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A Randomized Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Adults*

Gattas, David J. MD, MMed (ClinEpi), FCICM, FRACP1,2; Rajbhandari, Dorrilyn RN Post Grad Dip (Clinical Nursing)1,2; Bradford, Celia MD, FCICM3; Buhr, Heidi RN, MClinTPrac1; Lo, Serigne PhD, AStat2; Bellomo, Rinaldo MBBS, MD (Hons), FRACP, FCICM, PG Dip Echo4,5

doi: 10.1097/CCM.0000000000001004
Clinical Investigations

Objective: To determine whether regional anticoagulation of continuous renal replacement therapy circuits using citrate and calcium prolongs circuit life and/or affects circulating cytokine levels compared with regional anticoagulation using heparin and protamine.

Design: Multicenter, parallel group randomized controlled trial.

Setting: Seven ICUs in Australia and New Zealand.

Patients: Critically ill adults requiring continuous renal replacement therapy.

Interventions: Patients were randomized to receive one of two methods of regional circuit anticoagulation: citrate and calcium or heparin and protamine.

Measurements and Main Results: The primary outcome was functional circuit life measured in hours, assessed using repeated events survival analysis. In addition, we measured changes in interleukin-6, interleukin-8, and interleukin-10 blood levels. We randomized 212 subjects who were treated with 857 continuous renal replacement therapy circuits (median 2 circuits per patient [interquartile range, 1–6], 390 in citrate group vs 467 in heparin group). The groups were well matched for baseline characteristics. Patients receiving regional continuous renal replacement therapy anticoagulation with heparin and protamine were more likely to experience circuit clotting than those receiving citrate and calcium (hazard ratio, 2.03 [1.36–3.03]; p < 0.0005; 857 circuits). The median lifespan of the first study circuit in each patient was 39.2 hours (95% CI, 32.1–48.0 hr) in the citrate and calcium group versus 22.8 hours (95% CI, 13.3–34.0 hr) in the heparin and protamine group (log rank p = 0.0037, 204 circuits). Circuit anticoagulation with citrate and calcium had similar effects on cytokine levels compared with heparin and protamine anticoagulation. There were more adverse events in the group assigned to heparin and protamine anticoagulation (11 vs 2; p = 0.011).

Conclusions: Regional citrate and calcium anticoagulation prolongs continuous renal replacement therapy circuit life compared with regional heparin and protamine anticoagulation, does not affect cytokine levels, and is associated with fewer adverse events.

Supplemental Digital Content is available in the text.

1Intensive Care Service, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

2Critical Care & Trauma Division, George Institute for Global Health, Sydney, NSW, Australia.

3Intensive Care Department, Royal North Shore Hospital, St Leonards, NSW, Australia.

4Australian and New Zealand Intensive Care Research Centre, Melbourne, VIC, Australia.

5Intensive Care Department, Austin Hospital, Melbourne, VIC, Australia.

*See also p. 1778.

This work was performed at Royal Prince Alfred Hospital, Sydney, NSW, Australia; Austin Hospital, Melbourne, VIC, Australia; Auckland City Hospital, Auckland, New Zealand; Monash Medical Centre, Melbourne, VIC, Australia; Royal North Shore Hospital, Sydney, NSW, Australia; Frankston Hospital, Melbourne, VIC, Australia; and Dandenong Hospital, Melbourne, VIC, Australia.

The Participating Sites and Investigators are listed in Appendix 1.

Trial Registration (ACTRN12609001079235): A randomized controlled study comparing the effect of two different anticoagulation regimens on filter life during Continuous Renal Replacement Therapy–The Heparin Citrate Study. Date registered December 16, 2009.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Supported, in part, by Intensive Care Foundation, Carlton, VIC, Australia, and Austin ICU Research Fund, Heidelberg, VIC, Australia. The study sponsors had no role or authority in the design, collection, management, analysis or interpretation of data, writing of the report, or decision to submit for publication.

Dr. Gattas lectured for Baxter. His institution received grant support from the Intensive Care Foundation (AUD$55K competitive grant from charitable foundation; no industry funding). Ms. Rajbhandari’s institution received grant support from Intensive Care Foundation. Dr. Bradford’s institution received grant support from the Intensive Care Foundation Grant. Ms. Buhr received support for article research from the Intensive Care Foundation. Her institution received grant support from the Intensive Care Foundation. Dr. Bellomo consulted for Baxter and BBraun. Dr. Lo has disclosed that he does not have any potential conflicts of interest.

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