Can J Gastroenterol Vol 27 No 4 April 2013207
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 firstname.lastname@example.org
Received for publication April 20, 2012. Accepted January 30, 2013
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).
elirium represents an acute confusional state or mental status
change associated with inattention and disorganized thinking or
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
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.
©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-
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-
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;
Le délire postopératoire à l’unité de soins intensifs
prédicteur d’issues plus négatives chez les greffés
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.
Lescot et al
Can J Gastroenterol Vol 27 No 4 April 2013 208
The present observational study was conducted in compliance with
published Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) guidelines (15), with slight adjustments
detailed below. The access to health information was approved by the
Director of Professional Services, who waived the need for individual
consent according to Quebec law (Loi sur les services de santé et les ser-
vices sociaux). Consecutive adult patients admitted to the ICU after
cadaveric OLT from January 2000 to May 2010 were studied. Exclusion
criteria were hospitalization in the ICU at the time of the transplanta-
tion, multiorgan transplantation, retransplantation and early death
defined as death occurring within the first four days after OLT.
OLT was performed as previously described (16,17). Briefly, transplant
recipients were admitted to the ICU after the transplantation proced-
ure, sedated and mechanically ventilated in the immediate postopera-
tive period. Extubation was performed after ICU admission once
hemodynamic and respiratory function were stabilized. Induction of
immunosupression included antithymocyte globulin (6 mg/kg/day
administered in divided doses starting on postoperative day 1 or 2),
tacrolimus (target levels of 8 ng/mL to 10 ng/mL) or cyclosporine (C2
target levels of 600 ng/mL to 800 ng/mL), mofetil myclophenolate or
azathioprine and steroids. Maintenance immunosupression included
tacrolimus (target levels of 8 ng/mL to 12 ng/mL) or cyclosporine (C2
target levels of 300 ng/mL to 600 ng/mL), mofetil myclophenolate, or
azathioprine and prednisone.
Factors from the pretransplant, post-transplantation and the intraopera-
tive periods describing the population and factors potentially associated
with outcomes were prospectively collected and entered into a dedi-
cated database. Age at the time of OLT, sex and etiology of liver dis-
ease were recorded. Transplant recipients were defined as elective if
patients came from home or semielective if they came from the ward.
Model for End-stage Liver Disease (MELD) scores were calculated at
the time of OLT. The MELD score, calculated from total bilirubin,
creatinine and international normalized ratio (INR) values, ranges
from 6 to 40 with higher score indicating more severe liver disease
(18). Child-Pugh score, a reflection of liver disease severity before
transplantation, was calculated based on INR, albumin and bilirubin
levels, and the presence of ascites and hepatic encephalopathy deter-
mined at the time of transplantation. Pretransplant hepatic encephal-
opathy grade ≥2, the need for renal replacement therapy (RRT) before
transplantation, as well as intraoperative features, including duration
of surgery and packed red blood cell (PRBC) transfusion requirements,
were recorded. The Acute Physiologic and Chronic Health Evaluation
(APACHE) II score was used to assess illness severity at ICU admis-
sion. APACHE II is based on 12 clinical and biological measurement
at admission (from 0 to 71), with a high score indicating high pre-
dicted in-hospital mortality (19). The serum sodium shift refers to the
difference between mean serum sodium level 48 h after liver transplant
and mean serum sodium level 48 h before liver transplant.
Immunosuppressant therapy provided while in ICU after liver trans-
plantation was reported.
For the present retrospective study, validated methods of delirium
assessment were not available. Neurological status was assessed daily
by the attending nurse and delirium/confusion status was confirmed by
the senior intensivist. Patients were diagnosed with delirium if they
presented with an acute confusional state or mental status changes
with inattention, disorganized thinking or altered level of conscious-
ness (1) that were not considered to be hepatic encephalopathy by the
physician in charge. Hepatic encephalopathy was considered in
patients presenting with mental status changes and concomitant signs
of liver dysfunction/failure. Patients underwent psychiatric assessment
when deemed necessary by the senior ICU physician. Charts of
patients who presented with delirium were reviewed. The primary
outcome was in-hospital mortality. Secondary end points were one-
year mortality and in-hospital length of stay.
Data are expressed as median with the interquartile range (IQR) for
normal and non-normal quantitative variables, and numbers with
percentages for qualitative variables. The Shapiro-Wilk test was used
to assess normality. The unpaired Student’s t test was used for data that
were normally distributed; the Mann-Whitney-Wilcoxon test was
used to compare non-normally distributed data; and Fisher’s exact
method was used to compare proportions. Stepwise logistic regression
was performed to identify independent risk factors for delirium. A
semiparsimonious approach was used and previously described clinical
relevant factors with P<0.1 in the univariate analysis were included in
the final model. OR with 95% CIs were reported for significant results.
