Evaluation of Regional Anticoagulation With Citrate in Extended Hemodialysis
Evaluation of Regional Anticoagulation With Citrate in Extended Hemodialysis
Data on regional citrate anticoagulation in patients with acute kidney injury (AKI) treated
 by hybrid or extended dialysis are scarce and heterogeneous. The path batch system (Genius®)
 or the proportion hemodialysis machines are well suited equipments to perform extended
 dialysis. However, clotting of the system might occur with relatively high frequency,
 especially in critically ill patients with high risk of clotting or in those with
 contraindication to the use of heparin.

 The aims of this study are: 1) to test and to validate a new protocol using citrate to
 perform regional anticoagulation in AKI patients admitted to the intensive care unit (ICU)
 and treated by extended dialysis, using a control group (use of heparin or intermittent
 saline flush) as comparison in the Heart Institute of the university medical complex "Clinics
 Hospital Medical School at São Paulo" (Hospital das Clínicas da Faculdade de Medicina do
 Estado de São Paulo) and at the Cancer Institute of the São Paulo State; 2) to evaluate the
 anticoagulation in these procedures with citrate and compare with the control group using
 heparin or saline flush, so the primary end point would be the rates of system clotting; 3)
 to study the calcium mass transfer in these procedures and its impact on bone metabolism in
 these patients. The inclusion criteria are all AKI patients admitted in these places and
 candidates to renal replacement therapy using the extended dialysis, age above 18 years. The
 exclusion criteria are acute liver failure, hemorrhagic stroke, platelets level below
 20,000/mm3, and active bleeding needing transfusional support (two or more red cell packs in
 24 hours).
The investigators conduct an open label randomized clinical trial with cross-over between the
 groups. The study will be performed in all the intensive care units (ICU) at the Heart
 Institute and the Cancer Institute, both hospitals related with the University of São Paulo
 Medical School, at the city of São Paulo, Brazil.

 All inpatients over 18 years in the ICU with acute kidney injury (AKI) who are arranged for
 extended hemodialysis will be invited to participate in the study. After signing an informed
 consent formulary, the patients went to randomization between two groups: citrate or control
 therapy. The research team randomly drawn the patients using a box with twenty entries for
 each group, totalizing forty units. Thus, after the inclusion of forty patients, it is
 guaranteed that half of them will start in the citrate group and the other half in the
 control group. Afterwards, the box is refilled to its maximum capacity of forty units for the
 next draw.

 The randomization process determine the type of anticoagulation that the patient will be
 submitted in the first dialysis session. Subsequently the subject will participate in the
 other group, alternating between the two modalities until the maximum of six extended
 dialysis for the protocol.

 In the control group, the decision on the use of heparin or continuous saline infusion as an
 anticoagulation method will be based on the presence of contraindications to the heparin use,
 which would be I) platelet levels <150,000/mm3; II) active or recent bleeding; III) reduction
 in hemoglobin levels of more than 2.0g/dl in less than 24 hours; IV) invasive procedures or
 surgeries realized in the last 7 days or scheduled to the next 24 hours.

 There may be a change in the choice of method (citrate versus control), if the nephrologist
 consultant team deems it necessary, due to demands of care, particularly if there is early or
 repeated coagulation of the system. The proper functioning of the hemodialysis catheter will
 be evaluated before the dialysis initiation, and in case of malfunction, it will be properly
 replaced before the procedure starts.

 The study foresees the inclusion of 800 dialytic procedures. Half of them are expected to be
 performed in the citrate group and half in the control group. As each patient can perform up
 to six procedures, it is estimated that approximately 200 patients will participate in this
 study. Data in the other intermittent dialysis not included in this trial and performed in
 the intensive care setting during the same period will be registered.

 Patients will be excluded if they present: I) acute liver failure; II) hemorrhagic stroke in
 the last 30 days; III) platelet levels below 20,000/mm3 and IV) active bleeding requiring
 transfusion of two or more red blood cell packs within 24 hours.

 Decisions about the need for renal replacement therapy, modality and time will be made by the
 nephrologist attendant. Intermittent methods are preferred performed in stable patients with
 no vasoactive drug, or with low doses of these drugs (norepinephrine <0.2 mcg/kg/min and
 dobutamine <5 mcg/kg/min).

 All slow extended dialysis (SLED) in this trial were performed in 6 to 8 hours using a
 single-pass batch machine (Genius 90 Therapy System® Fresenius Medical Care, Bad Homburg,
 Germany), initiated by a nephrology specialized nurse and managed by an exclusive attendant.
 In this device, blood and dialysate flow rates are equal and set in 180 ml/min. We used only
 high-flux polysulfone filter (Ultraflux® AV 600S, Fresenius Medical Care). In the SPB device,
 the dialysate is stored in an air-free 90 liters glass container (batch system). Dialysate
 solution after proper reconstitution has sodium 138 mEq/l, bicarbonate 32.6 mEq/l, magnesium
 1.0 mEq/l, chloride 111 mEq/l, potassium 2.0 or 3.0 mEq/l and calcium 2.5 mEq/l (5.0 mg/dl).
 Dialysate temperature was set in 36-37°C.

 Citrate dose was tailored to achieve 3 mmol per filtered blood liter using a citric acid
 solution 2.2% 800 ml bag (each 100 mL of the solution contains 730 mg of citric acid, 2.45 g
 of dextrose and 2.2g of sodium citrate). Calcium replacement began if the patient has a serum
 ionized calcium less than 4.4 mg/dl (or 1.10 mmol/l) before it starts or during the session.
 We obtained blood samples at every two hours to adjust the calcium infusion rate targeting
 serum calcium from 4.4 to 5.3 mg/dl (or 1.10 to 1.32 mmol/l), using a calcium solution with
 10% calcium chloride solution (concentration at 0.133 mmol/ml). The post filter ionized
 calcium addressed was 2.4 to 2.8 mg/d (or 0.6 to 0.7 mmol/l). Furthermore, in the control
 group, the equipment receive continuous saline in a infusion rate of 180 ml per hour or
 unfractionated heparin 1,000 units in bolus at the initiation of the procedure and maintained
 at 500 units per hour in a specific syringe pump in the device.
Inclusion Criteria:

 -  All patients with acute kidney injury admitted to the intensive care unit and
 candidates for extended dialysis (renal replacement therapy)

 -  Age over 18 years.

 Exclusion Criteria:

 -  Acute liver failure

 -  Hemorrhagic stroke in the last 30 days

 -  Patients with platelet levels below 20,000/mm3

 -  Active bleeding requiring transfusion (two or more red blood cell packs within 24
 hours)