Prevalence of postoperative delirium according to the intraoperative general anesthetic agents in patients undergoing cardiac surgery: A retrospective and propensity-score matched study

Background: Postoperative delirium (PD) is still an issue in post-cardiac surgery patients despite the constant efforts to reduce it. Although various risk factors for PD after cardiac surgery have been identied, there is limited clinical data regarding the effect of intraoperative anesthetic agents on the PD. Methods: The medical records of 534 patients, who had undergone heart valve surgery or coronary artery bypass graft surgery with cardiopulmonary bypass (CPB) between January 2012 and August 2017, were investigated. They were divided into two groups according to the main anesthetic agent: sevourane with dexmedetomidine (sevo-dex group, n = 340) and propofol (propofol group, n = 194). The incidence of PD was evaluated as the primary outcome. PD was dened as the positive Confusion Assessment Method for the Intensive Care Unit during the intensive care unit stay. Patient-, surgery-, and anesthesia-related factors and postoperative complications were investigated as secondary outcomes. To reduce the risk of confounder effects between the two groups, 194 patients were selected from the sevo-dex group after propensity-score matching. Results: After propensity-score matching, the incidence of PD was not signicantly different between the sevo-dex (6.2%) and propofol (10.8%) groups (P = 0.136). In comparison of the incidence of each type of PD, only hyperactive PD occurred signicantly less in the sevo-dex group than in the propofol group (P = 0.021). Older age, lower preoperative albumin levels, and emergency surgery were signicant risk factors for PD. Conclusions: The overall incidence of PD after cardiac surgery with CPB is not associated with the main anesthetic agents, sevourane and dexmedetomidine-based vs. propofol-based anesthesia. Only hyperactive PD occurred less frequently after in patients receiving sevourane and dexmedetomidine-based anesthesia.


Background
Delirium is associated with many adverse hospital outcomes, including increased mortality, nosocomial complications, poor one-year functional recovery, and even postoperative cognitive decline (Chaput and Bryson 2012;Saczynski et al., 2012). Postoperative delirium (PD) is still an issue in cardiac surgery patients despite the constant efforts to reduce it, such as various pharmacologic agents, reorientation, sleep protocols, early mobilization, nutrition, and so on (Evans et al., 2016).
Various risk factors for PD after cardiac surgery have been identi ed, such as advanced age, preexisting cognitive impairment, cerebrovascular disease, metabolic syndrome, and type and duration of surgery (Hollinger et  show an additional PD-sparing effect than propofol did. Accordingly, the aim of this retrospective study was to investigate and compare the incidence of PD after cardiac surgery according to the intraoperative main anesthetic agents. Patients were divided into groups of sevo urane with dexmedetomidine and propofol, and the incidence of PD was evaluated in patients who underwent cardiac surgery with cardiopulmonary bypass (CPB).

Study population and data collection
After obtaining approval from the Institutional Review Board at Seoul National University Bundang Hospital (B-1510/318-04), electronic medical records from January 2012 to July 2017 were reviewed retrospectively. The requirement for informed consent was waived.
Adult patients aged 20 years or over, who had undergone heart valve or CABG surgery with CPB were included in this retrospective study. Patients who had been preoperatively diagnosed with neuropsychological diseases, such as dementia or Parkinson's disease, were excluded. Patients with visual disturbances, hearing loss, or reoperation due to postoperative complications were excluded. Also, patients requiring postoperative sedation for any reason were excluded because PD might be unnoticed due to sedation.

