Liver transplantation in the critically ill cirrhotic

Constantine (Dean) Karvellas MD SM FRCPCAssistant Professor of Medicine

Divisions of Critical Care Medicine and GastroenterologyUniversity of Alberta

Current Sources of Funding

• NIH/NIDDK U01 58369

• US Acute Liver Failure Study Group (Co-PI)

Speakers Bureau

• Gambro

DISCLOSURES

Objectives

1. Understand classic indications and

contraindications for liver transplant (LT).

2. Examine the impact of critical illness and patient

factors on post-LT outcomes and complications.

3. Understand the impact of donor factors on LT

outcomes (in ACLF).

Cirrhosis, ACLF and LT: Social Justice

• “In 2013, 5000 Canadians died due to complications of

cirrhosis with a significant number dying in ICU”

• Liver transplants per year in Canada ~ 400 -450

• LT for cirrhosis is associated with good outcomes

– 1 year survival > 80%

• Shortages of donors/increasing waiting times

– patients deteriorate necessitating ICU admission

– organ support awaiting LTx

• “Social Justice”

– Which cirrhotic patients would benefit the most from LT

4

Considerations for Liver Transplantation

• Medical need for transplant

– MELD > 15 (< 50% survival at 1 year)

– “Sickest patient”

• Are there any medical contra-indications for

transplant

– See next slide

• Psychosocial contra-indications for liver transplant

– Alcohol/substance abuse

– Social support

Contraindications to Liver transplantation

• Malignancy

• Severe cardiopulmonary disease

• Neuropsychiatric conditions

– Uncontrolled psychiatric disease

• Uncontrolled Infection

– HIV*

– Ongoing sepsis

Acute on Chronic Liver Failure (ACLF)

EASL-AASLD consensus group

‘an acute decompensation (AD) of hepatic function

in cirrhotic patients, either secondary to

superimposed liver injury or due to system

precipitating factors culminating in multiple organ

dysfunction and associated with increased mortality

at 3 months’(5) Jalan R et al. Acute-on chronic liver failure. J Hepatol. 2012;57(6):1336

Factors in Liver transplant in ACLF

1. Medical comorbidity

– Cardiopulmonary disease

2. Severity of illness

– MELD/CTP

– SOFA/ CLIF SOFA

3. Donor factors

– Donor risk index

– Decease cardiac donation (DCD)

Medical comorbidity

C-statistic 0.63

CADDMCOPDCKDCTD

N=0 390N=1 100N> 1 134

Cardoso et al, Annals of Hepatology Vol 14 No 4 2015.

Co-morbidities in Canadian Setting: Not so

Canadian LT centers exclude many patients with significant cardiopulmonary comorbidity

2. Severity of Illness

MELD, CTP, SOFA, CLIF-SOFA

Cardoso et al, Annals of Hepatology 2015

Cox proportional hazards regression new predictive model of 5-year mortality after transplant.

C-statistic 0.64 (pre-transplant recipient factors only)

Cardoso et al, Annals of Hepatology 2015.

First aim (n=198) Second Aim (n=106)

Age (years) 53 (10) 54 (9.5)

Female 67 (34%) 31 (29%)

Hepatitis C 62 (31%) 30 (29%)

Alcohol 30(15%) 24(23%)

Charlson Score* 1 (1) 0.7(1)

Hepatic encephalopathy 107 (94%) 67 (79%)

Hepatorenal syndrome 84 (63%) 71 (69%)

SBP 34 (41%) 37 (44%)

INR 2.1 (1.7-2.8) 2.2 (1.8-3.3)

Bilirubin (μmol/L) 273 (95-575) 239 (95-469)

Lactate (mmol/L) 2.8(1.6-4.6) 3.6(2.4-7.8)

Creatinine (μmol/L) 197 (109-308) 207 (122-301)

MELD (admit) 34 (26-39) 36 (27-40)

MELD (transplant) 34 (27-40)

SOFA (admit) 12.5 (4) 14 (4)

SOFA (48 hours) 13 (5) 17 (4)

SOFA (transplant) 14 (4)

Methods:

