Citrate Versus Heparin in Continuous Renal Replacement Therapy :

Citrate Versus Heparin in Continuous Renal Replacement Therapy : Effect on Cardiovascular System and Clot Circuit in Critically Ill Patients

This study is a prospective, multicenter, open-label randomized trial comparing regional citrate anticoagulation (RCA) with heparin-free protocol. The function mode was continuous venovenous hemodiafiltration (CVVHDF) in post-dilution mode. The investigators measured hemodynamic changes at certain time points after starting CRRT (0, 6, 12, 24, 48, 72 hr).Levels of inflammatory cytokine (IL-1β, IL-6, IL-8, IL-10 and TNF-ɑ) were measured at day 1 and day 3

Study Overview

• Status: Completed
• Conditions: Acute Kidney Injury; Cytokines; Citrate; Hemodynamic Responses
• Intervention / Treatment: Procedure: Regional citrate anticoagulation

Detailed Description

Twenty patients were randomized into heparin group and 11 patients were in citrate group. The cardiac performance were not significantly different between 2 groups at every time point. The inflammatory cytokines declined similarly in both treatment arms. The maximum filter survivial time was longer in a RCA group but not reach statistically significant (44.64±26.56 hr vs p=0.693 in citrate and heparin free group respectively).There was no serious side effects dung both treatment arm even in the group of liver dysfunction patients.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Thailand
  • Bangkok, Thailand, 10300
    • Faculty of Medicine ,Vajira hospital,Navamindradhiraj University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• need for CRRT,
• no contraindication to CRRT

Exclusion Criteria:

• patients with previous history of chronic kidney disease (CKD) (baseline serum creatinine > 2 mg/dL (male) or > 1.5 mg/dL (female)
• history of renal transplantation
• known pregnancy
• previous dialysis within 30 days
• severe liver disease
• end stage heart disease or untreatable malignancy
• moribund patients with expected survival less than 30 days
• previous use of heparin or other anticoagulant, antiplatelet within 7 day except use for deep vein thrombosis
• active bleeding at the time of enrollment and/or severe coagulopathy
• receiving blood or blood components prior to enrollment
• hemoglobin less than 7.5 g/dL and/or platelet count less than 100,000/mm3
• previous underlying clotting disorders such as hypercoagulable state
• severe malnutrition (Body mass index (BMI ) less than 18)
• underwent CRRT for other reasons besides acute kidney injury (AKI)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Citrate; The RCA group CRRT were performed with Prisma flex or (Baxter Healthcare/Gambro Spain) or Informed machine with citrate pump. The function mode was continuous venovenous hemodiafiltration (CVVHDF) in postdilution mode with ST 150 filter sets. The substitution fluid was Accusol or Prismocal B22 .The dose of dialysis was 20-25 ml/kg/hr with blood flow 150-200 ml/min. Trisodium citrate solution (4%,136mmol/L) was infused into the arterial line prior to the blood pump at a dose of 4 mmol/L of plasma flow. Calcium chloride (5% 340 mmol/L elemental calcium) was infused into the venous return to maintain systemic ionized calcium in the normal range (0.99-1.30 mmol/L) and the targets values for ionized calcium (iCa2+) after the dialysis membrane were 0.25-0.35 mmol/L. The rale of calcium infusion was adjusted in a timely manner based on repeated measurements of calcium concentration	Procedure: Regional citrate anticoagulation; The investigators collected patient's plasma at study start (day 0) and at day 3, 5, 7, 14, 28) .Samples were used to measure inflammatory markers (Il 6, IL 8, IL 10 and TNFα) . . Markers of dialysis efficiency (BUN, creatinine) and other parameters related to AKI (acid base status, calcium, phosphorus, hemoglobin). The recorded variables also included adverse events, dialysis clotting, hemodynamic status, duration of mechanical ventilation, inotropic support. The hemodynamic parameters were monitored by EV 1000 clinical platform .The investigators measured cardiac performance data, which includes cardiac output (CO), cardiac index (CI), stroke volume (SV), and stroke volume indexes (SVI). Moreover, it also provides information about systemic vascular resistance (SVR). Thus, patient hemodynamic parameters as mentioned above were measured at the following 6 time-point: after the initiation of CRRT (T1), every 6 hours later for 24 hours (T2, T3, T4, T5), and at hour-72 (T6).; Other Names: Heparin-free
Placebo Comparator: Heparin-free; The heparin- free group The circuit was periodically flushed with 50 ml saline via access limb every 30 minutes .When pre-filter pressure started to rise, additional saline flushes would be given.	Procedure: Regional citrate anticoagulation; The investigators collected patient's plasma at study start (day 0) and at day 3, 5, 7, 14, 28) .Samples were used to measure inflammatory markers (Il 6, IL 8, IL 10 and TNFα) . . Markers of dialysis efficiency (BUN, creatinine) and other parameters related to AKI (acid base status, calcium, phosphorus, hemoglobin). The recorded variables also included adverse events, dialysis clotting, hemodynamic status, duration of mechanical ventilation, inotropic support. The hemodynamic parameters were monitored by EV 1000 clinical platform .The investigators measured cardiac performance data, which includes cardiac output (CO), cardiac index (CI), stroke volume (SV), and stroke volume indexes (SVI). Moreover, it also provides information about systemic vascular resistance (SVR). Thus, patient hemodynamic parameters as mentioned above were measured at the following 6 time-point: after the initiation of CRRT (T1), every 6 hours later for 24 hours (T2, T3, T4, T5), and at hour-72 (T6).; Other Names: Heparin-free

