Effects of statins on delirium following cardiac surgery - Evidence from literature

Abstract

Delirium is a common complication after cardiac surgery, being associated with significant mortality and morbidity. The pathogenesis of postoperative delirium (POD) is complex and multifactorial, involving an interaction of multiple predisposing and precipitating factors. There are several hypothesis regarding the underlying mechanisms of POD, and the most recent emerging one involves neuroinflammation, which is exacerbated by the cardiopulmonary bypass-induced systemic inflammatory response. Experimental and clinical studies have re- cently documented improved perioperative central neural protection exerted by statins because of their anti-inflammatory, immunomodulatory, and antithrombotic properties. The present review will focused on the possible protective effect exerted by preoperative statin adminis- tration on delirium following cardiac surgery.

Full text

Psychiatr. Pol. 2015; 49(6): 1359–1370
PL ISSN 0033-2674 (PRINT), ISSN 2391-5854 (ONLINE)
www.psychiatriapolska.pl
DOI: http://dx.doi.org/10.12740/PP/60139
The study was not sponsored.
Effects of statins on delirium following cardiac surgery
– evidence from literature
Giovanni Mariscalco1, Silvia Ma ria n i1, Fausto Bi a nca r i2, Maciej Ba nach 3
1 Department of Cardiovascular Sciences, University of Leicester, Gleneld Hospital,
Leicester, United Kingdom
2 Division of Cardiac Surgery, University of Oulu, Oulu, Finland
3 Department of Hypertension, Medical University of Lodz, Lodz, Poland
Summary
Delirium is a common complication after cardiac surgery, being associated with signicant
mortality and morbidity. The pathogenesis of postoperative delirium (POD) is complex and
multifactorial, involving an interaction of multiple predisposing and precipitating factors.
There are several hypotheses regarding the underlying mechanisms of POD, and the most
recent emerging one involves neuroinammation, which is exacerbated by the cardiopul-
monary bypass-induced systemic inammatory response. Experimental and clinical studies
have recently documented improved perioperative central neural protection exerted by statins
because of their anti-inammatory, immunomodulatory, and antithrombotic properties. The
present review will focused on the possible protective effect exerted by preoperative statin
administration on delirium following cardiac surgery.
Key words: delirium, cardiac surgery, complications
Diagnosis and epidemiology
Despite renements in surgical and anaesthesiological techniques, delirium remains
a frequent complication following coronary artery bypass grafting (CABG) [1–10].
The incidence of postoperative delirium (POD) largely varies among studies, ranging
from 1% to 50% [1–10]. Plausible explanations of this variation refer to the adopted
denition, the mode of its detection and the clinical prole of patient populations [1–10].
Several denitions of POD have been proposed along with different diagnostic tools
[10]. POD is generally dened as an acute deterioration of brain function characterised

