General Hospital Psychiatry xxx (2014) xxx–xxx

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General Hospital Psychiatry

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Preexisting cognitive status is associated with reduced behavioralfunctional capacity in patients 3 months after cardiac surgery: anextension study☆,☆☆

Simone Messerotti Benvenuti, Ph.D. a,⁎, Elisabetta Patron, M.S. a, Paolo Zanatta, M.D. b, Elvio Polesel, M.D. c,Daniela Palomba, M.D. a

a Department of General Psychology, University of Padova, 8–35131 Padova, Italyb Department of Anesthesia and Intensive Care, Treviso Regional Hospital, Italyc Department of Cardiovascular Disease, Treviso Regional Hospital, Treviso, Italy

a b s t r a c ta r t i c l e i n f o

☆ Acknowledgments of research support. Funds for thEuropean Social Fund (ref. 2105/101/1/722/2009) for tS.M.B. and by Motta di Livenza Hospital, Treviso, for theWe would like to thank Carlotta Bonfà for her contribucollection. We also thank the team members of the Cardin Treviso Regional Hospital for their help in supportingclinical practice.☆☆ Competing interest statement: The authors declar

interests to report.⁎ Corresponding author. Tel.: +39 049 827 6617; fax

E-mail address: simone.messerotti@unipd.it (S. Mes

0163-8343/$ – see front matter © 2014 Elsevier Inc. Alhttp://dx.doi.org/10.1016/j.genhosppsych.2014.02.009

Please cite this article as: Messerotti Benvenin patients 3 months after cardiac surgery:

Article history:

Received 20 September 2013Revised 4 February 2014Accepted 6 February 2014Available online xxxx

Keywords:Behavioral functional capacityCardiac surgeryCognitive impairmentCognitive–behavioral assessmentNeuropsychology

Objective: To examine whether preexisting cognitive status rather than short- andmiddle-term postoperativecognitive decline (POCD) may differentially account for behavioral functional capacity 3 months after cardiacsurgery.Method: Seventy-nine patients completed a psychological evaluation, including the Trail Making Test Part B,the memory with 10-s interference, the phonemic fluency and the Instrumental Activities of Daily Living(IADLs) questionnaire for cognitive functions and behavioral functional capacity, respectively, before surgery,at discharge and at 3-month follow-up.Results: Thirty-one (39%) and 22 (28%) patients showed POCD at discharge and at 3-month follow-up,respectively. Preoperative cognitive status was significantly associated with change in behavioral functionalcapacity 3 months after surgery (Psb.003), whereas short- and middle-term POCD and intraoperative riskfactors were unrelated to residualized change in IADLs scores (all PsN.095).

Conclusions: Preexisting cognitive deficit, especiallyworkingmemorydeficit, rather than short- andmiddle-termPOCD related to intraoperative risk factors is associated with poor behavioral functional capacity 3 months aftercardiac surgery. The present study therefore suggests that a preoperative cognitive evaluation is essential toanticipate which patients are likely to show a decline in behavioral functional capacity after cardiac surgery.

© 2014 Elsevier Inc. All rights reserved.

1. Introduction

The development of cardiopulmonary bypass (CPB) was the rate-limiting step to the development of modern cardiac surgery. The CPB(or heart–lung apparatus) was designed to perform the functions ofboth the human heart and lungs and therefore enables surgeons torepair defects in the heart while the patient's cardiac muscle andcirculation are stopped. The first successful application of the CPBmachine in 1954 led to important advances in cardiac surgery,perfusion technique and anesthesia and made many types of cardiac

is study were provided by thehe Ph.D. student grant for Dr.Ph.D. student grant forMs. E.P.tion to the psychological dataiovascular Disease Departmentthis work during their routine

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: +39 049 827 6600.serotti Benvenuti).

l rights reserved.

uti S., et al, Preexisting cogn..., Gen Hosp Psychiatry (201

surgery eventually possible — including heart valve or coronary arterybypass graft (CABG) surgery [1–3]. Such technological advances over thepast six decades have decreased the major complication or mortality ofpatients undergoing cardiac surgery with CPB (e.g., CABG, valvularsurgery) [4,5]. In spite of the clinical medical benefits, a significantnumberof patients suffer fromadverse cognitive outcomes [6],whichareassociated with cardiac surgery procedures (manipulation of a diseasedaorta, duration of CPB, cerebral microembolization or hypoperfusion)[e.g., 7–11]. Most importantly, there is evidence that postoperativecognitive decline (POCD) is related to a persistent, measurable reductionof patient's behavioral functional capacity and, therefore, may limit thelong-term (≥1 year) quality of life of patients after cardiac surgery[12,13]. In particular, Phillips-Bute et al. [12] have observed that bothshort- and long-termPOCD are significantly related to impaired ability toengage in activities of daily living 1 year after CABG surgery and,therefore, may limit the quality of life of postsurgical patients.

