Elevated Procalcitonin and Depression As Risk Factors For Postoperative Delirium In The Elderly After Cardiac Surgery – A Prospective Observational Study.

One of the most common complications after cardiac surgery is delirium. Determining the origin of this complication from possible pathomechanisms is dicult. The activation of an inammatory response during surgery has been suggested as one possible mechanism of delirium. The usefulness of the inammatory marker procalcitonin (PCT) as a predictor of delirium after cardiac surgery with cardiopulmonary bypass (CBP) has not yet been investigated. The purpose of this study was to prospectively investigate the risk of developing postoperative delirium in a group of elderly patients using a multivariate assessment of preoperative (PCT, comorbidities, functional decline, depression) and intraoperative risk factors. 149 elderly patients were included. Delirium was assessed using the Confusion Assessment Method for the ICU. Thirty patients (20%) developed post-operative delirium: hypoactive in 50%, hyperactive in 33%, mixed in 17%. Preoperative PCT above the reference range (> 0.05 ng/mL) was recorded more often in who postoperatively developed delirium than in the non-delirium group (50% vs. 27%, p=0.019). After surgery, PCT was signicantly higher in the delirium than the non-delirium group: ICU admission after surgery: 0.08 ng/mL, IQR 0.03-0.15 vs. 0.05 ng/mL, IQR 0.02-0.09, p=0.011), and for consecutive days (day 1: 0.59 ng/mL, IQR 0.25-1.55 vs. 0.25 ng/mL, IQR 0.14-0.54, p=0.003; day 2: 1.21 ng/mL, IQR 0.24-3.29 vs. 0.36 ng/mL, IQR 0.16-0.76, p=0.006; day 3: 0.76 ng/mL, IQR 0.48-2.34 vs. 0.34 ng/mL, IQR 0.14-0.66, p=0.001). Patients was performed the day before the operation by a trained anesthesiologist and included the following evaluation of the patient’s ability to care for him- or herself with I.) an Activities of Daily Living scale (ADL); II.) an Instrumental Activities of Daily Living scale (IADL); an evaluation of the occurrence of cognitive decline using the III.) Mini-Mental State Examination score (MMSE); and an assessment of the occurrence of depression with an IV.) Geriatric Depression Scale (GDS-15). of four features of delirium: changes in mental status, inattention, an altered level of consciousness, and disorganized thinking. delirium multifactorial. to multivariate logistic regression the best


Abstract Background
One of the most common complications after cardiac surgery is delirium. Determining the origin of this complication from possible pathomechanisms is di cult. The activation of an in ammatory response during surgery has been suggested as one possible mechanism of delirium. The usefulness of the in ammatory marker procalcitonin (PCT) as a predictor of delirium after cardiac surgery with cardiopulmonary bypass (CBP) has not yet been investigated.

Methods
The purpose of this study was to prospectively investigate the risk of developing postoperative delirium in a group of elderly patients using a multivariate assessment of preoperative (PCT, comorbidities, functional decline, depression) and intraoperative risk factors. 149 elderly patients were included. Delirium was assessed using the Confusion Assessment Method for the ICU.

Conclusion
A preoperative PCT test and assessment of functional decline and depression may help identify patients at risk for developing delirium after cardiac surgery.

