General Hospital Psychiatry xxx (2014) xxx–xxx

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Postoperative cognitive dysfunction after liver transplantation Paola Aceto, M.D., Ph.D. a,⁎, Valter Perilli, M.D. a, Carlo Lai, Ph.D. b, Pierpaolo Ciocchetti, M.D. a, Francesca Vitale, M.D. a, Liliana Sollazzi, M.D. a a b

Department of Anesthesiology and Intensive Care, “A. Gemelli” Hospital, Rome, Italy Dynamic and Clinical Psychology Department, Sapienza University of Rome, Rome, Italy

a r t i c l e

i n f o

Article history: Received 14 August 2014 Revised 30 November 2014 Accepted 2 December 2014 Available online xxxx Keywords: Neurocognitive deficits Minimal hepatic encephalopathy Neuroinflammation Cerebral oxygenation

a b s t r a c t Objective: Postoperative cognitive dysfunction (POCD) in liver transplant (LT) recipients is defined as a “more than expected” postoperative deterioration in cognitive domains, including short-term and long-term memory, mood, consciousness and circadian rhythm. It is diagnosed, after exclusion of other neurological complications, by using specific neuropsychological tests that need preoperative baseline. The aim of this systematic review was to assess the prevalence of POCD after LT and to analyze patients’ symptoms, type and timing of assessment used. Methods: PubMed, MEDLINE and The Cochrane Li-brary were searched up from January 1986 to August 2014. Study eligibility criteria are as follows: prospective and retrospective studies on human adult subjects describing prevalence of POCD and/or its sequelae after LT episodes were included. Results: Eighteen studies were identified. The timing of testing for POCD may vary between different studies and within the single study, ranging from 0.5 to 32weeks. POCD occurs in up to 50% of LT recipient. Conclusion: Future studies should be focused on detecting preoperative and intraoperative factors associated to POCD in order to carry out appropriate strategies aimed at reducing this disabling health condition. Relationship between POCD and long-term outcome needs to be investigated. © 2014 Elsevier Inc. All rights reserved.

1. Introduction Over the last decade, it has been highlighted that postoperative cognitive dysfunction (POCD) is a threatening complication and is independently associated with increased mortality in the first year after nontransplant surgery [1]. POCD, in the area of nontransplant surgery, is defined as an impairment of the mental processes of perception, memory and information processing occurring in the postoperative period [2]. It refers to the altered performance in two or more neuropsychological tests that investigate cognitive function measured as short-term or long-term memory and attention. It does not include the effect of residual sedation that, in the elderly, may persist long after the expected drug clearance [3]; also, postoperative delirium is a separate entity and may be diagnosed on the basis of clinical symptoms [4] and has been associated with early POCD [5]. In the area of noncardiac surgery, the POCD frequency seems to be around 20% among patients over 60years old [1]. The onset of POCD is most evident in the days immediately following surgery, with a maximum incidence around the seventh postoperative day. It may then persist for days or weeks, showing a tendency to shrink and eventually disappear beyond the third week after surgery, persisting at a distance of 1–2years in 1% of patients [1]. The higher incidence in old patients may be attributed to ⁎ Corresponding author. Department of Anesthesiology and Intensive Care, “A. Gemelli” Hospital, Largo A. Gemelli, 8 00168 Rome, Italy. Tel.: + 39-0630154507; fax: + 39-063013450. E-mail addresses: [email protected], [email protected] (P. Aceto).

frequent deterioration of the general conditions, to the preexisting cerebrovascular disease and to a stronger sensitivity of the CNS [6]. Age N60years is an independent risk factors associated with the development of POCD, together with preoperative hypertension and/or cardiovascular disease, preoperative mental impairment identified by the minimental state examination (MMSE) score less than 20, history of neurological or psychiatric diseases and chronic alcohol or drug abuse [6,7]. Other known risk factors for POCD occurrence include duration of surgery and postoperative infections [8–11]. Moreover, patients with longer hospital stays have been found to be more likely to exhibit POCD at hospital discharge [1]. It has been hypothesized that the deleterious effects of longer hospitalization on neurocognitive tests performance at hospital discharge may depend on sleep deprivation [1]. Interestingly, diabetes has not been identified as an independent risk factor [12]. Residual cognitive deficits are common immediately after liver transplant (LT) and it may depend on the extent of pretransplant morbidity [13–15]. Moreover, the possible persistence of some neurocognitive deficits within months, even in case of successful LT, raises the question of whether these deficits are completely reversible [15]. Neurological complications that may occur after LT, including embolic stroke, cerebral hemorrhage and central nervous system (CNS) infections, cause cognitive dysfunction of variable degree [15]. Differently from neurological complications, which are associated with a detectable damage in the CNS, POCD is a cognitive dysfunction diagnosed by specific tests after exclusion of other neurological complications. POCD has been attributed to several pathogenetic factors in LT

http://dx.doi.org/10.1016/j.genhosppsych.2014.12.001 0163-8343/© 2014 Elsevier Inc. All rights reserved.

