Effect of liposomal bupivacaine for iliac fascia block on postoperative cognitive dysfunction in patients with femoral neck fractures

Abstract

BACKGROUND

Neuroinflammation and circadian rhythm disruption caused by pain are the primary causes of postoperative cognitive dysfunction. We hypothesize that the administration of liposomal bupivacaine (LB) for fascia iliaca compartment block (FICB) can alleviate pain intensity in patients with femoral neck fractures and reduce the incidence of postoperative cognitive dysfunction.

AIM

To explore the efficacy of LB for postoperative analgesia through FICB and their role in reducing cognitive dysfunction.

METHODS

Eighty patients aged ≥ 65 years with femoral neck fractures were enrolled and randomly divided into the LB group and the control group according to different analgesic methods. The LB group received 0.266% LB solution via ultrasound-guided supra-inguinal FICB 1 day before surgery, while the control group did not receive FICB. Both groups were connected to a patient-controlled intravenous analgesia pump for postoperative analgesia. Comparisons were made between the two groups regarding resting and exercise visual analog scale (VAS) scores at 12 hours, 24 hours, and 48 hours after surgery, the dosage of sufentanil in the analgesia pump, the mini-mental state examination (MMSE) scores 1 day before surgery and 1 day, 3 days, and 7 days after surgery, the Pittsburgh Sleep Quality Index (PSQI) scores, postoperative blood glucose and serum cortisol levels, and related adverse reactions.

RESULTS

The mean arterial pressure was lower upon entering the operating room (T1) (P = 0.009) and 12 hours after surgery (T3) (P = 0.037) in the LB group than in the control group. The hazard ratio (HR) was lower at T1 (P = 0.000) and T3 (P = 0.000) in the LB group than in the control group. The blood glucose at T1 (P = 0.008), 6 hours after surgery (P = 0.000), T3 (P = 0.009), and 48 hours after surgery (T5) (P = 0.000) were lower in the LB group than in the control group. The serum cortisol levels at T1 (P = 0.028) and T3 (P = 0.14) were lower in the LB group than in the control group. The resting and exercise VAS scores at T1 (P = 0.000), T3 (P = 0.002), 1 day after surgery (P = 0.000) and T5 (P = 0.000) were lower in the LB group than in the control group. The sufentanil dose was significantly lower in the LB group than in the control group (P = 0.004). The MMSE scores at T1 (P = 0.000), 3 days after surgery (P = 0.000), 7 days after surgery (P = 0.000) were lower in the control group than in the LB group. The PSQI scores were lower in the LB group than in the control group (P = 0.000). The incidences of postoperative nausea and vomiting (P = 0.041) and excessive sleepiness (P = 0.01) were significantly lower in the LB group than in the control group.

CONCLUSION

FICB with liposomal bupivacaine can provide continuous analgesia for patients undergoing femoral neck fracture surgery, significantly alleviating pain and anxiety, improving sleep quality, reducing opioid consumption, lowering the incidence of nausea and vomiting, and accelerating postoperative recovery.

Key Words: Liposomal bupivacaine; Fascia iliaca compartment block; Femoral neck fracture; Postoperative cognitive dysfunction; Postoperative pain; Postoperative analgesia

Core Tip: This study employed an innovative approach by utilizing a bupivacaine liposome solution for preoperative iliofascial block in patients with femoral neck fractures. By assessing cognitive function scores, plasma cortisol levels, sleep quality evaluation scales, and resting and exercise visual analog scale scores, we found that patients receiving this anesthetic technique experienced enhanced postoperative recovery quality. Consequently, this approach also mitigated the severity of postoperative cognitive dysfunction.