Giovanni Mariscalco et al.
1360
by uctuating mental status with inattention and disturbances in consciousness and
presents clinically different subtypes, with or without accompanying agitation [11,
12]. Hyperactive delirium is characterised by active symptoms such as agitation and
restlessness, characterised by excessive motor or verbal behaviour that interfere with
patient care, patient or staff safety, and medical therapy [6, 11]. Conversely, hypoac-
tive delirium is characterised by unresponsiveness and motionlessness [11]. However,
POD is often confounded with postoperative cognition dysfunction [9, 13]. Patients
affected by POD immediately report an impaired recent memory but an intact remote
memory, while in patients affected by postoperative cognitive dysfunction it is not
associated with a change in consciousness that requires sensitive test methods to be
diagnosed [13]. Although there are several tools to diagnose and classify delirium,
the most widely used tools in intensive care units (ICU) are the confusion assessment
method-ICU (CAM-ICU) and the intensive care delirium screening checklist (ICDSC)
[14, 15] (Table 1).
Pathogenesis of postoperative delirium
The pathogenesis of POD is complex and multifactorial, involving an interaction of
multiple predisposing and precipitating factors [1–10] (Table 2). Among predisposing
factors, older age, history of stroke and peripheral vascular disease are the most impor-
tant ones, being mainly related to increased cerebral atherosclerosis, with a consequent
inhibition of the cerebral blood ow, exacerbation of inhibition of ow, and increased
cerebral embolisation risk [2, 4, 9, 16–18]. In addition, older age is associated with
lack of cholinergic reserve, predisposing patient to delirium [2, 4–6, 19–21]. Earlier
meta-analyses [10] showed that every one year increase of age was associated with
an increase in the chance of POD by 8%. Several POD precipitating factors has also
been reported, including duration of surgery, type of surgery, prolonged intubation,
and red blood cell transfusion (RBC) [1–10].
Afonso et al. [22] evaluated 112 adult postoperative cardiac surgical patients, ob-
serving a 30% increase in delirium per 30 minutes of CPB (cardiopulmonary bypass).
On the other hand, Kazmierski et al. [4] reported a vefold increase of delirium when
intubation was prolonged over 24 hours in a population of 846 consecutive cardiac
surgery subjects. The same group observed a fourfold increase risk of POD in patients
receiving more than 4 RBC units [4].
Table 1. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)a
Delirium is diagnosed when both features: 1 and 2 are positive, along with either feature 3 or 4.
Feature 1. Acute onset of mental status changes or uctuating course
• Is there evidence of an acute change in mental status from the baseline?
• Did the (abnormal) behaviour uctuate during the past 24 hrs, that is, tend to come and go or
increase and decrease in severity?
a Adapted from Ely EW et.al. Evaluation of delirium in critically ill patients: Validation of the Confusion
Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 2001; 29:1370-1379.

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Effects of statins on delirium following cardiac surgery – evidence from literature
Sources of information: Serial Glasgow Coma Scale or sedation score ratings over 24 hrs as well as
readily available input from the patient’s bedside critical care nurse or family.
Feature 2. Inattention
• Did the patient have difculty focusing attention?
• Is there a reduced ability to maintain and shift attention?
Sources of information: Attention screening examinations by using either picture recognition or
Vigilance random letter test. Neither of these tests requires verbal response, and thus they are ideally
suited for mechanically ventilated patients.
Feature 3. Disorganised Thinking
• Was the patient’s thinking disorganised or incoherent, such as rambling or irrelevant conversation,
unclear or illogical ow of ideas, or unpredictable switching from subject to subject?
• Was the patient able to follow questions and commands throughout the assessment?
1. “Are you having any unclear thinking?”;
2. “Hold up this many ngers.” (examiner holds two ngers in front of the patient);
3. “Now, do the same thing with the other hand.” (not repeating the number of ngers).
Feature 4. Altered Level of Consciousness
• Any level of consciousness other than “alert”;
• Alert – normal, spontaneously fully aware of environment and interacts appropriately;
• Vigilant – hyperalert;
• Lethargic – drowsy but easily aroused, unaware of some elements in the environment, or not
spontaneously interacting appropriately with the interviewer; becomes fully aware and appropriately
interactive when prodded minimally;
• Stupor – difcult to arouse, unaware of some or all elements in the environment, or not spontaneously
interacting with the interviewer; becomes incompletely aware and inappropriately interactive when
prodded strongly;
• Coma – unarousable, unaware of all elements in the environment, with no spontaneous interaction
or awareness of the interviewer, so that the interview is difcult or impossible even with maximal
prodding.
Table 2. Predisposing and precipitating factors of delirium following cardiac surgery
Predisposing factors Precipitating factors
Age Urgent surgery
Acute myocardial infarction Intraoperative intra-aortic balloon pump (IABP)
Left ventricular ejection function CPB duration
Preoperative atrial brillation Aortic cross clamp time duration
Hypertension Hypoperfusion
Diabetes Anaemia
Renal function Hypoxia
Peripheral vascular disease Low cardiac output
Cognitive impairment Valve surgery
Dementia Red blood cells transfusion
Depression Respiratory failure
table continued on the next page

