Perioperative Blood Transfusion and Delirium after Total Knee or Hip Arthroplasty: Retrospective Analysis

We investigated the type of blood component transfusion associated with increased postoperative delirium. Adult patients who underwent total knee arthroplasty (TKA) or total hip arthroplasty (THA) between 2017 and 2022 were included. Delirium was evaluated and treated within two days after surgery. A total of 6737 patients (4112 TKA/2625 THA) were retrospectively studied; 2.48% of patients in the TKA (n = 102) and THA (n = 65) groups had postoperative delirium. The blood transfusion (BT) and non-BT groups had similar percentages of patients who experienced postoperative delirium (3.34 vs. 2.35%, p = 0.080). In the multivariable logistic regression model, BT was not associated with postoperative delirium—adjusted odds ratio (aOR): 1.03, confidence interval (CI): 0.62, 1.71; p = 0.917. Moreover, transfusion of packed red blood cells (p = 0.651), platelets (p = 0.998), and cryoprecipitate (p = 0.999) were not associated with delirium. However, transfusion of fresh frozen plasma was associated with a 5.96-fold higher incidence of delirium—aOR: 5.96, 95% CI: 2.72, 13.04; p < 0.001. In conclusion, perioperative BT was not associated with postoperative delirium in patients who underwent TKA or THA. However, FFP transfusion was associated with an increased incidence of postoperative delirium.


Introduction
Total joint arthroplasty (THA) is one of the most effective medical treatments for hip and knee osteoarthritis.It significantly lowers pain, restores function, and improves quality of life [1].Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are the most common surgical procedures for treating osteoarthritis [2,3].THA and TKA rates have significantly increased and are predicted to continue rising in the United States and Europe [4,5].As a result, THA and TKA are becoming a bigger public health risk.
Transfusion rates for TKA vary from 3 to 67%, whereas those for THA vary from 4 to 68%, because there is no clear consensus on the appropriate indications for transfusion [6].While transfusing blood components can treat anemia following perioperative blood loss, it carries risks such as blood-borne infections, allergic reactions, and transfusion reactions, as well as significant costs to the healthcare system [7].Furthermore, several studies have shown that perioperative blood transfusions can trigger inflammation and are independent risk factors for postoperative delirium in older patients undergoing surgery [8,9].With a reported prevalence of 2.21%, delirium is a serious consequence that might slow patient recovery and increase hospital stay after THA and TKA [10].Some risk factors such as opioid use, benzodiazepine use, and general anesthesia have been reported [10].However, the relationship between perioperative blood transfusion and postoperative delirium in patients who underwent TKA or THA is not fully understood.Therefore, we aimed to determine the type of blood component transfusion that increases the incidence of postoperative delirium.We hypothesized that blood transfusion might increase the risk of delirium in patients who had undergone TKA or THA.

Ethical Statement
This retrospective cohort study was approved by the Institutional Review Board (IRB) of our institution (IRB approval number: B-2307-843-111).The requirement for informed consent was waived by the IRB.This manuscript adheres to the Strengthening the Reporting of Observational Studies (STROBE) guidelines.

Data Source and Study Population
We included 6737 cases from 5195 consecutive patients at a single tertiary academic hospital that employs BESTCare [11] for electronic health records.We retrospectively evaluated adult patients (18 years or older) who had undergone elective TKA, THA, or revision TKA/THA under general or neuraxial anesthesia between 1 January 2017, and 31 December 2022.We excluded patients who had died in the hospital postoperatively and those who lacked pertinent medical information.Diagnoses and procedures were based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).

Study Endpoints (Diagnosis of Delirium)
The primary endpoint was the diagnosis of delirium.We extracted data on delirium observed and treated within two days after surgery, based on the evaluation of psychiatrists or medications for treatment, such as IV or oral benzodiazepine (lorazepam and alprazolam) or antipsychotics (haloperidol, quetiapine, olanzapine, and risperidone) at low doses.

