术后谵妄
Incidence,Predictive Factors,and Effect of Delirium After Transcatheter Aortic Valve Replacement
Masieh Abawi,BS C ,*Freek Nijhoff,MD,*Pierfrancesco Agostoni,MD,P H D,*Marielle H.Emmelot-Vonk,MD,P H D,y Rehana de Vries,MS C ,y Pieter A.Doevendans,MD,P H D,*Pieter R.Stella,MD,P H D *
elirium is an acute organic brain syndrome that often complicates the post-operative course of cardiac surgery (1,2).The incidence
of post-operative delirium (POD)after cardiac surgery ranges between 8%and 31%(3–7),increasing with age to 25%to 52%in patients age $60years (8–10)and 31%to 66%in patients age $70years (11–13).Differ-ences in study design and diagnostic criteria are likely responsible for the variance in the reported
incidence of POD,as delirium is a clinical diagnosis easily overlooked.A hallmark of delirium is the acute onset and ?uctuating course of symptoms related to cognitive dysfunction,including decre-ased consciousness,inattention,disorientation,and impaired memory (1).Depending on the presence of psychomotor disturbances,delirium can be classi-?ed as either hyperactive,hypoactive,or mixed (14).The
etiology
of
delirium
involves
a
complex
From the *Department of Cardiology,University Medical Center Utrecht,Utrecht,the Netherlands;and the y Department of Geriatrics,University Medical Center Utrecht,Utrecht,the Netherlands.Dr.Stella is a physician for Edwards Lifesciences.All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.Manuscript received April 13,2015;revised manuscript received June 24,2015,accepted September 24,
2015.
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interaction among predisposing factors(e.g., advanced age,pre-existing cognitive impairment, and previous stroke)and precipitating factors(e.g., surgery,medication changes,and hospitalization)(1).
Although mostly transient,delirium is not a benign cognitive disorder.After cardiac surgery,delirium prolongs mechanical ventilation time(14,15)and intensive care unit and hospital stay(7,15–17),and is associated with sepsis(18)and increased perioperative mortality(13,15).Furthermore,it negatively affects early functional and cognitive performance(6,19,20) and is related to increased mortality for up to10 years(6,17,21).Moreover,delirium in general is linked to an elevated risk of dementia(22)and dramatically accelerates cognitive decline in Alzheimer disease (23).Whether delirium itself can induce dementia remains controversial,although there is evidence supporting this theory(24).
Nonpharmacological strategies have shown effec-tiveness in the prevention of delirium in surgical patients,reducing the incidence by30%to40%, resulting in less morbidity,shorter length of stay, and reduced medical costs(25).Knowledge of the predictive factors of POD is crucial to identify pa-tients who are at increased risk,and most likely to bene?t from preventive measures and intensi?ed post-operative monitoring.Numerous predictors of POD after cardiac surgery have been identi?ed,of which higher age(3–5,7,11,15,26),cognitive impair-ment(3,4,7,8,10,13),active depression(4,7,10,14), atrial?brillation(4,5,7),and cardiopulmonary bypass time(3,5,13,14)are most consistently reported.
Patients undergoing operations that involve valve replacement appear at higher risk of POD than pa-tients subjected to coronary artery bypass surgery alone(8,27–29).Nowadays,transcatheter aortic valve replacement(TAVR)is used as an alternative to sur-gical aortic valve replacement(SAVR)in patients with severe aortic stenosis(AS)who are deemed to be inoperable or at high surgical risk(30).Char-acterized by advanced age,frailty,and extensive comorbidities,patients undergoing
TAVR seem particularly prone to develop
POD.Despite the potential effect of delirium
on outcomes and the vulnerability of
typical candidates for the procedure,little is known regarding POD after TAVR.By means of this retro-spective,descriptive study,we sought to investigate the incidence,predictive factors,and effect of POD among patients treated with TAVR. METHODS
This is a retrospective single-center study.All patients who underwent TAVR for severe native
AS
A B B R E V I A T I O N S
A N D A C R O N Y M S
POD=post-operative delirium
TAVR=transcatheter aortic
valve replacement
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at the University Medical Center Utrecht were iden-ti ?ed in our institutional database and included in the study.Eligibility for TAVR was discussed by the heart team and required the consensus of at least 1interventional cardiologist and 1cardiac surgeon.Motivations to refuse SAVR in patients were high operative risk (as assessed by logistic EuroSCORE-I $15%)or the presence of contraindications to cardiac surgery (e.g.,porcelain aorta,frailty,or patent grafts in proximity of the sternum).Frailty was subjectively measured before allocating TAVR by an interventional cardiologist and/or cardiothoracic surgeon on the basis of the informal “eyeball test ”(including cognition
function,physical weakness,and walk speed).Pa-tients
previously
diagnosed with pre-cognitive impairment
were
excluded.