INTRODUCTION

With the rapid aging of the global population, femoral fractures have become a major public health concern worldwide. It is estimated that by 2050, the number of cases will reach 2.26 million[1]. Surgical treatment is crucial for restoring fracture stability and function. However, elderly patients who do not receive adequate perioperative analgesia are significantly more likely to experience postoperative delirium and postoperative cognitive dysfunction (POCD)[2,3]. POCD refers to a sudden decline in orientation, memory, and spatial cognitive abilities following surgery and anesthesia in patients with no preoperative abnormalities. Studies have shown that the incidence of POCD within 1 week after major non-cardiac surgery in elderly patients is as high as 25%[4]. Research has found that among elderly patients undergoing total hip replacement and total knee replacement, the median incidence of POCD is 19.3% within 1 week, decreasing to 10% at 3 months[5]. Transient cognitive dysfunction is often overlooked, but such neurological impairment may persist long-term and even progress to dementia. POCD is associated with postoperative recovery outcomes, prolonged hospital stays, increased hospitalization costs, long-term rehabilitation, and higher mortality rates. Therefore, effectively preventing POCD in elderly patients is of paramount importance.

The pathophysiological mechanisms underlying POCD remain unclear, and interventions for POCD continue to be a major focus of clinical anesthesia research. Factors such as neuroinflammation, oxidative stress, β-amyloid protein, and phosphorylated Tau protein have partially explained the pathogenesis of cognitive dysfunction[6]. Neuroinflammation is a primary contributing factor in elderly POCD patients. Surgical trauma leads to hippocampal neuronal apoptosis, reduced neuronal plasticity, and impaired synaptic plasticity, while activating hippocampal microglia and astrocytes. This activation triggers the release of large amounts of chemokines, cytokines, reactive oxygen species, and pro-inflammatory mediators, ultimately inducing neuroinflammation and affecting cognitive function[7]. Another significant factor influencing POCD is circadian rhythm disruption. Decreased melatonin secretion, increased corticosteroid secretion, reduced sleep quality, and acute sleep deprivation caused by pain all contribute to postoperative POCD in elderly patients[8].

Based on the analysis of the influencing factors of POCD mentioned above, comprehensive perioperative analgesia is important in reducing the incidence of POCD. The fascia iliaca compartment block (FICB) is a commonly used regional nerve block technique for lower limb surgery. It works by injecting local anesthetics into the space between the iliaca fascia and the iliopsoas muscle, blocking nerve conduction in related nerves within the compartment, including the femoral nerve, obturator nerve, and lateral femoral cutaneous nerve, thereby providing anesthesia and analgesia[9,10]. Compared to lumbar plexus nerve block, FICB involves shallower puncture depth, higher safety, and reliable analgesic effects, making it particularly suitable for pain management in hip, femoral, and lower limb surgeries[11].

Liposomal bupivacaine (LB) injection is a novel ultra-long-acting local anesthetic. It is a multivesicular liposomal formulation containing bupivacaine, which slowly degrades through internal fusion and splitting. A single dose provides postoperative wound analgesia for up to 72 hours, significantly extending the duration of action of local anesthetics[12]. Low-concentration LB solutions offer prolonged analgesic effects without compromising postoperative limb motor function. LB exhibits steady release and stable blood concentrations, making it an ideal choice for multimodal postoperative analgesia[13].

Based on the above theoretical support, this study proposes that using LB to perform FICB may alleviate the pain and stress response caused by femoral neck fractures in elderly patients, improve their perioperative sleep quality, and ultimately reduce the degree of POCD.

MATERIALS AND METHODS

Study design

The prospective, double-blind, randomized controlled clinical trial was conducted from April 2023 to December 2024 at the First Affiliated Hospital of Hebei North University. The trial conformed to the Declaration of Helsinki and was approved by hospital ethics committee (No. K2023384). The study registered with the Chinese Clinical Trial Registry (https://www.chictr.org.cn/, Identifier: ChiCTR2400082621) on April 2, 2024. Before enrolling, all patients provided written informed consent. The primary endpoint was the incidence of POCD at 1 week after surgery.

