Citrate Versus Heparin Anticoagulation in Continuous Venovenous Hemofiltration (CASH-CVVH)
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|ClinicalTrials.gov Identifier: NCT00209378|
Recruitment Status : Completed
First Posted : September 21, 2005
Last Update Posted : April 4, 2013
|Condition or disease||Intervention/treatment||Phase|
|Acute Kidney Injury||Other: regional anticoagulation with citrate Other: HfCitPre||Not Applicable|
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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.
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:
- Total to ionised calcium ratio of more than 2.5.
- Persistent metabolic alkalosis with a B.E. of more than 10.
- Clinical signs of hypocalcaemia: tetanic symptoms or prolonged QT interval
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||139 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Citrate Versus Heparin Anticoagulation in Continuous Venovenous Hemofiltration in Critically Ill Patients With Acute Renal Failure: A Randomized Clinical Trial|
|Study Start Date :||May 2005|
|Actual Primary Completion Date :||May 2012|
|Actual Study Completion Date :||May 2012|
Active Comparator: heparin
Citrate regional anticoagulation is compared with standard systemic heparinization.
Other: regional anticoagulation with citrate
Regional anticoagulation with trisodium citrate is compared with standard systemic heparinization.
Other Name: HFCitPre
Active Comparator: Citrate
regional anticoagulation with citrate containing replacement solution
regional anticoagulation with citrate containing replacement solution
- Mortality [ Time Frame: Day 28 after ICU admission ]
- Laboratory markers of inflammation, endothelial dysfunction and coagulation [ Time Frame: 72 hours ]
- Filter life (first filter and total amount of filters in 72 hours) [ Time Frame: 72 hours ]
- Bleeding complications [ Time Frame: 28 days ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00209378
|Medical Center Alkmaar|
|Alkmaar, Netherlands, 1815 JD|
|Amsterdam, Netherlands, 1066 EC|
|St Lucas Andreas Ziekenhuis|
|Vrije Universiteit Medical Center|
|Groningen, Netherlands, 9713 GZ|
|Spaarne Hospital Hoofddorp|
|Hoofddorp, Netherlands, 2134 TM|
|Leiderdorp, Netherlands, 2353 GA|
|The Hague, Netherlands, 2545 CH|
|Study Director:||Piet M ter Wee, MD, PhD||VU University Medical Center|
|Study Director:||Johan Groeneveld, MD, PhD||VU University Medical Center|
|Principal Investigator:||Shaikh A Nurmohamed, MD||VU University Medical Center|