All
patients
gave
informed consent for the procedure,and due to the retrospective nature of the study design,ethics com-mittee approval was waived.
STUDY ENDPOINTS.The primary outcome of this study
was the presence of delirium on any day during the in-hospital stay after TAVR.In case of suspected delirium observed by the nurse or attending physician,a delirium observational score (DOS)was used for further assessment.The DOS combines an assessment of the patient ’s level of consciousness with an evalu-ation of mental status,inattention,and disorganized thinking.When scoring $3points,a trained geriatri-cian was consulted to establish or exclude the diag-nosis of delirium on the basis of Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria (Table 1).If the diagnosis of delirium was established,a standardized work-up to exclude precipitating factors was set up (31).Other clinical outcomes were adjudicated in compliance with the Valve Academic Research Consortium 2criteria (32).Vascular complications were documented for all pro-cedural “access sites,”de ?ned as any location tra-versed by a guidewire,a catheter,or a sheath during the procedure,including arteries,veins,left ventric-ular apex,and the aorta.Post-discharge survival status was established by contacting the Municipal Civil Registries.
IMPLANTATION PROCEDURE.Patients were admitted
1day before the procedure at our institution (if they were not already admitted because of clinical instability).
Valve
implantation
was
performed
per the transfemoral,transapical,or transaortic approach,in order of our institutional preference,depending on the presence of suitable access https://www.sodocs.net/doc/4412469958.html,mon access techniques were used.All trans-femoral procedures involved a fully percutaneous technique.Conscious sedation was the default anes-thetic
method
in
transfemoral
procedures;in nontransfemoral
TAVR,
general
anesthesia
was
instituted.For the transfemoral approach,conscious sedation was established by intravenous infusion of the sedative propofol and the analgesic remifentanil.Sedation was assessed according to the Ramsay sedation scale and was maintained between 3and 5.Local anesthesia of the access sites was performed by lidocaine in ?ltration.After the procedure,trans-femoral patients were transferred directly to the ward,avoiding any intensive care stay (including
the coronary care unit).Nontransfemoral patients stayed for at least 1night in the intensive care
unit,
POD ?post-operative delirium;TAVR ?transcatheter aortic valve replacement.
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followed by the surgical medium care unit and thereafter the ward.
STATISTICAL ANALYSIS.Categorical variables are expressed as frequencies and percentages and were compared with the chi-square or Fisher exact test. Continuous variables are expressed as mean and SD if normally distributed or as median(interquartile range[IQR])if skewed and compared with the Student t test or its nonparametric equivalents,respectively.
Univariable variables with p values<0.10were entered in the backward stepwise multivariable lo-gistic regression to identify the pre-procedural risk factors of POD.Collinearity diagnostics were evalu-ated for all variables considered for multivariable analysis.In case of multicollinearity,the variable with the higher odds ratio(OR)was incorporated into the model.The association between POD and mor-tality was analyzed using Kaplan-Meier survival es-timates and the log-rank test.To isolate the association of POD with all-cause mortality,a Cox
regression model was developed including possible confounders(i.e.,age,sex,any post-procedural complication,and logistic EuroSCORE).The propor-tional hazards assumption was tested for each vari-able by visual inspection of the log-minus-log plots. Nonproportionality was accounted for by incorpora-tion of time-dependent covariates.Results are re-ported as ORs or hazard ratios(HRs),where appropriate,with95%con?dence intervals(CIs).All tests were2-tailed,and a p value<0.05was consid-ered statistically signi?cant.All statistical analyses were carried out using the IBM Statistical Package for Social Science for Windows,version21.0(IBM Corp., Armonk,New York)and GraphPad Prism,version6 (GraphPad Software,La Jolla,California).