Background
In recent decades we have seen a signi cant ageing of the population in developed countries. Over 70% of people above the age of 60 are burdened with cardiovascular disease [1]. Consequently, the number of elderly and very elderly patients undergoing cardiac surgery is increasing [2]. As the elderly are more burdened with comorbidities, this group is at high risk of perioperative complications, including death [3]. Therefore, perioperative care for elderly patients subjected to cardiac surgery becomes a big challenge for everyone -the surgeon, anaesthesiologist, and intensivist -as is taking care of the patient after surgery. One of the most common complications after on-pump cardiac surgery, with reported incidence rates ranging up to 50%, is postoperative delirium, de ned as uctuating attention and awareness disturbances. Perioperative factors and the type of cardiac surgery are associated with postoperative delirium. In our previously published study, it was shown that cardiopulmonary hyperoxia episodes might be a risk factor associated with the occurrence of postoperative delirium [4]. Three subtypes of delirium have been differentiated: hypoactive, hyperactive, and mixed [5]. All of them have been associated with prolonged hospitalization, increased death rate [6], increased risk of ICU and hospital readmission [7], and possible long-term consequences such as lower quality of life or cognitive decline after the operation [8].
It is di cult to determine the origin of this complication as the pathomechanisms are little understood, and there are many potential systemic homeostasis disorders which can lead to delirium. Several hypotheses have been described, including neuroin ammation, oxidative stress, neuroendocrine dysregulation, circadian dysregulation, and a neuronal ageing hypothesis [9]. Our knowledge of perioperative delirium risk factors in heart surgery is continuously growing, but there is still much that is unknown. The activation of an in ammatory response after surgery has been suggested as one of the possible mechanisms of delirium [9]. The use of cardiopulmonary bypass leads to the activation of a systemic in ammatory response and is associated with increased production of various in ammatory mediators during and after surgery [10] [11]. An in ammatory marker, procalcitonin (PCT), may be considered a good predictor of postoperative complications early after cardiac surgery with cardiopulmonary bypass. High levels of PCT have been associated with postoperative complications such as infection [12], organ dysfunction [13], and increased mortality [14] [15]. The usefulness of procalcitonin as a predictor of postoperative delirium caused by surgery and cardiopulmonary bypass (CBP) has not yet been investigated. Therefore, we have prospectively studied the risk of developing postoperative delirium in a group of elderly patients undergoing cardiac surgery with CPB, using a multivariate assessment of perioperative risk factors.

Methods
The study was approved by the local Bioethics Committee (permission number 219/2016), and informed consent was collected from all patients participating in the study. Inclusion criteria were: planned cardiac surgery with cardiopulmonary bypass (CBP), age 65 years old or more, and full participation of the patient in the preoperative evaluation. Exclusion criteria were: inability to get informed consent, urgent operation, off-pump surgery, diagnosis of dementia before surgery, a different protocol of anaesthesia (total venous anaesthesia), or deep hypothermia procedures.

Procalcitonin measurement
The PCT concentrations were routinely measured before surgery (baseline) and on day 0 (ICU admission after surgery), 1, 2, and 3 after surgery. All measurements were performed in the hospital laboratory (normal serum values are below 0.05 ng/mL) by using a chemiluminescent microparticle immunoassay (ARCHITECT B·R·A·H·M·S PCT, Abbott). The limit of quanti cation of the test was 0.01 ng/mL, and the analytical sensitivity was 0.00 ng/mL.

Preoperative assessment
A preoperative assessment was performed the day before the operation by a trained anesthesiologist and included the following evaluation of the patient's ability to care for him-or herself with I.) an Activities of Daily Living scale (ADL); II.) an Instrumental Activities of Daily Living scale (IADL); an evaluation of the occurrence of cognitive decline using the III.) Mini-Mental State Examination score (MMSE); and an assessment of the occurrence of depression with an IV.) Geriatric Depression Scale (GDS-15). I) ADL and II) IADL are both parts of a comprehensive geriatric assessment [16] and are used to assess functional decline. The ADL questionnaire consists of 6 questions assessing basic functional activities as: 1.) using the toilet, 2.) controlling urination and defecation, 3.) bathing, 4.) eating, 5.) getting out of bed, and 6.) dressing oneself [17]. The ADL scale ranges from 0 to 6 pts., with 0 being the worst and 6 pts. being the best. A score of 6 indicates the full function and a score below 6 pts. indicates compromised daily functioning. The IADL consists of 8 questions about everyday activities as the ability: 1.) to use a phone, 2.) to do shopping, 3.) to do housekeeping, 4.) to handle nances, 5.) to use a mode of transportation, 6.) to be responsible for one's own medication, 7.) to prepare meals, and 8.) to do laundry or craftwork [18]. The IADL score ranges from 8 to 24 points (1-3 pts. for each question), with 8 pts. being the worst and 24 pts. being the best. A score below 24 indicates compromised activities related to independent living, As older populations are at risk of cognitive impairment, cognitive decline was measured with III) the Mini-Mental State Examination (MMSE), one of the most common scores used for screening. It can also be easily used by physicians who aren't psychiatrists. The MMSE assesses seven different cognitive domains: 1) orientation to time (range 0-5), 2) orientation to place (range 0-5), 3) word registration (range 0-3), 4) delayed recall (range 0-3), 5) working memory (range 0-5), 6) language (range 0-8), and 7) visuospatial (range 0-1). The total MMSE score ranges from 0 to 30 points. A score of 27-30 indicates no cognitive impairment, 24 to 26 indicates cognitive impairment without dementia, 19 to 23 shows mild dementia, 11 to 18 moderate dementia, and less than 10 indicates severe dementia [19].
Besides, we assessed the occurrence of depression with IV) a 15-point Geriatric Depression Scale GDS-15 with 0 pts. being the best and 15 pts. being the worst. A score ≥ 5 indicates depression with a sensitivity of 80% and speci city of 75% [20]. The GDS-15 score results were divided into two categories: no depression with GDS-15 < 5 and depression present with GDS-15 ≥ 5. In addition, information on comorbidities was recorded. The European System for Cardiac Operative Risk Evaluation (Euroscore II) was used to predict the risk of death after heart surgery, as calculated by the available online Euroscore II calculator (euroscore.org). According to WHO criteria, preoperative anaemia was de ned, setting the haemoglobin cut off below 12 g/dL for females and 13 g/dL for males [21].

