The Risk Factors of Postoperative Delirium in Patients Aged Over 60 after Major Surgery: A Prospective Cohort Study

Abstract

Background Postoperative delirium (PD) is a frequent and serious complication of surgery that is associated with a prolonged hospital stay, increased mortality, and decreased quality of life. Identifying the risk factors for PD in elderly patients exposed to anesthetic agents during the perioperative period has the potential to improve patient response to surgery. This prospective cohort study aims to delineate the role of analgesic drugs in the onset of PD in elderly patients undergoing major surgery.

Methods A total of 732 patients aged 60 years or more and scheduled for elective major surgery were enrolled in the study. All patients underwent general or combined anesthetic management. The type of analgesia, whether patient-controlled intravenous analgesia or patient-controlled epidural analgesia, depended on the type of surgery and the individual's condition. PD assessment was performed for 7 consecutive days using the Confusion Assessment Method for the Intensive Care Unit.

Results Overall, PD occurred in 47 (6.5%) patients from the postoperative day (POD) 1 to POD 5. Multivariate analysis revealed that age (odds ratio [OR]: 1.076; 95% confidence interval [CI]: 1.027–1.128; p = 0.002), cardiac surgery (OR: 2.823; 95% CI: 1.152–6.915; p = 0.023), tramadol administration (OR: 2.060; 95% CI: 1.079–3.933; p = 0.028), and ondansetron administration (OR: 2.158; 95% CI: 1.132–4.111; p = 0.019) were the independent risk factors for PD after major surgery, and the use of sufentanil is a protective factor (OR: 0.317; 95% CI: 0.153–0.656; p = 0.002). The incidence of PD increased with both age and the dose of tramadol. Moreover, gender, preoperative analgesia, preoperative Mini-Mental State Examination score, type of analgesia, anesthetics during surgery, postoperative pain score, rescue analgesics, and medications including fentanyl, flurbiprofen, midazolam, droperidol, and anticholinergics appeared not to associate with PD occurrence.

Conclusion Older age, cardiac surgery, and the perioperative use of tramadol and ondansetron are independent risk factors for PD in patients aged ≥60 years, whereas sufentanil serves as a protective factor when used for analgesia. These results indicate that using sufentanil instead of tramadol may help decrease the occurrence of PD in elderly patients following major surgery.

Keywords

postoperative delirium - cardiac surgery - ondansetron - tramadol - 5-HT

Introduction

With the rapid increase in the aging population, the number of older adults undergoing major surgical procedures is expected to rise significantly. Postoperative delirium (PD) is a common and severe complication in this demographic, characterized by cognitive dysfunction such as disorientation, hallucinations, and impairments in memory and attention. Elderly patients are particularly vulnerable to PD,[1] [2] with an overall incidence rate of approximately 36.8%, which increases with age.[3] PD is associated with adverse outcomes, including prolonged hospital stays, increased morbidity and mortality, delayed recovery of cognitive and physical functions, and elevated health care costs.[4] [5] [6] [7] [8] [9]

The development of PD is influenced by a combination of pre-, peri-, and postoperative factors. Among the predisposing factors, advanced age and preexisting cognitive impairment are consistently highlighted as significant risks in various cohort studies.[10] However, the impact of other perioperative risk factors varies widely across clinical investigations.

One important area of focus is the role of perioperative medications in the development of PD. Tramadol, a synthetic opioid commonly used for postoperative pain management, has been linked to an increased risk of delirium in several studies. Its analgesic effect is mediated by a dual mechanism: inhibition of norepinephrine and serotonin reuptake and activation of μ-opioid receptors, with lesser effects on δ- and κ-opioid receptors.[11] Additionally, tramadol may directly induce serotonin release.[12] This could explain why its analgesic effects are only partially reversed by naloxone. These serotonergic and noradrenergic actions raise concerns about the potential interaction with other perioperative drugs that influence serotonin pathways.

Ondansetron, a selective 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, is another drug commonly used during the perioperative period, primarily to prevent nausea and vomiting. Notably, ondansetron has demonstrated the potential to prevent cognitive deficits in animal models and is considered a promising agent for reducing the risk of PD.[13] Given that tramadol and ondansetron exert opposing effects on the serotonergic system, their concurrent use could have significant implications for PD risk. However, there is a lack of clinical data on this interaction.

