Effect of preoperative liposomal bupivacaine single-injection pericapsular nerve group (PENG) block on lower extremity deep vein thrombosis in elderly patients with hip fractures: a randomised controlled, double-blind, prospective clinical study protocol

Abstract

Introduction

Deep vein thrombosis (DVT) of the lower limbs has a significantly higher incidence among elderly populations than that observed in other types of fractures, prolonged immobilisation and the systemic inflammatory response triggered by preoperative pain are the main risk factors. Liposomal bupivacaine (LB) single-injection pericapsular nerve group (PENG) block has demonstrated effective analgesia both before and after surgery, while preserving motor function in patients with hip fracture. Although regional nerve block is a well-established component of preoperative multimodal analgesia, its potential role and underlying mechanisms in the prevention of DVT in elderly patients with hip fracture remain largely unexplored.

Methods and analysis

This study will be conducted as a double-blind, randomised, sham-controlled, prospective clinical trial. On admission, a total of 132 participants will be randomly assigned using block randomisation to receive either treatment group (LB single-injection PENG block) or sham group (saline solution single-injection PENG block). The primary outcome was the incidence of DVT, while secondary outcomes included perioperative inflammatory and immune-related stress levels and functional-based pain scores.

Ethics and dissemination

This study protocol complies with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 guidelines and has been approved by the Ethics Committee of Shunde Hospital, Guangzhou University of Traditional Chinese Medicine (Approval No KY-2025005). The raw data are planned to be made publicly available on the ResMan raw data–sharing platform (IPD sharing platform) of the Chinese Clinical Trial Registry in December 2027 and can be accessed at http://www.medresman.org.cn.

Trial registration number

ChiCTR2500100799.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• A double-blind, randomised, sham-controlled design is used to rigorously evaluate the perioperative effects of a pre-operative pericapsular nerve group block on perioperative deep vein thrombosis and its underlying mechanisms.

• Functional pain assessment tools are incorporated into the perioperative analgesic protocol to provide standardised outcome evaluation.

• Custom-designed light-shielding syringe and extension tubing are used to minimise potential unblinding related to visual appearance and injection resistance (associated with liposomal bupivacaine and normal saline).

• Anaesthesiologists perform all pericapsular nerve group blocks with more than 10 years of experience in ultrasound-guided nerve block techniques to ensure procedural consistency.

Introduction

Deep vein thrombosis (DVT) of the lower limbs is a serious complication that can occur during the perioperative period, particularly in elderly patients with hip fractures. It is the most common complication in this population, with preoperative incidence rates ranging from 8% to 34.9%, and some studies reporting perioperative incidences exceeding 50%.^{1 2} This rate is significantly higher than in patients with other types of fractures, such as ankle fracture (2.6%) or bilateral calcaneus fracture (8.1%).^{3 4} Advanced age, trauma and prolonged immobility are key predisposing factors for DVT, linked to decreased vascular wall elasticity, endothelial injury triggering coagulation and reduced venous return in the lower limbs.⁵

The development of DVT in patients with hip fractures during the perioperative period was a significant burden on the healthcare system, and the length of stay was the major contributor. The costs of hospitalisation for patients developing DVT have been reported to be up to twice those for patients without this complication in a number of studies.⁶ In addition, when DVT is diagnosed following hospital admission, the preoperative waiting time is often extended by more than 48 hours because anticoagulant therapy and consultations with specialists are needed. Such delays could impede the accomplishment of guideline-based time-to-surgery. Although postoperative DVT is thought to be more common than preoperative DVT in this group, screening is not universally performed, and there is a high potential for underdiagnosis.⁷ If a thrombus dislodges, it can lead to life-threatening complications by obstructing major vessels in the heart, lungs or brain.⁸ Therefore, exploring effective strategies to reduce the incidence of perioperative DVT in hip fracture patients is of critical importance.

