Cigarette smoking is linked to an increased risk of delirium following arthroplasty in patients suffering from osteoarthritic pain

Abstract Aims Postoperative delirium (POD) is a common postoperative complication, and the potential relationship between cigarette smoking and POD is still unclear. The current study evaluated the relationship between preoperative smoking status in patients suffering from osteoarthritic pain and POD after total knee arthroplasty (TKA). Methods A total of 254 patients who had undergone unilateral TKA were enrolled between November 2021 and December 2022, with no gender limitation. Preoperatively, patients' visual analog scale (VAS) scores at rest and during movement, hospital anxiety and depression (HAD) scores, pain catastrophizing scale (PCS) scores and smoking status were collected. The primary outcome was the incidence of POD, which was evaluated by the confusion assessment method (CAM). Results A total of 188 patients had complete datasets for final analysis. POD was diagnosed in 41 of 188 patients (21.8%) who had complete data for analysis. The incidence of smoking was significantly higher in Group POD than in Group Non‐POD (22 of 41 patients [54%] vs. 47 of 147 patients [32%], p < 0.05). The postoperative hospital stays were also longer than those of Group Non‐POD (p < 0.001). Multiple logistic regression analysis showed that preoperative smoking (OR: 4.018, 95% CI: 1.158–13.947, p = 0.028) was a risk factor for the occurrence of POD in patients with TKA. The length of hospital stay was correlated with the occurrence of POD. Conclusions Our findings suggest that patients who smoked preoperatively were at increased risk of developing POD following TKA.


| INTRODUC TI ON
Osteoarthritis (OA) is the most common joint disease that occurs frequently in the elderly and primarily affects knee joints, with an estimated 240 million adults worldwide suffering from symptomatic knee OA. 1,2 Pain is the prevailing symptom of OA and leads to limited physical function and disability.Total knee arthroplasty (TKA) is considered a cost-effective therapy for end-stage OA. 3,4 The demand for artificial total hip replacement and total knee replacement is expected to increase by 174 and 673% by 2030, respectively. 5Despite the increasing demand for joint replacement surgery, there are still many patients who suffer postoperative distress unrelated to the knee or hip itself, and the occurrence of postoperative complications such as postoperative delirium (POD) deserves our attention. 6lirium is a state in which the patient experiences changes in consciousness, orientation, memory, perception, and behavior. 7D is associated with poor prognosis in the perioperative period and increases the risk of long-term cognitive impairment and reduces quality of life after surgery. 8Approximately 5-31% of patients experience POD after joint replacement surgery. 9,10Unfortunately, the underlying pathogenesis mechanism of delirium is ambiguous.To optimize the postsurgical management of knee OA patients, it is of great significance to study the risk factors associated with POD.[13] Interestingly, the presence of smoking behavior is quite common in patients complicated with chronic pain, such as OA. 14,15Among patients with OA, clinical findings estimated that one in five patients regularly smoke or use tobacco. 16Smoking has been implicated in the development of pain perception and pain experience in OA.
Smokers have more severe pain than non-smokers and are more than twice as likely as non-smokers to have severe cartilage loss. 14 addition to pain experience, previous studies have illustrated that smoking causes neuroadaptations in the central nervous system; for example, cigarette smoking is associated with the psychopathology of anxiety/depression. 17There is also evidence that long-term tobacco use increases the risk of developing anxiety symptoms and can exacerbate the severity of such symptoms. 18However, whether smoking in OA patients is related to POD incidence after TKA is unclear.In this study, we aimed to determine whether there is an association between smoking and POD in patients suffering from osteoarthritic pain.

| Studydesign
This is a prospective and observational study conducted at the First Affiliated Hospital of the University of Science and Technology of China (USTC).The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee.All patients were informed of how the study protocol was carried out and signed an informed consent form.

| Subjects
From November 2021 to December 2022, patients who were scheduled for TKA were assessed prior to the study.The inclusion criteria were as follows: patients aged from 18 to 65 years, body mass index (BMI) of 18-30 kg/m 2 , male or female, American Society of Anesthesiologists (ASA) class I-III, voluntary participation and the ability to complete all questionnaire assessments accurately.
All patients received general anesthesia, and they were given a femoral nerve block by the same staff after surgery.If the resting visual analog scale (VAS) pain score was >3 during postoperative hospitalization, additional flurbiprofen 50 mg was added for rescue analgesia.The anesthesiologist and the surgeon are the same.