It is very likely, however, that patients undergoing cardiac surgerymay suffer from preexisting cognitive dysfunctions related tocardiovascular risk factors such as hypertension [14], diabetes [15]and peripheral vascular disease [16], independently of surgicalprocedures (for review, see Ref. [7]). Consistent with these findings,

itive status is associated with reduced behavioral functional capacity4), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.009

Table 1Demographic, biomedical and surgical characteristics of patients enrolled in the study

Variable Patients (N=79)

Age (years) 63.8 (11.0)Education (years) 8.6 (4.2)Male sex (N, %) 54 (68)EuroSCORE (%) 4.5 (3.7)Surgical procedureCABG (N, %) 13 (16)Heart valve (N, %) 47 (60)Combined (N, %) 19 (24)Duration of aortic cross-clamping (min) 89 (31)Duration of CPB (min) 120 (33)Duration of mechanical ventilation (h) 8 (7)

Notes: Data are M (S.D.) of continuous and N (%) of categorical variables.

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Silbert et al. [17] observed that 35% of patients awaiting cardiacsurgery had preoperative cognitive dysfunctions, which, in turn, mayaccount for the high incidence of POCD [6].

Intriguingly, it has been recently shown that lower preexistingcognitive status, but not POCD related to intraoperative variables suchas the duration of aortic cross-clamping and/or CPB, is associated withstrong decline in long-term behavioral functional capacity 1 year aftercardiac surgery [18]. Specifically, Messerotti Benvenuti et al. [18] havesuggested that preoperative cognitive impairment may furtherpredispose patients to poor long-term behavioral functional capacityand outcome by reducing the patient's ability to concentrate or to payattention, which, in turn, may result in patient's psychological distressand complaints [13].

Although there is growing and consistent evidence showing theimportance of patient-related as opposed to procedure-related vari-ables on long-term (≥1 year) postoperative patient's outcomes[18,19], the influence of such factors on behavioral functional capacityat middle-term follow-up (i.e., 3 months after cardiac surgery) hasbeen poorly investigated. The latter period of time is crucial inpostsurgical recovery: although it has been shown to be stillinfluenced by both patient- and procedure-related risk factors[8,20], it has been also indicated as the first time interval forpostconvalescent assessment relevant to functional outcomes [21].Accordingly, the primary aim of the present study was to examinewhether preexisting cognitive status rather than short- and middle-term POCD and intraoperative risk factors (i.e., the duration of aorticcross-clamping and CPB) would account for change in behavioralfunctional capacity in patients 3 months after cardiac surgery, whilecontrolling for common preoperative risk factors.

2. Method

2.1. Participants

After local ethics committee approval, 79 patients admitted forfirst-time elective cardiac surgery with CPB were enrolled in thestudy after giving written informed consent. All patients underwentcardiac surgery at an Italian northeastern regional hospital from June2009 to April 2013. Each patient's selection was performed by thesame clinical psychologist, anesthesiologist and operating surgeonafter patients were admitted to the surgical unit. Given that theclinical psychologist was not always present at the department ofcardiovascular disease, the patients were not enrolled consecutivelyin the study. In order to increase the sample size, maintaining thehomogeneity of the sample, 32 patients from a previous report wereincluded in the present study [18]. Inability to read or understandItalian; visual or auditory impairments; inaccessibility for follow-up;conflicting research protocol; use of anxiolytic and/or antidepressantdrugs; psychiatric illness; life-threatening condition such as meta-static cancer, endstage renal disease or plasma creatinine≥2.0 mg/dl;a history of symptomatic cerebrovascular disease (with residualdeficit); and/or neurological deficit as obtained from patient's medicalrecords and confirmed by medical staff were the exclusion criteria.Given that it is well-established that older age increases the attritionrate in longitudinal studies [22], patients with age greater than85 years were also excluded from our study. The risk of mortalityassociated with cardiac surgery was calculated for each patientapproximately a week before surgery using the European System forCardiac Operative Risk Evaluation (EuroSCORE) [23]. The presentstudy was carried out in accordance with the Declaration ofHelsinki.

2.2. Anesthesia and surgical management

Before surgery, all patients were premedicated in the ward with anintramuscular injection of 100 μg of fentanyl and 5 mg of midazolam.

