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Intraoperative continuous renal replacement therapy during liver transplantation: a pilot randomized-controlled trial (INCEPTION)

  • Constantine J. Karvellas
  • Samantha Taylor
  • David Bigam
  • Norman M. Kneteman
  • A. M. James Shapiro
  • Adam Romanovsky
  • R. T. Noel Gibney
  • Derek R. Townsend
  • Glenda Meeberg
  • Timur Özelsel
  • Edward Bishop
  • Sean M. BagshawEmail author
Reports of Original Investigations

Abstract

Purpose

To evaluate the feasibility of intraoperative continuous renal replacement therapy (IoCRRT) during liver transplantation (LT), in terms of recruitment, protocol adherence, and ascertainment of follow-up.

Methods

In this pilot randomized open-label controlled trial in adults receiving LT with a Model for End-Stage Liver Disease (MELD) score ≥ 25 and preoperative acute kidney injury (RIFLE - RISK or higher) and/or estimated glomerular filtration rate < 60 mL·min−1·1.73 m−2, patients were randomized to receive IoCRRT or standard of care (SOC). Primary endpoints were feasibility and adverse events. Primary analysis was intention-to-treat (n = 32) and secondary analysis was per-protocol (n = 28).

Results

The trial was stopped early because of slow patient accrual and inadequate funding. Sixty patients were enrolled and 32 (53%) were randomized (n = 15 IoCRRT; n = 17 SOC). Mean (standard deviation) MELD was 36 (8), 81% (n = 26) had cirrhosis; 69% (n = 22) received preoperative RRT; 66% (n = 21) received LT from the intensive care unit. Four patients (n = 2 IoCRRT, n = 2 SOC) did not receive LT post-randomization. Seven patients (41%) allocated to SOC crossed over intraoperatively to IoCRRT. Three patients were lost to follow-up at one year. No adverse events occurred related to IoCRRT. There were no differences in survival at one year (IoCRRT, 71% [n = 10/14] vs SOC, 93% [n = 14/15]; risk ratio, 0.77; 95% confidence interval, 0.54 to 1.1). In the per-protocol analysis (n = 28 received IoCRRT after randomization - n = 20 IoCRRT, n = 8 SOC), one-year survival was 92% and perioperative complications were similar between groups. Only one patient was receiving dialysis one year after LT.

Conclusion

In this pilot randomized trial, IoCRRT was feasible and safe with no difference in complications. Crossover rates were high. Despite high preoperative severity of illness, one-year survival was excellent. These data can inform the design of a larger multicentre trial.

Trial registration

www.clinicalTrials.gov (NCT01575015); registered 12 April, 2012.

Traitement substitutif peropératoire continu de l’insuffisance rénale pendant une greffe hépatique: une étude randomisée contrôlée pilote (INCEPTION)

Résumé

Objectif

Notre but était d’évaluer la faisabilité d’un traitement substitutif peropératoire continu de l’insuffisance rénale pendant une greffe hépatique, notamment en matière de recrutement, d’adhésion au protocole, et de suivi.

Méthode

Dans cette étude randomisée contrôlée non aveugle pilote réalisée auprès d’adultes recevant une greffe hépatique avec un score MELD (Model for End-Stage Liver Disease) ≥ 25 et une insuffisance rénale aiguë préopératoire (RIFLE - RISQUÉ ou plus élevé) et/ou un taux de filtration glomérulaire estimé < 60 mL·min−1·1,73 m−2, les patients ont été randomisés à recevoir un traitement substitutif peropératoire continu de l’insuffisance rénale (le traitement) ou les soins habituels (la norme). Les critères d’évaluation principaux étaient la faisabilité et les événements indésirables. L’analyse principale était l’analyse du projet thérapeutique (intention-to-treat; n = 32) et l’analyse secondaire était l’analyse selon le protocole (n = 28).

Résultats

L’étude a été précocement interrompue en raison du recrutement lent de patients et du manque de fonds. Soixante patients ont été recrutés et 32 (53 %) ont été randomisés (n = 15 traitement; n = 17 norme). Le score MELD moyen (écart type) était de 36 (8), 81 % (n = 26) des patients souffraient de cirrhose; 69 % (n = 22) ont reçu un traitement substitutif de l’insuffisance rénale préopératoire; 66 % (n = 21) ont reçu une greffe hépatique à partir de l’unité de soins intensifs. Quatre patients (n = 2 traitement, n = 2 norme) n’ont pas reçu de greffe hépatique après la randomisation. Sept patients (41 %) alloués au groupe norme sont passés dans le groupe traitement en période peropératoire. Trois patients ont été perdus au suivi au cours de la première année. Aucun événement indésirable n’est survenu en association au traitement substitutif peropératoire continu de l’insuffisance rénale. Aucune différence en matière de survie à un an n’a été observée (traitement, 71 % [n = 10/14] vs norme, 93 % [n = 14/15]; risque relatif, 0,77; intervalle de confiance 95 %, 0,54 à 1,1). Dans l’analyse selon le protocole (n = 28 ont reçu un traitement après la randomisation - n = 20 traitement, n = 8 norme), la survie à un an était de 92 % et les complications périopératoires étaient semblables dans les deux groupes. Un seul patient recevait de la dialyse un an après la greffe hépatique.

