Regional Citrate Anticoagulation in Continuous Renal Replacement Therapy: Is Metabolic Fear the Enemy of Logic? A Systematic Review and Meta-Analysis of Randomised Controlled Trials

Rita Jacobs, Walter Verbrugghe, Karolien Dams, Ella Roelant, Marie Madeleine Couttenye, Dirk Devroey, Philippe Jorens, Rita Jacobs, Walter Verbrugghe, Karolien Dams, Ella Roelant, Marie Madeleine Couttenye, Dirk Devroey, Philippe Jorens

Abstract

Background: Anticoagulation is recommended to maintain the patency of the circuit in continuous renal replacement therapy (CRRT). However, anticoagulation-associated complications can occur. We performed a systematic review and meta-analysis to compare the efficacy and safety of citrate anticoagulation to heparin anticoagulation in critically ill patients treated with CRRT.

Methods: Randomised controlled trials (RCTs) evaluating the safety and efficacy of citrate anticoagulation and heparin in CRRT were included. Articles not describing the incidence of metabolic and/or electrolyte disturbances induced by the anticoagulation strategy were excluded. The PubMed, Embase, and MEDLINE electronic databases were searched. The last search was performed on 18 February 2022.

Results: Twelve articles comprising 1592 patients met the inclusion criteria. There was no significant difference between the groups in the development of metabolic alkalosis (RR = 1.46; (95% CI (0.52-4.11); p = 0.470)) or metabolic acidosis (RR = 1.71, (95% CI (0.99-2.93); p = 0.054)). Patients in the citrate group developed hypocalcaemia more frequently (RR = 3.81; 95% CI (1.67-8.66); p = 0.001). Bleeding complications in patients randomised to the citrate group were significantly lower than those in the heparin group (RR 0.32 (95% CI (0.22-0.47); p < 0.0001)). Citrate showed a significantly longer filter lifespan of 14.52 h (95% CI (7.22-21.83); p < 0.0001), compared to heparin. There was no significant difference between the groups for 28-day mortality (RR = 1.08 (95% CI (0.89-1.31); p = 0.424) or 90-day mortality (RR 0.9 (95% CI (0.8-1.02); p = 0.110).

Conclusion: regional citrate anticoagulation is a safe anticoagulant for critically ill patients who require CRRT, as no significant differences were found in metabolic complications between the groups. Additionally, citrate has a lower risk of bleeding and circuit loss than heparin.

Keywords: anticoagulation; citrate; continuous renal replacement therapy; filter lifespan; heparin; metabolic complications.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Prisma flowchart.
Figure 2
Figure 2
Risk of bias.
Figure 2
Figure 2
Risk of bias.
Figure 3
Figure 3
Forest plots, funnel plots and TSA of acid-base disorders.
Figure 3
Figure 3
Forest plots, funnel plots and TSA of acid-base disorders.
Figure 4
Figure 4
Forest plots and TSA of bleeding, HIT and transfusion.
Figure 4
Figure 4
Forest plots and TSA of bleeding, HIT and transfusion.
Figure 4
Figure 4
Forest plots and TSA of bleeding, HIT and transfusion.
Figure 5
Figure 5
Forest plot of filter lifespan. Due to heterogeneity (p < 0.0001, I2 = 81.6%, H2 = 5.42), random effects model for filter lifespan was used. A significant difference of 14.52 h with 95% CI [7.22,21.83]; p < 0.0001 was found between citrate and heparin.