Please cite this article as: Messerotti Benvenuti S., et al, Preexisting cognin patients 3 months after cardiac surgery:..., Gen Hosp Psychiatry (201

The anesthesia induction was established with 5-μg/kg fentanyl,0.2-mg/kg midazolam, 1-mg/kg propofol and 0.1-mg/kg cisatracuriumbefore performing the tracheal intubation. The maintenance ofanesthesia was performed with 3 to 5 mg/kg/h of propofol and 0.2 to0.4 μg/kg/min of remifentanil just tomaintain the bispectral index valuelower than 40. Closed and mini-invasive-coated extracorporeal circuitswith a centrifugal pump were used for CABG patients. Other surgicalinterventions were performed using coated open circuits with acentrifugal pump. An α-stat moderately hypothermic CPB strategywas used for each patient. All the details of intraoperative managementhave been previously reported [24]. Each preoperative, intraoperativeand postsurgical characteristic of patients is reported in Table 1.

2.3. Cognitive evaluation

The cognitive evaluation was performed preoperatively (approx-imately 2 weeks before surgery), at discharge from the hospital(approximately 7 days after surgery) and at follow-up (approximately3 months after surgery). The cognitive evaluation included a shortclinical interview and three cognitive tests assessing the mostcommonly affected cognitive domains in cardiac surgery patients[21]. All cognitive tests were administered individually by a trainedpsychologist, blind to the patient's surgical procedure, in a quiet andisolated room at the hospital. The cognitive test battery included theTrail Making Test part B (TMT-B) [25,26] for attention and cognitiveswitching skills, the memory with 10-s interference [27] for workingmemory and the phonemic verbal fluency [28] for lexical access andstrategic search processes (for the details of each cognitive test, seeRefs. [18,20,29–31]).

The InstrumentalActivities ofDaily Living (IADLs) [32] self-reportingquestionnaire was administered on the same day of the cognitiveevaluation in order to evaluate the patient's behavioral functionalcapacity inperformingcommon, yet complex, tasksof everyday life suchas shopping for groceries and using public/private transportation. TheIADLs adjusted score varying between 0.24 and 1 was obtained bydividing the total score of the answered itemsby the sumof scores of thesame items in the assumption of complete dependency [33]. A higherscore indicates worse behavioral functional capacity.

2.4. Statistical analysis

Statistically significant short- and middle-term POCD have beenrespectively defined as a decline in individual patient's score atdischarge and at 3-month follow-up in at least one test of greater than1 standard deviation (S.D.) of the baselinemean as determined for thestudy patients as a group. This statistical approach, namely, theincidence analysis, was used to estimate the individual change inperformance from the preoperative to postoperative periods [2].

A preliminary analysis was conducted in order to quantify changesin cognitive performance from the preoperative to postoperative

itive status is associated with reduced behavioral functional capacity4), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.009

Table 2Mixed ANOVAs on TMT-B, memory with 10-s interference and phonemic verbal fluencyscores before cardiac surgery and at discharge in patients with short-term POCD andwithout short-term POCD

Variable Beforesurgery

Discharge P Group ×time ηp2

Incidenceof POCD (%)

TMT-Ba .003 .11 18Group withshort-term POCD

271 (167) 317 (169) .001

Group withoutshort-term POCD

126 (64) 119 (48) .51

Memory with 10-s interferenceb .33 .01 20Group withshort-term POCD

4.5 (2.8) 4.6 (2.8)

Group withoutshort-term POCD

6.9 (1.9) 7.4 (1.7)

Phonemic verbal fluencyb .008 .09 24Group withshort-term POCD

6.8 (2.9) 5.2 (2.9) .008

Group withoutshort-term POCD

10.6 (3.6) 10.9 (3.8) .33

Notes: Data are M (S.D.).a Higher scores indicate worse functions.b Higher scores indicate better functions.

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periods: patients were then classified into one of two groups based onthe results of the incidence analysis: those with short (N=31) ormiddle term POCD (N=22) and those without short (N=48) ormiddle term POCD (N=57), respectively (see Results). In the case ofshort-term POCD, separatemixed analyses of variance (ANOVAs) withgroup (with short-term POCD and without short-term POCD) as thebetween-subjects factor and time (before surgery and discharge fromthe hospital) as a within-subjects factor were used as secondaryanalyses to compare the preoperative and postoperative (i.e., atdischarge) scores of each cognitive test in both groups. The sameANOVAs were conducted to compare the preoperative and follow-upscores of each cognitive test in patients with middle-term POCDversus those without middle-term POCD. Significant interactionswere explored using Fisher's LSD post-hoc tests. Partial eta-squared(η2p) is reported as a measure of the effect size. The η2p valuesconsidered to represent small, medium and large effects are .01, .06and .14, respectively [34]. Patients who failed to complete cognitiveevaluation at discharge (i.e., one patient for phonemic verbal fluency)or at 3-month follow-up (i.e., six patients for TMT-B) were excludedfrom the above-mentioned statistical analyses.