Potential Confounders
We extracted patients' baseline medical information, including age, sex, preoperative hemoglobin (Hb) level, medical history, American Society of Anesthesiologists (ASA) physical status, and body mass index (BMI), from the electronic health record system.Preoperative anemia was defined if Hb was recorded below the following values: 12.0 g/dL for women, 13.0 g/dL for men [12].We used standard BMI categories: BMI groupings of less than 18.5 kg/m 2 (underweight), 18.5-24.9kg/m 2 (healthy), 25.0-29.9kg/m 2 (overweight), and 30.0 kg/m 2 or above (obese) [13].Medical history included diabetes mellitus, hypertension, carotid artery disease, cerebrovascular disease, liver disease, dementia, chronic kidney disease, and mental illness.We searched for preoperative assessments recorded by anesthesiologists and admission records by ward nurses.In this study, we defined mental illness as a diagnosis of depressive, bipolar, or psychotic disorder, regardless of medication.For chronic kidney disease, we only included patients with end-stage renal disease who were undergoing dialysis.Regarding surgery-related information, we collected data on whether patients received continuous intravenous infusion of magnesium sulfate during surgery, duration of anesthesia (in minutes), type of anesthesia (general or regional), adjuvant sedatives used (dexmedetomidine, propofol, or midazolam) in addition to the primary anesthetics, postoperative transfer (to the general ward or intensive care unit), year of surgery, type of surgery, and whether each surgery was the first, second, or a revision.One group of patients underwent a second TKA or THA on the other side, with an interval of one week between the procedures.An anesthesiologist or registered nurse recorded the estimated blood loss during surgery.In addition, we collected data on whether a patient had received any type of blood transfusion-red blood cells, fresh frozen plasma (FFP), platelets, or cryoprecipitate-on the day of surgery.

Statistical Analysis
All statistical analyses were performed using the Statistical Package for the Social Sciences Statistics for Windows (version 25.0;IBM Corp., Armonk, NY, USA), and statistical significance was set at p < 0.05.The baseline characteristics of the patients were presented as mean values with standard deviations (SDs) for continuous variables and as numbers with percentages for categorical variables.Multivariable logistic regression modeling was used to identify factors associated with postoperative delirium after TKA or THA.To study the effect of transfusion on delirium incidence, we included essential covariates such as estimated blood loss and anemia and other covariates that had a p-value larger than 0.1 from the univariable logistic regression model.In Model 1 of the multivariable logistic regression analysis, we included patients who received any type of blood component in the blood transfusion group and compared them with those who did not receive any blood transfusions.Model 2 differentiated the blood transfusion group into blood component groups for comparison.We performed subgroup analyses for age, sex, surgery type, and anemia status.

Study Population
A total of 6737 patients were enrolled in this study, of whom 4112 had undergone TKA and 2625 had undergone THA between January 2017 and December 2022.The demographic and clinical data of the enrolled patients are shown in Table 1.While 2.48% of the TKA (n = 102) and THA (n = 65) groups had postoperative delirium, more patients in the THA group received postoperative blood transfusion and experienced a larger amount of estimated blood loss than those in the TKA group.Patients in the TKA group were significantly more anemic than those in the THA group.

Blood Transfusion
Table 2 compares the characteristics of patients who received any type of blood component postoperatively and those who did not.The blood transfusion (BT) group was younger, had greater estimated blood loss, and had more patients with anemia than the non-BT group, whereas there was no difference between the two groups in the incidence of delirium.

Subgroup Analyses
Table 4 shows the results of the subgroup analyses for postoperative delirium according to age, sex, surgery type, and hemoglobin level.However, subgroup analyses did not show statistically meaningful results (all p > 0.05).