Giovanni Mariscalco et al.
1362
MOTOR ACTIVITY
THOUGHT AND
PERCEPTION
ATTENTION
LEVEL OF AROUSAL
SLEEP
LEARNING AND MEMORY
INLAMMATION
STRESS
↕↓
TRAUMA
DELIRIUM
CARDIAC SURGERY
↕↑
Figure 1. Simplied pathways of delirium following cardiac surgery
(adapted from Hall et al. [23])
Prior delirium Postoperative atrial brillation
Functional impairment Postoperative acute kidney injury
Previous stroke Infection/sepsis
Table 3. Published studies with reference to the effect of statins
on delirium after cardiac surgery
First Author
Mariscalco [1] Katznelson [2]
Year of Study 2004–2011 2005–2006
Type of study Retrospective (PM) Retrospective
Number of Patients 4,079 1,059
Age (years) 67.8 ± 7.2 64%a
Female (%) 21% 29%
Elective (%) 92% n.a.
Statins (%) 39% 64%
Type of surgery
Isolated CABG (%) 75% 83%
CABG + Valve (%) 25% 17%
Hospital mortality (%) 2% n.a.
POD incidence (%) 3% 11.5%
table continued on the next page

1363
Effects of statins on delirium following cardiac surgery – evidence from literature
POD assessment CAM-ICU CAM-ICU
POD predictors CABG + Valve RBC (> 5Units)
Postop AKI Intraop IABP
LVEF Preop depression
Postop AF Preop Creat > 150 µm
Hypertension Age ≥ 60 years
Age CABG + Valve
COPD Preop Statins
History of CVA
Statins effect on POD None Protective
(OR 1.49, 95%CI, 0.97–2.29) (OR0.54, 95%CI 0.35–0.84)
AF – atrial brillation; AKI – acute kidney injury; CABG – coronary artery bypass grafting; CAM –
confusion assessment method; COPD – chronic obstructive pulmonary disease; CVA – cerebrovascular
accident; IABP – intra-aortic balloon pump; ICU – intensive care unit; LVEF – left ventricular
ejection fraction; PM – propensity matching score; POD – postoperative delirium; RBC – red blood
cell; n.a. – not available
a percentage of patients ≥ 60 years
Inammation and delirium
Although there are several hypotheses of the pathophysiology of POD, the most
recent one involves neuroinammation [23, 24]. This is caused by the hyper-respon-
siveness of brain immune cells to stimulation from peripheral inammation, making
the brain susceptible to the consequences of systemic inammation [23, 24]. In a sys-
tematic review, Hall et al. [23] investigated the correlation between cerebrospinal uid
biomarkers and delirium, including 235 patients from 8 prospective studies. Delirium
was associated with elevated levels of pro-inammatory markers such as inteleukin-8
(IL-8), and neuronspecic enolase. Kazmierski et al. [25] conducted a prospective
study enrolling 113 patients undergoing CABG surgery with CPB, investigating
whether increased levels of IL-2 and TNF-α were associated with POD. An increased
concentration of pro-inammatory cytokines was independently associated with POD,
and related to advancing age along with duration of CPB [25]. Peripheral cytokines
can act directly through neurodegeneration, or indirectly through neurotransmission
[26, 27]. Interleukins in human and animal models have been demonstrated to induce
symptoms of delirium, also mediating exotoxic neurodegeneration [28–30]. Cytokine
dysregulation possibly causes neuronal injury through altered neurotransmission, apop-
tosis, and activation of brain immune cells which leads to production of free radicals,
complement factors, and nitric oxide [25]. Cytokine dysregulation has been observed to
be related with aging as well as infection, trauma and (surgical) stress [26]. Therefore,
the CPB-induced systemic inammatory response should be considered as one of the