Two linear regression models were used to predict residualizedchange in IADLs scores from preoperative period to 3 months aftersurgery. Residualized change scores were calculated by regressing thepreoperative score of IADLs questionnaire on its postoperative scoreand calculating the residual of the resultant regression [18,20,29,30].Then, raw scores of the three tests administered at each assessmentwere converted to z-scores using the sample mean and S.D. of eachtest [35,36]. Given that improved performance in TMT-Bwas reflectedby a lower score, z-scores in this test were reversed so thatimprovements in TMT-B gave rise to positive z-scores. In order toquantify the overall cognitive function, the resultant z-scores (mean=0, S.D.=1) were averaged to obtain a continuous composite cognitiveindex (CI) for each subject including all the three cognitive tests.Therefore, CI was calculated to yield a single, continuous measure ofcognitive function at each assessment, that is, prior to surgery, atdischarge and at 3-month follow-up. The greater the CI, the better thecognitive performance. Then, changes in CI were calculated for eachsubject by subtracting the preoperative score from the score atdischarge (ΔCI1) or at 3-month follow-up (ΔCI2). ΔCI1 or ΔCI2 wasentered as predictor of residualized change in IADLs scores in the twolinear regression models, while adjusting for preexisting cognitivestatus as calculated with CI, education, EuroSCORE and the duration ofaortic cross-clamping and CEC. In order to calculate the effect size (thevariation of R2) of each predictor, we also conducted two hierarchicallinear regression analyses in otherwise identical regression modelsdescribed immediately above. The independent variables wereentered in four blocks: (a) education and EuroSCORE (which includessex, age and cardiac- and operation-related factors), (b) the durationof aortic cross-clamping and CPB procedure, (c) the CI and (d) theΔCI1 or ΔCI2.

As secondary analysis, preoperative scores of each cognitive testand dichotomous short- and middle-term POCD were entered aspredictors of residualized change in IADLs scores instead of CI, ΔCI1and ΔCI2, respectively. Specifically, the independent variables wereentered in four blocks: (a) education and EuroSCORE, (b) the durationof aortic cross-clamping and CPB procedure, (c) the preoperativescores of each cognitive test and (d) the occurrence of generalizedshort- (at discharge) and middle-term (3 months after surgery)cognitive decline (coded: absent=0, present=1).

Furthermore, an a posteriori analysis with the Mann–Whitney Utest was conducted to test difference in residualized change in IADLsscores of two groups classified based on the presence of preexistingimpaired memory with 10-s interference performance (N=15) (i.e.,scores at least 1 S.D. below the sample mean) or on the absence ofimpaired memory with 10-s interference performance (N=64)before surgery (see Results).

Please cite this article as: Messerotti Benvenuti S., et al, Preexisting cognin patients 3 months after cardiac surgery:..., Gen Hosp Psychiatry (201

3. Results

3.1. Preoperative, postoperative and 3-month cognitive function

Patients were mostly men (N=54, 68%), with a mean (S.D.) age of63.8 (11.0) and a mean (S.D.) education of 8.6 (4.2). The mean (S.D.)logistic EuroSCORE was 4.5% (3.7%), which represents a moderate riskfor mortality in cardiac surgery (i.e., EuroSCORE ranges from 3% to 5%)[23]. Each demographic and biomedical characteristic of patients isreported in Table 1. Thirty-one (39%) and 22 (28%) patients showed astatistically significant cognitive decline at discharge from the hospital(i.e., short-term POCD) and at 3-month follow-up (i.e., middle-termPOCD), respectively. In the case of short-term POCD, 16 (20%) patientsshowed a decline in one test, 12 (15%) patients in two tests and 3 (4%)patients in three tests. The ANOVAs showed a significant group × timeinteraction effect on TMT-B, F(1, 77)=9.41, P=.003, η2

p=.11, andphonemicfluency, F(1, 76)=7.54, P=.008,η2

p=.09. Fisher's LSDpost-hoc tests revealed that patients with short-term POCD, but not thoseindividuals without short-term POCD, had a significant decline fromthe preoperative to discharge in TMT-B (P=.001) and phonemicfluency (P=.008). Patients with short-term POCD also had worseperformance at discharge in TMT-B (Pb .001) and phonemic fluency(Pb .001) compared to those individuals without short-term POCD. Bycontrast, no significant group × time interaction effect on memorywith 10-s interference, F(1, 77)=0.97, P=.33, η2

p=.01, was noted.The descriptive statistics for each cognitive test are reported in Table 2.