Please cite this article as: Aceto P., et al, Postoperative cognitive dysfunction after liver transplantation, Gen Hosp Psychiatry (2014), http://dx.doi. org/10.1016/j.genhosppsych.2014.12.001

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P. Aceto et al. / General Hospital Psychiatry xxx (2014) xxx–xxx

recipients, such as comorbidities [14], poor graft function, recurrence of liver disease [13], anoxic and ischemic intraoperative damage, infections, immunosuppressant toxicity and metabolic and nutritional alterations. On the other hand, neuroinflammatory process in response to major surgery or infection seems to be the most recognized determinant factor for POCD, in the absence of other causes [16]. The aim of this systematic review was to assess the prevalence of POCD after LT and analyze patients’ symptoms, in order to identify avoidable factors and appropriate strategies aimed at reducing this disabling health condition. 2. Methods The literature search was conducted using computerized databases including PubMed, The Cochrane Li-brary and MEDLINE in order to identify the relevant articles that have been published from January 1986 to August 2014. Articles were retrieved using the following keywords: “postoperative cognitive dysfunction” AND “liver transplant”, and “hepatic encephalopathy” and “cognitive function” and “transplant”. Abstracts were read thoroughly before complete articles were obtained and the references from the relevant publications were manually explored to ascertain further potential articles. Inclusion criteria were human adult subjects, prevalence of POCD and/or cognitive sequelae and English language. Observational studies and retrospective analysis were not eliminated. Case reports/case series and review were not considered. 3. Results Based on the search results, 61 titles and abstract were examined. A total of 45 articles did not met the inclusion criteria (20 review articles, 2 non-English manuscript, 1 nonhuman study, 3 nonadult study, 16 for lack of cognitive sequelae description, 1 living donor study, 2 case series). Another 3 relevant studies were identified through checking reference lists of the studies found to be eligible within the study. In the end, 19 publications were reviewed (see Table 1 for details). 3.1. POCD in LT recipients The incidence and risk factors for POCD after LT have been poorly investigated. Some authors reported an incidence of POCD (44%) greater in LT recipients compared to other surgical populations [17]. They also have found a significant increase of serum C-reactive protein (CRP) and β-amyloid protein at 24h after surgery, in LT recipient with POCD [17]. The serum levels of these two biological markers correlate with the severity of cognitive impairment in Alzheimer's disease (AD) and other cognitive diseases [18,19]. This finding supports the hypothesis that POCD is due to a process similar to that seen in AD [20]. Some patients with POCD appear to exhibit a rapid aging in brain function that is similar to AD [21]. Rovira et al. used magnetic resonance imaging (MRI) to measure the volume of supratentorial focal brain white matter lesions and neuropsychological examination to assess cognitive function before LT as well as 6 and 14months after LT in 27 patients with cirrhosis without signs of hepatic encephalopathy (HE) [22]. These abnormalities, which are radiologically indistinguishable from the features of small-vessel disease of normal aging, were found to be partially reversible and parallel to the improvement of cognitive functions [23]. It has been demonstrated that patients with POCD had a greater severity of the hepatic illness before LT (model for end-stage liver disease score around 25) [17]. The authors also noted a more complicated surgical course, reflected by a large amount of blood transfused and a longer ventilation time, in those patients with POCD [17]. Moreover, the association between CRP and neurocognitive decline suggests the role of inflammation in the genesis of the POCD [24]. POCD in patients with liver disease is defined as a “more than expected” postoperative deterioration in cognitive domains, including short-term and long-term memory, mood, consciousness and circadian

