Effects of sub-anesthetic dose esketamine on serum matrix metalloproteinase-9 and postoperative delirium in elderly patients undergoing hip replacement

doi:10.12092/j.issn.1009-2501.2026.05.007

Abstract

Abstract:

AIM: To evaluate the effects of subanesthetic dose of esketamine on serum matrix metalloproteinase-9 (MMP-9) and postoperative delirium (POD) in elderly patients undergoing hip replacement. METHODS: From February 2024 to March 2025, 110 elderly patients aged 65-79 years undergoing elective hip replacement under general anesthesia in our hospital were randomly divided into esketamine group (group E, n=55) and control group ( group C, n=55). Patients in group E were given esketamine (loading dose 0.2 mg/kg, followed by continuous infusion at a rate of 0.1 mg·kg^?¹·h^?¹), while patients in group C were given an equal volume of normal saline (loading dose 0.2 mL/kg, followed by continuous infusion at a rate of 0.1 mL·kg^?¹·h^?¹). POD was assessed by the confusion assessment method for the intensive care unit (CAM-ICU) at 3 days after operation. The serum concentrations of MMP-9, interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected by venous blood sampling before operation, 1 d and 3 d after operation. The quality of recovery was assessed using the 15-item quality of recovery questionnaire (QoR-15) at 1 and 2 days after surgery, and the time to first ambulation and length of hospital stay were recorded. RESULTS: Compared with Group C, Group E showed a significantly lower incidence of POD (9.1% vs. 23.6%, χ²=4.251, P=0.039), along with reduced severity (3.1±1.1 vs. 4.2±1.6 score, t=4.201, P<0.001) and shorter duration of POD (1.1±0.7 vs. 2.2±0.9 days, t=7.155, P<0.001). Serum concentrations of MMP-9, IL-6, and IL-1β in Group E were significantly lower than those in Group C at postoperative day 1 and day 3 (all P<0.001). Compared to Group C, Group E demonstrated significantly higher QoR-15 scores [postoperative day 1: (114.1±7.4) vs. (91.3±5.3) score; postoperative day 2: (126.1±8.5) vs. (103.2±6.3) score, both P<0.001] and earlier ambulation time (27.6±3.7 vs. 31.4±3.3 h, P<0.001). The total incidence of intraoperative and postoperative adverse events was similar between the two groups (P>0.05). CONCLUSION: Subanesthetic-dose esketamine significantly reduces the incidence of POD and serum levels of MMP-9, IL-6, and IL-1β, improves postoperative recovery quality, and does not increase perioperative adverse events in elderly patients undergoing hip replacement, providing an effective strategy for optimizing anesthesia management in geriatric populations.

Key words: esketamine, matrix metalloproteinase-9, postoperative delirium, orthopedic surgery, elderly

CLC Number:

R614
R687.3

Guangli JIN, Lisha SU, Lipin WANG, Qimin WANG. Effects of sub-anesthetic dose esketamine on serum matrix metalloproteinase-9 and postoperative delirium in elderly patients undergoing hip replacement[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(5): 631-638.