To address this gap, we conducted a prospective study to identify perioperative factors contributing to PD in patients aged ≥60 years undergoing major surgery. We also specifically investigated whether perioperative analgesic medications, including tramadol and ondansetron, influence the incidence of PD.

Methods

Ethical Considerations

Ethical approval for this study (Approval No. 2010–57) was granted by the Medical Ethics Committee of Peking University People's Hospital, Beijing, China (Chairperson: Dr. Xueguang Zhu). This study was conducted in accordance with the principles of the Declaration of Helsinki. All participants or their legal representatives understood the implications of participating in the study and provided written informed consent.

Participants

A cohort of 743 patients, aged ≥60 years and scheduled for elective major surgery from October 2010 to June 2011, in Peking University People's Hospital were prospectively screened. Herein, major surgery included liver, gastric, colorectal, pancreatic, and esophageal resection by laparotomy, lung and esophageal resection by thoracotomy, major bone surgery of more than 3 hours, and off-pump cardiac surgery. Patients who met any of the following criteria were excluded from the study: (1) a previous history of psychiatry diseases; (2) a score of less than the norm for the Mini-Mental State Examination (MMSE; [Table 1]) at screening; (3) prior neurological surgery; (4) severe visual or auditory disorders; or (5) American Society of Anesthesiologists (ASA) physical status classification III or above.

Table 1 Cut-off scores used for the Mini-Mental State Examination (MMSE)

Education	Normal score
Illiterate	≥17
Primary school	≥18
Junior high	≥20
High school/junior college	≥22
College	≥23

Note: Patients with an MMSE score below the normal score were excluded from the study.

Perioperative Period

Preoperative period: Patients underwent a preoperative evaluation 1 to 3 days before surgery, including an MMSE test and a detailed review of patient information, educational status, and medical history.

Surgical and anesthetic procedures: All patients received general anesthesia, which may be combined with spinal, epidural, or nerve block techniques. Both surgical and anesthetic procedures complied with standard clinical practice and were conducted by a surgical/anesthetic team that was blinded to the study design.

Postoperative analgesia: Postoperative analgesia was administered for 48 hours after the patients were discharged from the operating room. The mode of analgesia included patient-controlled intravenous analgesia (PCIA) or patient-controlled epidural analgesia (PCEA) depending on the type of surgery and patients' condition. PCEA was applied in thoracic or abdominal surgery when patients had no contraindications such as severe perioperative blood loss, were not undergoing anticoagulant therapy, had stable hemodynamics, and had consented to the procedure. Otherwise, PCIA was applied. Epidural analgesia was administered using 0.125% ropivacaine (continuous infusion 3 mL/h, with a bolus 3 mL, and a lockout interval of 15 minutes). Intravenous analgesic medications included one or two of the following: sufentanil (1 μg/mL, 250 mL), fentanyl (10 μg/mL, 250 mL), tramadol (4 mg/mL, 250 mL), and flurbiprofen (1 mg/mL, 250 mL) administered via PCIA with a continuous infusion rate of 3 mL/h, a bolus dose of 3 mL, and a lockout interval of 15 minutes. For PCIA, sufentanil combined with flurbiprofen was administrated when the patient was estimated to endure moderate to severe pain postoperatively unless contraindicated. Fentanyl was used as an alternative to sufentanil to prevent hypotension or for economic reasons. Tramadol was used as an alternative for flurbiprofen when the latter was contraindicated, for example, gastrointestinal surgery, peptic ulcer, coronary artery disease, bleeding, and coagulation dysfunction. Tramadol or flurbiprofen was also administered alone via PCIA when the patient was expected to experience mild to moderate pain. Flurbiprofen was preferred when inflammation response was involved perioperatively, while tramadol was preferred when higher pain severity was expected, or when there were possible contraindications for opioids and/or flurbiprofen. Ondansetron (5 mg i.v.) was administered at the end of surgery to prevent postoperative nausea and vomiting (PONV) in patients considered at high risk, such as women, those with hypovolemia, anxiety, or a history of PONV.

Postoperative period: Patients were followed up for 7 consecutive days by well-trained staff who were blind to anesthetic and analgesic procedures. Assessment of PD was performed at around 4 p.m. every day using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), which is a validated and useful tool to diagnose PD.[14] The CAM-ICU detects four features: (1) acute and fluctuating changes in mental status, (2) inattention, (3) disorganized and incoherent thinking, and (4) altered level of consciousness. PD was considered positive when the patient exhibited features (1) and (2) along with either (3) or (4).