RESULTS
Between November2011and December2014,270pa-tients underwent TAVR because of severe symptom-atic AS at the University Medical Center Utrecht.Two patients(0.7%)were excluded because of known Alz-heimer disease,leaving268patients for further anal-ysis.There were no cases of delirium observed before the procedure.The overall incidence of POD diagnosed in accordance with DSM-IV criteria was13.4%(n?36). Baseline characteristics and procedural and hospital outcomes of the study population strati?ed according to the occurrence of POD are summarized in Tables2to 4.Pre-operatively,the POD versus non-POD groups differed signi?cantly in the rates of carotid disease (33%vs.9%;p<0.001),peripheral artery disease(50% vs.9%;p<0.001),and current smoking habit(22%vs. 18%;p?0.013).Regarding procedural features,patients who developed POD more frequently under-went nontransfemoral procedures(50%vs.10%;p< 0.001),more frequently received general anesthesia (50%vs.15%;p<0.001),and underwent longer pro-cedures(140min vs.124min;p?0.014).Concerning clinical outcomes,stroke(8%vs.1%;p?0.034),car-diac tamponade(11%vs.2%;p?0.013),post-operative atrial?brillation(11%vs.0%;p<0.001),infectious disease(11%vs.0.4%;p?0.001),and acute kidney injury(8%vs.2%;p?0.053)were more prevalent in the POD group.Of the36POD cases,18were associ-ated with at least1post-procedural
complication,
Abbreviations as in Figure1.
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including major vascular complications/bleeding
(n ?4),stroke (n ?3),acute kidney injury (n ?3),atrial ?brillation (n ?4),and infectious disease (n ?4).
Delirium was most frequently diagnosed on day 2(IQR:1to 5days)after TAVR (Figure 1)and was asso-ciated with prolonged in-hospital stay regardless of complications (in uncomplicated TAVR:6days [IQR:5to 10days]vs.5days [IQR:4to 5days];p <0.001;and in complicated TAVR:9days [IQR:8to 15days]vs.6days [IQR:5to 9days];p <0.001)(Figure 2).Multivariable logistic regression analysis showed that nontransfemoral access (OR:7.74;95%CI:3.26to 18.10),current smoking (OR: 3.99;95%CI: 1.25to 12.80),carotid artery disease (OR:3.88;95%CI:1.50to 10.10),atrial ?brillation (OR: 2.74;95%CI: 1.17to 6.37),and age (OR: 1.08;95%CI: 1.00to 1.17)were independent predictors of POD (Table 5).General anesthesia was not incorporated in the model because of multicollinearity with nontransfemoral access.
After a median follow-up of 16months (IQR:6to 27months),overall mortality was 18%.Patients who developed POD demonstrated higher mortality in transfemoral TAVR (39%vs.13%;p ?0.003)but not in nontransfemoral TAVR (33%vs.36%;p ?0.841).POD remained a signi ?cant predictor of mortality in transfemoral TAVR (HR:2.81;95%CI:1.16to 6.83),but not in nontransfemoral TAVR (HR:0.43;95%CI:0.10to 1.76),independent of age,sex,logistic EuroSCORE,and the occurrence of complications (Online Table 1,Figures 3and 4).
DISCUSSION
In the present study,we investigated the incidence,predictors,and effect of POD after TAVR.The inci-dence of POD (on the basis of DSM-IV criteria)was 13.4%
in
this
cohort.