Figures/Tables 6

References 21

1	Mao M, Wang LY, Zhu LY, et al. Higher serum PGE2 is a predicative biomarker for postoperative delirium following elective orthopedic surgery in elderly patients [J]. BMC Geriatr, 2022, 22(1): 685. Erratum in: BMC Geriatr, 2022, 22(1): 735.
2	Deblois S, Bergeron N, Vu TTM, et al. The prevention and treatment of postoperative delirium in the elderly: a narrative systematic review of reviews[J]. J Patient Saf, 2025, 21 (3): 174- 192. doi: 10.1097/PTS.0000000000001318
3	Marshall TJ, Watne LO, Sanders RD. Mechanisms of perioperative neuronal injury and the search for therapies[J]. Br J Anaesth, 2025, 134 (4): 906- 908. doi: 10.1016/j.bja.2024.12.032
4	Hu Y, Hu XD, He ZQ, et al. Anesthesia/surgery activate MMP9 leading to blood-brain barrier disruption, triggering neuroinflammation and POD-like behavior in aged mice[J]. Int Immunopharmacol, 2024, 135, 112290. doi: 10.1016/j.intimp.2024.112290
5	Swarbrick CJ, Partridge JSL. Evidence-based strategies to reduce the incidence of postoperative delirium: a narrative review [J]. Anaesthesia, 2022, 77Suppl1: 92-101.
6	Zheng H, Zhang P, Shi S, et al. Sub-anesthetic dose of esketamine decreases postoperative opioid self-administration after spine surgery: a retrospective cohort analysis[J]. Sci Rep, 2024, 14 (1): 3909. doi: 10.1038/s41598-024-54617-5
7	Wang C, Zhang L, Li Y, et al. Esketamine for prevention of postoperative delirium in elderly patients undergoing orthopedic surgery: a randomized controlled trial[J]. J Clin Anesth, 2024, 89, 111567.
8	Salis F, Costaggiu D, Mandas A. Mini-mental state examination: optimal cut-off levels for mild and severe cognitive impairmen t[J]. Geriatrics (Basel), 2023, 8 (1): 12. doi: 10.3390/geriatrics8010012
9	Xie K, Chen J, Tian L, et al. Postoperative infusion of dexmedetomidine via intravenous patient-controlled analgesia for prevention of postoperative delirium in elderly patients undergoing surgery[J]. Aging Clin Exp Res, 2023, 35 (10): 2137- 2144. doi: 10.1007/s40520-023-02497-6
10	Lorenzen MD, Pedersen CF, Carreon LY, et al. Measuring quality of recovery (QoR-15) after degenerative spinal surgery: a prospective observational study[J]. Brain Spine, 2024, 4, 102767. doi: 10.1016/j.bas.2024.102767
11	Mattimore D, Fischl A, Christophides A, et al. Delirium after cardiac surgery-a narrative review[J]. Brain Sci, 2023, 13 (12): 1682. doi: 10.3390/brainsci13121682
12	Desikan SK, Mayorga-Carlin M, Dux MC, et al. Lack of association between cognitive impairment and systemic inflammation in asymptomatic carotid stenosis[J]. J Vasc Surg, 2022, 75 (5): 1643- 1650. doi: 10.1016/j.jvs.2021.11.061
13	Ji Y, Huang W, Chen Y, et al. Inhibition of MMP-2 and MMP-9 attenuates surgery-induced cognitive impairment in aged mice[J]. Brain Res Bull, 2023, 204, 110810. doi: 10.1016/j.brainresbull.2023.110810
14	Wang Y, Cao M, Zhang Y, et al. The CB2-PKC pathway is involved in esketamine-induced anti-inflammation in BV-2 microglial cells exposed to lipopolysaccharides[J]. Am J Transl Res, 2024, 16 (9): 4466- 4478. doi: 10.62347/RRZF5229
15	Han C, Ji H, Guo Y, et al. Effect of subanesthetic dose of esketamine on perioperative neurocognitive disorders in elderly undergoing gastrointestinal surgery: a randomized controlled trial[J]. Drug Des Devel Ther, 2023, 17, 863- 873. doi: 10.2147/DDDT.S401161
16	谢海辉, 杜巍, 周建平, 等. 老年肺叶切除术患者围术期血清基质金属蛋白酶-9及脂联素浓度与术后谵妄的关系[J]. 临床麻醉学杂志, 2019, 35 (2): 152- 155.
17	Ha WS, Choi BK, Yeom J, et al. Development and validation of machine learning models to predict postoperative delirium using clinical features and polysomnography variables[J]. J Clin Med, 2024, 13 (18): 5485. doi: 10.3390/jcm13185485
18	Wei Q, Li M, Du Q, et al. Effect of esketamine on postoperative depression in women with breast cancer and preoperative depressive symptoms: the EASE randomized trial[J]. J Clin Anesth, 2025, 103, 111821. doi: 10.1016/j.jclinane.2025.111821
19	Myles PS. Structural validity of the 15-item quality of recovery scale[J]. Br J Anaesth, 2021, 127 (4): e138- e139. doi: 10.1016/j.bja.2021.07.006
20	李宁, 张会, 周俊辉. 亚麻醉剂量艾司氯胺酮对乳腺癌根治术后慢性疼痛的影响[J]. 中国临床药理学与治疗学, 2024, 29 (6): 671- 679.
21	康小雨, 宋思明, 钟玉玲, 等. 艾司氯胺酮联合胸横肌平面阻滞对心脏瓣膜置换术患者应激反应和炎症水平的影响[J]. 实用医学杂志, 2024, 40 (21): 3082- 3089.