rhythm. It is diagnosed by specific neuropsychological tests, which are conducted before and after anesthesia. As delirium is the only specific sign of POCD, but it is not always present (see Table 2), preoperative assessment is mandatory. A higher incidence of delirium after nontransplant surgery has been found in patients with lower preoperative MMSE scores [1]. The decreased cognitive reserve (e.g., in patients with history of stroke), as a result of preexisting brain dysfunction, has been recognized as the main etiology of delirium in POCD patients [1]. In LT recipients, other factors may play a role in the etiology of delirium, such as inhibition of GABAErgic tone induced by calcineurin inhibitors (CIs), electrolyte, pH and osmotic disorders, systemic inflammation and infections [25]. LT recipients seem to be more vulnerable to neurological injury than other surgical patients [26]. It has also been suggested that a history of HE is associated with persisting neurological deficits 18months following LT [27], as measured after by the psychometric hepatic encephalopathy score (PHES) battery [27]. In patients with liver cirrhosis, the presence of preoperative HE seems to be an important risk factor for the persistence of cognitive deficits after LT [28,29]. Several previous studies have demonstrated substantial improvement in neuropsychological tests months to years after LT [22,30–34], especially for those patients with overt HE (OHE) [27], even if the return-to-normal value is less frequent [35]. The residual poor cognitive functions after LT in patients with previous HE could be attributed to a permanent structural component of HE that, contrary to the metabolic reversible component, persists regardless successful LT [28]. It has been reported that HE may cause brain damage, including neuronal loss, and animal models provide convincing evidence that several neuronal cell death mechanisms are activated in HE [36]. In patients awaiting LT without symptoms of OHE, preoperative neurocognitive tests may disclose the presence of minimal cognitive impairment so-called “minimal hepatic encephalopathy” (MHE). It is well know that MHE has high prevalence in patients with liver cirrhosis, ranging from 10% to 70% [28,29,22,37]. Instead, the prevalence of POCD across the studies ranges from 0% to 50% (see Table 1). The type cognitive assessment throughout the studies includes several components that are affected in MHE, such as attention, concentration, psychomotor speed and verbal and visuospatial short-term memory. Therefore, most of the studies consider also the persistence or worsening of preexisting cognitive deficits as POCD [27–29,22,37–42], in accordance with the statement that successful LT should remove HE [27,31,32]. MHE predicts OHE [43], but it is often clinically missed [44]. Some factor responsible for liver cirrhosis, such as hepatitis C virus (HCV) infection and, even more, alcohol abuse, can act as a confounder in MHE detection. Accurate screening for MHE in patients awaiting for LT may improve interpretation of cognitive disorders occurring after transplantation [25]. In fact, an incomplete reversal of preexisting cognitive dysfunction in patients with MHE after LT can occur [39]. Tarter et al. found a typical profile of MHE in 62 patients before LT was characterized by deficits of selective attention and fine motor skills, with spared general intellectual ability and, after LT, cognitive function was not completely restored [45]. Also Mattarozzi et al. observed that selective attention, visuospatial short-term and long-term memory and language tasks improved after 6months post-LT. Only selective attention continued to improve slightly, but significantly, until an 18-month assessment, whereas no other cognitive functions varied over time [34]. In a prospective study by Mechtcheriakov et al., a significant number of patients showed no improvement of the altered visuospatial and visuomotor abilities on average, retested around 21months after LT [39]. Neuroimaging studies support these results. On MRI, the typical hyperintensity T1-weighted pictures of basal ganglia, possibly due to manganese accumulation, seen in patients with cirrhosis decrease after LT but are still evident after 6months following the procedure [46]. Among cirrhosis-related factors, alcohol/drug abuse has been found to affect POCD occurrence [28]. Moreover, it has been hypothesized that brain damage resulting from chronic alcohol misuse and HCV infection

Please cite this article as: Aceto P., et al, Postoperative cognitive dysfunction after liver transplantation, Gen Hosp Psychiatry (2014), http://dx.doi. org/10.1016/j.genhosppsych.2014.12.001

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Table 1 Clinical studies on POCD after LT Authors

Year

Tryc et al.

Lin et al.

Patients population

Psychometric tests used

Timing of preoperative assessment

Timing of postoperative assessment

Type of cognitive dysfunction occurring after LT

Patients with POCD (%)

2014 Prospective

MHE (32%)

PHES, ICT, CFF, RBANS

Within 6months of LT

6 and 12months

Range from 10.8 to 40.5

2014 Prospective, controlled 2014 Prospective

MHE (100%)

NS

6–12months

NS

3, 6, 9 and 12months

Li et al.

2013 Prospective

NS

1week

SM impairment

44

Ishihara at al.

2013 Prospective, controlled

Unimpaired HE (100%) MHE (% not specified)

Just before LT

6months

Executive functions and memory disturbance

NS

Mattarozzi et al.

2012 Retrospective

MHE (100%)

NS

7–10years

None

0

Pegum et al.