Discrimination of the final models was assessed using the area under
the curve and calibration using the goodness-of-fit statistic. Kaplan-
Meier curves were used for graphical representation of hospital length
of stay and one-year mortality, the log rank test was used to assess dif-
ferences between patients with delirium and patients without. Cox
proportional hazards models was constructed to obtain HR with 95%
CIs measuring the association between delirium in ICU and outcome
including hospital length of stay, in-hospital mortality and one-year
mortality. Baseline covariates were chosen a priori based on their pre-
viously described clinical relevance and included APACHE II score,
MELD score and age. Because MELD and APACHE II scores were
collinear, two different models were constructed independently. To
assess one-year mortality, patients were censored if they were alive at
one year. For in-hospital mortality analysis, patients were censored if
they were alive at hospital discharge. For in-hospital length of stay
analysis, patients were censored at the time of hospital death.
Collinearity between variables was assessed by examining the variance
inflation factor, with variance inflation factor ≥10 indicating col-
linearity. P values were two-tailed and P<0.05 was considered to be
statistically significant. Statistical analysis was performed using JMP
version 8.0 (SAS Institute, USA).
During the 10-year study period, 421 OLT were performed in 369 patients
(35 patients were transplanted two times, seven patients were trans-
planted three times and one patient four times). Of these 369 patients,
88 were excluded for the following reasons: death before day 5 (n=14),
combined transplantation (n=14 [kidney-liver in 12 patients and
heart-liver in two patients]), lost to follow-up (n=14), acute liver fail-
ure (n=11) and hospitalized in the ICU at the time of the transplanta-
tion (n=35). This left 281 patients who were admitted to the ICU
after OLT. The median ICU length of stay was five days (IQR three to
five days). Of the 281 patients, 28 (10.03%) developed delirium in two
days (IQR one to seven days) after OLT.
Risk factors for delirium following OLT
Table 1 summarizes the pre-OLT and ICU admission features in
patients diagnosed with delirium and patients without. Neither age
nor etiology of cirrhosis was significantly associated with delirium. The
risk of developing delirium was greater in patients with pretransplanta-
tion encephalopathy (P=0.02) and in patients who underwent RRT
during the pretransplantation period (P<0.01). Delirium was not sig-
nificantly associated with age, MELD or Child-Pugh score. The
median number of intraoperative transfused PRBC units in patients
with delirium was more than double that of in patients without delir-
ium (P=0.001). Patients who developed delirium post-OLT had sig-
nificantly higher APACHE II scores on ICU admission (24 versus 21;
P=0.02). Importantly, immunosuppressant therapy did not differ
Delirium after liver transplantation
Can J Gastroenterol Vol 27 No 4 April 2013209
significantly between the two groups. To avoid overfitting, only three
factors that were associated with delirium were entered into the final
model using a semiparsimonious approach: number of transfused units
of PRBC; pre-OLT need for dialysis; and high APACHE II score
(Table 2). The final model demonstrated good discrimination (area
under the curve = 0.77) and calibration (testing showed no significant
lack of fit: goodness-of-fit test P=0.9).
Short- and long-term consequences of delirium following OLT
Primary and secondary outcomes are shown in Table 3. Patients with
ICU delirium experienced significantly more frequent episodes of sepsis/
septic shock in the ICU, spent significantly more time on mechanical
ventilation and had longer median ICU stays. Patients who developed
delirium in the ICU had a significantly longer median hospital length
of stay compared with controls. A Kaplan-Meier plot for the probabil-
ity of remaining in hospital in patients with or without delirium is
presented in Figure 1. Cox proportional hazards models were used to
adjust for baseline covariates including age, MELD and APACHE II
scores. Because MELD and APACHE II scores were collinear, two
separate models were constructed. When adjusting on MELD score
and age, the adjusted risk for transplant patients with delirium remain-
ing in hospital was more than twice as high as controls (Table 4). A
similar result was found after adjustment on APACHE II score and
Of the 280 patients included in the study, 22 (7.6%) died in hospi-
tal and 39 died at one year (13.9%). In-hospital and one-year mortal-
ity rates were significantly increased in transplant patients who
developed delirium during their ICU stay (Table 3). Kaplan-Meier
curve estimating one-year survival in patients with and without delir-
ium is shown in Figure 1B. After adjustment for baseline covariates,
delirium was associated with an almost fourfold increased risk of dying
in hospital and an almost threefold increased rate of death by one year
in both models (Table 4).