Conclusion

Dans cette étude randomisée pilote, le traitement substitutif peropératoire continu de l’insuffisance rénale s’est avéré faisable et sécuritaire, et aucune différence en matière de complications n’a été observée. Les taux de transfert d’un groupe à l’autre étaient élevés. Malgré une sévérité préopératoire élevée de la maladie, la survie à un an était excellente. Ces données peuvent être utiles pour concevoir une étude multicentrique plus importante.

Enregistrement de l’étude

www.clinicalTrials.gov (NCT01575015); enregistrée le 12 avril 2012.

Notes

Acknowledgement

Sean M. Bagshaw is supported by a Canada Research Chair in Critical Care Nephrology.

Conflicts of interest

Sean M. Bagshaw reports having received honoraria and unrestricted research support from Baxter Healthcare Corp. While all CRRT services in this study (like all of Alberta and Canada) are provided by Baxter, Baxter did not provide any funding for this trial, nor were they involved in any aspect of its design, conduct, analysis, reporting, or decision to publish the manuscript. All other authors have no personal or funding conflicts of interest.

Editorial responsibility

This submission was handled by Dr. Philip M. Jones, Associate Editor, Canadian Journal of Anesthesia.

Author contributions

Constantine J. Karvellas performed analysis and interpretation of the data, and drafted the final manuscript. Samantha Taylor significantly contributed to study design, patient enrolment/randomization, data collection/compilation of the final data set, and revision of the final manuscript. David Bigam, Norman M. Kneteman, A. M. James Shapiro, Adam Romanovsky, R. T. Noel Gibney, Derek R. Townsend, Glenda Meeberg, Timur Özelsel, and Edward Bishop contributed to study design, patient enrolment, and critically revised the final manuscript. Sean M. Bagshaw conceived the idea of the study and its design, obtained funding, assisted in analysis and interpretation of data, and drafted and critically revised the final manuscript for important intellectual content.

Financial support

This work was supported by a grant from the University of Alberta Hospital Foundation. The funding agency had no role in the design or conduct of the study, in the collection, management, analysis, or interpretation of the data, or in the preparation, review, or approval of the manuscript.

Supplementary material

12630_2019_1454_MOESM1_ESM.pdf (161 kb)
Supplementary material 1 (PDF 161 kb)