2011 Prospective

MHE (% not specified)

WAIS-III, CASI, Wisconsin Card Sorting Test TMT-A and TMT-B, digit span, VFT, DSST, memory with interference task at 10s and at 30s, immediate and delayed story recall memory MMSE, VFT, DSTs, item memory, source memory (SM) MMSE, TMT-A and TMT-B, SCT, DSST, digit span, visual reproduction (plus delayed recall) VM, COAT, TMT-A and TMT-B, SCT, digit span, Corsi test, VMT, RWIR, RWDR, brief story, PAL, supraspan learning, RCFRT, FAS, PC, Pcopy, PCopy, RCFT, DSST; Elithorn maze test WAIS-R, WAIS-III, TMT-A and TMT-B, WMS, RCFT

Impairment of immediate and delayed memory, attention, language and visuospatial/constructional domains Impaired executive functions Impaired attention, memory and executive functions

NS

12months

5 and 2, respectively

Garcia-Martinez 2011 Prospective et al.

MHE (54%)

RAVLT, TMT-A, SDMT, GPT, COWAT, HVOT, JLO

Within 2months of LT

6–12months

Garcia-Martinez 2010 Prospective, et al. controlled

MHE (% not specified)

TMT-A, DSST, GPT, RAVLT, JLO, HVOT, COWAT

Shortly before LT

6–9months and 6–9years

Sotil et al.

2009 Retrospective, controlled

Not specified PHES, RBANS, CFF

ND

18months on average

Senzolo et al.

2009 Prospective, controlled

MHE (% not specified)

WAIS, WMS, Corsi test, VFT, SCT, TMT-A and TMT-B

NS

1 and 10years

Mardini et al. Rovira et al.

2008 Prospective 2007 Prospective

MHE (100%) MHE (33%)

NS NS

16±14months 6–14months

O’Carrol

2003 Prospective, MHE (% not controlled specified) 2004 Prospective, MHE (100%) repeated measure, controlled

CDR, PHES SCT, TMT-A, DSMT, GPT, AVL, JLO, HVOT, COWAT RBMT, SRT, CRT, NART

Decreased performance on visual motor processing and mental flexibility Impairment of memory, attention and psychomotor function Long-term memory impairment; short-term and long-term global cognitive function impairment Impaired attention, language, visual motor domains Impaired frontal tasks and visuospatial memory (at 1year) No long-term improvement None Executive function

Campagna et al.

Mattarozzi et al.

Study design

MHE (32%)

Mechtcheriakov et al.

2004 Prospective, controlled

MHE (100%)

Pantiga et al.

2003 Retrospective, controlled 2000 Prospective, repeated measure, controlled 1991 Prospective, controlled

Not specified

Moore et al.

Aria et al.

MHE (% not specified)

VM, COAT, TMT-A and TMT-B, SCT, digit span, Corsi test, VMT, RWIR, RWDR, brief story, PAL, supraspan learning, RCFRT, FAS, PC, Pcopy, PCopyF, RCFT, DSST, Elithorn maze test TMT-A and TMT-B, DSST, RCFT, tests for short-term and long-term memory; VFT, verbal intelligence test DSTs, TMT-A and TMT-B, Raven’s Progressive Matrices Test WAIS-R, COWAT, RCFT

MHE (around Signature time, Finger tapping, 50%) GPT, block design, TMT-A and TMT-B, SCT, DSST, DSTs, Benton visual retention test

NS 11

13

18 and 9, respectively

NS

20

0 3.7

Range from 0.5 12months to 32weeks NS 6 and 18months

Impairment of memory and psychomotor speed Slow recovery of selective attention and verbal short-term memory

NS

21months later on average

Impairment of visuomotor and visuoconstructive performance

ND

range 9–36months 1, 3 and 9months

Impairment of visuomotor NS and mental flexibility None 0

12months

Impairment of memory, psychomotor, visuopractice and perceptual speed domains

Shortly before LT 2.71weeks on average

NS NS

50 (confidence interval=23–77)

Range from 10 to 20

RBANS, repeatable battery for the assessment of neuropsychological status; WAIS-III, Wechsler Adult Intelligence Scale, Third Edition; CASI, Cognitive Ability Screening Instrument; VFT, verbal fluency test; TMT-A, Trail Making Test, A; TMT-B, Trail Making Test, B; DSTs, Digit Span Forward and Digit Span Backward tests of the Wechsler Adult Intelligence Scale; DSST, digit symbol substitution test; WAIS-R, Wechsler Adult Intelligence Scale, Revised; NS, not stated; ND, not done; RAVLT, Rey auditory verbal learning test; COWAT, Controlled Oral Word Association Test; JLO, Judgment of Line Orientation; SDMT, Symbol digit modalities test; RCFT, Rey–Osterrieth Complex Figure Recall Trial; GPT, Grooved Pegboard test; HVOT, Hooper Visual Organization Test; WMS, Wechler Memory scale; SCT, Stroop color test; RBMT, Rivermead Behavioral Memory Test; SRT, simple reaction time; CRT, choice reaction time; NART, National Adult Reading Test; COAT, crossout a test; VM, visual matrices; VMT, Immediate Visual Memory Test; RWIR, Rey Auditory Verbal Learning Test immediate; RWDR, Rey Auditory Verbal Learning Test 15-min delay recall; PAL, paired associate learning; PC, Phrase Construction; FAS, word fluency; PCopy, Painting Copy; PCopyF, Painting Copy with Facilities; RCFC, Rey–Osterrieth Complex Figure Copy.