Items	C group	E group	χ2 value/t value	P value
Gender (male/female, cases)	32/23	29/26	0.331	0.565
Age (years, $ \overline{x} $±s)	71.4±3.7	71.9±3.9	0.690	0.492
ASA grade (Ⅱ/Ⅲ, cases)	38/17	40/15	0.176	0.675
BMI (kg/m², $ \overline{x} $±s)	22.7±2.6	22.3±2.8	0.776	0.439
Smoking history [n(%)]	15(27.3)	13(23.6)	0.192	0.661
Drinking history [n(%)]	17(30.9)	19(34.5)	0.165	0.685
Hypertension [n(%)]	10(18.2)	9(16.4)	0.064	0.800
Diabetes [n(%)]	7(12.7)	10(18.2)	0.626	0.429
Coronary heart disease [n(%)]	3(5.5)	5(9.1)	0.539	0.463
LVEF (%, $ \overline{x} $±s)	64.5±4.6	64.9±5.2	0.427	0.670
Preoperative FEV₁/FVC (%, $ \overline{x} $±s)	75.7±5.5	76.0±5.6	0.284	0.777
Preoperative PaO₂ (mmHg, $ \overline{x} $±s)	95.9±4.8	96.2±4.6	0.335	0.739
Preoperative PaCO₂ (mmHg,$ \overline{x} $±s)	40.9±3.3	41.1±3.1	0.328	0.745
Basic oxygen saturation (%, $ \overline{x} $±s)	97.4±1.8	97.1±1.6	0.924	0.358
Years of education (years, $ \overline{x} $±s)	12.5±1.6	12.9±2.1	1.124	0.264
MMSE scale (score, $ \overline{x} $±s)	28.3±1.9	28.7±2.0	1.075	0.285
Operation time (min, $ \overline{x} $±s)	116.7±8.9	114.5±9.3	1.267	0.208
Duration of anesthesia (min, $ \overline{x} $±s)	130.6±8.6	132.6±8.6	1.220	0.225
Remifentanil consumption (mg, $ \overline{x} $±s)	2.1±0.6	2.2±0.5	0.950	0.345
Sufentanil consumption (μg, $ \overline{x} $±s)	154.0±19.5	150.9±21.1	0.800	0.425
Propofol consumption (mg, $ \overline{x} $±s)	685.5±89.3	678.2±92.1	0.422	0.674
Mean intraoperative BIS value (score, $ \overline{x} $±s)	48.2±3.5	49.1±3.8	1.292	0.199
Blood loss (mL, $ \overline{x} $±s)	145.6±28.1	141.6±27.8	0.751	0.455
Fluids intake (mL, $ \overline{x} $±s)	1238.5±322.8	1224.3±288.6	0.243	0.808
Duration of mechanical ventilation (h, $ \overline{x} $±s)	143.7±12.5	144.2±11.9	0.215	0.830
Awakening time (min, $ \overline{x} $±s)	9.5±4.0	9.8±3.8	0.403	0.688
PACU stay time (min, $ \overline{x} $±s)	56.5±6.2	57.0±8.5	0.352	0.725