Routine general anesthesia practice
On arrival in the operating room, standard monitoring (pulse oximetry, electrocardiogram, and noninvasive arterial pressure), bispectral index (BIS TM , Covidien Icn., USA), cerebral oximeter, and invasive arterial monitoring were established. Central vein catheterization was performed after induction of general anesthesia.
During the investigation period, different general anesthetic agents had been administered to patients in our institution. Based on these different main anesthetic agents, patients were divided into two groups: sevo-dex and propofol groups. In the sevo-dex group, anesthesia was induced with intravenous propofol, remifentanil (target effect-site concentration 4 ng/ml), and sevo urane. During the intraoperative period, anesthesia was maintained with sevo urane and dexmedetomidine. Dexmedetomidine (Precedex TM , Hospira Inc., Lake Forest, IL, USA) was diluted with 0.9% saline to make a concentration of 4 μg/ml and administered continuously at 0.5 μg/kg/h. In the propofol group, total intravenous anesthesia was performed as follows: 2% propofol (Fresofol®, Fresenius Kabi, Korea Ltd, Korea) and remifentanil (Ultiva®, GlaxoSmithKline, United Kingdom) diluted to 50 μg/mL were administered using a target-controlled infusion device (Orchestra®, Fresenius vial, France) until the effect-site concentration reached 4 μg/ml and 4 ng/ml, respectively. During surgery, propofol and remifentanil was maintained within 2.0-5.0 μg/ml and 0.5-3.0 ng/ml. Dexmedetomidine was not used in the propofol group.
Bispectral index was monitored to maintain suitable anesthetic depth (40-60) in all patients. Rocuronium was administered as a neuromuscular blocking agent in both groups.
Assessment of postoperative delirium PD was de ned as the positive Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) during the ICU stay. According to the standard ICU practice of our institution, CAM-ICU was examined and recorded twice a day by directed bedside nurses, who had been well trained. The type of PD was determined according to the Richmond Agitation and Sedation Scale (RASS) score. When the RASS level was positive or negative, PD was classi ed as hyperactive or hypoactive, respectively. When a patient presented with mixed positive and negative RASS scores, they were diagnosed with mixed-type PD.
After patients were transferred to the general ward, PD was assessed until postoperative day 5 by nurses based on the Nursing Delirium Screening Scale per nursing shift. While PD was identi ed with psychomotor retardation, it was categorized as hypoactive PD. The duration of delirium was de ned as the total number of days presenting PD in ICU and general ward.

Statistical analysis
Data are expressed as median (interquartile range) or number (proportion). All continuous data were assessed for normality using the Shapiro-Wilk test. Incidence was analyzed using the chi-square test or Fisher's exact test. The Mann-Whitney U test or Wilcoxon signed rank test was performed to compare the numerical data, as appropriate. A binary logistic regression model was used to evaluate the predisposing factors of PD. The dependent variable was the occurrence of PD and the independent variables were the main anesthetic drug, age, sex, BMI, surgery type, ASA class, anesthesia time, CPB time, estimated blood loss, intraoperative and postoperative RBC transfusion amount, and preoperative and postoperative hematocrit, electrolytes, creatinine levels, and albumin level.
Propensity-score matching was performed to reduce the risk of confounder effects between the sevo-dex and propofol groups (Austin 2011 All analyses were carried out using IBM ® SPSS ® Statistics, version 22.0 (IBM Corporation, NY, USA). P < 0.05 was considered to indicate statistical signi cance.

Results
A total of 1,283 patients were evaluated for eligibility, 534 of whom were nally analyzed. According to the main general anesthetic agent, 340 and 194 patients were assigned to the sevo-dex and propofol groups, respectively.
After propensity-score matching, 194 patients were selected from the sevo-dex group ( Figure 1).
The characteristics of patient, surgery, and anesthesia were comparable between the two groups, except for the estimated blood loss volume, intra-and postoperative RBC transfusion amount, and ICU stay period, which became comparable after propensity-score matching ( Table 1).
The overall incidence, onset, and duration of PD were not signi cantly different between the sevo-dex and propofol groups, even after propensity-score matching ( Table 2). In comparison of the incidence of each type of PD, only hyperactive PD occurred signi cantly less in the sevo-dex group than in the propofol group. Incidences of other postoperative complications (seizure and acute kidney injury) were comparable between the two groups ( Table 2).
Preoperative hematocrit, sodium, potassium, creatinine, and albumin levels were comparable between the two groups. However, in the propofol group, lower hematocrit and potassium, and higher albumin levels were observed postoperatively compared to the sevo-dex group. These different laboratory ndings became comparable after propensity-score matching ( Table 3).
The following parameters were con rmed as signi cant determinants for the occurrence of PD by the binary logistic regression analysis (