References

    1. Bagshaw S.M., Berthiaume L.R., Delaney A., Bellomo R. Continuous versus intermittent renal replacement therapy for critically ill patients with acute kidney injury: A meta-analysis*. Crit. Care Med. 2008;36:610–617. doi: 10.1097/01.CCM.0B013E3181611F552.
    1. Ostermann M., Bellomo R., Burdmann E.A., Doi K., Endre Z.H., Goldstein S.L., Kane-Gill S.L., Liu K.D., Prowle J.R., Shaw A.D., et al. Controversies in acute kidney injury: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference. Kidney Int. 2020;98:294–309. doi: 10.1016/j.kint.2020.04.020.
    1. Oudemans-van Straaten H.M., Kellum J.A., Bellomo R. Clinical review: Anticoagulation for continuous renal replacement therapy—Heparin or citrate? Crit. Care. 2010;15:202. doi: 10.1186/cc9358.
    1. Flanigan M.J., Pillsbury L., Sadewasser G., Lim V.S. Regional hemodialysis anticoagulation: Hypertonic tri-sodium citrate or anticoagulant citrate dextrose-A. Am. J. Kidney Dis. 1996;27:519–524. doi: 10.1016/S0272-6386(96)90162-6.
    1. Fiaccadori E., Pistolesi V., Mariano F., Mancini E., Canepari G., Inguaggiato P., Pozzato M., Morabito S. Regional citrate anticoagulation for renal replacement therapies in patients with acute kidney injury: A position statement of the Work Group “Renal Replacement Therapies in Critically Ill Patients” of the Italian Society of Nephrology. J. Nephrol. 2015;28:151–164. doi: 10.1007/s40620-014-0160-2.
    1. Kramer L., Bauer E., Joukhadar C., Strobl W., Gendo A., Madl C., Gangl A. Citrate pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients. Crit. Care Med. 2003;31:2450–2455. doi: 10.1097/01.CCM.0000084871.76568.E6.
    1. Sigwalt F., Bouteleux A., Dambricourt F., Asselborn T., Moriceau F., Rimmelé T. 40 Years of Continuous Renal Replacement Therapy. Karger Medical and Scientific Publishers; Basel, Switzerland: 2018. Clinical Complications of Continuous Renal Replacement Therapy; pp. 109–117.
    1. Cerdá J., Tolwani A.J., Warnock D.G. Critical care nephrology: Management of acid–base disorders with CRRT. Kidney Int. 2012;82:9–18. doi: 10.1038/ki.2011.243.
    1. Morgera S., Scholle C., Voss G., Haase M., Vargas-Hein O., Krausch D., Melzer C., Rosseau S., Zuckermann-Becker H., Neumayer H.-H. Metabolic Complications during Regional Citrate Anticoagulation in Continuous Venovenous Hemodialysis: Single-Center Experience. Nephron Clin. Pract. 2004;97:c131–c136. doi: 10.1159/000079171.
    1. Fall P., Szerlip H.M. Continuous Renal Replacement Therapy: Cause and Treatment of Electrolyte Complications. Semin. Dial. 2010;23:581–585. doi: 10.1111/j.1525-139X.2010.00790.x.
    1. 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;3:CD012467. doi: 10.1002/14651858.CD012467.pub2.
    1. Page M.J., McKenzie J.E., Bossuyt P.M., Boutron I., Hoffmann T.C., Mulrow C.D., Shamseer L., Tetzlaff J.M., Akl E.A., Brennan S.E., et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J. Clin. Epidemiol. 2021;134:178–189. doi: 10.1016/j.jclinepi.2021.03.001.
    1. Sterne J.A.C., Savović J., Page M.J., Elbers R.G., Blencowe N.S., Boutron I., Cates C.J., Cheng H.Y., Corbett M.S., Eldridge S.M., et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi: 10.1136/bmj.l4898.
    1. Guyatt G.H., Oxman A.D., Schünemann H.J., Tugwell P., Knottnerus A. GRADE guidelines: A new series of articles in the Journal of Clinical Epidemiology. J. Clin. Epidemiol. 2011;64:380–382. doi: 10.1016/j.jclinepi.2010.09.011.
    1. Wei J.-J., Lin E.-X., Shi J.-D., Yang K., Hu Z.-L., Zeng X.-T., Tong T.-J. Meta-analysis with zero-event studies: A comparative study with application to COVID-19 data. Mil. Med. Res. 2021;8:41. doi: 10.1186/s40779-021-00331-6.