Items	C group	E group	χ2 value/t value	P value
Gender (male/female, cases)	32/23	29/26	0.331	0.565
Age (years, $ \overline{x} $±s)	71.4±3.7	71.9±3.9	0.690	0.492
ASA grade (Ⅱ/Ⅲ, cases)	38/17	40/15	0.176	0.675
BMI (kg/m², $ \overline{x} $±s)	22.7±2.6	22.3±2.8	0.776	0.439
Smoking history [n(%)]	15(27.3)	13(23.6)	0.192	0.661
Drinking history [n(%)]	17(30.9)	19(34.5)	0.165	0.685
Hypertension [n(%)]	10(18.2)	9(16.4)	0.064	0.800
Diabetes [n(%)]	7(12.7)	10(18.2)	0.626	0.429
Coronary heart disease [n(%)]	3(5.5)	5(9.1)	0.539	0.463
LVEF (%, $ \overline{x} $±s)	64.5±4.6	64.9±5.2	0.427	0.670
Preoperative FEV₁/FVC (%, $ \overline{x} $±s)	75.7±5.5	76.0±5.6	0.284	0.777
Preoperative PaO₂ (mmHg, $ \overline{x} $±s)	95.9±4.8	96.2±4.6	0.335	0.739
Preoperative PaCO₂ (mmHg,$ \overline{x} $±s)	40.9±3.3	41.1±3.1	0.328	0.745
Basic oxygen saturation (%, $ \overline{x} $±s)	97.4±1.8	97.1±1.6	0.924	0.358
Years of education (years, $ \overline{x} $±s)	12.5±1.6	12.9±2.1	1.124	0.264
MMSE scale (score, $ \overline{x} $±s)	28.3±1.9	28.7±2.0	1.075	0.285
Operation time (min, $ \overline{x} $±s)	116.7±8.9	114.5±9.3	1.267	0.208
Duration of anesthesia (min, $ \overline{x} $±s)	130.6±8.6	132.6±8.6	1.220	0.225
Remifentanil consumption (mg, $ \overline{x} $±s)	2.1±0.6	2.2±0.5	0.950	0.345
Sufentanil consumption (μg, $ \overline{x} $±s)	154.0±19.5	150.9±21.1	0.800	0.425
Propofol consumption (mg, $ \overline{x} $±s)	685.5±89.3	678.2±92.1	0.422	0.674
Mean intraoperative BIS value (score, $ \overline{x} $±s)	48.2±3.5	49.1±3.8	1.292	0.199
Blood loss (mL, $ \overline{x} $±s)	145.6±28.1	141.6±27.8	0.751	0.455
Fluids intake (mL, $ \overline{x} $±s)	1238.5±322.8	1224.3±288.6	0.243	0.808
Duration of mechanical ventilation (h, $ \overline{x} $±s)	143.7±12.5	144.2±11.9	0.215	0.830
Awakening time (min, $ \overline{x} $±s)	9.5±4.0	9.8±3.8	0.403	0.688
PACU stay time (min, $ \overline{x} $±s)	56.5±6.2	57.0±8.5	0.352	0.725

Group	Time points	MMP-9 concentration (ng/mL)	IL-6 concentration (pg/mL)	IL-1β concentration (pg/mL)
C	Preoperative 1 d	177.8±34.6	23.9±5.5	37.4±9.6
	Postoperative 1 d	467.3±56.7	60.8±9.6	75.6±13.8
	Postoperative 3 d	334.0±43.2	49.6±7.8	59.8±11.3
E	Preoperative1 d	183.5±37.3	24.4±5.2	38.7±10.7
	Postoperative 1 d	332.3±41.6	51.7±8.4	60.3±12.1
	Postoperative 3 d	220.3±39.7	41.3±7.6	48.5±8.6
	F_{between-group}/P_{between-group}	27.416/<0.001	18.953/<0.001	24.657/<0.001
	F_time/P_time	112.358/<0.001	89.247/<0.001	67.519/<0.001
	F_interaction/P_interaction	15.732/<0.001	9.846/<0.001	12.394/<0.001

Group	Time points	MMP-9 concentration (ng/mL)	IL-6 concentration (pg/mL)	IL-1β concentration (pg/mL)
C	Preoperative 1 d	177.8±34.6	23.9±5.5	37.4±9.6
	Postoperative 1 d	467.3±56.7	60.8±9.6	75.6±13.8
	Postoperative 3 d	334.0±43.2	49.6±7.8	59.8±11.3
E	Preoperative1 d	183.5±37.3	24.4±5.2	38.7±10.7
	Postoperative 1 d	332.3±41.6	51.7±8.4	60.3±12.1
	Postoperative 3 d	220.3±39.7	41.3±7.6	48.5±8.6
	F_{between-group}/P_{between-group}	27.416/<0.001	18.953/<0.001	24.657/<0.001
	F_time/P_time	112.358/<0.001	89.247/<0.001	67.519/<0.001
	F_interaction/P_interaction	15.732/<0.001	9.846/<0.001	12.394/<0.001

Group	Postoperative 1 d	Postoperative 2 d	Duration of first ambulation after operation (h)	Length of postoperative hospital stay (d)
C	91.3±5.3	103.2±6.3	31.4±3.3	9.2±1.9
E	114.1±7.4	126.1±8.5	27.6±3.7	9.0±1.4
t value	18.580	16.050	5.684	0.629
P value	<0.001	<0.001	<0.001	0.531