| CigaretteSmoking
The criteria for the assessment of smoking were: 19,20 Current smokers: current smoking or stopped smoking for <1 year.
Former smokers: smoking more than 10 packs a year but quitting smoking.
Never smokers: (1) people with no history of smoking and those who smoke <10 packs a year but stop smoking; (2) secondhand smoke (SHS): exposure to tobacco smoke from others at home or workplace for at least 15 min per day, 1 day per week and at least 2 years of the past 10 years.

| Postoperativedelirium
The confusion assessment method (CAM) delirium assessment tool is a widely used, delirium diagnostic scale developed by Inouye et al in the United States in 1990 for use by non-psychiatrists."The CAM diagnostic algorithm is based on four cardinal features of delirium: (1) acute fluctuating course, (2) attention disorder, (3) disturbance in thinking and (4) altered level of consciousness.According to CAM, the diagnosis of delirium requires the presence of features 1, 2 and 3 or 4". 21The CAM scale has good sensitivity (94-100%) and specificity (90-95%), is short, easy to understand and use, and is therefore highly regarded by clinicians. 22POD is defined as any symptom of confusion that appears within 5 days of surgery. 7,23"Delirium was assessed twice per day, between 06:00-08:00 and 18:00-20:00, with Chinese version of the CAM for non-intubated patients and CAM-ICU for intubated patients". 24Patients who met the diagnostic criteria for CAM were classified as Group POD; otherwise, they were classified as Group Non-POD.

| Psychologicalvariables
The hospital anxiety and depression (HAD) scale and pain catastrophizing (PCS) scale were also collected before TKA.HAD scored a total of 14 items, half of which were rated as depression and the other half as anxiety.Scores of 0 to 7 indicate no symptoms; scores of 8 to 10 indicate suspected anxiety/depression and scores of 11 to 21 indicate that anxiety/depression occurs definitely. 25If the PCS score is >30, the patient is considered to have pain catastrophizing. 1

| Primary outcome
The primary outcome was the incidence of POD.

| Other outcomes
Knee OA duration, duration of surgery, intraoperative blood loss, intraoperative midazolam, propofol, remifentanil and sufentanil dosage, postoperative rescue analgesia use, length of hospital stays, intensive care unit (ICU) admission, nausea/vomiting, blood transfusion, hypothermia and VAS scores were recorded for each patient.

| Samplecapacity
In our preliminary study, patients were grouped according to whether POD occurred after surgery.According to the study, the incidence of POD in the smoking population undergoing TKA was 44%.Furthermore, the overall incidence of POD was 19%, and the detection of significant differences between study groups was achieved by PASS 15.0 (NCSS, USA) software.Each group of 94 patients was required to provide 95% power with an alpha of 0.05.
A 10% loss to follow-up was taken into account, and we enrolled a total of 188 patients.Normal data were compared by independent sample t-tests, and skewness comparisons were made using Mann-Whitney U-tests.

| Statisticalanalysis
After univariable analysis, a binary logistic regression model was used for multivariable analysis.A two-sided p value <0.05 was considered statistically significant.

| Characteristicsofpatientswithandwithout POD
Of the 299 patients who were assessed, 45 patients were ineligible due to changes in surgical types by surgeons and patients' own reasons, and 254 patients were qualified.Of these, 66 patients were excluded for the reasons described in the flow diagram, leaving 188 patients for the analysis (Figure 1).Patients were divided into POD and Non-POD groups based on the results of the delirium assessment.Patient characteristics are presented in Table 1.