In the case of middle-term POCD, 14 (18%) patients showed adecline in one test, 7 (9%) patients in two tests and 1 (1%) patients inthree tests. The ANOVAs yielded a significant group × time interactioneffect on TMT-B, F(1, 71)=7.57, P=.008, η2

p=.10, memory with 10-sinterference, F(1, 77)=11.58, P=.001, η2

p=.13, and phonemicfluency, F(1, 77)=4.38, P=.04, η2

p=.05. Patients with middle-termPOCD exhibited a significant decline from the preoperative to 3-month follow-up in TMT-B (P=.01) and memory with 10-sinterference (P=.02). By contrast, scores for memory with 10-sinterference (P=.01) and phonemic fluency (Pb .001) significantlyimproved from the preoperative to 3-month follow-up in patientswithout middle-term POCD. Fisher's post-hoc tests also revealed that,compared to patients without middle-term POCD, those havingmiddle-term POCD had worse performance in TMT-B (Pb .001),memory with 10-s interference (Pb .001) and phonemic fluency(Pb .001) at 3-month follow-up. The descriptive statistics for eachcognitive test are reported in Table 3.

itive status is associated with reduced behavioral functional capacity4), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.009

Table 3Mixed ANOVAs on TMT-B, memory with 10-s interference and phonemic verbal fluencyscores before cardiac surgery and at 3-month follow-up in patients with middle-termPOCD and without middle-term POCD

Variable Beforesurgery

Three-monthfollow-up

P Group ×time ηp2

Incidenceof POCD (%)

TMT-Ba .008 .10 6Group withmiddle-term POCD

264 (173) 297 (209) .01

Group withoutmiddle-term POCD

152 (103) 135 (66) .33

Memory with 10-s interferenceb .001 .13 18Group withmiddle-term POCD

4.3 (2.9) 3.4 (2.0) .02

Group withoutmiddle-term POCD

6.6 (2.1) 7.2 (1.8) .01

Phonemic verbal fluencyb .04 .05 15Group withmiddle-term POCD

6.0 (2.7) 6.1 (3.6) .90

Group withoutmiddle-term POCD

10.2 (3.5) 11.6 (4.2) b .001

Notes: Data are M (S.D.).a Higher scores indicate worse functions.b Higher scores indicate better functions.

Table 5Results of linear regression analysis with independent variables predicting residualizedchange scores in IADLs

Variable B S.E. B Beta P

Education (years) 0.003 0.003 0.119 .373EuroSCORE (%) 0.001 0.003 0.049 .664Duration of aortic clamping (min) −0.001 0.0005 −0.172 .301Duration of CPB (min) 0.0003 0.0005 0.121 .481CIa −0.061 0.016 −0.542 b .001ΔCI2b 0.015 0.022 0.079 .497

Notes: ΔCI2=change in composite index from the preoperative to 3-month follow-up.F=3.649, P=.003, R2=.233.

a Higher scores indicate better functions.b Higher scores indicate worse functions.

Table 6Results of the hierarchical multiple linear regression analysis with independentvariables predicting residualized change scores in IADLs

Variable B S.E. B Beta P R2 Variation

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3.2. Relationship between preoperative cognitive status, perioperativerisk factors and behavioral functional capacity 3 months after cardiacsurgery

Linear regression analyses showed that residualized change inIADLs scores 3 months after surgery was predicted only by CI but notby intraoperative risk factors, that is, the duration of aortic cross-clamping and CPB procedures. Consistent with these results, ΔCI1 andΔCI2 were unrelated to residualized change in IADLs scores, as shownin Tables 4 and 5. It is also worth noting that demographic andbiomedical risk factors were not significantly associated withresidualized change in IADLs scores in patients 3 months after cardiacsurgery. Hierarchical linear regression models showed that the effectsize of CI was medium-to-large (variation of R2=.15, Pb .001),whereas the effect size for ΔCI1 or ΔCI2 was small or small-to-medium (ΔCI1: variation of R2=.03, P=.095; ΔCI2: variation of R2=.005, P=.497).

Similarly, when we replaced CI, ΔCI1 and ΔCI2 with thepreoperative scores of each cognitive test and the dichotomousshort- and middle-term POCD, respectively, a significant effect ofmemory with 10-s interference scores was noted (Table 6). Bycontrast, demographic, biomedical and intraoperative variables aswell as short- and middle-term POCD did not predict residualizedchange in IADLs scores from the preoperative to 3 months aftercardiac surgery. The remaining cognitive scores were also unrelated toresidualized change scores in IADLs.

