Citrate Versus Heparin Anticoagulation: Effect on Molecules Clearances (RCA-SHA)

Regional Citrate Versus Systemic Heparin Anticoagulation for Super High-flux Continuous Hemodialysis in Septic Shock: Effect on Middle Molecular Weight Molecules Clearances

Sepsis is responsible for 50% of all acute kidney injury (AKI) in intensive care units (ICUs), contributing greatly to multiple organ dysfunction syndrome (MODS). Special types of continuous renal replacement therapies (CRRT) have been proposed as adjuvant therapies for septic shock due to their ability to remove middle molecular weight molecules such as inflammatory mediators involved in MODS pathophysiology. These therapies are called extracorporeal " blood purification " therapies.

When CRRT is used, an anticoagulation is required to prevent clotting of the extracorporeal circuit, possibly causing bleeding in selected patients. Many anticoagulation strategies have been proposed and the most commonly used in 2013 is still unfractionated heparin. Regional citrate anticoagulation (RCA) is an interesting alternative as it dramatically decreases the bleeding risk.

The investigators hypothesize that the use of citrate with Super High Flux Continuous Veno-Venus Hemodialysis (SHF-CVVHD) would be highly beneficial over time by preserving the filter effectiveness via limiting protein adhesion (which subsequently reduces filter pore sizes (protein cake)), as compared to heparin. Consequently, higher clearances of the inflammatory mediators could be maintained over time with citrate as compared to heparin anticoagulation. In other words, for the same duration of filter use, middle molecular weight molecules and cytokines clearances would be greater with citrate as compared to heparin. To test this hypothesis, the investigators will perform a clinical randomized controlled trial which aim would be to compare middle molecular weight molecules and cytokines clearances in SHF-CVVHD using RCA versus systemic heparin anticoagulation in septic patients with AKI.

Study Overview

• Status: Unknown
• Conditions: Septic Shock
• Intervention / Treatment: Drug: Anticoagulation to prevent clotting of the extracorporeal circuit. (regional citrate anticoagulation); Drug: Anticoagulation to prevent clotting of the extracorporeal circuit (Unfractionated heparin)

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thomas Rimmelé, Dr; Phone Number: +33 4 72 11 02 13; Email: th.rimmele@gmail.com
• Study Contact Backup: Name: Pr Bernard Allaouchiche, Pr; Phone Number: +33 4 72 11 02 13; Email: bernard.allaouchiche@chu-lyon.fr

Study Locations

• France
  • Lyon, France, 69003
    • Recruiting
    • Service de Réanimation - Pavillon P, Hôpital Edouard Herriot
    • Contact: Thomas Rimmelé, Dr; Phone Number: +33 4 72 11 02 13; Email: th.rimmele@gmail.com
    • Contact: Bernard Allaouchiche, Pr; Phone Number: +33 4 72 11 02 13; Email: bernard.allaouchiche@chu-lyon.fr
    • Principal Investigator: Thomas Rimmelé, Dr
    • Sub-Investigator: Bernard Allaouchiche, Pr
    • Sub-Investigator: Charles-Eric Ber, Dr
    • Sub-Investigator: Jullien Crozon, Dr
    • Sub-Investigator: Mathieu Page, Dr
    • Sub-Investigator: Johanne Prothet, Dr
    • Sub-Investigator: Jean-Jacques Baillon, Dr
    • Sub-Investigator: Françoise Christin, Dr
    • Sub-Investigator: Bernard Floccard, Dr
    • Sub-Investigator: Christian Guillaume, Dr
    • Sub-Investigator: Olivier Martin, Dr
    • Sub-Investigator: Guillaume Marcotte, Dr
    • Sub-Investigator: Etienne Hautin, Dr
    • Sub-Investigator: Alexandre Faure, Dr
    • Sub-Investigator: Thomas Geffriaud, Dr
    • Sub-Investigator: François Malavieille, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female critically ill patients over the age of 18 years old
• Acute Kidney Injury requiring CRRT defined using the Risk, Injury, Failure, Loss, End-stage renal disease (RIFLE) classification with criterion I or worse.
• Septic shock as defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference.
• Written informed consent obtained from the patient or a patient's legal representative
• Patient patient's legal representative able to agree to patient's enrollment in the study with informed consent.