Giovanni Mariscalco et al.
1364
most relevant determinants of POD, leading to and exacerbating the afore-mentioned
neuroinammation [25]. Cardiac surgery with CPB is associated with a profound
systemic inammatory response due to surgical trauma, and the interaction between
blood and articial circuit surfaces, leading to blood barrier dysfunction, cerebral in-
ammation, and glial cell injury [31, 32]. The CPB-related inammation may cause
neuronal damage through microglia activation, oedema, microvascular thrombosis and
alterations in local blood ow [33–35]. However, other mechanisms of delirium fol-
lowing cardiac surgery should be mentioned such as direct brain insults due to hypoxia,
ischemia, and metabolic derangement [23, 24], which are not mutually exclusive with
neuroinammation [23, 24].
Impact of delirium on outcomes
POD is associated with increased morbidity and mortality, prolonging the ICU
and hospital stay, at considerable expense of resources [1–8, 36]. In a cohort of 4,659
patients undergoing CABG, our group demonstrated that POD was associated with
a ten-fold increased risk of hospital mortality, and with three-day increase in hospital
stay [1]. POD is also accompanied by increased late mortality, as well as poorer cog-
nitive and functional outcomes [19]. Koster et al. [19] by prospectively enrolling 112
patients undergoing cardiac surgery observed that POD patients had a higher rate of
follow-up mortality (13% in patients with delirium versus 5% in patients without it),
readmissions to the hospital (48% vs. 33%), dysfunction in memory (32% vs. 23%),
concentration problems (37% vs. 20%), and sleep disturbance (47% vs. 24%). More
importantly, POD severely contributes to the development of post-discharge cognitive
decline [37].
Effects of statins on delirium
Due to the relevant prognostic impact of POD, its prevention is of utmost im-
portance. Experimental and clinical studies have proved that statins (3-hydroxy-
3-methylglutaryl coenzyme A reductase inhibitors) have the potential to improve
perioperative central neuronal protection [38–40]. Statins have important pleiotropic
effects, including anti-inammatory, immunomodulatory, and antithrombotic proper-
ties [38–40]. Wang et al. [41] demonstrated that statin treatment markedly reduced
functional neurological decits after traumatic brain injury in mice. In addition, histo-
logical reduction in degenerating hippocampal neurons and suppression of inamma-
tory cytokine mRNA expression in brain parenchyma was observed; Statin treatment
also improved cerebral hemodynamics following the head injury [41]. Similarly, in
a mouse model of cerebral ischemia, acute termination of statin administration resulted
in a rapid loss of cerebral protection [42]. Statins prevent inammation by interfering
with multiple steps of leukocyte recruitment and migration into the central nervous
system, including decreasing circulating monocyte expression of cytokines and inhib-
iting chemokine production in endothelial cells [43, 44]. Statins may also upregulate
eNOS, leading to decreased leukocyte adhesion [45].