Risk factors associated with DVT in this population include age, sex, time from injury to admission and D-dimer levels. However, the underlying mechanisms remain poorly understood.9,11 Adequate analgesia has been proposed as a potential method to reduce DVT incidence, as it can alleviate the body’s hypercoagulable state caused by excessive physiological stress and reduce pain-related immobility. According to a Cochrane evaluation, peripheral nerve block can shorten the time to first postoperative mobilisation, which may in turn help prevent DVT.¹²

In hip fracture patients, the most intense pain typically occurs immediately after the fracture rather than postoperatively. This severe pain can significantly elevate inflammatory stress responses, which in turn promote thrombosis through activation of coagulation pathways (eg, tissue factor) and immune thrombotic mechanisms such as neutrophil extracellular traps (NETs).^{13 14} Therefore, addressing pain management during the preoperative waiting period is essential. Currently, there is a lack of clinical studies evaluating the effect of various preoperative analgesia protocols on the incidence of perioperative DVT. It is worth noting that most existing research on DVT in hip fracture patients is retrospective, and there is a significant shortage of randomised controlled trials (RCTs) in this area. Therefore, our study aims to address this gap through a double-blind, RCT. We present this article following the guidelines outlined in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) reporting checklist.

Methods

Trial objective

This study will evaluate outcomes in elderly hip fracture patients who receive a pericapsular nerve group (PENG) block using liposomal bupivacaine (LB) or saline solution after admission. Key assessments will include changes in perioperative DVT detected by colour Doppler ultrasound, perioperative stress markers (interleukin (IL)1, IL6, C-reactive protein, procalcitonin and interferon alpha), immune thrombus-related biomarkers (myeloperoxidase (MPO)-DNA complex, citrullinated histone H3, D-dimer), as well as patient-reported pain levels.

Participants and recruitment

The study will recruit patients aged≥65 years diagnosed with hip fractures. Patient recruitment, screening, randomisation, blinding, intervention administration, follow-up, data collection and data management will be conducted by dedicated study personnel from the Pain Management Center of Shunde Hospital, Guangzhou University of Traditional Chinese Medicine.

Trial design

This trial is designed as a prospective, double-blinded, randomised controlled study based on the SPIRIT 2013 statement. Eligible patients received intravenous analgesia with flurbiprofen axetil (50 mg two times per day at 8-hour intervals). Patients will be randomised, using block randomisation, to receive either LB or a sham block. Ultrasound-guided PENG block was performed on the affected side at the time of admission to the hospital. The perioperative care will be standardised and conducted by the orthopaedic team. To balance analgesic efficacy and safety, a maximum daily dose limit is defined for the morphine rescue analgesia pump, whereby the total morphine dose within 24 hours shall not exceed 60 mg (the dose of intravenous morphine per activation: 5 mg). The interval between consecutive activations is fixed at 30 min to prevent excessive administration over a short period. Patients who demand more analgesic treatment in addition to the rescue pump shall be assessed and treated by the attending orthopaedic surgeon with a detailed recording of all additional interventions. This dosing strategy is based on the pharmacokinetic characteristics of elderly patients with hip fractures and relevant clinical safety guidelines.¹⁵

Bilateral lower-limb DVT will be examined by ultrasonography at three specified time points: before the nerve block, pre-surgery and pre-discharge. Daily preoperative pain assessments will be conducted, along with measurements of inflammatory stress markers and immune-related indicators. Pain assessment parameters are shown in table 1. Figure 1 presents a schematic diagram of the experimental design. The full participant schedule is provided in online supplemental table 2).

Table 1. Pain score based on functional assessment in patients with hip fracture.

Time Items		Day of admission	The second day of admission	The third day of admission
Static pain scores	Most comfortable posture
Dynamic pain scores	Raised the leg to 15°
Functional motor pain score	When eating in a sitting position (hip flexion angle >70°)
	When caring for the body sideways (hip fracture end rotation)
	When moving over bed (horizontal dislocation of hip fracture end)

Figure 1. Flow chart of experimental design. The treatment group received liposomal bupivacaine single-injection PENG block; the sham block group received normal saline single-injection PENG block. PENG, pericapsular nerve group.