Patients were randomly divided into two groups, the LB group and the control group, using the random number table method, with 50 patients in each group. In group LB, supra-inguinal FICB (S-FICB) on the affected side was performed under ultrasound guidance at 18:00 the day before surgery. Patients were placed in the supine position with the affected lower limb slightly abducted (15°-20°). The groin ligament area of the affected limb was disinfected. A SonoScape color Doppler ultrasound high-frequency linear array probe (6-13 MHz) was selected and covered with a sterile ultrasound probe sheath. The probe was placed in the sagittal plane across the groin ligament, and the abdominal wall muscles, sartorius muscle, ilium, iliacus muscle, and iliac fascia were sequentially located by sliding the probe. Using the in-plane puncture technique, a 22 G puncture needle was inserted caudal to the probe. The iliac fascia was punctured below the deep circumflex iliac artery. After aspiration to confirm the absence of blood, 1 mL of drug solution was injected to confirm the needle tip position. After confirming the correct position, LB solution (10 mL of LB + 40 mL of 0.9% normal saline; for patients weighing < 50 kg: 20 mL; 50-70 kg: 25 mL; > 70 kg: 30 mL) (Jiangsu Hengrui Medicine Co., Ltd., National Medicine Approval Number: H20223899, specification: 20 mL: 266 mg) was administered according to the patient's body weight. During drug administration, drug solution diffusion between the iliac fascia and the iliopsoas muscle was observed under ultrasound. After drug administration, the patient’s vital signs were monitored. The control group received no treatment. Thirty minutes after drug injection, alcohol cotton balls were used to test temperature sensation and compared with the non-blocked area on the contralateral side. The absence of sensation in the blocked area indicated successful nerve block.

Participants

A total of 100 patients with femoral neck fractures were recruited for the study. The inclusion criteria were as follows: (1) Age ≥ 65 years; (2) American Society of Anesthesiologists (ASA) classification I to III; and (3) Complete data that align with the diagnosis of femoral neck fracture. The exclusion criteria included: (1) Severe dysfunction of vital organs; (2) Language barriers or central nervous system diseases; (3) Mini-mental state examination (MMSE) score below[14] the minimum threshold corresponding to their educational level (≤ 20 points for those with primary school education, and ≤ 24 points for those with secondary school education or above); (4) Mental disease, drug dependency, or alcoholism; and (5) Patients with dementia before surgery.

Power calculation and estimated sample size

Due to the extreme difficulty in evaluating POCD in elderly patients with fractures, many patients already have cognitive dysfunction before surgery. Therefore, estimating the sample size based on the incidence of POCD after surgery would lead to significant bias. Thus, this study did not calculate the incidence of POCD before and after surgery, but estimated the sample size to a certain extent through the difference in the MMSE score of the cognitive function scale. Moreover, because the pre-experimental MMSE score data were not normally distributed and showed unequal variances, a two-sample unequal-variance t-test was used for sample size estimation based on the pre-experimental results. Using the observed difference in the most recent MMSE scores before and after surgery in patients with femoral neck fractures, a sample size of 43 patients per group provides 80.093% power to reject the null hypothesis of equal means at a significance level (α) of 0.10. This calculation assumes a population mean difference of -2.7 (24.4 vs 27.2) with standard deviations of 6.3 and 3.4 in the two groups, respectively, using a two-sided unequal-variance t-test.

Randomization and blinding

The patients were randomly assigned to either the LB group or control group at a 1:1 ratio. A nurse not involved in the trial generated a set of random numbers using a computer program (SPSS version 25.0, IBM, Armonk, NY, United States). The group assignment was hidden in opaque envelopes, which were opened only upon researcher arrival in the treatment room. The data collectors and evaluators were blinded to the group assignments and the patients were asked not to disclose treatment details to other researchers.