References

  1. 1.
    Wiklund RA. Preoperative preparation of patients with advanced liver disease. Crit Care Med 2004; 32: S106-15.CrossRefGoogle Scholar
  2. 2.
    Angeli P, Bezinover D, Biancofiore G, et al. Acute kidney injury in liver transplant candidates: a position paper on behalf of the Liver Intensive Care Group of Europe. Minerva Anestesiol 2017; 83: 88-101.Google Scholar
  3. 3.
    Gill RQ, Sterling RK. Acute liver failure. J Clin Gastroenterol 2001; 33: 191-8.CrossRefGoogle Scholar
  4. 4.
    Pawarode A, Fine DM, Thuluvath PJ. Independent risk factors and natural history of renal dysfunction in liver transplant recipients. Liver Transpl 2003; 9: 741-7.CrossRefGoogle Scholar
  5. 5.
    Rymarz A, Serwacki M, Rutkowski M, et al. Prevalence and predictors of acute renal injury in liver transplant recipients. Transplant Proc 2009; 41: 3123-5.CrossRefGoogle Scholar
  6. 6.
    Uchino S, Bellomo R, Morimatsu H, et al. Continuous renal replacement therapy: a worldwide practice survey. The Beginning and Ending Supportive Therapy for the Kidney (B.E.S.T. Kidney) Investigators. Intensive Care Med 2007; 33: 1563-70.Google Scholar
  7. 7.
    Davenport A, Will EJ, Davison AM, et al. Changes in intracranial pressure during haemofiltration in oliguric patients with grade IV hepatic encephalopathy. Nephron 1989; 53: 142-6.CrossRefGoogle Scholar
  8. 8.
    Korbet SM, Casey C, Rodby RA, Williams W. The use of continuous arteriovenous hemofiltration in orthotopic liver transplantation. Clin Nephrol 1995; 43: 134-6.Google Scholar
  9. 9.
    Bellomo R, Harris C, Kang Y, Daniel E, Fung JJ, Bronsther O. Combined veno-venous bypass and high volume hemofiltration during orthotopic liver transplantation. ASAIO J 1993; 39: 954-6.CrossRefGoogle Scholar
  10. 10.
    Townsend DR, Bagshaw SM, Jacka MJ, Bigam D, Cave D, Gibney RT. Intraoperative renal support during liver transplantation. Liver Transpl 2009; 15: 73-8.CrossRefGoogle Scholar
  11. 11.
    Salord F, Bailly MP, Gaussorgues P, Workineh S, Pouyet M, Robert D. Continuous arteriovenous haemodialysis during emergency hepatic retransplantation: two case reports. Intensive Care Med 1990; 16: 330-1.CrossRefGoogle Scholar
  12. 12.
    Vitin A, Muczynski K, Bakthavatsalam R, Martay K, Dembo G, Metzner J. Treatment of severe lactic acidosis during the pre-anhepatic stage of liver transplant surgery with intraoperative hemodialysis. J Clin Anesth 2010; 22: 466-72.CrossRefGoogle Scholar
  13. 13.
    Parmar A, Bigam D, Meeberg G, et al. An evaluation of intraoperative renal support during liver transplantation: a matched cohort study. Blood Purif 2011; 32: 238-48.CrossRefGoogle Scholar
  14. 14.
    Bellomo R, Kellum JA, Ronco C. Defining acute renal failure: physiological principles. Intensive Care Med 2004; 30: 33-7.CrossRefGoogle Scholar
  15. 15.
    Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604-12.CrossRefGoogle Scholar
  16. 16.
    Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001; 33: 464-70.CrossRefGoogle Scholar
  17. 17.
    Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative Workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204-12.Google Scholar
  18. 18.
    Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373-83.CrossRefGoogle Scholar
  19. 19.
    Nadim MK, Annanthapanyasut W, Matsuoka L, et al. Intraoperative hemodialysis during liver transplantation: a decade of experience. Liver Transpl 2014; 20: 756-64.CrossRefGoogle Scholar
  20. 20.
    Agopian VG, Dhillon A, Baber J, et al. Liver transplantation in recipients receiving renal replacement therapy: outcomes analysis and the role of intraoperative hemodialysis. Am J Transplant 2014; 14: 1638-47.CrossRefGoogle Scholar
  21. 21.
    LaMattina JC, Kelly PJ, Hanish SI, et al. Intraoperative continuous veno-venous hemofiltration facilitates surgery in liver transplant patients with acute renal failure. Transplant Proc 2015; 47: 1901-4.CrossRefGoogle Scholar
  22. 22.
    Bittermann T, Hubbard RA, Serper M, et al. Healthcare utilization after liver transplantation is highly variable among both centers and recipients. Am J Transplant 2018; 18: 1197-205.CrossRefGoogle Scholar
  23. 23.
    Zimmerman MA, Selim M, Kim J, et al. Outcome analysis of continuous intraoperative renal replacement therapy in the highest acuity liver transplant recipients: a single-center experience. Surgery 2017; 161: 1279-86.CrossRefGoogle Scholar

Copyright information

© Canadian Anesthesiologists' Society 2019

Authors and Affiliations

  • Constantine J. Karvellas
    • 1
    • 2
  • Samantha Taylor
    • 3
  • David Bigam
    • 4
  • Norman M. Kneteman
    • 4
  • A. M. James Shapiro
    • 4
  • Adam Romanovsky
    • 1
  • R. T. Noel Gibney
    • 1
  • Derek R. Townsend
    • 1
    • 3
  • Glenda Meeberg
    • 4
  • Timur Özelsel
    • 3
  • Edward Bishop
    • 3
  • Sean M. Bagshaw
    • 1
    Email author
  1. 1.Department of Critical Care Medicine, Faculty of Medicine and DentistryUniversity of AlbertaEdmontonCanada
  2. 2.Division of Gastroenterology (Liver Unit)University of AlbertaEdmontonCanada
  3. 3.Department of Anesthesia and Pain Medicine, Faculty of Medicine and DentistryUniversity of AlbertaEdmontonCanada
  4. 4.Department of Surgery, Faculty of Medicine and DentistryUniversity of AlbertaEdmontonCanada

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