To the best of our knowledge, the present study was the first cohort
analysis investigating the incidence and risk factors for delirium in
OLT recipients in the ICU. In our single-centre study, delirium
occurred in almost 10% of elective and semielective liver transplant
recipients and was associated with increased ICU length of stay, in-
hospital mortality and one-year mortality. Multivariate analysis
Logistic regression multivariate analysis of factors present
at intensive care admission and associated with delirium
during intensive care unit stay
OR (95% CI)
PRBC (per PRBC unit increase)
RRT preliver transplant
APACHE II score (per unit increase)
C-statistic = 0.77. APACHE Acute Physiologic and Chronic Health Evaluation;
PRBC Packed red blood cells; RRT Renal replacement therapy
Postoperative outcome for patients with/without delirium
following orthotopic liver transplant (OLT)
Sepsis during ICU stay
Mechanical ventilation after OLT,
days, mean (IQR)
RRT in ICU after OLT
ICU length of stay after OLT,
days, mean (IQR)
Hospital length of stay after OLT,
days, mean (IQR)
Graft failure during ICU stay
37 (25–84) 20 (14–32) <0.001
Data presented as n (%) unless otherwise indicated. ICU Intensive care unit;
IQR Interquartile range; RRT Renal replacement therapy
Comparison of admission, etiology of liver transplant and
perioperative characteristics for patient with/without
intensive care unit (ICU) delirium following liver transplant
P Yes (n=28)
Male sex, n (%)
etiologies of liver transplant, n (%)
Alcoholic liver disease
Primary biliary cirrhosis
Primary sclerosing cholangitis
Child-Pugh class, n (%)
International normalized ratio
Serum sodium, mmol/L
Encephalopathy ≥grade 2, n (%)
Renal replacement therapy, n (%)
Duration of surgery, h
Packed red blood cells, U
Fresh frozen plasma, U
Post-liver transplant ICU admission
Mean arterial pressure, mmHg
Apache II score
Serum sodium, mmol/L
Serum sodium shift (−48h/+48h)
Immunosupressant during ICU stay, n (%)
Data presented as mean (interquartile range) unless indicated otherwise.
Bolded values indicate statistical significance. APACHE Acute Physiologic and
Chronic Health Evaluation; INR International normalized ratio; IQR Interquartile
range; MELD Model for End-stage Liver Disease; NASH Nonalcoholic steato-
Lescot et al
Can J Gastroenterol Vol 27 No 4 April 2013210
identified intraoperative PRBC transfusions, APACHE II score and
pretransplantation need for dialysis as admission risk factors of ICU
In previous studies, neurological complications were reported in
almost 30% of patients, and occurred preferentially during the first
month after OLT (20-22). These included both preventable and treat-
able complications such as delirium, seizure, calcineurin inhibitor
neurotoxicity and central pontine myelinolysis. Importantly, these
studies did not differentiate complications occurring in the ICU from
those developing on the hospital ward. In our analysis, which was
restricted to delirium in the ICU, delirium prevalence was 10%, which
is similar to the value of 11% of patients with diffuse encephalopathy
after OLT reported by Lewis and Howdle (23) and not far from the
16% of patients with delirium in the postoperative period after OLT
reported by Burkhalter et al (24). Although similar prevalences have
been reported in other solid organ transplant recipients, such as heart
transplant patients (25), higher prevalences have also been observed
when considering the postoperative period in surgical patients (2) or
medicosurgical ICU populations in which the incidence of delirium
has been reported to be as high as 80% (26,27). These differences in
reporting delirium incidence across studies may be ascribed, in part, to
the methods used for measuring delirium. Due to the retrospective
nature of our study and the lack of use of a validated delirium score, we
likely underestimated the true incidence of delirium in our population
(28,29). This, however, should be tempered by the fact that the per-
formance of scoring methods between the research setting and clinical
practice has been shown to be different, with low sensitivity when
validated scoring methods were routinely performed (26).
Risk factors for delirium following OLT
We identified early risk factors for delirium in the ICU: intraopera-
tive transfusion of PRBC, pretransplantation RRT and high APACHE
II score. All three factors can be easily assessed at admission, which
may help to stratify patients presenting post-OLT. Only a few clinical
studies are available for comparison. Dhar et al (20) found that only
pre-OLT encephalopathy was associated with delirium occurring
within the first month after the transplant procedure. In our popula-
tion, the etiology of liver disease was not associated with delirium,
which is in contrast to a previous report that showed a significantly
increased rate of postoperative acute confusional state in patients
receiving liver transplants for alcoholic cirrhosis (30). We did not
observe acute brain dysfunction induced by drug toxicity from agents
such as calcineurin inhibitors. This complication most commonly
occurs seven to 10 days after OLT (31), which is more than the five-
day median ICU length of stay observed here and corresponding to the
study period. Although our perioperative anesthesia protocol was not
detailed, Marcantonio et al (32) found that anesthesia or intraopera-
tive complications were not associated with postoperative delirium. In
a second analysis, the same authors found that only hematocrit <30%
was associated with an increased risk of delirium, suggesting an asso-
ciation between blood loss and PRBC transfusion (33). In the current
study, PRBC transfusion was associated with an increased risk of pos-
toperative delirium in the ICU. An association between PRBC trans-
fusion and delirium has been shown previously in cardiac (34,35) and
vascular surgery patients (36). Difficult surgery or transient hypoper-
fusion and consequent liver injury have been proposed to explain this
association. We also found a strong association between pretransplant
RRT and delirium. RRT has been previously associated with ICU delir-
ium (37). Such association between acute renal failure and postopera-
tive delirium has also been found in elderly patients after cardiac
surgery (38). Serum sodium and other electrolyte imbalances due to
dialysis may constitute one possible explanation. Nevertheless, in our
population, sodium shift did not significantly differ between patients
who presented with delirium and patients who did not. The associa-
tion between APACHE II score and delirium has been previously
reported and it has been suggested that patients presenting with more
severe illness when admitted in the ICU were more sensitive to
developing delirium (39,40).
