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Yan Zou Y, Wu Y, Wei A, et al. Serum HMGB1 as a predictor for postoperative delirium in elderly patients undergoing total hip arthroplasty surgery [published online as ahead of print on August 29, 2024]. Adv Clin Exp Med. 2025. doi:10.17219/acem/189227

Serum HMGB1 as a predictor for postoperative delirium in elderly patients undergoing total hip arthroplasty surgery

Yan Zou^1,A,D,E, Yuan Wu^2,B,C, An Wei^3,B,C, Hao Nie^1,B,D, Shan Hui^1,C, Cuizhong Liu^2,C, Tingzhi Deng^1,A,E,F

¹ Department of Geriatrics, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China

² Department of General Medicine, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China

³ Department of Ultrasound, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China

Graphical abstract

Abstract

Background. Postoperative delirium (POD) is an acute mental disorder that occurs after surgery requiring general anesthesia. In animal studies, high-mobility group box 1 (HMGB1) plays a key role in mediating postoperative neuroinflammation and may have a direct impact on POD.

Objectives. The objective of this prospective observational study was to investigate the serum levels of HMGB1 in elderly POD patients undergoing total hip arthroplasty.

Materials and methods. This prospective observational study included 287 elderly patients who underwent total hip arthroplasty in our hospital from October 2019 to September 2022. Patients were assessed for the presence of POD using the Confusion Assessment Method (CAM) within 72 h of surgery. Serum HMGB1, interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) levels were measured using enzyme-linked immunosorbent assay (ELISA) before surgery, as well as at 24 h, 48 h and 72 h after surgery. Demographic and clinical data of all elderly patients were collected.

Results. The anesthesia time and surgical time in the POD group were significantly higher than those in the non-POD group. The serum levels of HMGB1, IL-6 and IL-1β in the POD group were significantly elevated compared to those in the non-POD group at all time points after surgery (p < 0.05). In addition, the serum levels of HMGB1 were positively correlated with TNF-α, IL-6 and IL-1β levels. HMGB1, IL-6 and IL-1β could be potential predictive biomarkers for the occurrence of POD in elderly patients undergoing total hip arthroplasty. Finally, we found that anesthesia time, surgical time, HMGB1, TNF-α, IL-6, and IL-1β were risk factors for POD in elderly patients undergoing total hip arthroplasty.

Conclusions. Serum HMGB1 levels were markedly elevated in elderly POD patients undergoing total hip arthroplasty. In addition, HMGB1 could serve as a potential predictive biomarker for POD in elderly patients undergoing total hip arthroplasty.

Key words: cytokines, prognosis, HMGB1, total hip arthroplasty, postoperative delirium

Background

Postoperative delirium (POD) is an acute mental disorder that manifests as confusion, cognitive dysfunction and reduced attention following general anesthesia surgery. It typically occurs within 24 to 72 h after surgery.¹^,² Elderly individuals, aged 65 years or older, are particularly susceptible to developing POD, with the risk increasing by 1.15 times for each additional year of age.³ Postoperative delirium is considered the most common surgical complication in elderly hip fracture patients, which significantly affects the postoperative recovery of patients and increases hospitalization time and costs.⁴^,⁵ Therefore, there is a pressing need for early preventive strategies and comprehensive care for elderly patients at risk of developing POD.

Postoperative delirium is associated with metabolic disorders, oxidative stress and inflammatory responses within the nervous system.⁶^,⁷^,⁸ High-mobility group box 1 (HMGB1) is a DNA-binding protein that is highly abundant within the nuclei of eukaryotic cells and is involved in a variety of physiopathological responses, including inflammation and oxidative stress.⁹^,¹⁰ The activation of immune cells and subsequent inflammatory responses can be induced by HMGB1.¹¹ Moreover, elevated levels of HMGB1 have been linked to poor prognoses in various inflammatory diseases and cancers.¹²^,¹³ In addition, in animal studies, HMGB1 plays a key role in mediating postoperative neuroinflammation and may have a direct impact on POD.¹⁴ However, there is a dearth of clinical research exploring the specific involvement of HMGB1 in the development of POD in elderly patients undergoing total hip arthroplasty.

Objectives

The objective of this prospective observational research was to investigate the serum levels of HMGB1 in elderly POD patients undergoing total hip arthroplasty. Our study aims to shed light on the clinical significance of HMGB1 in elderly POD patients.

