Retrospective Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jan 27, 2018; 10(1): 62-72
Published online Jan 27, 2018. doi: 10.4254/wjh.v10.i1.62
Predicting early outcomes of liver transplantation in young children: The EARLY study
Rashid Alobaidi, Natalie Anton, Dominic Cave, Elham Khodayari Moez, Ari R Joffe
Rashid Alobaidi, Natalie Anton, Dominic Cave, Ari R Joffe, Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Alberta and Stollery Children’s Hospital, Edmonton, Alberta T6G 1C9, Canada
Elham Khodayari Moez, School of Public Health, University of Alberta, Edmonton, Alberta T6G 2B7, Canada
Author contributions: Alobaidi R, Anton N, Cave D and Joffe AR contributed to conception and design of the study, interpretation of data and revision of the manuscript critically for intellectual content, and have read and approved the version to be published; Moez EK contributed to interpretation of data, confirmation of statistical analyses and revision of the manuscript critically for intellectual content, and has read and approved the version to be published; Joffe AR contributed to acquisition and interpretation of data, wrote the first draft of the manuscript, and had final approval of the version to be published; Alobaidi R contributed to acquisition and interpretation of data and revision of the manuscript critically for intellectual content, and had final approval of the version to be published; Joffe AR, Alobaidi R and Moez EK had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis; all authors participated sufficiently in the work to take public responsibility for the manuscript content.
Institutional review board statement: This study was approved by the University of Alberta Health Research Ethics Board (Pro00031805).
Informed consent statement: The need for written informed consent was waived for this retrospective chart review study by the Research Ethics Board.
Conflict-of-interest statement: The authors declare that there is no conflict of interest.
Data sharing statement: The dataset is available from the corresponding author at ari.joffe@ahs.ca upon reasonable request. Consent was not obtained but the presented data are anonymized and risk of identification is low.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ari R Joffe, MD, Full Professor, Department of Pediatrics, Division of Pediatric Critical Care Medicine, University of Alberta and Stollery Children’s Hospital, 4-546 Edmonton Clinic Health Academy, 11405 87 Avenue, Edmonton, Alberta T6G 1C9, Canada. ari.joffe@ahs.ca
Telephone: +1-780-2485435 Fax: +1-888-7901283
Received: October 19, 2017
Peer-review started: October 26, 2017
First decision: December 1, 2017
Revised: December 20, 2017
Accepted: December 29, 2017
Article in press: December 29, 2017
Published online: January 27, 2018
Processing time: 93 Days and 10.8 Hours
ARTICLE HIGHLIGHTS
Research background

Postoperative intensive care unit complications after liver transplantation in young children are common, and associated with significant morbidity and mortality. Risk factors for these early complications are poorly studied.

Research motivation

Postoperative intensive care unit complications in young children can require reoperation, threaten liver graft viability, and prolong length of stay. These complications include thrombosis of vessels necessary for blood flow to the liver graft (i.e. hepatic artery thrombosis and portal vein thrombosis), other life-threatening events requiring intensive care management (i.e. bile leak, bowel perforation, intraabdominal infection, or retransplant), or death. Identifying risk factors for these complications can generate hypotheses for future research testing, leading to improved outcomes after liver transplantation.

Research objectives

The authors aimed to determine potentially modifiable prespecified acute care variables that may be associated with prespecified primary and secondary acute intensive care postoperative outcomes in young liver transplant recipients at our center over the past 10 years. In addition, the authors aimed to explore novel potential predictors of adverse outcomes, including written comments made about abnormal liver vessels or biliary anatomy in the dictated operating report, measures of postoperative fluid balance, and measures of post-operative coagulation status. The authors identified risk factors that are potentially modifiable and that should be confirmed by future research.