Although the exact causes of postoperative and ICU delirium are
unknown, the role of predisposing and precipitating factors have been
well described: major surgery, including abdominal and cardiac surgery,
and ICU admission have been identified as precipitating factors lead-
ing to the development of delirium (3,38). Because liver disease may
affect the brain, it may represent a predisposing situation that is pre-
cipitated by surgery and ICU admission. Neuroinflammation has been
proposed to be associated with delirium and various putative theories
Figure 1) Kaplan-Meier plot describing the length of stay. A Log-rank test
(P<0.001) and one-year survival experience. B Log-rank test (P=0.02) of
liver transplant patients with and without delirium in the intensive care unit
adjusted HR for delirium in intensive care unit (ICU) and
clinical outcome defined by hospital length of stay,
in-hospital mortality and one-year mortality
Delirium in ICU
Hospital length of stay
Hospital length of stay
adjusted HR (95% CI)P
*HR adjusted on baseline covariate Model for End-stage Liver Disease score
and age; †HR adjusted on baseline covariate including Acute Physiologic and
Chronic Health Evaluation II score and age
Delirium after liver transplantation
Can J Gastroenterol Vol 27 No 4 April 2013211
have been discussed in which microglia activation appears to play a
crucial role (41,42). Furthermore, altered astrocyte morphology (43),
brain metabolism (8), brain perfusion (44) and blood-brain barrier
permeability associated with hepatic encephalopathy put the liver
transplant recipient at a particularly high risk for subsequent develop-
ment of delirium in the ICU.
Consequences of delirium following OLT
Patients who presented with delirium in the ICU post-OLT experi-
enced increased hospital length of stay, and increased in-hospital and
one-year mortality consistent with previous studies indicating worse
outcome both in medical ICU and postoperative patients who
developed delirium (6,40). Modifiable factors, such as environment,
have been shown to be associated with ICU delirium. Patients with
isolation, lack of visible daylight, absence of visitors and physical
restraints are more likely to develop ICU delirium and implementa-
tion or re-enforcement of nonpharmacological measures have been
proven to decrease ICU delirium. Such measures include prevention
of sleep deprivation, multiple psychoactive medications, support of
mobilization, reorientation, vision and hearing aids, and targeted man-
agement of pain and sedation (11,45,46). One unresolved question is
whether delirium that appears as a reversible condition may affect
long-term outcome as observed in our study and in others (6,7).
There are several limitations to our study. First, our study was retro-
spective in nature; therefore, causality cannot be established. Delirium
could be a marker of disease, the results of damage from previous
exposures or related to comorbidities. Second, the relatively small
number of patients and the low number of cases limits the value of the
multivariate analysis (ie, overfitting) to identify event predictors such
as preoperative blood transfusion, duration of delirium, serum levels of
tacrolimus or cyclosporine. Further prospective studies that include a
larger patient population and formal assessment of delirium are
required to confirm our findings. Third, our data from a single centre
may not apply to all other centres and the selected population (‘elect-
ive’ cirrhotic liver transplant recipients) does not allow generalization
to all OLT. Finally, the absence of details regarding sedation protocol
and medication used in the ICU constitutes a potential weakness
because it has been shown that sedative administration may be
independently linked to delirium.
ACKNOWLEDGEMENTS: Thomas Lescot received research fellow-
ship grants from La Fondation des Gueules Cassées (Paris, France) and the
Assistance Publique-Hôpitaux de Paris (AP-HP; Paris, France). This work was
performed at Royal Victoria Hospital – McGill University Health Centre,
Montréal, Quebec, and should be attributed to this institution.
DISCLOSURES: The authors have no finacial disclosures, competing
interests or conflicts of interest to declare.
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