Exclusion Criteria:

• Pregnancy
• Participation in another research study protocol
• Known heparin induced thrombopenia or contraindication to heparin
• Pre-existing chronic renal failure on chronic dialysis
• Therapeutic anticoagulation with heparin for another reason (e.g. chonic arrhythmia)
• Severe liver failure (15% prothrombin time)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RCA Group; SHF-CVVHD with regional citrate anticoagulation	Drug: Anticoagulation to prevent clotting of the extracorporeal circuit. (regional citrate anticoagulation); Anticoagulation to prevent clotting of the extracorporeal circuit. Unfractionated heparin and regional citrate anticoagulation will be compared. Ci-Ca protocole for MultiFiltrate® CRRT machine : 4% trisodium citrate solution; Calcium chloride solution (100 mmol/L); Dialysate flow rate: 35 ml/kg/h; Blood flow rate: adjusted to maintain a ratio blood flow rate / dialysate flow rate of 3; Citrate infusion titrated to maintain postfilter ionized calcium between 0.25 and 0.35 mmol/L.; Calcium chloride infusion titrated to maintain systemic ionized calcium between 1.12 and 1.2 mmol/L.; Blood flow adapted to the acid-base status
Experimental: Heparin group; SHF-CVVHD with systemic heparin anticoagulation	Drug: Anticoagulation to prevent clotting of the extracorporeal circuit (Unfractionated heparin); Anticoagulation to prevent clotting of the extracorporeal circuit. Unfractionated heparin and regional citrate anticoagulation will be compared.; Continuous infusion of unfractionated heparin: starting infusion rate at 600 IU/h then adjusted to maintain partial thromboplastin time at 1-1.4 times the normal value.; Standard dialysate for CRRT : Prismasol® K2 solution; Dialysate flow rate: 35 ml/kg/h; Blood flow rate: adjusted to maintain a ratio blood flow rate / dialysate flow rate of

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Middle molecular weight molecules clearances	At each time point of the study (T=1h,T=4h,T=12h,T=24h, T=48h, and T=72h), blood and post-filter samplings will be taken in order to calculate kappa and lambda light chains of immunoglobulin clearances.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
mortality		28th day
Clearances of cytokines and molecules of interest	At each time point of the study (T=1h,T=4h,T=12h,T=24h, T=48h, and T=72h), sampling will be simultaneously collected from blood and post-filter in order to determine cytokines (IL-1 ra, IL-10, IL-6, IL-8, β2microglobuline), urea, creatinine and albumin clearances.	T=1h,T=4h,T=12h,T=24h, T=48h, and T=72h
Hemodynamic parameters	At each time point of the study (T=1h,T=4h,T=12h,T=24h, T=48h, and T=72h), clinical data and blood sampling will be collected in order to assess mean arterial pressure, heart rate, vasopressor requirement and lactate level.	T=1h,T=4h,T=12h,T=24h, T=48h, and T=72h
Respiratory parameters	At each time point of the study (T=1h,T=4h,T=12h,T=24h, T=48h, and T=72h), PaO2/FIO2 ratio will be measured by blood sampling and clinical data collection.	(T=1h,T=4h,T=12h,T=24h, T=48h, and T=72h),

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Publications and helpful links

General Publications

• Tsujimoto H, Tsujimoto Y, Nakata Y, Fujii T, Takahashi S, Akazawa M, Kataoka Y. Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy. Cochrane Database Syst Rev. 2020 Dec 14;12(12):CD012467. doi: 10.1002/14651858.CD012467.pub3.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Anticipated): November 1, 2014
• Study Completion (Anticipated): April 1, 2015

Study Registration Dates

• First Submitted: April 22, 2013
• First Submitted That Met QC Criteria: April 24, 2013
• First Posted (Estimate): April 25, 2013

Study Record Updates

• Last Update Posted (Estimate): August 27, 2014
• Last Update Submitted That Met QC Criteria: August 26, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: cytokines; blood purification; super high flux hemodialysis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Shock, Septic; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Calcium heparin
• Other Study ID Numbers: 2012.724