Table 4Results of linear regression analysis with independent variables predicting residualizedchange scores in IADLs

Variable B S.E. B Beta p

Education (years) 0.002 0.003 0.094 .466EuroSCORE (%) 0.003 0.003 0.107 .353Duration of aortic clamping (min) −0.0004 0.0005 −0.133 .396Duration of CPB (min) 0.0003 0.0004 0.116 .473CIa −0.051 0.016 −0.448 .002ΔCI1b −0.045 0.026 −0.185 .095

Notes: B=nonstandardized regression coefficient; S.E. B=standard error; beta=standardized regression coefficient; ΔCI1=change in composite index from thepreoperative to discharge. F=4.17, P=.001, R2=.258.

a Higher scores indicate better functions.b Higher scores indicate worse functions.

Please cite this article as: Messerotti Benvenuti S., et al, Preexisting cognin patients 3 months after cardiac surgery:..., Gen Hosp Psychiatry (201

The a posteriori analysis with theMann–Whitney U test of the datashowed that patients with preexisting impaired memory with 10-sinterference had significantly greater decline in IADLs scores thanpatients without impaired memory with 10-s interference (Mann–Whitney U=257.0, P=.005) performance before surgery, as shown inFig. 1.

4. Discussion

The present study examined whether change in behavioralfunctional capacity 3 months after cardiac surgery was differentiallypredicted by preexisting cognitive deficit rather than short- andmiddle-term POCD and/or intraoperative risk factors. The presentfindings showed that preexisting cognitive deficit (CI) but not short-andmiddle-term cognitive decline (ΔCI1 or ΔCI2) was associated withpoor behavioral functional capacity at 3-month follow-up, asmeasured by residualized change in IADLs scores. Consistent withthis result, intraoperative risk factors, that is, the duration of aorticcross-clamping and CPB, which have been previously found to beassociated with both short- and middle-term POCD [e.g.,8,10,35,37,38], were unrelated to behavioral functional capacity 3months after cardiac surgery. It is also worth noting that theassociation between preexisting cognitive status and behavioralfunctional capacity 3 months after cardiac surgery was independentof level of education and EuroSCORE, which includes patient- (e.g.,age, sex), cardiac- (e.g., left ventricular dysfunction, recentmyocardialinfarct) and operation-related risk factors (e.g., surgery on thoracicaorta, emergency operation).

of R2

Block 1 .067 .067Education (years) 0.002 0.003 0.086 .519EuroSCORE (%) 0.001 0.003 0.049 .688Block 2 .075 .008Duration of aorticclamping (min)

−0.001 0.0005 −0.186 .263

Duration of CPB (min) 0.0003 0.0005 0.106 .527Block 3 .242 .167⁎

TMT-Ba 0.0001 0.0001 0.158 .238Memory with10-s interferenceb

−0.011 0.005 −0.313 .022

Phonemic verbal fluencyb −0.002 0.003 −0.080 .573Block 4 .255 .013Short-term POCD −0.002 0.028 −0.009 .952Middle-term POCD 0.029 0.028 0.148 .298

a Higher scores indicate worse functions.b Higher scores indicate better functions.⁎ Pb .01.

itive status is associated with reduced behavioral functional capacity4), http://dx.doi.org/10.1016/j.genhosppsych.2014.02.009

Fig. 1. Comparison of the mean residualized change scores in IADLs between patientswith impaired memory with 10-s interference performance (N=15) and those withoutimpaired memory with 10-s interference performance (N=64) preoperatively. The“whiskers” at the top and bottom of each box represent the maximal and minimalvalues of the distribution, respectively, the top and bottom of each box the 75th and25th percentiles, and the square in the box the 50th percentile (i.e., the median).Significant difference at P=.005 (Mann–Whitney U test) between groups inresidualized change in IADLs scores was noted. aHigher scores indicate a greaterdecline in behavioral functional capacity; bImpaired preoperative memory with 10-sinterference performance was defined as scores at least 1 S.D. below the sample mean.

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These novel findings add to the literature by showing thatpreexisting cognitive status, but not short- and middle-term POCD,is associated with reduced behavioral functional capacity 3 monthsafter cardiac surgery. These findings complement a recent studyrevealing that preexisting cognitive dysfunctions rather than cogni-tive decline predispose patients to poor behavioral functional capacity1 year after cardiac surgery [18]. The finding that both short- andmiddle-term cognitive decline were unrelated to residualized changein IADLs scores is at odds with a previous study reporting anassociation between short- and long-term POCD and impaired qualityof life at 1-year follow-up [12]. Specifically, using multivariable linearregression models, Phillips-Bute et al. [12] found that POCD maydiminish long-term quality of life in patients who underwent CABGafter controlling for baseline cognitive status and the most commonsociodemographic (e.g., age, race) and biomedical (e.g., Charlsoncomorbidity) confounding variables.