Discussion
No correlation was found between the incidence of delirium in patients who underwent TKA or THA and blood transfusions in this retrospective population-based cohort study conducted in a single institution.However, among blood products, FFP transfusion was linked to an increased risk of delirium.Our main conclusions are derived from a variety of risk variables for delirium; however, our findings also suggest that additional studies are necessary to corroborate these conclusions.
Several previous studies reported that blood transfusion was associated with an increased risk of delirium after orthopedic surgeries [9,14,15].However, another cohort study reported no significant association between blood transfusion and postoperative delirium [16].This lack of consistency can be attributed to variations in the threshold for the amount of blood transfused, types of blood components, indication of blood transfusion, and diverse characteristics and conditions of the targeted patients across different studies.Thus, the relationship between blood component transfusion and delirium risk in patients undergoing orthopedic surgery, especially TKA or THA, remains debatable.
Although overall blood transfusion was not associated with the risk of postoperative delirium, transfusion of FFP was associated with an increased risk of postoperative delirium in this study.Andrási et al. identified FFP transfusion as a risk factor for postoperative delirium after cardiac surgery [17].Consistent with this, we also observed an elevated likelihood of postoperative delirium associated with FFP transfusion.One possible explanation for the development of postoperative delirium is the initiation of an inflammatory response triggered by blood transfusion; systemic inflammation could contribute to the pathogenesis of delirium by compromising the blood-brain barrier integrity [18].Furthermore, transfusion of FFP induces a spontaneous and dose-dependent release of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) [19], which is related to a hyperactive form of delirium [20].Systemic TNF crosses the blood-brain barrier, and the excessive presence of circulating TNF is associated with cognitive dysfunction [21], which can result in postoperative delirium.
FFP was obtained through a freeze/thaw process; however, leukocyte reduction was not observed.As a result, FFP contains a large number of white blood cells and inflammatory mediators, such as mitochondrial damage-associated molecular patterns (DAMPs) and TNF-α, resulting from the rupture of cellular components.DAMPs, which are detected significantly more frequently in FFP than in other blood components, trigger an inflammatory response upon release into the plasma [22].Receiving multiple units of FFP may expose patients to a quantity of pro-inflammatory cytokines and mediators that can exacerbate an existing inflammatory cascade caused by surgery.
Beyond blood transfusion, it is possible that the development of delirium was associated with anemia in the patient requiring transfusion.In patients with anemia, low hemoglobin concentrations lead to reduced cerebral oxygen delivery [23].Moreover, low hemoglobin concentrations reflect an inflammatory state associated with chronic diseases [24].Both explanations are considered possible pathological mechanisms underlying delirium.Unlike other risk factors for postoperative delirium, preoperative anemia can be corrected with medical treatments, such as tranexamic acid, iron supplements, or erythropoietin-stimulating agents.
Previous studies demonstrated that pre-existing dementia or psychiatric disorders are associated with an elevated risk of postoperative delirium [25,26], which is consistent with our findings.Despite the well-established status of dementia as a risk factor for delirium, the underlying mechanism remains elusive.Robinson et al. explained the link between pre-existing dementia and postoperative delirium through the "threshold theory", which posits that a decline in cognitive reserve heightens vulnerability to cognitive clinical deficit and results in delirium [27].Some prior research proposed that neuropathophysiological changes contribute to increased susceptibility to postoperative delirium.These changes, indicative of reduced "brain reserves", are characterized by slower cerebral metabolism, cholinergic deficiency, and inflammation [28].
Among the various psychiatric disorders, depression is recognized as a risk factor for postoperative delirium by the European Society of Anesthesiology [29].Depressive symptoms might lead to underlying cerebral dysfunction, such as abnormal stress or brain inflammatory responses, which predisposes patients to an exaggerated risk of postoperative delirium [30].Elevated cortisol levels (stress hormones) associated with depression can induce structural changes in hippocampal neurons and disrupt the hypothalamic-pituitary axis.These changes may increase susceptibility to episodes of postoperative delirium, thus providing evidence for a potential connection between depression, cortisol, and the development of postoperative delirium [31].
This study had several limitations.First, due to its retrospective nature, we could not identify patients with postoperative delirium using standardized and consistent assessment tools, such as the Confusion Assessment Method or the Delirium Rating Scale.We relied on observations made by physicians or nurses, consultations, and medication orders.Consequently, this might have resulted in under-recognition of the hypoactive form of delirium.Second, owing to the challenges associated with electronic medical records, we could not extract the exact quantity of blood units administered to each patient.We could not account for the potential impact of massive blood transfusions or the dose-dependent effects of blood transfusions in our analysis.

Conclusions
In this retrospective analysis of 6737 adult patients who underwent TKA or THA, we found no association between blood transfusions and delirium incidence.Nonetheless, among blood products, FFP transfusion was associated with a higher risk of delirium.Moreover, some risk factors for postoperative delirium were identified, such as anemia, dementia, or mental illness.Our study suggests the need for limited and conservative blood transfusions to prevent delirium after TKA or THA.This also shows that FFP transfusion should only be performed after careful consideration.Nevertheless, numerous studies indicate that there is still an ongoing debate regarding this subject, emphasizing the importance of exercising caution when interpreting the findings and implementing them in a clinical setting.Further investigation should prioritize the examination of blood transfusion components and criteria, as well as explore the correlation between anemia and the potential for postoperative delirium.
Institutional Review Board Statement: This retrospective cohort study was approved by the Institutional Review Board (IRB) of our institution (IRB approval number: B-2307-843-111; approval date: 2023.5.2).The requirement for informed consent was waived by the IRB.This manuscript adheres to the Strengthening the Reporting of Observational Studies (STROBE) guidelines.
Informed Consent Statement: Patient consent was waived due to the retrospective design.

Table 1 .
Baseline information of patients.

Table 2 .
Comparison of characteristics between two groups: Blood transfusion (BT) vs. Non-BT Group.

Table 3 .
Multivariable logistic regression analysis for delirium after TKA and THA.