Inclusion criteria

Participants must meet all the following criteria to be included in the study:

1. Diagnosis of hip fracture, including femoral neck fractures and intertrochanteric fractures.

2. Age≥65 years.

3. Body mass index between 18 and 30 kg/m2 (inclusive).

4. American Society of Anesthesiologists score I-III.

5. Ability to provide informed consent and willingness to sign the consent form.

Exclusion criteria

Participants will be excluded if they meet any of the following criteria:

1. Presence of multiple trauma or compound injuries involving sites other than the hip.

2. Positive findings of bilateral lower limb DVT on ultrasound prior to the nerve block.

3. Known contraindications to LB: History of hypersensitivity to liposomes, local anaesthetic drugs (including bupivacaine, ropivacaine and their derivatives), severe cardiovascular and respiratory dysfunction.

4. Contraindications to nerve block, including infection at the puncture site, lower limb neurological disorders, local or systemic infections.

5. Time from injury to hospital admission exceeding 24 hours.

6. Severe hepatic and renal insufficiency. Severe organ dysfunction is defined as Common Terminology Criteria for Adverse Events grade>2. Specifically, severe renal insufficiency is defined as a serum creatinine level greater than three times the upper limit of normal (ULN). Severe hepatic insufficiency is defined as a total bilirubin level greater than three times the ULN, or aspartate aminotransferase or alanine aminotransferase levels greater than five times the ULN.¹⁶

7. History of drug addiction or abuse.

8. Minimum Mental State Examination (MMSE) score≤20.

9. History of deep venous thrombosis of lower limbs.

10. Known abnormal coagulation profile.

11. Current use of anticoagulants.

12. ECG findings of ventricular rate<50 bpm or prolonged Q-T interval

13. Conditions requiring ongoing blood transfusions or other haematological disorders.

14. Participation in other clinical studies.

Grouping and randomisation

This study will target elderly participants with hip fractures, a population with relatively uniform clinical characteristics. To ensure balanced group sizes and minimise bias, block randomisation will be used. If the block length is set at 4, there are six possible allocation sequences as follows: AABB, ABAB, ABBA, BAAB, BABA and BBAA. For each block the assignment sequence will be determined using a random number table. For example, if the first number is 5, the corresponding block arrangement will be BABA (where A represents the experimental group and B is the control group). The final randomisation schedule is shown in online supplemental table 1. Participants will be assigned to either the LB or sham block according to this pre-established block randomisation table.

Blinding

This study is designed as a double-blind RCT. However, due to the noticeable visual difference between the interventions LB injection (white or off-white liquid) and normal saline (colourless and clear solution), complete visual blinding is inherently challenging. To address this, several measures will be implemented: A specially designed opaque syringe and extension tube (as shown in figure 2) will be used to conceal the visual appearance of the injectates. The bolus injection resistance of LB is significantly increased in clinical practice. For this reason, a dedicated nurse anaesthetist not involved in any other studies will be responsible for preparing and administering the interventions according to the concealed group assignment. The randomisation sequence will be sealed in sequentially numbered, opaque and tamper-proof envelopes. Only designated nurse anaesthetists will access these envelopes and administer the injection accordingly. To maintain blinding throughout the study, the patient, orthopaedic surgeons, nerve block operators and follow-up staff will remain unaware of the group allocation. The nerve block operator, an anaesthesiologist, will be responsible for the treatment of special events such as local anaesthetic toxicity to ensure patient safety. Emergency unblinding procedures will be predefined and permitted in cases of visual analogue scale (VAS) >7 min for 2 hours or respiratory depression (respiratory rate<8 beats/min). Figure 3 presents the specific blinding method used in this study.

Figure 2. Dark-coloured syringes and connecting tubes with colour shielding. The syringe on the left contains liposomal bupivacaine, while the syringe on the right contains normal saline. A visual inspection alone is insufficient to identify the medication within the syringes, which supports the effective implementation of a blinded study.

Figure 3. Study blinding. The Venn diagram illustrates the specific blinding method implemented in this study. DSMB, data and safety monitoring committee.

