Critical Care Considerations in the Management of Acute Liver Failure

• Author / Creator

  MacDonald, Andrew J

• Acute Liver Failure (ALF) is a rare syndrome involving rapid deterioration of liver function in patients without pre-existing liver disease or cirrhosis. Within North America, acetaminophen (APAP)-induced ALF represents the most common etiology. Regardless of etiology, ALF patients are critically ill and may develop multi-organ failure, intracranial hypertension (ICH), or cerebral edema (CE). Improving transplant-free survival (TFS) remains the goal of critical care management. Extracorporeal liver support systems, specifically the molecular adsorbent recirculating system (MARS), remove water-soluble and albumin-bound toxins and aim to create an environment for native organ recovery or, in those failing medical therapy, bridging to liver transplantation (LT). The role of MARS in TFS remains in question.

  This thesis aimed to:

  1. Evaluate changes in clinical interventions, psychosocial profile and important clinical outcomes over a 21-year period in APAP-ALF using data from the ALF Study Group (ALFSG) registry.
  2. Evaluate the association MARS, compared to standard medical therapy (SMT), with TFS in all-etiology ALF using data from the ALFSG registry.

  First, a retrospective review of the prospective, multicentre ALFSG cohort study of all APAP-ALF patients enrolled over 1998-2018 was completed. Primary outcomes evaluated were 21-day TFS and neurological complications. Covariates evaluated included enrollment cohort (early: 1998-2007; recent: 2008-2018), overdose intentionality, psychiatric comorbidity and the use of organ support including continuous renal replacement therapy (CRRT).

  Second, a retrospective review of all ALF patients treated with MARS between January 2009 and 2019 at three North American transplant centres was completed. Propensity scores (PS) were used to match SMT-treated patients using data from the US ALFSG registry. Primary outcome was 21-day TFS and was evaluated using multivariable conditional logistic regression, adjusting for imbalanced covariates following matching. Secondary outcomes included change in clinical and biochemical parameters post-treatment in MARS patients.

  Of 1190 APAP-ALF patients (early: n=582; recent: n=608); recent cohort patients had significantly improved TFS (recent: 69.8% vs. early: 61.7%; p=0.005). Recent cohort patients were more likely to receive CRRT (22.2% vs. 7.6%; p<0.001), less likely to develop ICH (29.9% vs. 51.5%; p<0.001), and less likely to die by day 21 due to CE (4.5% vs. 11.6%; p<0.001). Grouped by TFS status (non-TFS: n=365 (died/transplanted) vs. TFS: n=704), there were no differences in pre-existing psychiatric comorbidity (51.5% vs. 55.0%; p=0.28) or overdose intention (intentional: 39.7% vs. 41.6%; p=0.58). On multivariable logistic regression adjusting for vasopressor support, development of grade 3/4 hepatic encephalopathy (HE), King’s College Criteria (KCC), and model for end-stage liver disease score, the use of CRRT (OR 1.62; p=0.023) was associated with significantly increased TFS (c-statistic 0.86). In a second model adjusting for the same covariates, recent enrollment was significantly associated with TFS (OR 1.42; p=0.034; c-statistic 0.86).

  Of 104 ALF patients that received MARS, 104 patients were PS-matched (4:1) to 416 SMT patients. Significant improvements in clinical and biochemical parameters were observed following MARS therapy, particularly in APAP-ALF patients. Using multivariable conditional logistic regression adjusting for ALF etiology, age, vasopressor support, international normalized ratio, and meeting KCC, MARS therapy was not associated with increased TFS (Main Model; MARS OR 1.60; p=0.093). Following addition of PS (MARS OR 1.90; p=0.030), and PS, mechanical ventilation, and development of grade 3/4 HE (MARS OR 1.91; p=0.029) to the Main Model, and in a model adjusting for ALF etiology and PS (MARS OR 1.86; p=0.033), MARS was associated with significantly increased 21-day TFS in sensitivity analyses.

  In conclusion, TFS in APAP-ALF has improved in recent years and rates of ICH/CE have declined, possibly related to increased CRRT use. Following MARS therapy, biochemical variables trended towards normalization and, in APAP-ALF, hemodynamic status improved. Treatment with MARS was associated with a trend towards increased TFS over SMT in ALF.

• Subjects / Keywords

  • extracorporeal liver support
  • continuous renal replacement therapy
  • liver transplantation
  • acute liver failure
  • molecular adsorbent recirculating system

• Graduation date

  Fall 2020

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-r1dv-7h97

• License

  Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.