Single center retrospective cohort study including 519 adult

cirrhotic patients who underwent OLT from 01/2002 to 06/2012

Study of MELD score ≥ 40 as a risk factor for a first ICU stay

after LT ≥ 10 days: Logistic regression

Survival analysis: Kaplan-Meier, Cox regression

Cardoso, et al. Can J Gastroenterol Hepatol Vol 29 No 5 2015

The tradeoff: Resource implications

Predictors of prolonged ICU stay post-LT (> 10 days)

Unadjusted Model 1 Model 2

OR (95% CI) P OR (95% CI) P OR (95% CI) P

Age (years) 1.01 (0.99-1.04) 0.37 1.01 (0.99-1.04) 0.301.01 (0.98-

1.04)0.61

Sex (male) 0.91 (0.56-1.49) 0.70 0.90 (0.54-1.50) 0.690.85 (0.46-

1.56)0.59

Biochemical MELD at LT (≥ 40) 6.73 (3.07-14.7) < 0.001 6.86 (3.12-15.1) < 0.0013.21 (1.12-

9.20)0.030

Hepatic encephalopathy (III/IV) 4.33 (2.59-7.25) < 0.0012.29 (1.14-

4.60)0.020

Hepatorenal syndrome 2.17 (1.22-3.87) 0.0090.81 (0.37-

1.74)0.58

Hepatopulmonary syndrome 5.06 (1.59-16.1) 0.0064.86 (1.23-

19.2)0.024

ICU admission prior to LT 5.33 (3.07-9.26) < 0.0012.42 (1.02-

5.71)0.044

Donor Risk Index 1.08 (0.57-2.07) 0.810.76 (0.36-

1.60)0.46

RBC in OR (≥ 5 units) 3.08 (1.92-4.96) < 0.0011.75 (0.97-

3.16)0.06

Model 1 goodness of fit (n = 513): χ2, 22 (Df, 3); p < 0.001; AUROC, 0.61 (95% CI, 0.54-0.67).

Model 2 goodness of fit (n = 399): χ2, 49 (Df, 9); p < 0.001; AUROC, 0.75 (95% CI, 0.68-0.81).

Severity of Illness: The tradeoffs

• Severity of illness

– differentiations those who go on to get a graft

• SOFA

– associated with increased resource use

• MELD

– Longer ICU stays

– Increased requirements for CRRT, MV, etc.

• Severity of illness (SOFA, MELD) does NOT predict outcome post-LT

– Be careful in older patients (age)

• There are no definitive “futility criteria” based on organ failures

alone

3. Donor Issues

Donor issues in ACLF LT: DBD vs. DCD

• Jacksonville 2003-2008

– 1215 LT performed; 85 from ICU

• Excluding retransplants and multiorgan transplants

• 8 DCD, 42 DBD

• 3 year graft survival 68% vs. 63%, p=NS

• 3 year patient survival 71% vs. 63%, p=NS

• Small numbers:

– “We believe that the experience of surgical, medical, critical care teams

is important for successful use of DCD grafts”

– Needs more exploration

Tanner et al., Annals of Hepatology 2012

Trade offs post-LT: ACLF

• ‘Bounce back’ readmissions

• Delirium post-LT

Log Rank P < 0.001

ICU re-admission post-LT impacts mortality

J Crit Care 2014

Independent predictors of ICU readmission post-LT

Unadjusted* Model 1* Model 2*

OR (95% CI) P OR (95% CI) P# OR (95% CI) P

#

Age (years) 1.01 (0.96,

1.06) 0.63

1.01 (0.95, 1.06)

0.85

Sex (male) 1.27 (0.58,

2.80) 0.55

1.24 (0.51, 3.00)

0.66

Respiratory ratea (breaths/min)

1.25 (1.07, 1.44)

0.004 1.24 (1.07,

1.44) 0.002

1.24 (1.05, 1.46)

0.002

Mechanical ventilationb

3.00 (1.09, 8.25)

0.033 2.15 (0.59,

7.82) 0.25

Vasopressorsb

2.13 (0.92, 4.92)

0.08 1.21 (0.38,

3.86) 0.80

Fluid balancec (ml)

1.00 (1.00, 1.00)

0.61 1.00 (1.00,

1.00) 0.68

SOFA scorea

1.00 (0.84, 1.18)

0.97 1.05 (0.85,

1.29) 0.68

* Cases (n= 52) vs. Controls (n = 52) # Multivariate analysis using conditional logistic regression after bootstrapping with 1000 samples (Model 1 Chi-square

test: 11 (degrees of freedom: 3); P = 0.014. Model 2 Chi-square test: 13 (degrees of freedom: 5); P = 0.025) a At discharge from the intensive care unit stay following liver transplant.

b During intensive care unit stay following liver transplant.

c In last 24 hours before discharge from the first intensive care unit stay following liver transplant.

