counteracted by calcium infusion after passage of blood
      through the filter. In addition, when too much citrate enters the circulation, a metabolic
      alkalosis may develop, since citrate is converted to bicarbonate by the liver.

      Moreover, continuous filtration techniques may attenuate a potentially harmful exaggerated
      immune response, particularly when high volume filtration (> 6 L/h) is used. Also, the type
      of anticoagulation may modulate immune responses, as known from biocompatibility studies in
      intermittent hemodialysis.

      In the first part of the research proposal concerning high bleeding risk patients a
      comparison will be made in a prospective sequential cohort study between no anticoagulation
      and citrate regarding filter survival time, bleeding risk, dialyser efficacy, circulating
      immune mediators (such as neutrophil elastase and myeloperoxidase, interleukins,
      platelet-activating factors, activated complement products, soluble cytokine receptors and
      adhesion molecules), metabolic balance, and acute renal failure duration. Also, filter
      survival time will be assessed. The purpose of the second part of the current research
      proposal is to evaluate in a randomised controlled clinical trial in 350 critically ill
      patients (18-80 years) with acute renal failure, (2 arms of 175 patients), without an
      increased bleeding risk (thrombocytes > 40 x 10^9/L, APTT < 60 sec, PT-INR < 2) whether
      citrate CVVH is better than bicarbonate-heparin CVVH in terms of the same parameters as in
      the first part of the study but with the addition of mortality as the primary endpoint.

      For this purpose a simple predilution system and citrate adjustment protocol will be used and
      compared to standard heparin dosing. This replacement solution shall be custom made,
      containing trisodium citrate, no lactate or bicarbonate, no calcium and a low sodium content.

      Main objective: Investigation of the mortality during continuous venovenous hemofiltration
      with systemic anticoagulation with heparin compared with regional anticoagulation with
      trisodium citrate and also the investigation of the filter survival. Our hypothesis is, that
      regional citrate anticoagulation with replacement solution containing trisodium citrate, will
      be associated with less bleeding complications compared to heparin, with also a better filter
      survival. Most important we want to evaluate the hypothesis that treatment with citrate will
      result in a lower mortality compared to treatment with systemic heparinization.

      Regional anticoagulation with trisodium citrate may also have some potential effects on the
      immune response as known from biocompatibility studies in intermittent hemodialysis.
      Bioincompatibility leads to polymorphonuclear cell degranulation as indicated by the release
      of intracellular granule products such as myeloperoxidase, lactoferrin, lysozyme and
      elastase. Citrate anticoagulation may lead to a lower polymorphonuclear cell degranulation,
      since cations play a pivotal role in the process of cell activation and citrate creates an
      almost calcium-free environment within the dialyser by its virtue to chelate calcium.

      Primary endpoints:

      Mortality at day 28 after inclusion will be evaluated. Survival time of the first hemofilter
      used will be determined, including the cause of filter termination and the number of filters
      used in the first 72 hours; the average filter patency time will be calculated.

      Citrate CVVH is stopped and thus also the study, if the patient fulfils one of the following
      criteria:

        1. Total to ionised calcium ratio of more than 2.5.

        2. Persistent metabolic alkalosis with a B.E. of more than 10.

        3. Clinical signs of hypocalcaemia: tetanic symptoms or prolonged QT interval

        4. Progressive non-lactic acidosis (pH < 7.20) during CVVH combined with an increase in
           anion gap (> 13) without the presence of endo- or exogenous acids other than citrate
           suggesting citrate accumulation

      Patients on heparin developing a HIT will continue CVVH with danaparoid anticoagulation.
      Patients on heparin developing a bleeding episode will continue CVVH with regional citrate
      anticoagulation.
    

Intervention name(s): regional anticoagulation with citrate; HfCitPre
Intervention type(s): Other; Other
Intervention description(s): Regional anticoagulation with trisodium citrate is compared with standard systemic heparinization.; regional anticoagulation with citrate containing replacement solution
Other intervention name(s): HFCitPre
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Continuous venovenous hemofiltration (CVVH); Continuous renal replacement therapy (CRRT); Acute Kidney Injury; Regional citrate anticoagulation; filter survival; trisodium citrate; bleeding complication; Hemofiltration