Data collection: Data collection included patients' characteristics, preoperative analgesia, preoperative MMSE score, type of surgery (off-pump cardiac surgery or noncardiac surgeries such as laparotomy, thoracotomy, and major bone surgery), type of analgesia (PCIA, PCEA, or none), anesthetic agents during surgery, postoperative pain score, rescue dose of analgesics, whether or not intraoperative medications were used including droperidol, anticholinergics (atropine, scopolamine, or phencyclidine hydrochloride), and serotonin antagonist (ondansetron). The onset date of PD was also recorded. A total of 19 variables of interest were included in this study; for each variable, at least 5 to 10 samples were required.

Statistical Analysis

Continuous data were expressed as mean ± standard deviation (SD) and categorical data were expressed as frequency and percent. Univariate logistic regression analysis was used to examine the correlation between PD and the following variables: age, gender, preoperative analgesia, preoperative MMSE score, type of analgesia (PCIA, PCEA, or none), postoperative pain score, rescue dose of analgesics, and medications including droperidol, anticholinergics (atropine, scopolamine, or phencyclidine hydrochloride), and analgesic medications including sufentanil, fentanyl, tramadol, and flurbiprofen, and medications including droperidol, anticholinergics (atropine, scopolamine, or phencyclidine hydrochloride), and ondansetron during the perioperative period. Variables associated with PD having a p-value of less than 0.2 in univariate analysis were subsequently entered into a multivariate logistic regression, provided there was no collinearity among the factors. A p-value of less than 0.05 was considered statistically significant.

Results

Patients' Characteristics

The study procedure is summarized in [Fig. 1]. A total of 743 patients were screened during the study period. Eleven patients were not enrolled because of ineligibility for inclusion criteria (n = 9) and refusals to participate in the study (n = 2). Thirteen additional patients were subsequently lost to follow-up, including those who could not be evaluated due to sedation treatment in the ICU. Eventually, 719 patients fulfilled the inclusion criteria and completed the study. The patients' characteristics and the types of anesthetic procedures are described in [Table 2]. The mean age of the patients was 70 ± 6 years, with the patient cohort consisting of 309 males and 410 females. The medications used for postoperative analgesia included sufentanil, fentanyl, and tramadol. Flurbiprofen, a nonsteroidal anti-inflammatory drug, was added as indicated. All analgesia was managed as PCIA with the setting of continuous infusion at 3 mL/h, bolus of 3 mL, and lockout of 15 minutes.

Table 2 Perioperative data and univariate logistic regression analysis of risk factors for postoperative delirium in 719 patients who underwent major surgery

Variables	All patients ( n  = 719)	Delirium (+), n  = 47	Delirium (–), n  = 672	Odds ratio (95%CI)	p -value
Age (y)	69.93 ± 6.45	72.34 ± 6.28	69.76 ± 6.43	1.061 (1.015–1.108)	0.009
Gender
Male	309	21	288	1.000	0.807
Female	410	26	384	0.929 (0.512–1.684)
Type of surgery
Noncardiac[a]	653	39	614	1.000	0.060
Cardiac	66	8	58	2.172 (0.969–4.867)
Preoperative analgesia	42	4	38	1.552 (0.529–4.550)	0.423
Preoperative MMSE score	29 (2)	29 (3)	29 (1)	1.019 (0.846–1.229)	0.840
Type of analgesia
None	85	4	81	1.000	0.622
PCIA	589	41	548	1.515 (0.529–4.342)
PCEA	45	2	43	0.942 (0.166–5.351)
Anesthetics during surgery
Propofol	692	46	646	1.851 (0.246–13.950)	0.550
Isoflurane	48	3	45	0.950 (0.284–3.179)	0.934
Sevoflurane	428	34	394	1.845 (0.956–3.561))	0.068
Other medications during analgesia
Tramadol	238	25	213	2.449 (1.350–4.442)	0.003
Sufentanil	415	16	399	0.353 (0.189–0.658)	0.001
Fentanyl	78	8	70	1.764 (0.793–3.926)	0.164
Flurbiprofen	416	25	391	0.817 (0.451–1.478)	0.503
Medications during the perioperative period
Midazolam	683	46	637	2.527 (0.339–18.866)	0.366
Droperidol	175	10	165	0.830 (0.404–1.707)	0.613
Anticholinergics[b]	460	31	429	1.097 (0.588–2.047)	0.770
Ondansetron	280	23	257	1.548 (0.856–2.799)	0.149
VAS ≥ 4	274	19	255	1.110 (0.607–2.028)	0.735
Rescue analgesia	196	15	255	1.272 (0.673–2.403)	0.459

Abbreviations: CI, confidence interval; MMSE, Mini-Mental State Examination; PCEA, patient-controlled epidural analgesia; PCIA, patient-controlled intravenous analgesia; VAS, visual analog scale.