Anesthesia methods

Patients in both groups fasted for 8 hours and were prohibited from drinking water for 2 hours before surgery. After entering the operating room, peripheral venous access was established, and electrocardiogram and blood oxygen saturation were monitored. Radial artery puncture was performed under local anesthesia to monitor invasive arterial pressure. Patients in both groups received subarachnoid block with the affected side upward. The L3-4 interspace was selected for puncture. After successful puncture, 2 mL of 0.5% ropivacaine (prepared by mixing 1.5 mL of 1% ropivacaine with 1.5 mL of sterile water for injection) via intrathecal block at an injection rate of 0.12 mL/second[15]. After completing the drug injection, the spinal needle was removed. The patient laid on their side with the fractured limb positioned upward for 10 minutes, then turned to a supine position. Anesthesia levels were monitored, and surgery proceeded once the sensory block reached the T10 dermatome. Changes in vital signs were observed during the operation, and fluid replacement therapy was given. Phenylephrine or ephedrine were used for adjustment according to blood pressure and heart rate (HR) to maintain the pre-operative basal blood pressure. After surgery, patients in both groups were given analgesia using a patient-controlled intravenous analgesia pump [100 μg sufentanil + 100 mL 0.9% normal saline (Yichang Humanwell Pharmaceutical Co., Ltd., National Medicine Approval No. AB50400521, Specification: 1 mL: 50 μg)]. The analgesia pump was set as follows: 2 mL/hour, single-press dose of 1.5 mL, and lock-out time of 15 minutes. During the use of the analgesia pump, if the score on the visual analogue scale (VAS) was still > 3 points, 30 mg ketorolac tromethamine was intravenously injected for rescue analgesia.

Outcomes

The primary outcome was the MMSE scores of patients in the two groups at four time points: 1 day before surgery (T0), 1 day after surgery (T4), 3 days after surgery (T6), and 7 days after surgery (T7). The evaluation criteria for cognitive dysfunction are as follows: ≤ 27 points: Impaired cognitive function; 21-26 points: Mild cognitive impairment; 10-20 points: Moderate cognitive impairment; ≤ 9 points: Severe cognitive impairment[16].

The secondary endpoints were as follows: (1) The mean arterial pressure (MAP) and HR of patients in the two groups at four time points: Preoperation (T0), upon entering the operating room (T1), 6 hours after surgery (T2), and 12 hours after surgery (T3); (2) Blood glucose and serum cortisol levels of patients at T0, T1, T2, and T3; (3) The VAS scores of patients in the two groups at rest and exercise at five time points: T0, T1,T3, 24 hours after surgery (T4), and 48 hours after surgery (T5); (4) The Pittsburgh Sleep Quality Index (PSQI) scores of patients in the two groups; (5) Sufentanil consumption after surgery; and (6) The incidence of nausea and vomiting after surgery.

Statistical analysis

SPSS 25 software was used to conduct statistical analysis on the experimental data. Measurement data conforming to the normal distribution were expressed as mean ± SD, and an independent-sample t-test was used for comparison between groups. Measurement data with non-normal distribution were expressed as median (M) and interquartile range (IQR), and the rank-sum test (Wilcoxon) was used for comparison between groups. Count data were expressed as rates n (%), and a χ² test was used for comparison between groups. A difference was considered statistically significant when (P < 0.05) (bilateral).

RESULTS

Baseline characteristics

A total of 86 patients were included in this study. Among them, 2 patients were excluded due to refusal to participate in the trial, 4 patients were removed because the operation duration was longer than 2 hours and blood loss exceeded 500 mL, and 1 patient was lost to follow-up due to death from postoperative thrombosis. Finally, a total of 80 patients were available for preliminary analysis. There were no statistically significant differences in age, body mass index (BMI), and ASA classification between the two groups of patients (Table 1).

Table 1 Comparison of general data between the two patient groups, n (%)/mean ± SD.

Group	Year	BMI (kg/m2)	ASA
			I	II	III
Control (n = 40)	61.0 ± 7.0	21.8 ± 2.4	5 (12.5)	15 (37.5)	20 (50.0)
LB (n = 40)	60.0 ± 6.5	21.7 ± 2.5	4 (10.0)	11 (27.5)	25 (62.5)
t/χ2 value	0.741	0.073	1.318
P value	0.461	0.942	0.529

BMI: Body mass index; LB: Liposomal bupivacaine; ASA: American Society of Anesthesiologists.

Comparison of MAP and HR at different time points between the two groups

The MAP and HR of patients in both groups progressively decreased at each time point following surgery. Compared with control group, the MAP was lower at T1 and T3 in the LB group, P < 0.05. Compared with control group, the HR was lower at T1 and T3 in the LB group, P < 0.05, (Table 2).

Table 2 Comparison of mean arterial pressure and heart rate at each time point between the two patient groups, median (25^th-75^th percentiles).