Research methods

This study was a retrospective chart review including all consecutive children of age less than 3-years-old having had a liver transplant done at the Western Canadian referral center from June 2005 to June 2015. Prespecified potential predictor variables and primary and secondary outcomes were recorded using standard definitions and a case report form. Associations between potential predictor variables and outcomes were determined using univariate and multiple logistic (odds ratio, OR; 95% confidence interval, CI) or linear (effect size, ES; 95%CI) regressions.

Research results

There were several important results from this study. First, although pediatric intensive care unit (PICU) patient (92%) and graft (80%) survivals were high, patients experienced a combination of significant postoperative complications, including hepatic artery thrombosis (19%), portal vein thrombosis (17%), bile leak (23%), bowel perforation (8%), intraabdominal bleeding (11%), abdominal compartment syndrome (12%), and intraabdominal infection (28%). These complications necessitated reoperation of the abdomen for 51% (median 2 episodes, interquartile range 1-4), retransplantation for 14%, and renal replacement therapy for 14% of all patients. Second, there were few independent predictors of our primary and secondary outcomes. When adjusted for prespecified clinically important variables (weight, year, pediatric end-stage liver disease score, and surgeon) and those variables significant at P ≤ 0.10 on univariate analysis, whole liver graft had higher risk of complications (of hepatic artery thrombosis, ventilator days, any severe complication, any thrombosis, and graft loss). A novel predictor, the lower the antithrombin level on day 2-5 post-operative, had higher risk of complications (ventilator days, any severe complication, any thrombosis, and graft loss). The independent association of surgeon with outcomes (of any thrombosis, any severe complication, and ventilator days) has not, to our knowledge, previously been reported. Third, the authors found no statistically significant change in outcomes over time on multiple regressions. Fourth, the authors found no statistically significant association of recipient weight with adverse outcomes on multiple regressions. Fifth, some of the novel predictors the authors examined were not associated with complication rates on multiple regressions. This included: growth failure (below 5th percentile on weight or height), surgical comments about concerning anatomy of the transplant vessels (hepatic artery or portal vein) or biliary tract, whether fascia was closed on admission to PICU, measures of postoperative fluid status (e.g., use of furosemide, lowest central venous pressure, and highest hemoglobin), and measures of anticoagulation (e.g., achieving a therapeutic heparin level). Future study is required to confirm our findings. Treatment with antithrombin concentrate intravenously should be considered for low antithrombin levels in studies of anticoagulation protocols.

Research conclusions

Patients under 3-years-old having liver transplant had high patient (92%) and graft (80%) survival. These patients not infrequently experienced a combination of significant postoperative complications, including hepatic artery thrombosis, portal vein thrombosis, bile leak, bowel perforation, intraabdominal bleeding, abdominal compartment syndrome, and intraabdominal infection, sometimes necessitating reoperation of the abdomen, retransplantation, and kidney dialysis. Whole liver graft was independently associated with a higher risk of complications. Surgeon was independently associated with a higher risk of complications. A novel predictor, the lower the antithrombin level on day 2-5 postoperative, was independently associated with a higher risk of complications. Antithrombin is an anticoagulant produced by the liver, with its effect mediated by irreversibly inhibiting plasma serine proteases (including activated factors X and thrombin); this effect is greatly accelerated by heparin. In addition, antithrombin has antiinflammatory properties. Although antithrombin does not have beneficial effects in critically ill patients in general, it has not been studied in the setting of liver transplant patients who are high risk for thrombosis. Other centers should determine whether antithrombin levels are associated with outcomes after liver transplant in young children, and a prospective trial comparing anticoagulation strategies that incorporate antithrombin treatment should be considered. In addition, more study is needed to determine what accounts for differences in outcomes among surgeons.

Research perspectives

The findings are hypothesis generating and require confirmation by other centers, ideally in prospective studies. Future prospective observational research is needed to confirm the findings that whole liver graft, surgeon, and low antithrombin postoperatively are risk factors for complications. If confirmed, future randomized controlled trials of anticoagulation strategies after liver transplant in young children are needed, and these should include monitoring and treatment of antithrombin levels.