Note: Data are expressed as the number of patients and the proportion in the corresponding population.

^a Including laparotomy, thoracotomy, and major bone surgery.

^b Including atropine, scopolamine, and phencyclidine hydrochloride.

Fig. 1 Flow diagram of the trial's process.

Incidence of PD in Elderly Patients after Major Surgery

Among the 719 patients included in this study, PD was observed in 47 patients (6.5%), according to the CAM-ICU criteria. In the patients who experienced PD, the first episode of PD occurred in 22 patients (46.8%) on postoperative day 1 (POD 1), in 13 patients (27.7%) on POD 2, in 9 patients (19.1%) on POD 3, in 2 patients (4.3%) on POD 4, and in 1 patient (2.1%) on POD 5 ([Fig. 2]). No additional PD occurred on POD 6 or 7 ([Fig. 2]).

Fig. 2 Time of postoperative delirium onset.

Univariate and Multivariate Logistic Regression Analyses of Risk Factors for PD

Univariate logistic regression analysis was performed to determine the risk factors for the occurrence of PD. Age (p = 0.014), tramadol administration (p < 0.001), and sufentanil administration (p < 0.001) were found to correlate negatively with the occurrence of PD. However, gender, preoperative analgesia, preoperative MMSE score, type of surgery, anesthetics during surgery, type of analgesia, postoperative pain score, rescue analgesics, and other medications, including fentanyl, flurbiprofen, midazolam, droperidol, anticholinergics, and ondansetron, appeared not to associate with PD occurrence ([Table 2]). Subsequently, factors identified by the univariate analysis with a p-value less than 0.2 were included in multivariate logistic regression analysis, which demonstrated the independent risk factors for the occurrence of PD: age (OR: 1.076; 95% CI: 1.027–1.128; p = 0.002), cardiac surgery (OR: 2.823; 95% CI: 1.152–6.915; p = 0.023), tramadol administration (OR: 2.060; 95% CI: 1.079–3.933; p = 0.028), and ondansetron administration (OR: 2.158; 95% CI: 1.132–4.111; p = 0.019) were associated with increased risks. In contrast, the use of sufentanil appeared to be a protective factor (OR: 0.317; 95% CI: 0.153–0.656; p = 0.002; [Table 3]).

Table 3 Multivariate logistic regression of risk factors for postoperative delirium

Variables	Odds ratio	95% CI	p -value
Age	1.076	1.027–1.128	0.002
Cardiac surgery	2.823	1.152–6.915	0.023
Sevoflurane	1.613	0.815–3.192	0.170
Tramadol	2.060	1.079–3.933	0.028
Sufentanil	0.317	0.153–0.656	0.002
Fentanyl	0.837	0.336–2.087	0.703
Ondansetron	2.158	1.132–4.111	0.019

Abbreviations: 95% CI, 95% confidence interval; MMSE, Mini-Mental State Examination.

Additionally, the incidence of PD increased with age and the dose of tramadol in postoperative analgesia. As shown in [Fig. 3], PD occurred in 18 patients (5.07%) aged between 60 and 69 years, 21 patients (6.75%) aged between 70 and 79 years, and 8 patients (15.38%) aged older than 80 years. Of 481 patients without perioperative treatment with tramadol, the incidence of PD accounted for only 4.57%; however, 7.45 and 22.00% of patients who received tramadol at a dose of ≤400 mg/d or greater than 400 mg/d for postoperative analgesia developed PD, respectively. Patients who did not receive tramadol or ondansetron showed an incidence of PD at 3.90%, the incidences were 5.53% with ondansetron and 8.28% with tramadol, but rose to 14.81% when both were used together ([Fig. 3]).

Fig. 3 The incidence of postoperative delirium (PD) in different groups by age or tramadol dose. (a) Age. (b) Patients received different doses of tramadol via an intravenous pump. (c) The incidence of PD as the different combination of tramadol and ondansetron was applied.