Methods

Patients

This prospective observational study included 287 elderly patients who underwent total hip arthroplasty in Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University; Changsha, China) from October 2019 to September 2022. The inclusion criteria for the patients were: 1) age over 65; 2) American Society of Anesthesiologists (ASA) grade I–III) planned unilateral total hip arthroplasty under spinal anesthesia. The exclusion criteria were: 1) patients with a Mini-Mental State Examination (MMSE) score ≤23 before surgery; 2) patients with a history of severe mental or neurological illness; 3) patients with severe infection, cardiac, hepatic, renal insufficiency, or malignancy; 4) patients with severe complications during or after surgery; and 5) patients treated with anti-inflammatory or immunosuppressive drugs before surgery. All patients received anesthesia, total hip arthroplasty and postoperative care from the same team in our hospital. Patients were assessed for the presence of POD using the Confusion Assessment Method (CAM)¹⁵ within 72 h of surgery. The CAM includes 4 aspects: 1) acute onset of cognitive changes, 2) inattention, 3) disorganized thinking, and 4) altered level of consciousness. If the patient demonstrates a positive reaction to 1, 2 and either 3 or 4 during the assessment, they are considered to have delirium at that particular time point. For the POD diagnosis, the same anesthesiologist evaluated the participant twice daily on postoperative days 1–3. This study received ethical approval from the ethics committee of Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University; approval No. Scientific Research 2023-29). Written informed consent was obtained from all participants.

Blood sampling measurement

Serum levels of HMGB1, interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) were assessed using the enzyme-linked immunosorbent assay (ELISA) method. Within 24 h of admission, fasting vena cava blood samples (5 mL) were collected from the patients for analysis and centrifuged at 2000 g for 15 min and tested according to a commercially available kit (HMGB1 MBS3803280, IL-6 MBS175877, IL-1β MBS3803011, TNF-α MBS824943, and CRP MBS8123937; MyBioSource, San Diego, USA). The serum biomarker levels were measured in all patients before surgery, as well as at 24 h, 48 h and 72 h after surgery.

Data collection and scale scoring

Before the operation, the clinical and demographic data of all elderly patients were collected, including age, gender, body mass index (BMI), comorbidities (hypertension, diabetes, coronary heart disease), diastolic blood pressure (DBP), systolic blood pressure (SBP), and ASA classification. In addition, we also recorded the surgical time, anesthesia time and intraoperative blood loss of all patients.

Statistical analyses

All statistical analyses were conducted using IBM SPSS v. 26.0 (IBM Corp., Armonk, USA). Normally distributed data were presented as means ± standard deviations (±SD), while non-normally distributed data were presented as medians (interquartile ranges (IQR)). To compare differences between the 2 study groups, the Mann–Whitney test, Student’s t-test or χ² test was utilized. The probability of a type 1 error was not controlled, and inferences about statistical significance may be unreliable. Pearson’s correlation analysis was employed to assess the relationship between serum biomarkers. Linear discriminant analysis (LDA) was used to classify whether elderly patients undergoing total hip arthroplasty would develop POD. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive value of HMGB1 in POD. Additionally, we established binary logistic regression models to identify risk factors for POD. We conducted Box–Tidwell tests to assess the linear relationship between the predictor variables and the logit of the response variables. Furthermore, variance inflation factor (VIF) tests were performed to examine the presence of multicollinearity among variables. Additionally, Cook’s distance test has been utilized to identify any extreme outliers. A p-value <0.05 was regarded as a significant difference.

Results

The clinical profiles of all enrolled individuals

Our prospective observational study included 287 elderly patients who underwent total hip arthroplasty surgery, and all patients were classified into a POD group (n = 83) or a non-POD group (n = 204) according to the CAM scale performed 72 h postoperatively. Compared to the non-POD group, the anesthesia time and surgical time in the POD group were remarkably increased (Table 1, p < 0.05). No significant differences were found between the 2 groups in terms of age, gender, BMI, SBP, DBP, comorbidities, ASA classification, and intraoperative blood loss.

Dynamic changes of HMGB1
and cytokines in the postoperative

Subsequently, we examined the serum HMGB1, IL-6, IL-1β, CRP, and TNF-α levels of all study participants before surgery, as well as at 24, 48 and 72 h after surgery. According to Figure 1, the serum HMGB1, IL-6, IL-1β, CRP, and TNF-α levels in elderly patients undergoing total hip arthroplasty were significantly elevated in the first 24 h after surgery, followed by a gradual decline. The serum levels of HMGB1 and IL-1β in the POD group were markedly elevated compared to those in the non-POD group at all time points after surgery (p < 0.05), although there were no significant differences in the serum levels of these biomarkers before surgery. Furthermore, we conducted Pearson’s correlation analysis on the serum levels of HMGB1 and inflammatory factors 24 h after surgery and found that the serum HMGB1 levels were positively correlated with IL-1β and IL-6 levels (Table 2, p < 0.05). This suggested an association between the patient’s serum IL-1β, IL-6 and HMGB1 levels at 24 h postoperatively.