Please cite this article as: Aceto P., et al, Postoperative cognitive dysfunction after liver transplantation, Gen Hosp Psychiatry (2014), http://dx.doi. org/10.1016/j.genhosppsych.2014.12.001

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Table 2 Signs of POCD after LT Postoperative delirium (not always present) Fine motor skills impairment Deficit of selective attention Memory impairment (visuospatial short-term and long-term memory) Language impairment Sleep disturbance Somnolence (exclude drugs effect)

could be a main cause of residual cognitive impairment after LT as it cannot be reversed by liver replacement [29]. Arria et al. have supposed that posttransplant memory impairment, typical of alcoholic patients, might be due to preexisting and irreversible alcohol-induced brain injury [37], even if it has never demonstrated. In contrast to these statements, an overall cognitive improvement has been reported in patients with alcohol-related liver disease 1year after LT [30]. In another study, no associations were found between cognitive dysfunction and cause of liver cirrhosis, including alcohol toxicity and hepatitis C [31]. A short duration of alcohol withdrawal seems to be a risk factor for an acute confusional state after LT that could also affect neuropsychological tests results used for POCD assessment [25]. As neuropsychological function improves with abstinence, most of the studies assessing POCD exclude patients with less than 6months sobriety [27,29,31,34,39]. Also HCV infection could act as a confounding factors in POCD diagnosis as selective deficits of attention and concentration of HCV-infected patients may alter both pre-LT and post-LT cognitive assessments [47]. Some donor characteristics may affect cognitive function, e.g., cadaveric LT is associated with greater incidence of cognitive dysfunction than living-donor LT (20.4% vs. 26.7%, respectively) [48]. The reason for this phenomenon remains unknown; it could be due to a better quality of the graft in living donors and also to longer cold ischemia time in cadaveric LT that may impair detoxification [48]. 3.2. Surgery-related factors Hardly ever cognitive dysfunction in patients undergoing LT has specific reasons, reflects the underling neurologic complications and must be distinguished from POCD. Surgery-related events mostly affect the CNS, mainly via cerebrovascular damage: changes in cerebral blood flow associated with the hemodynamic imbalance, especially during reperfusion phase of LT, may alter brain perfusion [14]. Hypotension, frequently caused by blood loss or air embolism, may lead to hypoxic ischemic cerebral damage [15]. Cerebral hemorrhage is often related to hypertension and coagulopathy [14]. Embolic stroke can be due to perioperative detachment of thrombotic material originating from carotid, intracranial arteries and deep leg or pelvic veins [14]. Prevention includes correction of coagulopathies before surgery, avoiding perioperative cerebral hypoperfusion and control of cerebrovascular risk factors after LT (especially hypertension) [14]. Metabolic dysfunction and electrolyte disorders are the most common finding in the case of graft primary nonfunctioning or rejection, as it occurs in the case of hypernatremia, with consequence on CNS [25]. Systemic or neurological infection may cause a confusional syndrome during the early postoperative period [13–15,25]. Neurotoxicity of CIs, cyclosporine (CS) and tacrolimus (FK506) is hardly correlated with their plasma levels and often occurs immediately after LT due to the high doses of drugs needed to induce immunosuppression or, later, possibly due to a cumulative effect of the drugs. The mechanisms by which CIs produce neurotoxic effects are not completely elucidated. Neurotoxicity may depend on their mechanisms of action [49]. Both CS and FK506 bind to immunophilins, and the high-affinity drug–immunophilins complex blocks the activity of calcineurin. Immunophilins are intracellular proteins ubiquitous in the CNS, with a protective action on neuronal function. Manifestations of neurological toxic effects of CS and FK506 include headaches, altered mental status, seizures, cortical blindness, auditory