Discussion

This study found that 6.5% of patients aged ≥60 years experienced PD from POD 1 to 5. Univariate and multivariate logistic regression analyses identified age, cardiac surgery, and the administration of tramadol and ondansetron as independent risk factors for PD. In contrast, sufentanil use in postoperative analgesia emerged as a protective factor. These findings contribute to the limited literature exploring the role of multiple analgesic medications in PD.

The relatively low incidence of PD observed in this study compared with previous reports (10–46%) may be attributed to the implementation of active postoperative analgesia at our institution and the inclusion of a younger elderly population (aged ≥60 years).[10] [15] [16] [17] Opioids are recommended in our hospital to control postoperative pain, as pain may exacerbate delirium.[18] Furthermore, our study excluded patients with preexisting cognitive impairments or psychiatric conditions, potentially reducing the baseline susceptibility to PD. Compared with the other screening tool, Nursing Delirium Symptom Checklist (NuDESC), CAM-ICU is less sensitive but highly specific to identifying delirium postoperatively, with a near-perfect positive predictive value in this postoperative population.[19]

Another aim of this study was to identify risk factors for PD after major surgery and investigate how to prevent and treat PD in elderly patients. The literature indicates that the risk factors for PD include old age, illness severity, cognitive impairment, psychopathological symptoms, preoperative depression, use of preoperative psychotropic drugs, greater comorbidity, and perioperative complications.[20] [21] Previous studies have demonstrated that advanced age is a well-established risk factor for the occurrence of PD. Our findings are consistent with them.

It is noteworthy that PD is a common and severe complication in patients undergoing major surgery, leading to poor outcomes.[22] Among perioperative medications, tramadol was identified as a risk factor, consistent with prior studies linking it to delirium through its serotonergic and noradrenergic actions.[23] [24] [25] Moreover, the other study using postoperative tramadol as a rescue analgesic has identified tramadol as an independent risk factor for PD in patients older than 75 years who underwent major abdominal surgery.[15] In healthy volunteers, tramadol administration induces agitation at a dose of 500 mg.[26] Tramadol functions as a μ-opioid receptor agonist and a serotonin/noradrenaline reuptake inhibitor. Both serotonin and norepinephrine are important neurotransmitters, and play complex roles in cognitive functioning. Some researchers believe that tramadol-induced delirium supports the “cholinergic deficiency hypothesis,” suggesting that delirium results from the imbalance between levels of acetylcholine and monoamine.[27]

5-HT has been proven to link with PD in previous studies.[28] The study has shown that a high level of 5-hydroxy indole acetic acid (5-HIAA), the major metabolite of 5-HT, was linked with delirium and cognitive impairment.[29] Ondansetron, acting as a 5-HT antagonist, has shown promise in preventing cognitive deficits in smaller studies.[13] [17] Our findings indicate its potential role as a PD risk factor, warranting further investigation through large-scale randomized controlled trials (RCTs).

Cardiac surgery was also confirmed as an independent risk factor for PD.[30] Furthermore, there is a higher risk associated with procedures involving cardiopulmonary bypass.[31] [32] Finally, sufentanil, an opioid with a favorable safety profile, demonstrated a protective effect against PD, though further research is needed to confirm this finding. Control of postoperative pain is important in preventing delirium.[33] Although there is a concern that opioid analgesic therapy may induce PD, a recent study has shown that opioid consumption is not a predictor of incident PD.[34] In a nested cohort study in older patients undergoing noncardiac surgery, despite more opioid use, patients with delirium reported greater pain, suggesting the role of pain as a potential etiological factor in PD.[34] There is a report that the combination of sufentanil and dexmedetomidine in PCIA improves cognitive function after general anesthesia.[35]

Conclusion

This study highlights the critical need for thorough evaluation of perioperative risk factors associated with PD. Our findings identify older age, cardiac surgery, and the perioperative use of tramadol and ondansetron as independent risk factors for PD in patients aged ≥60 years. In contrast, the use of sufentanil for analgesia appears to offer a protective effect against PD. These results suggest that opting for sufentanil instead of tramadol may help reduce the incidence of PD in elderly patients undergoing major surgery, underscoring the importance of tailored analgesic strategies to mitigate this serious postoperative complication.

Conflict of Interest

None declared.

Acknowledgments

We thank Qi Yan and Miao He (Department of Anesthesiology, Peking University People's Hospital) for their assistance in data collection.

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Publication History

Article published online:
25 April 2025