Predictive value of HMGB1 for POD in elderly patients undergoing total hip arthroplasty

We performed LDA to classify whether elderly patients undergoing total hip arthroplasty would develop POD using significantly different serum cytokines (HMGB1, IL-6, IL-1β, and TNF-α) as independent variables. The results, as shown in Table 3, demonstrated that the LDA achieved a sensitivity of 75.9%, specificity of 79.9% and accuracy of 78.7% in the classification. To further evaluate the classification performance of LDA for POD in elderly patients undergoing total hip arthroplasty and assess the predictive value of HMGB1 and inflammatory factors for POD, we conducted a ROC curve analysis. The results showed that HMGB1, IL-6 and IL-1β could be potential predictive biomarkers for the occurrence of POD in elderly patients undergoing total hip arthroplasty, with HMGB1 showing a better diagnostic value (Figure 2). The AUC of HMGB1 was 0.789, the cutoff value was 319.2 pg/mL, the sensitivity was 75.90%, and the specificity was 67.16%. This suggested that based on these cytokine levels, it might be possible to predict the occurrence of POD in elderly patients undergoing total hip arthroplasty.

Risk factors of POD in elderly patients undergoing total hip arthroplasty

We conducted a logistic regression analysis using the enter method to identify risk factors for POD in elderly patients undergoing total hip arthroplasty. We used 2 models: Model 1 including demographic and clinical data (age, sex, BMI, SBP, DBP, ASA classification, surgery time, anesthesia time, and intraoperative blood loss), with the results of the Hosmer–Lemeshow test (p = 0.100) and Nagelkerke R² (0.435) showing a well goodness of fit. Model 2 including cytokines (HMGB1, TNF-α, CRP, IL-6, and IL-1β), with the results of the Hosmer–Lemeshow test (p = 0.261), and Nagelkerke R² (0.510) and showed a well goodness of fit. Both models satisfied the assumptions of logistic regression, including the presence of a linear relationship between the predictor variables and the logarithm of the response variables, the absence of multicollinearity among variables and the absence of extreme outliers. The results showed that anesthesia time, surgical time, HMGB1, IL-1β, IL-6, and TNF-α were risk factors for POD in elderly patients undergoing total hip arthroplasty (Table 4).

Discussion

The occurrence of POD has significant implications for patient outcomes and prognosis. In severe cases, it can even pose a life-threatening risk. As a result, experts increasingly recommend the implementation of systematic interventions through various approaches to reduce the incidence and duration of delirium. Therefore, predicting elderly patients who are at risk of developing POD in advance and intervening is of great significance.¹⁶^,¹⁷ In this research, we investigated serum biomarkers for predicting POD and found that the serum level of HMGB1 24 h after surgery can be used to predict the occurrence of POD in elderly patients undergoing total hip arthroplasty.

Postoperative patients often experience a massive release of inflammatory mediators in the body, such as cytokines, inflammatory cells and immune cells, all of which can pass through the blood-brain barrier to trigger an inflammatory response that causes toxic effects on neurons, resulting in the occurrence of POD.¹⁸^,¹⁹ A growing body of research has demonstrated a strong association between the inflammatory state of patients after surgery and the development of POD. Zhang et al. showed that serum levels of IL-6, CRP and TNF-α in POD patients increased significantly early after surgery, and gradually decreased on the 3^rd day after surgery, which is consistent with our research results.²⁰ Other evidence also suggested that high preoperative plasma IL-6 levels were significantly correlated with the onset of POD.²¹ In addition, a meta-analysis indicated that IL-6 appears to be a consistent predictor of delirium in surgical samples, while CRP cannot predict the occurrence of delirium in patients after surgery.²² Interestingly, another meta-analysis confirmed that early postoperative CRP levels in POD patients were substantially increased compared to non-POD patients and could predict the onset of POD. The results in Figure 1 showed that postoperative serum IL-1β and IL-6 levels in POD patients were significantly elevated compared to non-POD patients, with no significant difference in CRP levels. The different results of these studies may be related to the age of the study participants, sample size and the time of serum collection.