Among cognitive domains assessed in the present study, we foundthat working memory, as evaluated with memory with 10-sinterference test, accounted for the greatest amount of variance inIADLs residualized change scores from the preoperative to 3-monthfollow-up. The a posteriori analyses also revealed that patients withpreoperative deficit in working memory (N=15, 19%) had greaterdecline in behavioral functional capacity from the preoperative to 3months after cardiac surgery compared to those individuals withoutpreoperative deficit. These data are in line with previous findingsshowing that 13% of patients who underwent cardiac surgery hadpreoperative cognitive dysfunctions, which further predisposedpatients to poor behavioral functional capacity long term aftersurgery [18]. The present findings, therefore, are consistent withconverging evidence suggesting that, in spite of beneficial effects ofcardiac surgery on quality of life for themajority of patients, a relevantminority of patients, especially those with preexisting cognitivedeficit, has no benefits from cardiac surgery [13,18,39].

Please cite this article as: Messerotti Benvenuti S., et al, Preexisting cognin patients 3 months after cardiac surgery:..., Gen Hosp Psychiatry (201

Intriguingly, it has been recently found that preexisting cognitivestatus, especially working memory ability, is sensitive to preoperativehypoperfusive brain lesions [30], which, in turn, have been suggestedas one plausible pathophysiological mechanism linking preoperativecognitive deficit to poor functional capacity after surgery incardiovascular patients [18]. Specifically, elderly patients withcardiovascular diseases and impaired circulation due to atheromatousstenosis of the cerebral arteries are vulnerable to watershed infarcts,ischemic neuronal damage and neuronal loss [40], whichmay accountfor preoperative working memory deficit. In turn, this cerebralhypoperfusion-related working memory deficit may reduce thepatient's ability to update and/or bring relevant information tomind, to pay attention or to concentrate, thus significantly contrib-uting to the poor behavioral functional capacity after cardiac surgery.In other words, it can be argued that the so-called “cardiogenicdementia” [41] — a cardiovascular-disease-related cognitive deterio-ration — is more likely than POCD and/or procedure-related variablesto account for the decline of behavioral functional capacity from thepreoperative to 3-month follow-up.

Another possible explanation of our findings is that the observeddecline in behavioral functional capacity may be associated withpostoperative delirium, an acute change in attention and cognitionthat occurs most commonly between postoperative Days 1 and 3 andis diagnosed by a detection of symptoms [42]. It has been shown,indeed, that postoperative delirium is independently associated withdecline in behavioral functional capacity in patients 1 month aftercardiac surgery [43]. Given that preexisting cognitive impairment is arisk factor for postoperative delirium [44,45], it is possible thatpostoperative delirium may underlie the relationship betweenpreexisting cognitive impairment and decline in behavioral functionalcapacity in postsurgical patients. Moreover, it is well-established thatpostoperative delirium is strongly associated with POCD, especiallywith short-term POCD and has been suggested that postoperativedelirium may be on a continuum with short-term POCD [46].Therefore, future research is warranted to include an assessment ofdelirium in order to examine its impact on behavioral functionalcapacity in patients after cardiac surgery.

As far as short-term and middle-term POCD is concerned, ourdata are in line with those of previous studies showing thatexecutive functions such as cognitive set shifting, working memoryand strategic search processes are likely to be sensitive tointraoperative procedures and therefore to decline after cardiacsurgery [e.g., 8,11,18,21]. Indeed, there is large evidence thatcognitive set shifting, working memory and strategic searchprocesses evaluated with TMT-B, memory with 10-s interferenceand phonemic fluency, respectively, involve medial and dorsolateralprefrontal cortices and basal ganglia, which, in turn, are susceptibleto intraoperative cerebral hypoperfusion [e.g., 11,37] and micro-embolization [e.g., 9,47,48]. Consistent with these findings, our studyshowed that TMT-B, memory with 10-s interference and phonemicfluency had a high level of sensitivity for detecting short- andmiddle-term POCD.

In addition to procedure-related variables, it should be noted thatpatient-related variables may also account for cognitive decline aftercardiac surgery, especially for middle- and long-term POCD [49].Indeed, it has been recently shown that while short-term (atdischarge) POCD is associated with procedure-related variables, themost important being the duration of CPB, long-term (≥1 year) POCDis more likely to be influenced by patient-related variables (i.e., thepreexisting depression) [29]. Moreover, given that there is prelimi-nary evidence that both preoperative and intraoperative factors mayinfluence cognitive decline 3 months after surgery [8,20], it is likelythat a combination of patient- and procedure-related variables mayaccount for middle-term POCD in the present study. Clearly, futureresearch is warranted to examine the differential impact of patient-and procedure-related factors on middle-term POCD.