    1. McGrath S., Sohn H., Steele R., Benedetti A. Meta-analysis of the difference of medians. Biom. J. 2020;62:69–98. doi: 10.1002/bimj.201900036.
    1. Zarbock A., Küllmar M., Kindgen-Milles D., Wempe C., Gerss J., Brandenburger T., Dimski T., Tyczynski B., Jahn M., Mülling N., et al. Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients with Acute Kidney Injury. JAMA. 2020;324:1629. doi: 10.1001/jama.2020.18618.
    1. Kutsogiannis D.J., Gibney R.T.N., Stollery D., Gao J. Regional citrate versus systemic heparin anticoagulation for continuous renal replacement in critically ill patients. Kidney Int. 2005;67:2361–2367. doi: 10.1111/j.1523-1755.2005.00342.x.
    1. Hetzel G.R., Schmitz M., Wissing H., Ries W., Schott G., Heering P.J., Isgro F., Kribben A., Himmele R., Grabensee B., et al. Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: A prospective randomized multicentre trial. Nephrol. Dial. Transplant. 2011;26:232–239. doi: 10.1093/ndt/gfq575.
    1. Gattas D.J., Rajbhandari D., Bradford C., Buhr H., Lo S., Bellomo R. A Randomized Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Adults*. Crit. Care Med. 2015;43:1622–1629. doi: 10.1097/CCM.0000000000001004.
    1. Schilder L., Nurmohamed S.A., Bosch F.H., Purmer I.M., den Boer S.S., Kleppe C.G., Vervloet M.G., Beishuizen A., Girbes A.R., Ter Wee P.M., et al. Citrate anticoagulation versus systemic heparinisation in continuous venovenous hemofiltration in critically ill patients with acute kidney injury: A multi-center randomized clinical trial. Crit. Care. 2014;18:472. doi: 10.1186/s13054-014-0472-6.
    1. Stucker F., Ponte B., Tataw J., Martin P.-Y., Wozniak H., Pugin J., Saudan P. Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: A randomized controlled trial. Crit. Care. 2015;19:91. doi: 10.1186/s13054-015-0822-z.
    1. Betjes M.G.H., van Oosterom D., van Agteren M., van de Wetering J. Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: Similar hemofilter survival but significantly less bleeding. J. Nephrol. 2007;20:602–608.
    1. Wu B., Zhang K., Xu B., Ji D., Liu Z., Gong D. Randomized Controlled Trial to Evaluate Regional Citrate Anticoagulation Plus Low-Dose of Dalteparin in Continuous Veno-Venous Hemofiltration. Blood Purif. 2015;39:306–312. doi: 10.1159/000381662.
    1. Oudemans-Van Straaten H.M., Bosman R.J., Koopmans M., van der Voort P.H.J., Wester J.P.J., van der Spoel J.I., Dijksman L.M., Zandstra D.F. Citrate anticoagulation for continuous venovenous hemofiltration. Crit. Care Med. 2009;37:545–552. doi: 10.1097/CCM.0b013e3181953c5e.
    1. Brain M.J., Roodenburg O.S., Adams N., McCracken P., Hockings L., Musgrave S., Butt W., Scheinkestel C. Randomised trial of software algorithm driven regional citrate anticoagulation versus heparin in continuous renal replacement therapy: The Filter Life in Renal Replacement Therapy pilot trial. Crit. Care Resusc. 2014;16:131–137.
    1. Fealy N., Baldwin I., Johnstone M., Egi M., Bellomo R. A Pilot Randomized Controlled Crossover Study Comparing Regional Heparinization to Regional Citrate Anticoagulation for Continuous Venovenous Hemofiltration. Int. J. Artif. Organs. 2007;30:301–307. doi: 10.1177/039139880703000404.
    1. Monchi M., Berghmans D., Ledoux D., Canivet J.-L., Dubois B., Damas P. Citrate vs. heparin for anticoagulation in continuous venovenous hemofiltration: A prospective randomized study. Intensive Care Med. 2004;30:260–265. doi: 10.1007/s00134-003-2047-x.
    1. Davenport A., Tolwani A. Citrate anticoagulation for continuous renal replacement therapy (CRRT) in patients with acute kidney injury admitted to the intensive care unit. Clin. Kidney J. 2009;2:439–447. doi: 10.1093/ndtplus/sfp136.