	Group	T0	T1	T2	T3
MAP (mmHg)	Control (n = 40)	116.0 (103.0-126.0)	102.0 (88.0-113.0)	91.0 (76.0-101.0)	101.0 (93.0-112.0)
	LB (n = 40)	110.0 (92.0-127.0)	92.0 (87.0-96.0)a	91.0 (80.0-101.0)	99.0 (90.0-100.0)a
z value		-1.261	-2.628	-0.284	-2.082
P value		0.207	0.009	0.776	0.037
Heart rate	Control (n = 40)	90.0 (79.0-108.0)	87.0 (76.0-87.0)	78.0 (71.0-85.0)	85.0 (78.0-92.0)
	LB (n = 40)	85.0 (79.0-94.0)	73 (70.0-76.0)a	76.0 (70.0-83.0)	74 (66.0-80.0)a
z value		-1.136	-4.797	-0.809	-5.109
P value		0.256	0.000	0.419	0.000

^aP < 0.05.

LB: Liposomal bupivacaine; MAP: Mean arterial pressure; T0: 1 day before surgery; T1: Upon entering the operating room; T2: 6 hours after surgery; T3: 12 hours after surgery.

Comparison of blood glucose and serum cortisol levels at different time points between the two groups

Postoperative blood glucose levels of the two groups decreased. Compared with control group, the blood glucose level was lower in the LB group (P < 0.05); compared with control group, the serum cortisol level was lower in the LB group (P < 0.05; Table 3).

Table 3 Comparison of blood glucose and serum cortisol levels at each time point between the two patient groups, median (25^th-75^th percentiles).

Indicator	Group	T0	T1	T2	T3
Blood glucose (mmol/L)	Control (n = 40)	5.18 (4.48-6.06)	4.84 (4.14-5.67)	6.58 (6.38-6.79)	8.85 (7.35-10.15)
	LB (n = 40)	5.12 (4.48-5.78)	4.18 (3.13-5.19)a	5.12 (4.34-6.29)a	7.91 (6.61-8.11)a
z value		-0.380	-2.656	-4.850	-2.622
P value		0.704	0.008	0.000	0.009
Serum cortisol (mmol/L)	Control (n = 40)	86.56 (63.37-110.64)	120.55 (102.65-140.87)		131.65 (113.65-151.87)
	LB (n = 40)	88.54 (70.65-108.87)	20.0 (15.0-27.0)a		126.39 (108.65-142.68)a
t value		-0.318	-2.204		-1.477
P value		0.751	0.028		0.140

^aP < 0.05.

LB: Liposomal bupivacaine; T0: 1 day before surgery; T1: Upon entering the operating room; T2: 6 hours after surgery; T3: 12 hours after surgery.

Comparison of VAS scores for resting pain and exercise pain at different time points between the two groups

Following the administration of anesthesia and intravenous analgesic pumps in both patient groups, VAS scores for both rest and exercise showed a significant reduction compared to preoperative levels. Compared with the control group, the exercise VAS scores at T1, T3, T4, and T5 were lower in the LB group (P < 0.05). Compared with the control group, the rest VAS scores at T1, T3, T4, and T5 were lower in the LB group (P < 0.05; Table 4).

Table 4 Comparison of visual analog scale scores for resting pain and exercise pain at each time point between the two patient groups, median (25^th-75^th percentiles).

Indicator	Group	T0	T1	T3	T4	T5
Rest VAS score	Control (n = 40)	6.0 (5.0-6.0)	6.0 (5.0-6.0)	2.0 (2.0-3.0)	4.0 (3.0-4.0)	4.0 (4.0-5.0)
	LB (n = 40)	6.0 (5.0-6.0)	3.0 (2.0-4.0)a	2.0 (1.0-2.0)a	2.0 (2.0-3.0)a	3.0 (3.0-4.0)a
z value		-0.045	-3.771	-3.053	-4.340	-3.748
P value		0.964	0.000	0.002	0.000	0.000
Exercise VAS score	Control (n = 40)	8.0 (8.0-9.0)	8.0 (6.00-8.00)	3.0 (3.00-4.00)	4.0 (4.00-5.00)	4.0 (4.0-5.0)
	LB (n = 40)	9.0 (8.0-9.0)	4.0 (3.00-4.00)a	2.00 (2.00-3.00)a	3.0 (2.00-4.00)a	4.0 (3.0-4.0)a
z value		-0.783	-2.962	-3.968	-4.547	-3.092
P value		0.433	0.003	0.000	0.000	0.002

^aP < 0.05.