and visual hallucinations, spasticity, paresis and ataxia. CIs have also been associated with a severe but reversible syndrome termed posterior reversible (leuko) encephalopathy syndrome (PRES) that typically occurs within 2months of LT in about 5% of LT recipients [50]. Clinical symptoms range from mental status changes to focal neurological symptoms. MRI remains the gold standard for the diagnosis, as diffusionweighted MRI imaging helps in identifying the typical vasogenic edema of PRES most commonly seen in parietal and occipital lobes [51]. The symptoms may be reversed by lowering arterial pressure, decreasing the dose of calcineurin inhibitors or shifting to oral administration or alternative immunosuppressants, such as mycophenolate mofetil and sirolimus that lack the neurotoxicity of CIs [15,49]. Also other drugs included in the immunosuppressive regimen have an important risk of neurotoxicity. OKT3 have rare neurological side effects with an encephalopathy-like syndrome with impairment of consciousness, myoclonic activity and seizures [15]. Corticosteroids are associated with neuropsychiatric side effects in 3–4% of patients with a wide range of cognitive, affective, psychotic and behavioral symptoms. The majority of documented side effects results from “pulsed” large doses to treat graft rejection and occurs within days of LT [52]. Therefore, as both immunosuppressant and corticosteroids are possible etiological factors of POCD in the immediate posttransplant period, possibility that cognitive impairment reflects side effects of these two drug classes should be always ruled out. Sometimes the cause–effect relationship can only be established from the remission of the symptoms after treatment discontinuation. The studies on postLT cognitive functions range from those in which the effect of immunosuppressive treatment had not been considered [30–32] to those in which a direct relationship cannot be determined due to the use of a mixed immunosuppressive regimen [28,22]. In this regard, only one study demonstrated that patients administered CS (n= 25) showed significantly greater improvement compared patients treated with tacrolimus (n= 37) in psychomotor speed at 1-year post-LT [42]. These interesting results, if replicable in further large studies, could have important implications for long-term cognitive outcome. 3.3. Role of anesthesia Although mechanisms involved in the development of POCD are not well established and seem to be multifactorial (see Table 3), it seems clear that all modern anesthetics (including nitrous oxide) are associated with some degree of POCD [16]. Animal studies indicate that volatile anesthetics may augment the pathological processes of AD by affecting amyloid-β processing [53]. Evidence suggests that cholinergic neurons in the basal forebrain regulate normal memory function. Choline reserves decrease with aging and this is felt to be the primary reason why the elderly are more prone to delirium following surgery [4]. Anesthetic agents affecting the release of CNS transmitters such as acetylcholine, dopamine and norepinephrine could potentially impair memory, especially in elderly patients [4]. However, the mechanisms of general anesthesia are poorly understood making it difficult to postulate the effects of anesthesia on memory and cognition. Since exposure to inhaled anesthetics has been suggested as a possible cause of POCD, early studies comparing regional and general anesthesia for cataract surgery, hip surgery and knee replacement have not showed any significant difference in cognitive outcome [54]. Table 3 Factors affecting POCD after LT Cirrhosis-related factors

Surgical factors

Anesthetic factors

HE or MHE Alcohol abuse (?)

Ischemia-reperfusion syndrome Neuroinflammation Postoperative infections Use of immunosuppressants and corticosteroids

Anesthesia depth Cerebral oxygen saturation Volatile anesthetics (?)

Please cite this article as: Aceto P., et al, Postoperative cognitive dysfunction after liver transplantation, Gen Hosp Psychiatry (2014), http://dx.doi. org/10.1016/j.genhosppsych.2014.12.001