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac output	cm3/min	72 hour
Cardiac index	L/min/m2	72 hour
Systemic vascular resistance	mmHg⋅min⋅mL-1	72 hour
Systemic vascular resistance index	dynes · sec/cm5/m2	72 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Filter life span	Hours of filter use	through study completion,an aveage of 72 hours
Changes of IL-1β	Unit/ml	day 1,day 3
Changes of IL-6	Unit/ml	day 1,day 3
Changes of IL-8	Units/ml	day 1,day 3
Changes of IL-10	Units/mL	day 1,day 3
Changes of TNF-ɑ	Uniys/mL	day 1,day 3
Mortality	patient survival	28 day
Renal survival	dialysis dependent	28 day

Collaborators and Investigators

• Sponsor: Bangkok Metropolitan Administration Medical College and Vajira Hospital
• Collaborators: King Chulalongkorn Memorial Hospital; Chiang Mai University; Department of Medicine, Somdech Phra Pinklao Hospital, Bangkok, Thailand.
• Investigators: Principal Investigator: Thananda Trakarnvanich, M.D., Renal unit,Faculty of Medicine,Vajira Hospital,Navamindradhiraj University

Publications and helpful links

General Publications

• Morabito S, Pistolesi V, Tritapepe L, Fiaccadori E. Regional citrate anticoagulation for RRTs in critically ill patients with AKI. Clin J Am Soc Nephrol. 2014 Dec 5;9(12):2173-88. doi: 10.2215/CJN.01280214. Epub 2014 Jul 3.
• Oudemans-van Straaten HM, Kellum JA, Bellomo R. Clinical review: anticoagulation for continuous renal replacement therapy--heparin or citrate? Crit Care. 2011 Jan 24;15(1):202. doi: 10.1186/cc9358.
• Gatward JJ, Gibbon GJ, Wrathall G, Padkin A. Renal replacement therapy for acute renal failure: a survey of practice in adult intensive care units in the United Kingdom. Anaesthesia. 2008 Sep;63(9):959-66. doi: 10.1111/j.1365-2044.2008.05514.x. Epub 2008 Jun 28.
• Borg R, Ugboma D, Walker DM, Partridge R. Evaluating the safety and efficacy of regional citrate compared to systemic heparin as anticoagulation for continuous renal replacement therapy in critically ill patients: A service evaluation following a change in practice. J Intensive Care Soc. 2017 Aug;18(3):184-192. doi: 10.1177/1751143717695835. Epub 2017 Mar 14.
• Cutts MW, Thomas AN, Kishen R. Transfusion requirements during continuous veno-venous haemofiltration: -the importance of filter life. Intensive Care Med. 2000 Nov;26(11):1694-7. doi: 10.1007/s001340000676.
• Tuerdi B, Zuo L, Sun H, Wang K, Wang Z, Li G. Safety and efficacy of regional citrate anticoagulation in continuous blood purification treatment of patients with multiple organ dysfunction syndrome. Braz J Med Biol Res. 2017 Nov 17;51(1):e6378. doi: 10.1590/1414-431X20176378.
• Schrezenmeier EV, Barasch J, Budde K, Westhoff T, Schmidt-Ott KM. Biomarkers in acute kidney injury - pathophysiological basis and clinical performance. Acta Physiol (Oxf). 2017 Mar;219(3):554-572. doi: 10.1111/apha.12764. Epub 2016 Aug 25.
• Kwon O, Molitoris BA, Pescovitz M, Kelly KJ. Urinary actin, interleukin-6, and interleukin-8 may predict sustained ARF after ischemic injury in renal allografts. Am J Kidney Dis. 2003 May;41(5):1074-87. doi: 10.1016/s0272-6386(03)00206-3.
• Liangos O, Kolyada A, Tighiouart H, Perianayagam MC, Wald R, Jaber BL. Interleukin-8 and acute kidney injury following cardiopulmonary bypass: a prospective cohort study. Nephron Clin Pract. 2009;113(3):c148-54. doi: 10.1159/000232595. Epub 2009 Aug 12.
• de Fontnouvelle CA, Greenberg JH, Thiessen-Philbrook HR, Zappitelli M, Roth J, Kerr KF, Devarajan P, Shlipak M, Coca S, Parikh CR; TRIBE-AKI Consortium. Interleukin-8 and Tumor Necrosis Factor Predict Acute Kidney Injury After Pediatric Cardiac Surgery. Ann Thorac Surg. 2017 Dec;104(6):2072-2079. doi: 10.1016/j.athoracsur.2017.04.038. Epub 2017 Aug 16.
• Trakarnvanich T, Sirivongrangson P, Trongtrakul K, Srisawat N. The effect of citrate in cardiovascular system and clot circuit in critically ill patients requiring continuous renal replacement therapy. J Artif Organs. 2022 Apr 12. doi: 10.1007/s10047-022-01329-0. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): February 4, 2019
• Primary Completion (Actual): January 15, 2021
• Study Completion (Actual): March 31, 2021

Study Registration Dates

• First Submitted: April 22, 2021
• First Submitted That Met QC Criteria: April 28, 2021
• First Posted (Actual): April 29, 2021

Study Record Updates

• Last Update Posted (Actual): April 29, 2021
• Last Update Submitted That Met QC Criteria: April 28, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Acute Kidney Injury; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin
• Other Study ID Numbers: COA033/61

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No