Anaesthesia and surgery
The induction of anaesthesia was conducted with sufentanil, propofol and rocuronium. Sufentanil and rocuronium infusion with inhaled sevo urane was applied to maintain the anaesthesia. After administering heparin and achieving an activated clotting time longer than 480 seconds, CBP was initiated. A hollow ber membrane oxygenator (Medtronic A nity, Medtronic, Inc. Minneapolis USA) with an integrated polyester arterial line lter of 40 mm pore size and a roller pump with a non-pulsatile ow 2.4-2.5 l/min/m 2 (Stockert S3, Sorin Group, Germany) was used in all patients. All patients were normothermic (37º C). After the operation, patients were transferred to the ICU. Sedation with propofol was continued, and patients were extubated if they were hemodynamically stable, with su cient oxygenation and without excessive bleeding. Postoperative pain was treated with Paracetamol 1 g every 6 hours and Oxycodone 3-4 mg every 4 hours. Procedure parameters and postoperative complications were noted, including the type of operation, aorta cross-clamping, CBP and operation time, and ICU stay and hospitalization lengths. Acute kidney injury was diagnosed according to KDIGO criteria [22].

Delirium assessment
Patients were evaluated for delirium every 12 hours, starting the morning after the operation for three subsequent days. We chose the Confusion Assessment Method for Intensive Care Unit (CAM ICU) to assess delirium. Its reported sensitivity is 83%, and speci city reaches up to 100% [23]. The CAM ICU is easy to perform and can be used by non-psychiatrists, physicians, or nurses. In our study, the CAM ICU assessment was performed by anaesthesiologists trained for that purpose. The scale includes the evaluation of four features of delirium: uctuating changes in mental status, inattention, an altered level of consciousness, and disorganized thinking.
The examination of consciousness was conducted with the Richmond Agitation-Sedation Scale (RASS). RASS is a 10-level score between − 5 and + 4 points, where − 5 pts. indicates unarousable, 0 pts. indicates alert and calm, and + 4 is combative. The CAM ICU can be used when the RASS ≥ -3. We used the RASS scale to identify subtypes of delirium. Hypoactive delirium was diagnosed in cases with − 3 ≤ RASS ≤ 0 pts., and hyperactive delirium was diagnosed in patients with RASS > 0 pts. A mixed type of POD was diagnosed in the case of a hyper-and hypoactive type switching from one to another during the day.

Statistical analysis
All analysis was performed with Statistica 13 software (StatSoft, Inc. Tulsa, USA). Continuous variables were expressed as median (interquartile range between the 25th and 75th percentiles); categorical data were expressed as numbers and percentages. The distribution was not normal based on the Shapiro-Wilk test. Therefore, statistical analysis was performed using nonparametric tests. The Mann-Whitney U test was used for comparison of the continuous variables between study groups. Categorical variables were analyzed using the chi-square test; contingency tables were used to summarize the relationship between several categorical variables. Multivariate logistic regression analysis was performed to create a model predicting the development of postoperative delirium; the results were reported as an odds ratio (OD) with 95% con dence intervals (CI). All the tests were conducted with a 5% signi cance level.