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The International Study of Post-Operative Cognitive Dysfunction group [55], prospective controlled and randomized trial in elderly patients undergoing major noncardiac surgery, showed that regional (spinal or epidural) anesthesia affects the incidence of POCD at 7days but not at 3months postoperatively. However, this study presented some limitations including the great number of patients who did not receive the allocated anesthesia, the use of propofol sedation in almost half of the patients receiving regional anesthesia and lack of data regarding use of premedication, even if benzodiazepines seems not affecting incidence of POCD 1week after surgery [56]. All general anesthetics produce cardiovascular depression that can be augmented in the aged patient, potentially exposing them to inadequate brain perfusion, and this might be related to the occurrence of POCD often reported in these patients [57,58]. Nonetheless, the brain is rarely monitored in routine practice. Near-infrared spectroscopy monitoring has been reported to provide information on the balance between oxygen delivery and demand. It has been demonstrated that significant cerebral oxygen desaturation occurs in up to 30% of patients during major noncardiac surgery and preliminary evidence indicates that continuous monitoring of cerebral oxygen saturation improves cognitive outcome minimizing brain exposure to potential hypoxia [58]. More recently, a prospective cohort study clearly demonstrated the advantages of optimization of anesthesia depth (bispectral index between 40 and 60) and cerebral oxygen saturation (rSO2 dropN15% of baseline or rSO2N50%) as a pragmatic interventions to reduce postoperative cognitive impairment [59]. In a study on LT recipients, the authors stated that intraoperative brain injury due to hemodynamic derangement (hypotension, ischemiareperfusion syndrome) cannot be excluded as possible concurrent cause of POCD [28]. These observations lead us to think over the importance of intraoperative monitoring that probably should not only include haemodynamic parameters in order to prevent graft dysfunction [60,61] but should also take into account monitoring of cerebral function. This could be a promising field of investigation in liver transplantations. 3.4. POCD assessment in LT recipients POCD could not be confirmed unless preoperative or postoperative neuropsychological tests are performed [62]. First of all, dementia need to be excluded by a score on the Minimental State Score N 23 before surgery; whereas, postoperatively, the Confusion Assessment Method should be used to identify patients with clinically significant delirium, who could develop POCD [4,5]. There is no accepted method for the assessment of POCD in patients who already suffer from neurocognitive defects, such as LT recipient with MHE. Therefore, some of the tests carried out to diagnose POCD are the same used for MHE [62]. These include the following: 1. PHES, a paper-and-pencil psychometric test battery composed of the five tests that detect changes in attention and psychomotor speed. Abnormality of N2 standard deviations from the mean of healthy controls in two or more tests is diagnostic of MHE [27,31,32]. 2. Inhibitory Control Test (ICT), a test of sustained attention, vigilance, working memory and response inhibition. It has been shown to diagnose MHE with a sensitivity of 87% and a specificity of 77% [31]. 3. Cognitive Drug Research (CDR) Test: this computerized psychometric test mainly explores five cognitive domains: attention, continuity of attention, speed of memory, quality of episodic and working memories. It was shown to worsen with nitrogen challenge and improve with liver transplantation [32]. 4. Critical Flicker Fusion (CFF) Test: this test is based on the ability of a human brain to identify flickering light as discrete light pulsations. It is influenced by cortical activity and by the efficiency of visual apparatus (which can be impaired due to hepatic retinopathy). A threshold ≤39Hz is diagnostic of MHE (sensitivity=55%; specificity close to 100%) [27,31].

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The neuropsychological test battery used to evaluate patients for POCD focus on memory and executive functions and evaluates the following: 1. Learning and short-term memory using the Rey Visual Verbal Learning Test. This test is administered to the patient by reading a list of 15 words, at the speed of one word per second. At the end of reading, the patient is asked to repeat as many words as possible he had just heard. This procedure is repeated, with the same list of words, for five consecutive times, recording each time the number of words recalled by the patient. After 15min, during which visual–spatial tests are performed, the patient is asked to recall the greatest possible number of words included in the list [39]. 2. Cognitive flexibility using the Concept Shifting Test, part C, based on the Trail Making Test, in which the patient is asked to connect numbers and letters in alternating order (1-A-2-B-3-C-4-D…), thus continuously switching between the alphabetical and the numerical sequences [62,63]. 3. Distractibility is verified by Stroop Color Word Interference Test. In the word trial, the patient is asked to read a random order of the words, all of which are colors (red, blue, green), printed in black ink. In the color trial, the subject identifies colors that appear as colored circles of the three previous tones disposed in a random order. Finally, in the color/word trial, the subject must rapidly recognize the color that the words are printed in, where the word that is always different from the color. The number of errors and the time spent by the patient in completing this third trial is used for analysis [10]. 4. Working memory is tested using the Letter-Digit Coding based on the Symbol Digit Substitution Test from the Wechsler Adult Intelligence Scale III, Third Edition. The patients are given a sheet with nine symbols corresponding to nine numbers and are asked to associate the symbols corresponding to the nine numbers in 90s [64]. The postoperative change for individual patients from baseline is calculated for each test and a control group is used to remove any learning effect and to provide the standard deviations for the Z score calculations according to Hanning [2]. This technique identifies patients with POCD by comparing the changes in test scores of an individual patient undergoing surgery with changes in the test scores of the age-matched control group over the same time interval. The sign is adjusted so that positive Z scores indicate deterioration from the baseline test. The composite score is calculated as the sum of the Z scores for an individual patient divided by the SD for the sum of the Z scores for the age-matched control group [Hanning formula for Z calculation: Meancontrol group− (Final Meanstudy group−Initial Meanstudy group)/DScontrol group]. A patient is classified as exhibiting POCD if the Z scores on two individual tests are 1.96 or greater (the higher the score is, the more deterioration there is) [2]. In evaluating cognitive function, clinicians need also to take into account demographic variables, such as age, gender, level of education and occupation [62]. Timing of testing is important as well. This should be 1day before surgery or even on the day of their operation for the preoperative assessment [8,9]. Especially in patients with cirrhosis, the neuropsychological evaluation needs to be done as close as possible to LT, as patients may exhibit worsening due to precipitating factors (i.e., infection or dehydration) or improvement after a successful antiencephalopathy treatment [62]. However, it is also possible that patients who undergo testing on the morning of operation might not score due to anxiety or depression. As a result, preoperatively, it remains important to also assess both anxiety and depression [64]. Postoperatively, when patients are tested shortly after surgery (up to 1week later), confounding variables that need to be measured are pain, anxiety, depression residual drugs effects and sleep–wake disturbances [64]. Moreover, as cognitive problems observed in the days immediately after surgery are often transitory, assessments conducted later in the recovery period (approximately 4weeks after surgery) are more likely to detect a persistent or permanent change [64].