High-mobility group box 1 can activate inflammatory cells and promote the release of inflammatory mediators such as IL-6 and IL-1β by binding to Toll-like receptors (TLR) 2, 4 and 9.²³ Additionally, HMGB1 can also activate the NF-κB signaling pathway, further promoting the occurrence and progression of inflammation.²⁴ Therefore, we analyzed the correlation between serum HMGB1 and inflammatory factor levels in elderly patients undergoing total hip arthroplasty. The results in Table 2 showed that serum HMGB1 levels were positively correlated with IL-6 and IL-1β, which is consistent with the results of Kim et al.,²⁵ Kamiya et al.²⁶ and Huo et al.²⁷ We further analyzed the difference in serum HMGB1 levels between POD patients and non-POD patients and found that serum HMGB1 levels were significantly elevated in POD patients (Figure 1). This may be related to the upregulation of HMGB1, which can promote neuroinflammation and enhance cognitive impairment in related brain diseases.²⁸ In addition, as shown in Figure 2, our study also revealed that HMGB1 can serve as a potential predictive biomarker for POD in elderly patients undergoing total hip arthroplasty, suggesting a potential underlying association between HMGB1 and the occurrence of POD. It has been reported that HMGB1 disrupts the blood–brain barrier and releases pro-inflammatory cytokines, which in turn impairs synaptic plasticity and disrupts memory formation and maintenance, leading to postoperative cognitive dysfunction.²⁹ Furthermore, evidence suggests that the inhibition of HMGB1-related signaling pathways can mediate hippocampal neuroinflammation and regulate M1/M2 polarization, thereby providing neuroprotective effects.³⁰ These studies elucidate the specific mechanisms underlying the association between HMGB1 and POD. Additionally, in Table 4, logistic regression analysis demonstrated that increased postoperative serum HMGB1 levels are a risk factor for POD, implying that HMGB1 may serve as a novel therapeutic target for POD. This possibility has already been explored in animal studies, such as by Li et al., who showed that the downregulation of HMGB1 may activate new protective measures, preventing delayed neurocognitive recovery after challenges such as anesthesia and surgery.28 Other evidence indicates that HMGB1 mediates postoperative neuroinflammation and may have a direct impact on POD and cognitive dysfunction¹⁴ while inhibiting the HMGB1/RAGE/TLR4 signaling pathway could emerge as a potential novel therapeutic approach for mitigating HMGB1-induced neuroinflammation, seizures and cognitive impairment.³¹

Limitations

This study has some limitations. First, the sample size was relatively small. Second, our analysis assessed only a small number of inflammatory factors, which may have excluded other potentially relevant variables. Third, the probability of type 1 errors was not controlled, and inferences about statistical significance may be unreliable. Lastly, the molecular mechanisms underlying the involvement of HMGB1 in POD development remain unclear and warrant further investigation.

Conclusions

Our results suggested that the serum HMGB1 levels were markedly enhanced in elderly POD patients undergoing total hip arthroplasty. In addition, HMGB1 could serve as a potential predictive biomarker for POD in elderly patients undergoing total hip arthroplasty. This study may provide new targets and a comprehensive approach for treating elderly patients with POD.

Supplementary data

The Supplementary materials are available at https://doi.org/10.5281/zenodo.11093429. The package includes the following files:

Supplementary Table 1. Data distribution.

Supplementary Table 2. SPSS output for homogeneity of variance teste and Student t-test.

Supplementary Table 3. SPSS output for paired sample t-test.

Supplementary Table 4. SPSS output for Student t-test bootstrap.

Supplementary Table 5. The assumptions of the LDA.

Supplementary Table 6. The assumptions of logistic regression.

Supplementary Table 7. SPSS output for logistic regression analysis.

Supplementary Fig. 1. Scatter plots of Pearson correlation.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Consent for publication

Not applicable.

Tables

Table 1. Demographic and clinical data of all study participants

Variable	POD group (n = 83)	non-POD group (n = 204)	p-value
Age [years]	76 (12)	77 (12)	0.275
Sex, female (%)	45 (54.22)	117 (57.35)	0.679
BMI [kg/m²]	25.35 ±2.18	25.34 ±2.31	0.996
SBP [mm Hg]	123.03 ±13.60	120.68 ±14.41	0.204
DBP [mm Hg]	76.63 ±8.23	77.31 ±8.51	0.536
History of disease
Hypertension, n (%)	38 (45.78)	89 (43.63)	0.760
Diabetes, n (%)	15 (18.07)	31 (15.20)	0.586
Coronary heart disease, n (%)	19 (22.89)	33 (16.18)	0.231
ASA classification	2 (2)	2 (2)	0.991
Surgical time [min]	152.49 ±17.47	135.65 ±15.88	<0.001
Anesthesia time [min]	176.60 ±21.63	155.32 ±18.22	<0.001
Intraoperative blood loss [mL]	31.23 ±6.50	31.38 ±6.25	0.851