Interventions and trial suspension

The intervention in this study consists of a single PENG block, administered under the SONIMAGE HS1 Ultrasound System (KONICA MINOLTA, Japan) guidance immediately after the participants are admitted to the orthopaedic ward. An anaesthesiologist with ten years of experience in ultrasound-guided nerve blocks is responsible for performing the blocks for all participants using the technique described by Girón-Arango.¹⁷ A successful block is indicated by the formation of an anechoic area on ultrasound between the iliopectineal eminence and the anterior inferior iliac spine, accompanied by upward displacement of the iliacus muscle tendon.¹⁸ All patients will bypass the emergency department. Prior to the block, all participants will undergo bilateral DVT screening via ultrasound. Those with positive findings will be excluded from the study and instead will receive standard perioperative analgesia under the supervision of an orthopaedic surgeon, following the same regimen used for hip fracture patients not enrolled in the study. Eligible patients will be randomly assigned to two groups by blinded study managers. The treatment group will receive 20 mL of LB (266 mg), while the sham block group will receive 20 mL of saline. Blind study personnel will be responsible for implementing the intervention using procedures that maintain blinding such as drawing the medication into opaque syringes and administering the injection only after proper needle placement. Routine ECG monitoring will be conducted before all interventions and continued for 24 hours post-procedure to ensure timely identification and management of any complications.

Potential side-effects of the PENG block include nerve damage, functional impairment, vascular injury, haematoma, injection site pain and quadriceps muscle weakness. Side effects associated with LB include fever, dizziness, headache, hypotension, pruritus, tachycardia, bradycardia, muscle spasms, drowsiness and delayed onset pain. Although no major blood vessels are typically found at the PENG block site, some studies have reported blood return from the analgesic pump catheters during continuous PENG block, as well as haematoma accumulation near the hip fracture area.¹⁹ Therefore, clinicians will remain vigilant for signs of local anaesthetic toxicity, and emergency tracheal intubation tools and resuscitation drugs will be readily available prior to performing the block. No cases of allergy to LB have been reported; however, any such occurrence will be managed according to the standard protocols for acute allergy. All adverse reactions will be closely observed and documented throughout this study.

In line with the multimodal analgesic strategy, all participants will be administered routine intravenous flurbiprofen axetil (50 mg twice daily) after admission. Moreover, the patients will hold a compressible electronic IV analgesia (EIA) pump that releases 5 mg of morphine per activation with a 30 min lockout interval. The pump is networked and can automatically record usage information, including the time and frequency of activations and the cumulative amount of morphine intake. If pain relief is still insufficient (resting VAS ≥4), patients can inform their responsible orthopaedic surgeon, who will assess and record any additional analgesic measures taken in the perioperative period.

Termination criteria

The study will be stopped automatically for each patient when he/she is discharged from the hospital. All procedures relating to the study will be performed only after written, formal consent has been obtained. Criteria for discontinuing the study are as follows: (1) Subjects have the right to withdraw from this trial at any moment without providing any reasons, and they will be offered standard perioperative management, nursing care and a treatment plan by the orthopaedic team. (2) Those who are not compliant with the protocol or who require perioperative medication that may affect the results of the study. (3) The investigator must withdraw a participant from the trial at any time during the perioperative period if a participant experiences any serious intervention-related complication, including but not limited to PENG block site infection, local anaesthetic systemic toxicity or anaphylaxis to the anaesthetic agent. (4) If an increasing frequency or a particular pattern of adverse event emerges in the course of the study, the trial will be halted for a full review of safety and a risk assessment. The study protocol has to be approved by the local ethics board at the hospital level before study start, and, if required, a modified protocol can be sent to the board for evaluation and approval before amendments can be implemented.

Follow-up period

The perioperative period will constitute the entire observation period for this study. During the preoperative waiting period, defined as the time from hospital admission to surgery, the observation is the patient’s pain level, assessed using the VAS. No VAS pain evaluations will be obtained after surgery. At 30 days postoperatively, a follow-up will be conducted by phone or at the next outpatient orthopaedic visit to assess functional recovery. This follow-up will be conducted by an orthopaedic according to a standardised protocol, including functional recovery, quality of life and chronic pain.