Nontransfemoral
TAVR,
increased age,carotid artery disease,current smoking habit,and AF were independent predictors of POD.The occurrence of POD was associated with prolonged in-hospital stay regardless of complications and remained an independent predictor of mortality in transfemoral TAVR but not in nontransfemoral TAVR when adjusted for age,sex,logistic EuroSCORE,and the occurrence of complications.Post-operative
delirium
is
an
outcome
that
certainly deserves attention in TAVR,as the typical target TAVR patient and several procedural aspects of TAVR designate this intervention as “high risk ”of being complicated by delirium.Advanced age and signi ?cant comorbidities may predispose all TAVR candidates to POD.Moreover,ischemic brain injury,1of the mechanisms suspected to cause POD through alteration of cerebral acetylcholine levels (33),is commonly encountered in TAVR.In cardiac surgery,a
higher microembolic load (34),elevated biomarkers of brain tissue damage (35),and clinical cerebrovascular events (5,10,26)have been associated with POD.In response to brain injury,increased microglia activity induced by neuroin ?ammation in the brain has been hypothesized to be 1of the mechanisms that may contribute to POD (36).Brain injury related to TAVR most often involves (micro)infarctions caused by cerebral embolization of aortic plaque or valve parti-cles dislodged during prosthesis positioning and deployment (37).Rapid ventricular pacing may also contribute to ischemic brain injury by causing episodic hypotension and cerebral hypoperfusion (38).Data on the incidence of delirium after TAVR are scarce,as the present study is 1of the ?rst on this topic.A previous small cohort study (including patients
treated in 2008and 2009,n ?122)reported a 12%incidence of POD after transfemoral TAVR and
53%
POD ?post-operative delirium;TAVR ?transcatheter aortic valve replacement.
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after transapical TAVR(39).This is in line with the 8%and45%POD rate after transfemoral and non-transfemoral TAVR in our analysis.Despite extensive comorbidities,POD appears to occur substantially less often after transfemoral TAVR(<10%)than after SAVR in elderly patients(31%to66%),whereas the incidence of POD after nontransfemoral TAVR(w50%)seems to approach that of SAVR(8,12).Recently,a non-randomized prospective study investigating POD in octogenarians after TAVR and SAVR reported SAVR as a risk factor for POD,with a22%higher incidence compared with TAVR(12).The reported44%rate of POD after TAVR in this study is dif?cult to interpret, however,due to the absence of data on procedural access and the use of a different diagnostic tool (confusion assessment method)for delirium.
Similar to previous data,nontransfemoral access was identi?ed as the strongest predictor of POD in the present analysis(39).A distinct feature of patients with nontransfemoral access is the presence of
advanced vascular disease,which may be indicative of coexisting cerebrovascular disease,creating increased potential for intraprocedural cerebral ischemia and POD.Otherwise,nontransfemoral pro-cedures involve a stronger noxious stimulus than transfemoral TAVR,due to the need for general anesthesia,the intensive care stay,and the dis-orienting effect of the frequent change of environ-ment,and is therefore more likely to precipitate delirium.Nontransfemoral access also comes with post-operative pain,increased opioid use,and post-operative in?ammation,all factors capable of triggering POD.Although signi?cantly associated with POD in the univariable analysis,the indepen-dent effect of general anesthesia could not be assessed in the present study because of multi-collinearity with nontransfemoral TAVR.General anesthesia has been linked to post-operative cogni-tive dysfunction,as general anesthetics exert an anticholinergic effect and interfere with many neural processes,involving intracellular calcium signaling, receptor functioning,and gene transcription(40). Clinical data on the relevance of anesthetic technique (general anesthesia vs.local anesthesia?sedation) in provoking delirium are inconclusive.However, considering the many procedural aspects that may promote delirium,it seems implausible that anes-thetic technique is solely causative for the higher rate of POD in nontransfemoral TAVR.
All remaining predictors found in this study, including older age(3–5,7,11,15,26),carotid artery dis-ease(5,26,41),atrial?brillation(4,5,7),and current smoking(42),have been previously related to POD in cardiac surgery.The common denominator of these factors may be their involvement in the causative chain of ischemic brain injury through an association with (cerebral)atherosclerosis or thromboembolism.Older age is also a risk factor of POD due to an age-dependent decrease in neurotransmitter release and overtime accumulation of cerebral tissue damage that aggravate susceptibly to brain dysfunction(1,43).Besides pro-moting atherosclerosis,active smoking has been hy-pothesized to contribute to POD by abrupt cessation during hospitalization,because nicotine withdrawal involves acetylcholine disturbances similar to POD (44).Pre-operative AF not only is postulated to pre-dispose to POD by in?icting thromboembolic brain damage,but may additionally provoke periods of hy-potension causing cerebral hypoperfusion(45).