| PODandsmoking
Forty-one (21.8%) of 188 patients developed POD.POD was newly diagnosed 1 day (n = 20, 48.8%), 2 days (n = 11, 26.8%), 3 days (n = 6, 14.6%), 4 days (n = 3, 7.3%) and 5 days (n = 1, 2.4%) after surgery, with fewer patients developing POD as time progressed (Figure 2).In this study, former smokers accounted for only two of the participants, and they did not develop POD.Therefore, "current smokers" were judged as smokers, "former smokers" and "never smokers" were judged as non-smokers.The incidence of smoking was significantly higher in Group POD than in Group Non-POD (54 vs. 32, p < 0.05; Figure 3).In the univariate analysis, there were significant differences in smoking, hospital stays and VAS scores at rest on the second day after surgery between the two groups (p < 0.05).Based on previously published literature 26  TA B L E 1 General characteristics of patients in both groups (n = 188).
considered as risk factors for the development of POD (Figure 4).
Pain is one of the main clinical manifestations of OA patients and a primary reason for undergoing TKA.Smoking frequently occurs in chronic pain conditions, such as OA, and has been identified as a risk factor for pain. 14Preoperative pain is associated with a 1.5-to 3-fold higher risk of POD. 27,28Additionally, the postoperative pain score positively correlates with the risk of POD. 29,30VAS scores at different time points in both groups are shown in Table 2.In this study, only two patients were admitted to the ICU after surgery and returned to the orthopedic ward 12 h later, so ICU admission was not included in the multivariate analysis.Finally, the risk factors associated with the occurrence of POD were included in the statistics, and binary logistic regression analysis was performed.
The results in Table 3 show that patients who smoked preoperatively had an increased risk of developing POD (OR: 4.018, 95% CI: 1.158-13.947,p = 0.028).Patients in Group POD had a longer hospital stay than those in Group Non-POD, which is consistent with other reports (OR: 3.469, 95% CI: 1.836-6.556,p < 0.001).

| Otheroutcomes
Eighteen patients developed nausea or vomiting.Four patients required blood transfusions.Three patients developed postoperative hypothermia.Two patients were admitted to the ICU postoperatively due to difficulty in removing the tracheal tube.In Table 4, the results show no significant difference.None of the patients developed wound infections or died after surgery.

| DISCUSS ION
Despite the increasing success rate of TKA surgery, there are still patients who express dissatisfaction due to a series of postoperative complications, such as POD, which can delay rehabilitation and hospital discharge. 6Smoking may represent a potentially modifiable risk factor for developing POD in patients with TKA.Considering the high prevalence of smoking among patients with OA, it is of great significance for smoking cessation or nicotine replacement in perioperative management in the clinic.Decreased acetylcholine and increased dopamine levels are thought to be important factors in this process of delirium, although the exact pathophysiological process of POD is unclear. 31Similarly, in the pathophysiological process of nicotine withdrawal, the relative deficiency of acetylcholine also A recent study showed a relationship between increasing years of smoking and pain severity/frequency. 37This co-occurrence of smoking behavior among patients suffering osteoarthritic pain is thought to be a result of reciprocal interactions in the manner of a positive feedback loop, leading to increased pain and cigarette smoking dependence. 38Smoking reduces pain for a short period of time, which in turn reinforces smoking behavior. 39On the other hand, anxiety/depression symptoms are emotional factors that regulate pain response and are also associated with cigarette smoking dependence. 40Increased catecholamine release due to anxiety may be the cause of peripheral sensitization, which leads to nociception. 41The positive correlation between pain-related anxiety and cigarette smoking dependence may be one reason why smoking is more prevalent in patients with osteoarthritic pain and why smokers with chronic pain are more likely to be nicotine dependent.It seems to be a cycle where anxiety leads to smoking and then people become addicted to nicotine and experience acute withdrawal symptoms similar to anxiety.Smoking increases the risk of anxiety and exacerbates its severity. 33 has been previously shown that pain and anxiety/depression are risk factors for POD (Figure 5).Delirium is a debilitating neuropsychological disorder caused by a variety of stressors, including infections, drug toxicity and metabolic abnormalities, which can lead to an acute stress response in the brain.Pain has a similar effect, dramatically inducing catecholamine release and producing a pro-inflammatory sympathetic response for a short period of time.
Dysfunction of the cortisol system and chronic hyperactivity of inflammatory cytokines may be affected by chronic pain.Thus, acute or chronic pain may increase the chance of delirium. 42Preoperative depression is common in patients with delirium, and depression is a recognized sequel in patients with delirium.Depression and delirium share similar risk factors and pathophysiological mechanisms, including disturbed physiological responses and monoaminergic and melatonin function. 43However, we did not conclude that pain or anxiety/depression influenced the association between smoking and delirium in this study by mediating analysis by linear regression.
Some researchers have found that nicotine acts as a doubleedged sword in terms of cognitive function.Cognitive enhancement does not usually occur under smoking conditions but rather during exposure to nicotine.5][46] On the other hand, in human studies, cognitive function could be improved by nicotine supplementation and short-term (<2 h) nicotine stimulation. 47,48However, it has been suggested that the mechanism of impaired cognitive function may be related to nicotinic acetylcholine receptor desensitization. 49 this study, the POD incidence was 21.8%, similar to the results of previous studies. 10The prevalence of smoking among POD patients was 54%, more than half of the people who developed POD.
We included the risk factors that have been previously shown to be associated with POD in the analysis.After excluding age, education, pain, anxiety, depression, hypertension, drinking, drug use and hospital stays, smoking was a risk factor for POD in patients with TKA.
Smokers have a 4.018-fold greater risk of developing POD than nonsmokers.Hospital stays were also significantly different.The length of hospital stay was correlated with the occurrence of POD.The occurrence of POD prolongs hospital stay.The mediating mechanism between smoking and POD needs to be studied.Does the incidence of POD after TKA decrease if a patient with knee OA has a history of smoking and quits for 2-4 weeks or longer before surgery?The duration of smoking cessation needs to be further determined.
However, some limitations should also be considered in this study.First, this study is a single-center study.To reduce bias and eliminate relevant interfering factors as much as possible, our results need to be demonstrated by multi-center research.Second, the amount and duration of cigarettes were not studied, so we did not conclude that the odds of POD were higher in patients who smoked for a long time/had a higher volume of smoking.Finally, this study was limited to patients with knee OA and cannot be extended to other knee conditions, such as rheumatoid arthritis.To reach a more accurate conclusion, the included diagnostic criteria should be expanded, and further studies should be conducted.