1365
Effects of statins on delirium following cardiac surgery – evidence from literature
Statins and delirium following cardiac surgery
Based on these substantiations, it has been suggested that the administration of
statins may represent a viable therapeutic and preventing strategy against POD. Aboy-
ans et al. [46] recognised the protective effects exerted by statins on stroke as rst in
a prospective cohort of 810 patients undergoing CABG. Moreover, intensive cholesterol
lowering with statins after CABG has been shown to decrease the long-term incidence
of stroke [47]. However, data on the protective statin effects on stroke following cardiac
surgery have not been subsequently conrmed [16, 48]. Conversely, statin administra-
tion in the critically ill patients has been shown to confer protection against delirium
[49, 50]. Page et al. [49] conducted a prospective study on 470 consecutive critical
care patients with 2,927 person/days follow-up. Statin administration in the previous
evening was associated with a reduction in incidence of delirium (odds ratio (OR),
2.28; 95% condence intervals (CIs), 1.01–5.13) [49]. Morandi et al. [50] performed
a multicentre, prospective cohort study enrolling 763 patients with acute respiratory
failure and shock, demonstrating that ICU statin users had a reduced incidence of
delirium, especially in early stages of sepsis, while discontinuation of statins was
associated with increased delirium. However, results of the statin effect on delirium
occurrence after cardiac surgery are markedly controversial [1, 2, 16, 51] (Table 3).
Only the observational study of Katznelson et al. [2], demonstrated that preoperative
administration of statins was associated with a reduce risk of POD by analysing 1,059
patients undergoing cardiac surgery with CPB. In addition, the protective POD effect
exerted by statins was more evident in patients with age ≥ 60 years [2]. Mathew et al.
[51], retrospectively enrolling 440 patients undergoing CABG, investigated the effect
of preoperative statin administration on cognitive dysfunction following CPB. They
documented that cytokines (IL-1 and TNF-α) and C-reactive protein did not differ in
patients affected by cognitive dysfunction independently of preoperative statin therapy
[51]. Our data were also in consonance with those presented by Mathew et al. [1, 51].
In the largest study to date, we retrospectively examined 4,569 CABG patients, founding
no association between POD and preoperative statin administration [1]. Interestingly,
although cardiac surgery population accounted for 9.7% of the entire study popula-
tion (9,272 out of 264,657 patients), Redelmeier et al. [16] retrospectively observed
that the rate of POD was higher among patients taking statins than among those not
taking them (OR: 1.28; 95% CI 1.12–1.46). Different plausible explanations for this
controversial statin effect on POD have been advocated, especially with reference to
the different and complex events that occur during cardiac surgery with CPB [1, 4, 6,
9, 48, 51]. Embolic events, postoperative cardiac output along with hypoperfusion and
hypoxia phenomena, and prolonged ICU stay can overcome the protective statin effects
on POD [1, 4, 6, 9, 48, 51]. In addition, the relevant pro-inammatory effects of CPB,
especially in complex and prolonged surgeries, may overwhelm the anti-inammatory
properties of statins [1, 51]. The sudden withdrawal of statins, especially in the rst
hours after surgery, may also reduce the protective statin effect [42]. Moreover, patient
selection, statin type, and administered doses could explain the different effect of
statins on POD, underlying the complex multifactorial pathophysiology of delirium

Giovanni Mariscalco et al.
1366
after cardiac surgery [1, 2, 16, 51]. Finally, possible effects of omega-3 polyunsaturated
fatty acids on delirium after cardiac surgery have not been investigated yet.
Conclusions
Delirium is a common complication after cardiac surgery, correlating with an in-
creased morbidity and mortality, at considerable expenses of resources [1–10, 48, 51].
Although several efforts have attempted to determine its exact pathogenesis, POD is
the consequence of interplay of different pathophysiologic mechanisms [9–11]. Among
these, neuroinammation is one of the most emerging causative hypotheses related to
POD occurrence [23, 24]. Experimental and clinical studies have documented neuro-
logical protective effect of statin administration because of their anti-inammatory,
immunomodulatory, and anti-thrombotic properties [38–40]. Although, statin admin-
istration has been associated with a reduction of POD in critically ill patients [49, 50],
conict results have been observed after cardiac surgery [1, 2, 16, 51]. The multifactorial
and complex pathogenesis of POD may explain this discrepancy [51–58]. Therefore,
no denitive conclusions on the protective effects of statins on POD can be determined
in the cardiac surgery setting. Randomised trials are required to clarify the effect of
preoperative statin administration and delirium following cardiac surgery.
Acknowledgements. The authors thank the Fondazione Cesare Bartorelli (Milan, Italy) for
support.
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Address: Giovanni Mariscalco
Department of Cardiovascular Sciences
University of Leicester
Clinical Sciences Wing
Gleneld Hospital
Leicester, LE3 9QP United Kingdom