Visual analogue scale score ranges from 0 to 10, 0 = no pain, 10 = worst pain. LB: Liposomal bupivacaine; VAS: Visual analogue scale; T0: One day before surgery; T1: Upon entering the operating room; T2: 6 hours after surgery; T3: 12 hours after surgery; T4: 24 hours after surgery; T5: 48 hours after surgery.

Comparison of MMSE scores at different time points between the two groups

Compared with the LB group, the MMSE scores at T1, T6 and T7 were lower in the control group (P < 0.05; Table 5).

Table 5 Comparison of mini-mental state examination scores of the two patient groups at each time point, median (25^th-75^th percentiles).

Indicator	Group	T0	T1	T6	T7
MMSE (score)	Control (n = 40)	27.0 (26.0-28.0)	27.0 (26.0-28.0)	24.0 (23.0-25.0)	25.0 (24.0-25.0)
	LB (n = 40)	27.0 (26.0-28.0)	28.0 (28.0-28.0)a	27.0 (26.0-280)a	27.0 (27.0-28.0)a
t value		-2.567	-3.624	-6.275	-5.662
P value		0.631	0.000	0.000	0.000

^aP < 0.05.

Mini-mental state examination score ranges from 0 to 30. LB: Liposomal bupivacaine; MMSE: Mini-mental state examination; T0: 1 day before surgery; T1: Upon entering the operating room; T6: 3 days after surgery; T7: 7 days after surgery.

PSQI of the two groups

There were statistically significant differences between the two groups in five aspects: Sleep duration, sleep disorders, hypnotic drugs, daytime dysfunction, and total PSQI score (P < 0.05, Table 6).

Table 6 Comparison of insomnia scale (Pittsburgh Sleep Quality Index) between the two patient groups, median (25^th-75^th percentiles).

Indicator	Group	Sleep quality	Bed time	Sleep duration	Sleep efficiency	Sleep disorder	Hypnotic drugs	Daytime dysfunction	Total score
PSQI	Control (n = 40)	2 (2-3)	3 (2-3)	2 (2-3)	2 (2-3)	3 (2-3)	2 (2-3)	2 (2-3)	17 (16-18)
	LB (n = 40)	2 (2-3)	2 (2-3)	2 (1-3)a	2 (2-3)	2 (1-3)a	2 (2-2)a	2 (2-2)a	14 (13-16)a
z value		-1.153	-1.045	-2.010	-0.437	-2.021	-4.117	-4.189	-4.608
P value		0.249	0.296	0.044	0.662	0.043	0.000	0.000	0.000

^aP < 0.05.

Total score: 21 points, > 5 points indicates poor sleep quality. LB: Liposomal bupivacaine; PSQI: Pittsburgh Sleep Quality Index.

Comparison of adverse reactions and remedial indicators between the two groups

Compared with the control group, the total consumption rate of sufentanil in the LB group was significantly lower (P = 0.004; Table 7). Within 48 hours postoperatively, the incidence of postoperative nausea and vomiting was significantly lower in the LB group (15.0% vs 37.5%; P = 0.041; Table 7); the incidence of excessive sleepiness was significantly lower in the LB group (40.0% vs 7.5%, P = 0.001; Table 7). There were no significant differences between the groups in terms of the incidence of shivering.

Table 7 Comparison of adverse reactions and remedial indicators between the two patient groups, median (25^th-75^th percentiles), n (%).

Group	Remedial indicator		Adverse reactions
	Sufentanil dose	Number of compressions	PONV	Shivering	Excessive sleepiness
Control (n = 40)	81.0 (70.0-91.0)	11.0 (8.0-16.0)	15 (37.5)	7 (17.5)	16 (40.0)
LB (n = 40)	68.0 (66.0-78.0)a	8.0 (5.0-9.0)a	6 (15.0)	3 (7.5)	3 (7.5)
z/χ2 value	-2.855	-3.393	5.230	1.829	11.665
P value	0.004	0.001	0.041	0.311	0.001

^aP < 0.05.