Discussion
This study showed that the overall incidence of PD in cardiac surgery with CPB was not affected by the intraoperative anesthetic agent (sevo urane with dexmedetomidine or propofol). However, hyperactive PD occurred less frequently when patients were anesthetized with sevo urane and dexmedetomidine compared to propofol.
Older age, emergency surgery, and preoperative lower albumin levels were factors contributing to PD occurrence in this study.
A recent meta-analysis reported that no signi cant difference was observed in the incidence of PD or postoperative cognitive impairment between the inhalation anesthetics and total intravenous anesthesia (TIVA) after CABG ( In the present study, dexmedetomidine was administered intraoperatively as an adjuvant to inhalation anesthesia, and consequently, no additional signi cant effect on PD reduction was observed. Interestingly, the present study also showed that hyperactive PD occurred signi cantly less in the sevo-dex group than in the propofol group when propensity-score matching was applied. In our previous study performed in the elderly patients who had undergone orthopedic surgery under regional anesthesia (Shin et al., 2017), the postoperative agitated behavior decreased more after intraoperative dexmedetomidine sedation compared to propofol sedation. Therefore, we should consider that dexmedetomidine might play a speci c role in reducing postoperative abnormal hyperactive behavior, such as agitation, confusion, and aggression. These behaviors are injurious to patients themselves and medical personnel; therefore, more studies are needed to determine if dexmedetomidine can be a potential preventive medication. factors were found in the present study, which included older age, emergency surgery, and preoperative lower albumin levels. In the present study, the included patients were the entire adult patients, not the elderly. Because increased age is the risk factor of PD in cardiac surgery, it is necessary to con rm whether different results can be drawn when only elderly patients are enrolled.
Before propensity-score matching, PD has occurred 12.1% in the sevo-dex group and 10.8% in the propofol group.
After propensity-score matching, the overall incidence of PD was 6% in the sevo-dex group and 10.8% in the propofol group. In the sevo-dex group, the incidence of PD decreased remarkably after propensity-score matching. First of all, mean age was decreased in the sevo-dex group by the propensity-score matching, which was proved one of the risk factor of PD occurrence. In addition, estimated blood loss, perioperative transfusion requirement, and ICU stay were corrected by the propensity-score matching. The severity of patients' condition might be corrected; therefore, the incidence of PD in the sevo-dex group seemed to be adjusted.
The present study had several limitations. First, due to the retrospective nature of this study, the anesthesia protocol was not randomized. For this reason, propensity score matching was necessary to reduce the effects of confounders in analyzing our data. Second, our sample size was lack to achieve statistical signi cance of the incidence of PD between the two groups. Based on a post hoc power analysis, this study has 6.3 % power with a type 1 error of 5% to detect our decreased incidence of postoperative delirium in the sevo-dex group. The power increased from 6.3% to 39.9% after propensity score matching. The small cohort in each group might not have been su cient for generalizability of results. To obtain statistical signi cance, more than 563 patients are required under 80% power and 0.05 type I error. Third, PD was evaluated by well-trained nurses using CAM-ICU and the Nursing Delirium Screening Scale. Because the pure hypoactive form of PD is usually more di cult to detect than the hyperactive form, the hypoactive form of PD might have been missed although the RASS score was assessed with CAM-ICU. Furthermore, although use of the CAM-ICU by nurses was previously validated (Ely et al., 2001), the consistency by which delirium was measured may not have been similar across all patients. Also, delirium is a waxing and waning condition, and delirious episodes could have been missed in some patients at the times delirium was measured. Finally, this study was performed using data from a single center; therefore, the generalizability may be compromised.
In conclusion, the overall incidence of PD after cardiac surgery with CPB is not associated with the main anesthetic agent, sevo urane and dexmedetomidine-based vs. propofol-based anesthesia. Only hyperactive PD occurred less frequently in patients receiving sevo urane and dexmedetomidine-based anesthesia. Further large randomized controlled trials are required to con rm the impact of the anesthetic on the postoperative delirium.

Declarations Financial disclosures
None.

Authors' contribution
Hyun-Jung Shin: concept/design, data collection, drafting article, approval of article. Soo Lyoen Choi: data collection, approval of article. Hyo-Seok Na: concept/design, critical revision of article, approval of article. All authors read and approved the nal manuscript.

Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available due to the regulation of Institutional Review Board, but are available from the corresponding author after getting permission from IRB for sharing the dataset on reasonable request.

Ethics approval and consent to participate
After obtaining approval from the Institutional Review Board at Seoul National University Bundang Hospital (B-1510/318-04), electronic medical records from January 2012 to July 2017 were reviewed. The requirement for informed consent was waived.

Consent for publication
Not applicable.

Competing interests
The authors declare that they have no competing interests Author details Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, 82, Gumi-ro 173beon-gil, Bundang, Seongnam 13620, South Korea.  Tables   Table 1 Characteristics   Data are expressed as the mean (SD) or number of the patients (proportion) PD, postoperative delirium. Sevo-Dex, sevo urane + dexmedetomidine.
*These data were calculated only in patients presenting PD of each group. Sevo-Dex, sevo urane + dexmedetomidine.