Results
Study sample 534 consecutive patients who underwent cardiac surgery between January 2017 and December 2018 were screened for inclusion/exclusion criteria. Of this number, 271 patients met the inclusion criteria and were invited to the study. Finally, informed consent was obtained from 151 patients, but two patients withdrew their consent after the operation; 149 patients were included in the nal analysis. The ow diagram of the study is presented in Fig. 1.
Thirty patients developed postoperative delirium (20%), and 119 patients (80%) did not. Hypoactive delirium was the most prevalent and was diagnosed in 50% (15/30) of patients. Hyperactive delirium was diagnosed in 33% (10/30) of patients, and 17% (5/30) of patients developed a mixed type of delirium (Fig. 2). Of all delirium cases, 23 patients experienced delirium lasting less than 12 hours, four patients between 12 and 24 hours, and three patients experienced longer delirium. The majority of delirium (19 incidences) occurred on the rst day postoperatively. Nine incidences were recorded on the second day, and ve on the third day ( Fig. 2).
Risk factors for delirium Procalcitonin Preoperative (baseline) PCT levels above the reference range (> 0.05 ng/mL) were found in 50% of patients who postoperatively developed delirium and in only 27% in the non-delirium group (p = 0.019). The median preoperative value was 0.05 ng/mL (IQR 0.01-0.08) in the delirium group and 0.03 ng/mL (IQR 0.01-0.06) in the non-delirium group (p = 0.207). The preoperative PCT value was a strong predictor of postoperative delirium development with an odds ratio of 3.05, as con rmed by the multivariate logistic regression model described in the section below.
After surgery, PCT levels were signi cantly higher in the delirium group than in patients without delirium on admission to the ICU 14-0.66, p = 0.001, respectively, in the delirium and non-delirium group), with a peak value on the second day after surgery (Fig. 3).

Age
The median age in the group of patients with postoperative delirium was higher than in the non-delirium group (74 years, IQR 70-76 vs 69 years, IQR 67-74; p = 0.038) ( Table 1).

Comorbidities
The distribution of comorbidities such as cerebrovascular disease, hypertension, atrial brillation, diabetes, or renal insu ciency was comparable in the study groups, and anaemia was more than two times more common in the group of patients who experienced postoperative delirium compared to the group without delirium (43% vs 19%, p = 0.006) ( Table 1).

Euroscore II
As estimated by the pre-surgery Euroscore II risk model, the risk of death after cardiac surgery was higher in patients who eventually developed delirium postoperatively than in the non-delirious group (2.5% vs 1.8%, p = 0.009). The observed mortality was 3.3% in the group with delirium and 0.8% in the non-delirium group (p = 0.32).  An analysis comparing the preoperative geriatric characteristics of subjects who developed delirium and those who did not is presented in Table 2. Table 2 Preoperative geriatric assessment: an analysis comparing the assessment of subjects who developed delirium and those who did not.

Surgery and postoperative indices
In the group with postoperative delirium, a complex procedure was used more often (40% vs. 14%, p = 0.009). As expected, cardiopulmonary bypass and aortic cross-clamp time were signi cantly longer in patients who eventually developed delirium than in the group without delirium, but anaesthesia time was similar in both study groups ( Table 3). The postoperative analysis showed that in the group of patients with delirium, respiratory support was signi cantly longer than in the group without delirium (290 vs. 200 minutes, p = 0.002), acute kidney injury was diagnosed three times more often (20% vs. 7%, p = 0.03), the hospital stay was longer (11 vs. 9 days, p = 0.002), and mortality was higher (3.3% vs. 0.8%, p = 0.323) ( Table 3). Table 3.
Perioperative characteristics: an analysis comparing the characteristics of subjects who developed delirium and those who did not.  Table 4. Table 4 Univariate and multivariate logistic regression analysis of the predictors of delirium.