LB: Liposomal bupivacaine; PONV: Postoperative nausea and vomiting.

DISCUSSION

This prospective randomized controlled trial demonstrated that preoperative administration of LB for FICB significantly reduced the degree of POCD following femoral neck fracture surgery. Furthermore, the study found that FICB substantially reduced intraoperative opioid analgesic consumption, alleviated postoperative pain, and lowered the incidence of postoperative nausea and vomiting.

Elderly patients often experience intense pain stimulation, limited mobility, and fear or anxiety about surgery following femoral neck injuries, making them highly susceptible to acute sleep deprivation, typically defined as sleep duration ≤ 4 hours. Studies using POCD models in aged rats have revealed that acute sleep deprivation can exacerbate POCD by inhibiting mitophagy[17]. Additionally, as the body gradually ages, the sleep patterns of elderly patients undergo changes, manifesting as decreased sleep quality, increased fragmentation, and abnormalities in the sleep-wake cycle, leading to circadian rhythm disruption. This imbalance accelerates the activation of microglia in the brain and is accompanied by increased expression of aging-related characteristic genes[18]. As a crucial component of the brain's immune system, microglia are closely associated with hippocampal inflammation and cognitive decline in POCD. Microglia activation promotes the amplification of immune cascades, leading to increased secretion of chemokines, cytokines, reactive oxygen species, and pro-inflammatory mediators, thereby contributing to the development of POCD[19]. In this study, an ultralong-acting local anesthetic was administered preoperatively to perform FICB on the affected lower limb. This effectively alleviated pain stimulation in the patients, facilitated their ability to fall asleep, and improved sleep quality. The PSQI scores were lower in the LB group than in the control group. This intervention is likely the primary reason for the reduction in POCD.

Postoperative pain is also a common cause of POCD. For major surgical trauma, intravenous patient-controlled analgesia pumps are used to alleviate pain. Studies have shown that the use of patient-controlled analgesia pumps alone increases the risk of POCD, while combining them with dexmedetomidine can reduce pain and improve POCD[20]. Currently, the analgesic methods frequently employed in clinical practice encompass oral or intramuscular analgesic medications, including acetaminophen, non-steroidal anti-inflammatory drugs, and opioids, as well as patient-controlled intravenous analgesic pumps and nerve block techniques[21]. While opioid medications can deliver effective analgesia, they often fail to provide adequate pain relief during limb movement. Prolonged use of high doses may result in adverse effects such as drowsiness, constipation, nausea, and even respiratory depression, ultimately leading to diminished patient satisfaction[22]. With the advancement of comfortable medical care and ultrasound technology, ultrasound-guided FICB has been applied for analgesia in hip surgeries due to its minimal impact on the respiratory system, circulatory system, and limb movement[23]. Compared with lumbar plexus block, FICB offers several advantages, including reduced trauma, enhanced efficacy, straightforward execution, and a high safety profile[24,25]. The FICB technique primarily includes two approaches: S-FICB and infrainguinal FICB. Because the surgery in this study involved the hip joint region and required a broader block coverage, we adopted S-FICB. The injection of local anesthetic between the fascia iliaca and the iliopsoas muscle enables the simultaneous “three-in-one” block of the femoral nerve, lateral femoral cutaneous nerve, and obturator nerve[26].

The patient's activities were profoundly hindered by severe pain stimulation, which resulted in marked increases in blood pressure and HR, alongside an exacerbation of the inflammatory response; these factors were detrimental to the patient's postoperative recovery[27]. This study revealed that patients who underwent FICB 1 day prior to the operation exhibited significantly lower blood pressure, HR, and blood glucose levels at each time point before and after the procedure. This suggests that the implementation of FICB considerably diminishes the stress response in patients, leading to a reduction in oxygen consumption rates and a corresponding decrease in the incidence of cardiovascular events. The average motor VAS score prior to the operation was notably high at 8 for both patient groups. However, following FICB, the motor VAS score decreased to 4, representing a significant reduction from preoperative levels. Furthermore, the sufentanil dose administered via analgesic pump was markedly reduced after FICB, indicating its efficacy in alleviating pain stimulation following femoral neck fractures.