    1. Tolwani A.J., Prendergast M.B., Speer R.R., Stofan B.S., Wille K.M. A Practical Citrate Anticoagulation Continuous Venovenous Hemodiafiltration Protocol for Metabolic Control and High Solute Clearance. Clin. J. Am. Soc. Nephrol. 2006;1:79–87. doi: 10.2215/CJN.00040505.
    1. Hamm L.L. Renal handling of citrate. Kidney Int. 1990;38:728–735. doi: 10.1038/ki.1990.265.
    1. Kelly A., Levine M.A. Hypocalcemia in the Critically Ill patient. J. Intensive Care Med. 2013;28:166–177. doi: 10.1177/0885066611411543.
    1. Schneider A.G., Journois D., Rimmelé T. Complications of regional citrate anticoagulation: Accumulation or overload? Crit. Care. 2017;21:281. doi: 10.1186/s13054-017-1880-1.
    1. 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;9:2173–2188. doi: 10.2215/CJN.01280214.
    1. Bakker A.J., Boerma E.C., Keidel H., Kingma P., van der Voort P.H.J. Detection of citrate overdose in critically ill patients on citrate-anticoagulated venovenous haemofiltration: Use of ionised and total/ionised calcium. Clin. Chem. Lab. Med. (CCLM) 2006;44:962–966. doi: 10.1515/CCLM.2006.164.
    1. Meier-Kriesche H.-U., Gitomer J., Finkel K., DuBose T. Increased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation. Crit. Care Med. 2001;29:748–752. doi: 10.1097/00003246-200104000-00010.
    1. Mariano F., Morselli M., Bergamo D., Hollo Z., Scella S., Maio M., Tetta C., Dellavalle A., Stella M., Triolo G. Blood and ultrafiltrate dosage of citrate as a useful and routine tool during continuous venovenous haemodiafiltration in septic shock patients. Nephrol. Dial. Transplant. 2011;26:3882–3888. doi: 10.1093/ndt/gfr106.
    1. Slowinski T., Morgera S., Joannidis M., Henneberg T., Stocker R., Helset E., Andersson K., Wehner M., Kozik-Jaromin J., Brett S., et al. Safety and efficacy of regional citrate anticoagulation in continuous venovenous hemodialysis in the presence of liver failure: The Liver Citrate Anticoagulation Threshold (L-CAT) observational study. Crit. Care. 2015;19:349. doi: 10.1186/s13054-015-1066-7.
    1. Khadzhynov D., Schelter C., Lieker I., Mika A., Staeck O., Neumayer H.-H., Peters H., Slowinski T. Incidence and outcome of metabolic disarrangements consistent with citrate accumulation in critically ill patients undergoing continuous venovenous hemodialysis with regional citrate anticoagulation. J. Crit. Care. 2014;29:265–271. doi: 10.1016/j.jcrc.2013.10.015.
    1. Tan J.-N., Haroon S.W.P., Mukhopadhyay A., Lau T., Murali T.M., Phua J., Tan Z.-Y., Lee N., Chua H.-R. Hyperlactatemia Predicts Citrate Intolerance with Regional Citrate Anticoagulation During Continuous Renal Replacement Therapy. J. Intensive Care Med. 2019;34:418–425. doi: 10.1177/0885066617701068.
    1. Venkatesh B. Stewart’s Textbook of Acid-Base, 2nd edition. Crit. Care. 2009;13:306. doi: 10.1186/cc7906.
    1. Naka T., Egi M., Bellomo R., Cole L., French C., Wan L., Fealy N., Baldwin I. Low-dose Citrate Continuous Veno-venous Hemofiltration (CVVH) and Acid-base Balance. Int. J. Artif. Organs. 2005;28:222–228. doi: 10.1177/039139880502800306.
    1. Egi M., Naka T., Bellomo R., Langenberg C., Li W., Fealy N., Baldwin I. The Acid-Base Effect of Changing Citrate Solution for Regional Anticoagulation during Continuous Veno-Venous Hemofiltration. Int. J. Artif. Organs. 2008;31:228–236. doi: 10.1177/039139880803100306.
    1. Jacobs R., Honore P.M., Diltoer M., Spapen H.D. Chloride content of solutions used for regional citrate anticoagulation might be responsible for blunting correction of metabolic acidosis during continuous veno-venous hemofiltration. BMC Nephrol. 2016;17:119. doi: 10.1186/s12882-016-0334-3.