DVT management

If an additive colour Doppler ultrasound reveals a lower limb DVT during the perioperative period, the patient will be evaluated by the hospital’s specialised venous thrombosis service, which is responsible for an individualised treatment approach. Our research unit has long maintained a multidisciplinary inpatient venous thrombosis management team with extensive clinical experience. This team operates based on standardised clinical protocols derived from established guidelines and follows clearly defined protocols for early warning of abnormal indicators, diagnosis and treatment of DVT and related complications.

Outcomes

Primary outcome: incidence of DVT in the lower limbs

All patients will undergo bilateral lower limb ultrasound screening for DVT before surgery and again prior to hospital discharge; a positive result is defined as the occurrence of DVT on either side.²⁰ If the initial ultrasound yields a positive result, a second examination will be conducted by a senior ultrasonographer to confirm the diagnosis. The patient will be diagnosed with DVT if both of the two ultrasound examinations are positive. Although venography is highly accurate in diagnosing DVT, its invasive nature and potential side effects result in lower acceptance rates among participants, particularly when this study requires two diagnostic procedures.²¹ Compression ultrasound is a commonly used clinical research protocol for diagnosing DVT in the lower limbs.^{22 23}

Secondary outcomes: perioperative stress levels, thrombus-related measures, pain assessment and opioid rescue

Venous blood samples will be collected on admission, before surgery and again before discharge. These samples will be analysed for inflammatory and immune-related markers such as blood IL1, IL6, C-reactive protein, MPO-DNA complex, citrullinated histone H3, D-dimer, procalcitonin and interferon alpha.

Pain will be evaluated during the preoperative waiting period using the VAS. A function-based pain assessment protocol will be implemented where pain will be assessed in three common scenarios, namely feeding in semi-sitting/sitting position, turning sideways for physical care and transferring to a carrier bed for examination. The timing for pain scores will be obtained through direct communication with patients, family members and nursing staff. At the same time, static and dynamic pain scores will be conducted to assess the effectiveness of the new protocol. Pain levels will be categorised as mild, moderate and severe based on the VAS score (VAS score, 0–10, 0 for painless, 10 for severe pain).

All patients will have access to a programmable EIA pump. Data extracted from the electronic system will include time of the first patient-initiated analgesia (first pump press) and total opioid dose administered. Additional analgesic interventions outside of the pump system will be documented, including the time of the request and the orthopaedic specialist response to ensure backup management in case of analgesic pump failure.

Other outcomes: patients’ preoperative waiting time, length of hospital stay, total hospitalisation cost, anaesthesia and surgical plan, recovery situation data, fracture-end function recovery and adverse events

All perioperative adverse events will be recorded, including opioid adverse reactions such as vomiting and delirium; PENG block-related event such as localised infection at the puncture site, haematoma, motor block of the lower limb; LB-related adverse events such as dizziness, vomiting, allergy, electrocardiographic abnormalities or cardiac function changes observed immediately after post-block. These events will be systematically monitored and recorded for safety analysis. QoR-15 scale records the pre-operative waiting period and the quality of early post-operative recovery. Mortality at 30 days post-surgery will be assessed by orthopaedic specialists or via telephone follow-up.

Data collection

This study will employ a double-blind design. Participants, block operators, pain score assessors and orthopaedic surgeons will all be blinded to the group assignments and the overall study design. Blood samples will be collected by a nurse anaesthetist who will not be informed of the study protocol and will have no other involvement in the research. Electronic analgesia pump data will be extracted by a dedicated person who will be independent of all other study procedures. All data will be documented and handled according to the predefined blinding procedures (as shown in figure 3). Online supplemental table 3 offers a comprehensive overview of the bedside follow-up activities during the perioperative period, whereas online supplemental table 4 specifies additional data that must be gathered.