The incidence of nausea and vomiting was significantly lower in the LB group compared with the control group, which may be associated with lower sufentanil doses.

In previous studies, ropivacaine was administered for a single FICB, with its analgesic effect lasting approximately 6-8 hours. This limited duration complicates the maintenance of continuous postoperative analgesia. Furthermore, continuous nerve block using an iliofascial catheter and local anesthetic injection may lead to significant complications, including infection and nerve injury[28-30]. Postoperative pain typically lasts for 48-72 hours, a period during which pain management is most challenging. Extending the duration of local anesthetic action is a key concern for anesthesiologists. This study uses LB as the local anesthetic for nerve blocks. As a novel ultra-long-acting local anesthetic, it consists of multivesicular liposomes that serve as drug carriers. Numerous vesicles encapsulate and load the drug, which is released only from ruptured vesicles, while intact vesicles remain unchanged. Therefore, after local injection, bupivacaine is slowly released over time, extending the drug’s duration of action. A single dose can provide local analgesic effects for up to 72 hours when injected postoperatively at the wound site. The similarity between the lipid bilayer of liposomes and the structure of nerve cell membranes allows them to fuse with the cell surface, enabling the drug to efficiently and slowly penetrate the nerve membrane. This mechanism not only prolongs the duration of anesthetic effects but also effectively reduces the peak drug concentration. Following local infiltration of LB, plasma concentrations often exhibit a typical biphasic pattern, with a smaller initial peak occurring 2-4 hours after administration and a second peak appearing 12-36 hours after administration[31]. In this study, the drug was administered at 18:00 on the day before surgery, coinciding with the period of greatest postoperative pain intensity 24 hours after surgery, thereby significantly alleviating pain. In clinical practice, LB is often administered after dilution. Research has shown that bupivacaine encapsulated within liposomes is not compromised by dilution. Physiological saline is absorbed by the surrounding tissues, while the liposomes continue to exert their effect locally, maintaining their original drug-release characteristics. Even in its diluted form, LB can sustain a nerve block effect for up to 72 hours[32,33]. Drug dilution does not impair its analgesic potency or duration of action. However, it should be noted that the concentration of free bupivacaine decreases upon dilution, which may lead to a prolonged onset time for the nerve block. In this study, based on findings from previous research and clinical observations, preoperative administration of low-concentration (0.266%) bupivacaine liposome via FICB provided effective analgesia without affecting postoperative mobility of the affected limb, thereby reducing the risk of deep vein thrombosis[34]. Postoperative pain intensity following femoral neck fracture surgery was significantly alleviated compared to preoperative levels, as multimodal analgesia combining nerve blockade with intravenous patient-controlled analgesia pumps was employed in this study, and no additional analgesic interventions were required within 48 hours after surgery.

This study has the following limitations: First, the sample size is relatively small, and patients at high risk of POCD (such as those taking sedatives or antidepressants) were excluded, which may introduce bias into the findings. Second, the control group was not administered a placebo, making it impossible to rule out the influence of the placebo effect. Third, neither the patients nor the researchers performing the FICB were blinded, allowing the Hawthorne effect to potentially confound the results. Finally, the study did not categorize participants by age, which may affect the scientific validity of the outcomes.

CONCLUSION

In conclusion, this randomized controlled trial indicates that the use of LB for FICB significantly reduces the degree of POCD in elderly patients undergoing femoral neck fracture surgery. In future studies, we will establish treatment groups with different concentrations of LB to explore the optimal therapeutic dosage. Additionally, FICB shows potential in preventing postoperative complications in lower limb fracture surgeries and holds broad prospects for application in perioperative multimodal analgesia.

ACKNOWLEDGEMENTS

Study nurse Xiao-Qing Xu (First Affiliated Hospital of Hebei North University) is acknowledged for their contribution to the study with a high level of expertise and commitment.