Discussion
The key nding of this study is that elevated preoperative procalcitonin, along with other preoperative factors such as age, depression, and compromised daily functioning, accompanied by prolonged CBP time, are the most critical factors in the development of postoperative delirium after cardiac surgery. To our knowledge, this is the rst study showing the usefulness of procalcitonin as a predictor of the development of postoperative delirium in patients undergoing cardiac surgery.
In the present study, it was observed that patients who experienced postoperative delirium had higher procalcitonin levels both before surgery and on the following days, compared to patients without delirium. PCT is a peptide precursor of calcitonin and a biomarker of in ammation. In ICU patients, PCT has been used to identify bacterial infections and monitor antibiotic therapy as part of standard care for septic patients. Procalcitonin levels may arise in the course of the in ammatory reaction in response to surgical trauma without infection, and a transient increase in the PCT level has been observed even during uncomplicated heart surgery [24]. In cardiac surgery, the systemic in ammatory response can be activated by many factors such as surgical trauma, CBP circuit, endotoxemia, and ischemia-reperfusion injury. Various in ammatory mediators, including PCT, are released and lead to systemic effects such as vasodilatation and disturbances in the microcirculation [10]. Long CBP is a powerful inductor of a systemic in ammatory reaction, and brain function may also be affected. Consistent with the neuroin ammatory hypothesis of postoperative delirium, in ammatory mediators released when the systemic in ammatory response has been activated cross the blood-brain barrier, activating microglial cells to produce in ammatory mediators. Consequently, damage to brain tissue, dysfunction of neuron activity, disturbances in the neurotransmitter system, impaired synaptic conduction, and leaking of intercellular connections of blood-brain barrier cells were detected [9] [25].
Here, we assessed PCT because daily PCT measurements are readily available as part of routine in-hospital monitoring, and the predictive value of PCT for diagnosing complications after cardiac surgery had been previously con rmed. Clementi et al. presented results that the PCT measurement performed 48 hours after the cardiac operation was a good predictor of postoperative renal and respiratory complications [14]. In another study, Klingele et al. showed that a single PCT measurement taken the day after surgery was a predictor of delayed complications such as prolonged hospitalization, ICU readmission, and hospital death [26].
The importance of procalcitonin as a predictor of delirium has not yet been established. Earlier, McGrane et al. demonstrated that in a population of non-cardiac ICU patients, high PCT values recorded on ICU admission predicted prolonged periods of acute brain dysfunction, linking in ammation as an essential mechanism in the pathophysiology of delirium [27]. In a later prospective study by Nemeth et al., the relationship between changes in the procalcitonin concentration measured on the rst day after surgery and the occurrence of postoperative cognitive dysfunction was assessed in a population of elderly patients undergoing on-pump cardiac surgery, and no relationship was found between in ammatory response and cognitive dysfunction [28]. In this study, according to the multivariate logistic regression analysis, a PCT concentration above normal before surgery signi cantly increased the risk of postoperative delirium with an odds ratio of 3.05 (p = 0.048) in a population of patients undergoing cardiac surgery. After the operation, the median level of PCT was elevated with a peak value on the second day. This observation was expected and could be explained by the activation of a systemic in ammatory response during surgery. However, it should be emphasized that in patients with postoperative delirium, PCT was signi cantly higher than in patients without delirium during the entire follow-up.
These observations con rm the utility of PCT measurements in predicting delirium. A PCT test is readily available (hospital laboratory, point of care testing), fast, and relatively cheap; therefore, a measurement before and after operation may be an additional indicator useful for the early identi cation of patients at risk for postoperative delirium.
The causes of delirium are multifactorial. According to multivariate logistic regression analysis, the best model for predicting delirium development after cardiac surgery included the preoperative PCT concentration, IADL score, the presence of depression, age, and the duration of CPB. The elderly are particularly sensitive to the development of postoperative delirium; in addition, delirium duration is longer in elderly patients than in younger patients subjected to cardiac surgery. Previously, Cereghetti et al.
found that each year of life signi cantly increased postoperative delirium risk with an OR of 1.06 [29]. These results coincide with our research; according to the multivariate logistic regression analysis, the patient's age was a signi cant factor of the model that predicted postoperative delirium with an odds ratio of 1.13.