J Crit Care 2014

• DDx

– Calcineurin neurotoxicity/gancyclovir (CMV)

– Osmotic shifts/demyelination (sodium)

– PRES

– Slow to resolve hepatic encephalopathy

• Independent predictors of Delirium post-LT

– Transfusions, RRT pre-LT, APACHE II

• Delirium and outcome

– fourfold increased risk of dying in hospital

– threefold increased rate of death by one year.

COPYRIGHT PULSUS GROUP INC. – DO NOT COPY

Can J Gastroenterol Vol 27 No 4 April 2013 207

Postoperative delirium in the intensive care unit

predicts worse outcomes in liver transplant recipients

Thomas Lescot MD PhD1, Constantine J Karvellas MD FRCPC2, Prosanto Chaudhury MD FRCSC FACS3,

Jean Tchervenkov MD FRCSC3, Steven Paraskevas MD PhD3, Jeffrey Barkun MD FRCSC FACS MSc3,

Peter Metrakos MD FRCSC FACS3, Peter Goldberg MD FRCPC1, Sheldon Magder MD FRCPC1

1Critical Care Division, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec; 2Division of Gastroenterology (Liver Unit) and Critical Care Medicine, University of Alberta, Edmonton, Alberta; 3Department of Surgery and Multi- Organ Transplant Program, Victoria Hospital, McGill University Health Centre, Montreal, Quebec

Correspondence: Dr Thomas Lescot, Réanimation chirurgicale, Département d’Anesthésie Réanimation, Hôpital Saint Antoine, 184 rue du Faubourg Saint Antoine, 75012 Paris, France. Telephone 33- 1- 49- 28- 2362, fax 1- 33- 49- 28- 2826, e- mail thomas. lescot@sat.aphp. fr

Received for publication April 20, 2012. Accepted January 30, 2013

Delirium represents an acute confusional state or mental status change associated with inattention and disorganized thinking or

an altered level of consciousness (1) . Delirium occurs frequently in patients hospitalized in the intensive care unit ( ICU) , and postopera-tively in older adults, cardiac and orthopedic surgery patients (2,3) . In the ICU, patients who develop delirium experience increased lengths of stay, higher short- and long- term mortality rates, and increased long- term cognitive impairment, which result in higher health care costs (4- 7) . Development of delirium is related to both predisposing and precipitating factors (3) . Accordingly, liver transplant recipients are at a particularly high risk for delirium, not only because they are hospitalized in the ICU — a recognized precipitating factor — but also because liver disease affects brain metabolism (8) and constitutes a predisposing factor for delirium development (9) .

Neurological complications can occur during the first few months post- orthotopic liver transplantation (OLT) , and acute brain dysfunc-tion, including encephalopathy, delirium or confusion, are the most common causes, with a prevalence of 12% to 32% in transplant recipi-ents (10) . However, little data regarding early risk factors and conse-quences of postoperative ICU delirium in liver transplant recipients are available. Identification of early risk factors for delirium could help detect high- risk patients and enable preventive, supportive and treat-ment strategies and pharmacological therapies and, thereby, improve outcome (11- 14) .

Accordingly, our objective in the present study was to identify risk factors on admission to the ICU for delirium in cirrhotic patients admitted to the ICU following OLT and to determine the effect of delirium on patient outcomes post- OLT.

ORIGINAL ARTICLE

©2013 Pulsus Group Inc. All rights reserved

T Lescot, CJ Karvellas, P Chaudhury, et al. Postoperative

delirium in the intensive care unit predicts worse outcomes in

liver transplant recipients. Can J Gastroenterol 2013;27(4):207-

212.