Analogous to observations in conventional cardiac surgery,POD after TAVR was related to an adverse outcome in the present analysis,characterized by prolonged in-hospital stay,and,in case of trans-femoral TAVR,elevated follow-up mortality.Strati?-cation according to the presence of post-operative complications(other than delirium)demonstrated that POD in itself leads to prolonged hospitalization after TAVR.To what extent increased morbidity and mortality can be truly attributed to POD is dif?cult to establish(46).Rather than being causally related to adverse events,POD may re?ect a patient’s decreased resilience against noxious stimuli(i.e.,fragility), merely identifying those individuals already predis-posed to worse treatment outcomes.Along similar lines,the occurrence of POD after less physically demanding transfemoral procedures may identify extremely frail patients,which may explain the higher mortality rate.Uncertainty regarding the Abbreviations as in Figure3.
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sequence of events also clouds the perception of the true effect of POD;for example,prolonged me-chanical ventilation has been reported as both a pre-dictor as well as a consequence of delirium,and the same holds true for cognitive impairment (7,9,14,15).Nevertheless,in view of the magnitude of evidence reporting unfavorable outcomes and increased med-ical costs in POD,it certainly seems like an entity to be avoided,especially in the elderly.Primary prevention
and
early
recognition
of
delirium have demonstrated effectiveness in reducing delirium incidence and falls.Moreover,prevention may decrease the length of in-hospital stay,reduce the need for institutionalization,and ultimately reduce medical costs (1,25).The predictors identi ?ed in this study can aid in the identi ?cation of TAVR patients who are at higher risk for developing POD and who will bene ?t most from intensi ?ed surveil-lance and targeted prevention.Although many pre-disposing and precipitating factors of delirium are nonmodi ?able,several nonpharmacological measures can be taken to prevent POD in susceptible patients,as summarized in Table 6(47).Speci ?cally,in the TAVR setting,it seems advisable to avoid non-transfemoral access whenever justi ?ed.To date,there is no consensus on the ef ?cacy of pharmacological therapy in the prevention and treatment of delirium (1).Whether a reduction of embolic burden by cerebral protection devices may positively affect the rate of POD in TAVR seems speculative considering the multifactorial nature of this cognitive disorder.
STUDY LIMITATIONS.The main limitations of this
study are related to its retrospective,single-center design.The retrospective assessment of delirium
may have led to underestimation of the incidence of delirium,as symptoms can be subtle,especially in the case of the hypoactive form.Furthermore,we were unable to reliably quantify in retrospect the presence of pre-operative cognitive impairment and active depression,important predictors of POD in cardiac surgery.Finally,the relatively small sample size (transfemoral and nontransfemoral groups)did not allow for exhaustive multivariable analysis to fully isolate the independent effect of delirium on follow-up mortality.
CONCLUSIONS
Despite their apparent susceptibility,only 1in 8TAVR patients develops delirium during the post-operative course.The incidence of POD heavily depends on procedural access,with a 5-fold higher rate in non-transfemoral compared with transfemoral TAVR.Be-sides procedural access,older age;carotid artery disease;current smoking;and pre-operative AF were identi ?ed as independent predictors of POD.Post-operative delirium after TAVR was associated with prolonged in-hospital stay and increased all-cause mortality during follow-up.Early recognition and prevention strategies may decrease the incidence of POD and improve outcomes in TAVR patients.Future large prospective studies are needed to con ?rm these ?rst ?ndings on POD after TAVR.
REPRINT REQUESTS AND CORRESPONDENCE:Dr.
Pieter R.Stella,Department of Cardiology,University Medical Center Utrecht,Heidelberglaan 100,Room E.04.210,3584CX,Utrecht,the Netherlands.E-mail:p.stella@umcutrecht.nl
.
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KEY WORDS post-operative delirium,
transcatheter aortic valve replacement
APPENDIX For a supplemental table,please
see the online version of this article.
Abawi et al.J A C C:C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L.9,N O.2,2016 Incidence,Predictive Factors,and Effect of Delirium After TAVR J A N U A R Y25,2016:160–8 168