Data and safety monitoring board

To ensure the reliability, authenticity and integrity of the data, a dedicated Data and Safety Monitoring Committee (DSMB) will be established. The DSMB will consist of three independent clinical experts and one statistician, who will review safety data every 6 months. The DSMB will be responsible for overseeing participant safety, trial monitoring, ethical compliance, data evaluation and the protection of participant privacy. It will also review on a regular basis all study-related adverse events for cause or immediately if needed. Any identified safety issues will be immediately reported through the hospital’s long-standing adverse event reporting system. The DSMB will be constituted in accordance with the WHO’s Operational Guidelines for the Establishment and Operation of DSMB. It will independently evaluate all study data and conduct periodic assessments of the data validity to determine whether the study should continue or be terminated for safety or ethical reasons. The DSMB will remain completely independent from the study implementations team and will not be involved in the conduct of any procedures.

Data statement

The raw data are expected to be made publicly available on the ResMan raw data sharing platform (IPD sharing platform) of the Chinese Clinical Trial Registry in December 2027, and can be accessed at: http://www.medresman.org.cn. This includes all study results and case report form data, which will be made publicly accessible for consultation. However, confidential documents such as participant personal information, informed consent form and the study manual will remain strictly protected and will not be shared publicly. The study director will centrally monitor all data. Privacy protection measures include data anonymisation and paper records stored in a safe. Investigators or institutions wishing to access specific parts of the dataset should email a formal request to the study director at wuxianping@gzucm.edu.cn.

Harms

The PENG block used in this study is an invasive procedure designed to relieve pain associated with hip fractures. Additionally, each participant will undergo a single 5 mL (three times) venous blood draw for biomarker examination, which may cause mild discomfort. To minimise the risk, all procedures will be performed by highly experienced nursing staff. Blood sampling will be carried out by trained and experienced nursing personnel. Nerve blocks will be performed by anaesthesiologists with over 10 years of experience in regional anaesthesia.

The primary foreseeable risk is local anaesthetic systemic toxicity. Although the PENG block is generally performed in a region with minimal vascular structures and is guided by real-time ultrasound, rare cases of blood reflux in continuous analgesia catheters have been reported, possibly due to haematoma formation at the fracture site.¹⁹ No cases of local anaesthetic poisoning from PENG block have been reported to date, but all necessary precautions will be taken to manage such events if they occur. Given this possibility, the following safety measures will be implemented: Puncture will be performed under oxygen inhalation and continuous ECG monitoring; repeated aspiration will be performed to confirm non-intravascular placement of the needle; patients’ vital signs will be monitored continuously for at least 30 min following the block; emergency resuscitation equipment including endotracheal intubation tools and antidotes for local anaesthetic toxicity will be readily available.

Statistical methods and sample size calculation

Data will be analysed using IBM SPSS Statistics V.25.0 (IBM, Armonk, New York, USA). Continuous variables will be presented as mean (SD) or as medians with IQRs. Categorical variables will be expressed as numbers (n) and percentages (%). Group comparisons will be performed using t-tests for normally distributed continuous variables and using non-parametric tests for other variables. All hypothesis tests will be two-sided, and two-sided p values less than 0.05 will indicate statistical significance.

To account for variability in preoperative waiting times, and the potential influence of surgery on outcomes such as pain scores and biomarkers, our analysis will use a modified intention-to-treat (mITT) approach. Participants who meet the exclusion criteria or fail to meet the inclusion criteria will be excluded from the analysis. All randomised patients who receive at least one study intervention (PENG block or sham block) and undergo at least one core outcome assessment (eg, pre-operative DVT ultrasonography, baseline pain assessment or biomarker testing) will be included in the mITT analysis, regardless of protocol deviations or subsequent withdrawal. Two exceptions apply: patients who do not receive any study intervention after randomisation and those with no available outcome data will be excluded from the final analysis. These exclusions and their reasons will be fully documented. For patients withdrawn due to non-compliance with study procedures, use of medications that may interfere with study outcomes or intervention-related serious complications, all available baseline, safety and partial outcome data collected before withdrawal will be included in the appropriate analyses to minimise bias. As part of the sensitivity analysis, we will conduct subgroup comparisons based on preoperative waiting times, with a key threshold of 48 hours, as supported by previous studies. Subgroup analysis will explore the influence of preoperative waiting time (48 hours) on the incidence of perioperative lower limb DVT before and after hours.