BACKGROUND: Delirium is common in intensive care unit patients and is associated with worse outcome. OBJECTIVE: To identify early risk factors for delirium in patients admitted to the intensive care unit following orthotopic liver trans-plantation (OLT) . METHODS: An observational study of patients admitted to the inten-sive care unit from January 2000 to May 2010 for elective or semi-elective OLT was conducted. The primary end point was delirium in the intensive care unit. Pre- and post- transplantation and intraopera-tive factors potentially associated with this outcome were examined. RESULTS: Of the 281 patients included in the study, 28 (10.03%) developed delirium in the intensive care unit at a median of two days ( interquartile range one to seven days) after OLT. According to multi-variate analysis, independent risk factors for delirium were intraopera-tive transfusion of packed red blood cells (OR 1.15 [95% CI 1.01 to 1.18]) , renal replacement therapy during the pretransplantation period (OR 13.12 [95% CI 2.82 to 72.12]) and Acute Physiologic and Health Evaluation (APACHE) II score (OR per unit increase 1.10 [95% CI 1.03 to 1.29]) . Using Cox proportional hazards models adjusted for baseline covariates, delirium was associated with an almost twofold risk of remaining in hospital, a fourfold increased risk of dying in hos-pital and an almost threefold increased rate of death by one year. CONCLUSION: Intraoperative transfusion of packed red blood cells, pretransplantation renal replacement therapy and APACHE II score are predictors for the development of delirium in intensive care unit patients post- OLT and are associated with increased hospital lengths of stay and mortality.

Key Words: Delirium; Intensive care unit; Liver transplantation; Neurological complication

Le délire postopératoire à l’unité de soins intensifs prédicteur d’issues plus négatives chez les greffés du foie

HISTORIQUE : Le délire est courant à l’unité de soins intensifs et est prédicteur d’issues plus négatives.OBJECTIF : Déterminer les facteurs de risque précoces de délire chez les parents admis à l’unité de soins intensifs après une transplantation hépatique orthotopique (THO).MÉTHODOLOGIE : Les chercheurs ont mené une étude d’observation de patients admis à l’unité de soins intensifs entre janvier 2000 et mai 2010 en vue d’une THO non urgente ou semi- urgente. Le délire à l’unité de soins intensifs en était le paramètre primaire. Ils ont examiné les facteurs post- transplantation et intraopératoires susceptibles de s’associer à cette issue.RÉSULTATS : Sur les 281 patients qui ont participé à l’étude, 28 (10,03 %) ont présenté du délire à l’unité de soins intensifs à une médiane de deux jours (plage interquartile de un à sept jours) après la THO. Selon l’analyse multivariée, les facteurs de risque indépendants de délire étaient une transfusion intraopératoire de culots globulaires (RRR 1,15 [95 % IC 1,01 à 1,18]) , une thérapie de substitution rénale avant la transplantation (RRR 13,12 [95 % IC 2,82 à 72,12]) et un score d’évaluation APACHE II de physiologie aiguë et de maladie chronique (augmentation du RRR par unité de 1,10 [95 % IC 1,03 à 1,29]) . Au moyen des modèles des risques proportionnels de Cox rajustés pour tenir compte des covariables de départ, le délire s’associait à presque deux fois le risque de demeurer hospitalisé et à quatre fois le risque de mourir à l’hôpital ainsi qu’à près de trois fois le nombre de décès au bout d’un an.CONCLUSION : La transfusion intraopératoire de culots globulaires, la thérapie de substitution rénale avant la transplantation et un score APACHE II sont des prédicteurs de délire à l’unité de soins intensifs après une THO et s’associent à une hospitalisation plus longue ainsi qu’à un plus fort taux de mortalité.

Can J Gastroenterol Vol 27 No 4 April 2013

Conclusions

• Liver transplant in ICU patients

– It’s complicated

– Need to incorporate complementary information• Age, retransplant?

• Medical comorbidity (CCI-OLT)

– Does not give important information in well selected patients (Canadian paradigm)

• Severity of illness (SOFA, MELD)

– Differentiate patients who will and will not receive transplant

– Correlate with resource utilization and complications (delirium) post-LT

– Do not define ‘futility’

dean.karvellas@ualberta.ca