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The current findings should be interpreted in light of a number ofpossible methodological limitations. First, in some of our analysesPOCD was defined using the S.D. method (i.e., the incidence analysis),that is, a change greater than 1 S.D. of the baselinemean in at least onecognitive test [2]. In particular, the 1 S.D. criterion involves anarbitrary convention to define POCD and the risk of “floor effect” [50–52]. However, compared to other methods to define POCD (e.g., groupmean changes or 20%–20% method), the 1 S.D. decline has severaladvantages, that is, each individual acts as his/her own control, it hasbeen widely used in the literature, and it is sensitive enough to detectclinically significant cognitive dysfunction and minimal POCD [e.g.,18,29,30; for a review, see Ref. [2]]. Most importantly, in our primaryanalysis, when cognitive decline was calculated as a change in acontinuous, composite score from baseline to discharge (ΔCI1) or 3-month follow-up (ΔCI2), the preoperative cognitive status was theonly significant predictor of decline in behavioral functional capacityafter cardiac surgery. To overcome the above-mentioned limitations,future research is warranted to include a nonsurgical control group inorder to use the reliable change index [53,54], which has recentlydemonstrated superior sensitivity and specificity in defining POCDcompared to other methods [50–52]. Second, another potentiallimitation is that we did not adjust for multiple comparisons, whichwould protect against rejecting the null hypothesis when it is correct(Type I error). However, it should be noted that adjusting for multiplecomparisons by changing the criterion for significance increases therisk of Type II error (the chance of missing a real effect). In order toovercome this issue, we calculated the effect size, which representsthe proportion of variance in the dependent variable that is uniquelyassociated with independent variable(s) and is independent ofsignificance level and sample size. Specifically, using hierarchicallinear regression, we were able to estimate the proportion of variance(i.e., the variation of R2) explained by each block of variables, namely,the sociodemographic and biomedical variables, the intraoperativevariables, the preexisting cognitive status and POCD. According toCohen [55], we found that preexisting cognitive status showedmedium-to-large effect size (variation of R2N .15) and thereforeexplained a good proportion of variance in residualized change inIADLs scores. By contrast, the effect size for intraoperative variablesand POCD was small (R2≤ .008 for the duration of aortic cross-clamping and CEC and for ΔCI2) or, at best, small-to-medium (R2≤ .03for ΔCI1, and dichotomous short- and long-term POCD). Third, giventhat higher years of education have been found to protect againstPOCD [56,57], the relatively low level of education of patients enrolledin the study may have led us to overestimate the incidence ofcognitive decline after cardiac surgery. Nonetheless, the level ofeducation of our patients was substantially equivalent to that of otherreports [35,58–60]. Most importantly, the incidence of short- andmiddle-term POCD was similar to that observed in previous studies[6,12]. Fourth, behavioral functional outcome was limited to residua-lized change scores in IADLs. Clearly, future studies should compre-hend a wide spectrum of quality of life measures such asquestionnaires assessing occupational function, social activities orsymptom limitations after cardiac surgery [61]. Finally, the cognitiveevaluation did not include specific visuospatial tasks, prevalentlyinvolving right hemisphere, such as Corsi block [62] or mentalrotation tests [63]. However, the cognitive battery used in the presentstudy has the advantage to show good psychometric properties aswell as to cover the most vulnerable cognitive functions in patientswith cardiovascular disease or in those who underwent cardiacsurgery, such as cognitive set shifting and attention (TMT-B), workingmemory (memory with 10-s interference) and lexical access andstrategic search process (phonemic verbal fluency), as suggested bythe detailed “Consensus Statements” by Murkin et al. [21].

In conclusion, our study shows that preexisting cognitive dys-functions rather than cognitive decline related to intraoperative riskfactors may account for the decline in behavioral functional capacity

Please cite this article as: Messerotti Benvenuti S., et al, Preexisting cognin patients 3 months after cardiac surgery:..., Gen Hosp Psychiatry (201

from the preoperative to 3 months after cardiac surgery. Our findingssuggest that a preoperative cognitive evaluation is crucial toanticipate which patients are likely to have poor behavioral functionalcapacity at 3-month follow-up, which, in turn, has been indicated asthe first reasonable time interval for postconvalescent assessment offunctional outcomes [21].

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