POD – postoperative delirium; BMI – body mass index; SBP – systolic blood pressure; DBP – diastolic blood pressure; ASA – American Society of Anesthesiologists. Continuous data presented non-normal distribution (age and ASA classification) were expressed as median (interquartile range (IQR)) and analyzed with Mann–Whitney U test. Continuous data presented normal distribution (BMI, SBP, DBP, surgical time, anesthesia time, and intraoperative blood loss) were expressed by mean ±standard deviation (±SD) and analyzed using Student’s t-test, while χ² test was used for comparing rates (sex and history of disease).

Table 2. Correlation analysis among HMGB1, TNF-α, IL-6, IL-1β, and CRP

Variables		HMGB1	CRP	IL-6	IL-1β	TNF-α
HMGB1	Pearson’s correlation	1	–0.001	0.136	0.221	0.089
HMGB1	p-value	–	0.988	0.021	<0.001	0.132
CRP	Pearson’s correlation	–0.001	1	0.066	0.060	0.090
CRP	p-value	0.988	–	0.267	0.315	0.129
IL-6	Pearson’s correlation	0.136	0.066	1	–0.003	0.026
IL-6	p-value	0.021	0.267	–	0.956	0.656
IL-1β	Pearson’s correlation	0.221	0.060	–0.003	1	0.123
IL-1β	p-value	<0.001	0.315	0.956	–	0.038
TNF-α	Pearson’s correlation	0.089	0.090	0.026	0.123	1
TNF-α	p-value	0.132	0.129	0.656	0.038	–

HMGB1 – high-mobility group box 1; IL – interleukin; TNF-α – tumor necrosis factor alpha; CRP-C –reactive protein. Pearson’s correlation analysis was employed to assess the relationship between serum biomarkers.

Table 3. Linear discriminant analysis for classify patients with postoperative delirium (POD)

Statistical method	Accuracy (%)	Error (%)	Sensitivity (%)	Specificity (%)
LDA	78.7	21.3	75.9	79.9

LDA – linear discriminant analysis.

Table 4. Logistic regression for POD in elderly patients undergoing total hip arthroplasty

Variables	Wald	OR	95% CI	p-value
Age	0.957	1.023	0.977–1.071	0.328
Sex	0.386	1.230	0.640–2.361	0.535
BMI	0.174	1.031	0.893–1.190	0.677
SBP	1.286	0.987	0.964–1.010	0.257
DBP	0.244	1.009	0.972–1.048	0.621
ASA classification	0.119	1.073	0.718–1.605	0.731
Intraoperative blood loss	0.008	0.998	0.947–1.051	0.927
Anesthesia time	32.653	0.950	0.934–0.967	<0.001
Surgical time	30.787	0.942	0.922–0.962	<0.001
HMGB1	40.774	0.954	0.940–0.968	<0.001
CRP	1.467	0.999	0.996–1.001	0.266
IL-6	12.601	0.923	0.883–0.965	<0.001
IL-1β	12.130	0.964	0.944–0.984	<0.001
TNF-α	15.898	0.914	0.874–0.955	<0.001

POD – postoperative delirium; OR – odds ratio; 95% CI – 95% confidence interval; BMI – body mass index; SBP – systolic blood pressure; DBP – diastolic blood pressure; ASA – American Society of Anesthesiologists; HMGB1 – high-mobility group box 1; IL – interleukin; TNF-α – tumor necrosis factor alpha; CRP-C – reactive protein.

Figures

Fig. 1. Dynamic changes of all serum biomarkers during the postoperative period

HGMB1 – high mobility group box 1; IL – interleukin; CRP – C-reactive protein; TNF-α – tumor necrosis factor alpha; POD – postoperative delirium.

Fig. 2. ROC curves of HMGB1 in the occurrence of POD in elderly patients undergoing total hip arthroplasty

ROC – receiver operating characteristic; AUC – area under the ROC curve; 95% CI – 95% confidence interval; HGMB1 – high mobility group box 1; IL – interleukin; CRP – C-reactive protein; TNF-α – tumor necrosis factor alpha; POD – postoperative delirium.

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