Please cite this article as: Aceto P., et al, Postoperative cognitive dysfunction after liver transplantation, Gen Hosp Psychiatry (2014), http://dx.doi. org/10.1016/j.genhosppsych.2014.12.001

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3.5. Impact of POCD on quality of life in LT recipient Lewis and Howdle found significant cognitive dysfunction and worse quality of life (QoL) than normal subjects 10years after LT [65]. Many factors may affect QoL after LT [66,67], including pretransplant psychological status, successful transplant, compliance to immunosuppressive treatment, recurrence of liver disease, anxiety about recurrence, inability to resume work with the ensuing economic restraints and changes in social relationships. It is difficult to establish the contribution of POCD to longterm QoL after LT, even if it remains an intriguing issue. No studies have investigated if POCD influences long-term QoL, particularly when cognition deteriorates to the point of frank dementia with impact on the patients’ daily activities and level of independence. The real importance of POCD will only be realized if a long-lasting and severe worsening of QoL will be demonstrated. Another poorly explored issue is the effect of POCD on clinical outcome in LT recipients. No relationship was found between POCD and 1-year survival in LT recipients [17], but this result from a small sample is insufficient to draw a conclusion. Key messages 1. POCD following LT is common, mainly due to increased inflammatory activity triggered by major surgery, but it is often missed by clinical staff. It is detectable only by using specific tests that need a preoperative baseline. 2. There are few data from the literature on preventable factors affecting POCD after LT, but there is a research line from general surgery that could be applied in LT. 3. On discharge from critical care, transplant recipients cognitive functions may still be impaired and may affect compliance to immunosuppressive treatment. Monitoring of cognitive functions should be a part of post-LT rehabilitation program. 4. No treatment is currently available for POCD. Consequently, preventive strategies should constitute a priority. 5. Optimization of anesthesia depth and cerebral oxygenation may be useful in reducing POCD in LT recipients. Acknowledgements The authors would to thank professor Stefano Faenza, Bologna, Italy, for his precious suggestions about immunosuppressant toxicity. References [1] Monk TG, Weldon BC, Garvan CW, Dede DE, van der Aa MT, Heilman KM, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008;108:18–30. [2] Hanning CD. Postoperative cognitive dysfunction. Br J Anaesth 2005;95:82–7. [3] Singh A, Antognini JF. Perioperative pharmacology in elderly patients. Curr Opin Anaesthesiol 2010;23:449–54. [4] Krenk L, Rasmussen LS. Postoperative delirium and postoperative cognitive dysfunction in the elderly — what are the differences? Minerva Anestesiol 2011;77:742–9. [5] Rudolph JL, Marcantonio ER, Culley DJ, Silverstein JH, Rasmussen LS, Crosby GJ, et al. Delirium is associated with early postoperative cognitive dysfunction. Anaesthesia 2008;63:941–7. [6] Rasmussen LS, Larsen K, Houx P, Skovgaard LT, Hanning CD, Moller JT, et al. The assessment of postoperative cognitive function. Acta Anaesthesiol Scand 2001;45: 275–89. [7] Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS, ISPOCD Group. Longterm consequences of postoperative cognitive dysfunction. Anesthesiology 2009; 110:548–55. [8] Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen H, Canet J, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet 1998;351:857–61. [9] Muller SV, Krause N, Schmidt M, Munte TF, Munte S. Cognitive dysfunction after abdominal surgery in elderly patients. Z Gerontol Geriatr 2004;37:475–85. [10] Newman S, Stygall J, Hirani S, Shaefi S, Maze M. Postoperative cognitive dysfunction after noncardiac surgery: a systematic review. Anesthesiology 2007;106:572–90. [11] Radtke FM, Franck M, Herbig TS, Papkalla N, Kleinwaechter R, Kork F, et al. Incidence and risk factors for cognitive dysfunction in patients with severe systemic disease. J Int Med Res 2012;40:612–20.

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Please cite this article as: Aceto P., et al, Postoperative cognitive dysfunction after liver transplantation, Gen Hosp Psychiatry (2014), http://dx.doi. org/10.1016/j.genhosppsych.2014.12.001