| CON CLUS IONS
Collectively, OA patients who smoke have a higher incidence of POD after TKA, and the co-occurrence of smoking behavior in OA We performed all statistical analyses with SPSS version 26 (SPSS, Inc., an IBM Company, Chicago, IL, USA).The Kolmogorov-Smirnov test and Shapiro-Wilk test were used to evaluate the normality of the continuous data.Quantitative variables were shown as the mean values (with SD) or medians (with interquartile range) depending on (normally or skewed) the distribution of data, and categorical data were shown as percentages.The chi-square test or Fisher's exact test was used to compare categorical data.

F I G U R E 1
Flow diagram of the recruitment process.| 3857 CHEN et al.

F I G U R E 3 F I G U R E 4
Newly diagnosed POD on postoperative days 1, 2, 3, 4 and 5 and overall.POD, postoperative delirium; TKA, total knee arthroplasty.Comparison of smoking rates between the two groups.All data are presented as n (%), *p < 0.05 vs. Group Non-POD.POD, postoperative delirium.Clinical manifestations of OA, risk factors for developing POD and poor prognosis after undergoing TKA.OA, osteoarthritis; POD, postoperative delirium; TKA, total knee arthroplasty.CHEN et al.
patients has clinical relevance to the neuropsychological outcome after TKA.AUTH O RCO NTR I B UTI O N S Conception and design of the study: DW and XQC.Literature search and collection and compilation of pictures and videos: JRC and JQC.Acquisition, analysis and interpretation of data: JCH, RSH, LS and HG.Drafting the article and revising it critically for important intellectual content: JRC, JQC, DW and XQC.Final approval of the article: all authors.JRC and JQC contributed equally to this work.

F I G U R E 5
Integrative reciprocal model of smoking and POD in chronic pain, such as osteoarthritic pain.POD, postoperative delirium.
and clinical experience, some characteristics such as age, education, pain, anxiety, depression, comorbidities (hypertension, diabetes and stroke), drinking, drug use and ICU admission were Note: Data are shown as number (%) or median (inter-quartile range).The Mann-Whitney U-tests to identify difference between two groups.Categorical data are analyzed using the chi-square or Fisher's exact test.Abbreviation: BMI, body mass index; HAD, hospital anxiety and depression; K-L, Kellgren-Lawrence; MMSE, Mini-Mental State Examination; OA, osteoarthritis; PCS, pain catastrophizing scale; POD, postoperative delirium; SHS: secondhand smoke; TKA, total knee arthroplasty.*The difference was statistically significant (p < 0.05).