Depression is frequent in older people and seems to be another critical risk factor of postoperative delirium. We reported here that the presence of preoperative depression was associated with a 5-fold increased risk of postoperative delirium. A study by Eshmawe et al. con rmed that a higher preoperative depression score was associated with an increased risk of postoperative delirium [30]. In another study, Oldham et al. demonstrated a relationship between the occurrence of preoperative depression and the development and severity of delirium after CABG. The authors used three different scales to diagnose depression, and only one scale (Patient Health Questionnaire 9) was predictive of delirium, while the results of two other scores (GDS-15 and HDRS) were shown to have little or no association with postoperative delirium [31]. Different scales have been used to measure depression, and it remains unclear which measure of depression may be most predictive of outcome.
Advanced age is one of the most important risk factors for functional deterioration assessed by the IADL score. It was estimated that 40% of men and more than 50% of women were limited in at least one IADL activity [32]. A decline in physical activity such as doing housework, travel, and shopping were more age-dependent than cognitive activities such as using a telephone, managing nances, or taking one's medication [33]. In our research, patients who developed postoperative delirium had signi cantly compromised physical activities assessed with the IADL score. Moreover, in the multivariate logistic regression analysis, a lower IADL score estimated before surgery was a signi cant risk factor for postoperative delirium. These results con rm the importance of examining depression or the deterioration of physical and cognitive activity before an operation in an elderly patient. As part of a comprehensive geriatric assessment, tools such as the IADL and GDS-15 should be a routine part of managing an elderly population to help identify cases of increased risk of postoperative delirium.
Comorbidities are known risk factors for the development of postoperative delirium [34]. In our study, a majority of patients were diagnosed with arterial hypertension; diabetes and chronic renal insu ciency were common. Except for anaemia, there was no difference in the distribution of comorbidities between groups. Anaemia was diagnosed in 43% of patients in the group who developed postoperative delirium, and only 19% in the group without delirium. Previous studies have shown that preoperative anaemia was considered a risk factor for the outcome in non-cardiac surgery; it was associated with a more extended hospital stay, a higher risk of perioperative complications, and higher mortality [35]. In a recent study of 800 patients undergoing elective noncardiac surgery, anaemia was associated with postoperative delirium and longer hospitalization [36]. The impact of preoperative anaemia on postoperative delirium in the cardiosurgical population is not yet well understood, and the results published so far have often been contradictory. In a systematic review based on 34 studies, several studies identi ed anaemia as an important risk factor for delirium following on-pump cardiac surgery, while others did not nd an association [37]. In a recently published study by Smulter et al, the preoperative haemoglobin level was not associated with postoperative delirium [38]. In our study, preoperative anaemia was more than twice as common in the group with postoperative delirium than in patients without delirium (43 vs 19%, p = 0.006); however, in a multivariate logistic regression analysis, the presence of preoperative anaemia was not included in the prediction model. It seems that this issue requires further evaluation in larger populations.
In the present study, more patients who postoperatively developed delirium required a complex procedure. This resulted in a signi cant prolongation of CBP time. Along with long aortic cross-clamping, prolonged CBP time has been one of the most important factors of postoperative delirium [6]. This observation was also con rmed in our study in the multivariate logistic regression analysis. The duration of CPB was a signi cant factor in the model predicting postoperative delirium with an odds ratio of 1.04. This observation leads to the conclusion that qualifying elderly patients for long and complex procedures require careful consideration and balancing the risks and potential bene ts.
Our study has several limitations. First, we didn't assess the long term consequences of delirium, postoperative cognitive decline, or a reduced quality of life after the operation. Second, our model was based on patients in one centre. Multi-centred research on the assessment of procalcitonin and other in ammatory markers is worth considering.

Conclusions
Preoperative factors such as procalcitonin above a normal range, older age, a diagnosis of depression, impaired functional status, along with the intraoperative factor of a longer cardiopulmonary bypass time are associated with an increased risk of developing postoperative delirium. Thus, a preoperative PCT test and assessment with an IADL and GDS-15 score may help identify patients at risk of developing postoperative delirium after cardiac surgery.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The study was approved by the Bioethics Committee of Wroclaw Medical University (permission number 219/2016). Informed consent was collected from all patients participating in the study.

Consent For Publications
Not applicable

AVAILABILITY OF DATA AND MATERIALS
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.