    1. Rewa O.G., Villeneuve P.-M., Lachance P., Eurich D.T., Stelfox H.T., Gibney R.T.N., Hartling L., Featherstone R., Bagshaw S.M. Quality indicators of continuous renal replacement therapy (CRRT) care in critically ill patients: A systematic review. Intensive Care Med. 2017;43:750–763. doi: 10.1007/s00134-016-4579-x.
    1. Tolwani A.J., Wille K.M. Anticoagulation for Continuous Renal Replacement Therapy. Semin. Dial. 2009;22:141–145. doi: 10.1111/j.1525-139X.2008.00545.x.
    1. Legrand M., Tolwani A. Anticoagulation strategies in continuous renal replacement therapy. Semin. Dial. 2021;34:416–422. doi: 10.1111/sdi.12959.
    1. Davenport A. Anticoagulation for Continuous Renal Replacement Therapy. Contrib Nephrol. 2004;144:228–238.
    1. Oudemans-van Straaten H.M., Wester J.P.J., de Pont A.C.J.M., Schetz M.R.C. Anticoagulation strategies in continuous renal replacement therapy: Can the choice be evidence based? Intensive Care Med. 2006;32:188–202. doi: 10.1007/s00134-005-0044-y.
    1. Ricci Z., Ronco C., D’amico G., de Felice R., Rossi S., Bolgan I., Bonello M., Zamperetti N., Petras D., Salvatori G., et al. Practice patterns in the management of acute renal failure in the critically ill patient: An international survey. Nephrol. Dial. Transplant. 2006;21:690–696. doi: 10.1093/ndt/gfi296.
    1. Warkentin T.E., Levine M.N., Hirsh J., Horsewood P., Roberts R.S., Gent M., Kelton J.G. Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin. N. Engl. J. Med. 1995;332:1330–1336. doi: 10.1056/NEJM199505183322003.
    1. Hirsh J., Raschke R. Heparin and Low-Molecular-Weight Heparin. Chest. 2004;126:188S–203S. doi: 10.1378/chest.126.3_suppl.188S.
    1. Ricci Z., Ronco C., Bachetoni A., D’amico G., Rossi S., Alessandri E., Rocco M., Pietropaoli P. Solute removal during continuous renal replacement therapy in critically ill patients: Convection versus diffusion. Crit. Care. 2006;10:R67. doi: 10.1186/cc4903.
    1. Joannidis M., Oudemans-van Straaten H.M. Clinical review: Patency of the circuit in continuous renal replacement therapy. Crit. Care. 2007;11:218. doi: 10.1186/cc5937.
    1. Baldwin I. Acute Kidney Injury. Karger Publishers; Basel, Switzerland: 2007. Factors Affecting Circuit Patency and Filter ‘Life’; pp. 178–184.
    1. Hoste E.A.J., Kellum J.A., Selby N.M., Zarbock A., Palevsky P.M., Bagshaw S.M., Goldstein S.L., Cerdá J., Chawla L.S. Global epidemiology and outcomes of acute kidney injury. Nat. Rev. Nephrol. 2018;14:607–625. doi: 10.1038/s41581-018-0052-0.
    1. Kramer P., Wigger W., Rieger J., Matthaei D., Scheler F. Arteriovenous haemofiltration: A new and simple method for treatment of over-hydrated patients resistant to diuretics. Klin. Wochenschr. 1977;55:1121–1122. doi: 10.1007/BF01477940.
    1. Khwaja A. KDIGO Clinical Practice Guidelines for Acute Kidney Injury. Nephron Clin. Pract. 2012;120:c179–c184. doi: 10.1159/000339789.
    1. Ye Z., Wang Y., Ge L., Guyatt G.H., Collister D., Alhazzani W., Bagshaw S.M., Belley-Cote E.P., Fang F., Hou L.M., et al. Comparing Renal Replacement Therapy Modalities in Critically Ill Patients with Acute Kidney Injury: A Systematic Review and Network Meta-Analysis. Crit. Care Explor. 2021;3:e0399. doi: 10.1097/CCE.0000000000000399.
    1. Li R., Gao X., Zhou T., Li Y., Wang J., Zhang P. Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: A meta-analysis of randomized controlled trials. Ther. Apher. Dial. 2022;26:1086–1097. doi: 10.1111/1744-9987.13850.
    1. Liu C., Mao Z., Kang H., Hu J., Zhou F. Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: A meta-analysis with trial sequential analysis of randomized controlled trials. Crit. Care. 2016;20:144. doi: 10.1186/s13054-016-1299-0.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する