Sample size calculation was estimated using PASS (Power Analysis and Sample Size) software (V.15. 0 (NCSS, Kaysville. Utah, USA)). According to previous studies, the incidence of perioperative lower limb DVT in patients with hip fracture ranges from 8% to 50%.^{1 2} Based on this, the incidence in the sham group was estimated at 29%, corresponding to the average of the reported range. We propose that the treatment group has the potential to lower the incidence of DVT to approximately the lower limit of the reported range, which is around 8%. With a two-sided α of 0.05 and a statistical power (1-β) of 0.8, a minimum of 55 participants per group is required. Considering an over 15% attrition rate, the final sample size was set to 66 participants per group, totalling 132 participants. This magnitude of reduction is considered clinically ambitious but plausible, given the proposed intervention mechanism, the elevated baseline risk of DVT in the elderly population and the goal of optimising perioperative thromboprophylaxis.

Production and management of specimens

Peripheral venous blood samples will be collected three times, at admission, before surgery and at a fixed time prior to discharge. At each time point, 5 mL of blood will be drawn, a total volume of 15 mL per participant. Samples will be collected in procoagulant tubes, followed by centrifugation at 2000 rpm for 5 min to isolate serum. The supernatant will be aliquoted and stored at −80°C until analysis. Quantitative measurements of MPO-DNA complexes and citrullinated histone H3 will be performed using ELISA kits. Other markers will be analysed in the hospital central laboratory. No tissue samples will be collected for this study.

Patient and public involvement

Participants and the public will not be involved in the study process. As the PENG block procedure is designed to alleviate pain in patients with hip fracture, this study will not provide any remuneration to participants. All potential risks and benefits with participation will be informed in detail before the informed consent process. However, if any harm results from the hidden trial intervention, free medical care and financial compensation will be provided.

Discussion

At present, clinical guidelines for preoperative analgesia in patients with hip fractures primarily recommend multimodal analgesia incorporating regional nerve block techniques, which have demonstrated clear analgesic benefits.²⁴ The most commonly used regional nerve blocks include the femoral nerve block, fascia iliac block and PENG block. To extend the duration of analgesia, clinicians may also opt for indwelling analgesic pumps or long-acting local anaesthetics.25,27 In our effort to identify the most suitable analgesia approach, we compared commonly used preoperative analgesia strategies for patients with hip fractures (as shown in table 2), taking into account analgesic efficacy, patient comfort, medical staff workload and feasibility for broader clinical implications. From this wide comparator, a single-injection PENG block using LB was the favoured option. Minimal impact of the PENG block on motor function, in addition to the extended duration of analgesia provided by LB, is also consistent with core DVT preventative guidelines, such as reducing immobility and optimising pain control efficacy.¹⁸

Table 2. Comparison of regional nerve block analgesia regimens in patients with hip fracture during the preoperative waiting period.

Indicator proposal	Analgesic effect	Patient comfort	Operator workload	Generalisability	Scoring
Ropivacaine single-injection PENG block	Clear analgesia, insufficient duration, about 8–12 hours	tall	Low technical requirements, no additional follow-up is required for a single injection	The operation of PENG block under ultrasound is simple, and the success rate of blind puncture is 85%, but the analgesic effectiveness is insufficient, which is not conducive to popularisation	Medium
LB single-injection PENG block	The analgesia is clear and the duration is sufficient, about 60–72 hours	Tall	Low technical requirements, no additional follow-up is required for a single injection	Simple and low motor block PENG block combined with long-acting local anaesthetic can achieve high comfort. for more than 60 hours and high generalisability	Excellent
Continuous FICB/continuous PENG block	Clear analgesia and controllable duration	Tall	High technical requirements, require additional follow-up to adjust speed, etc	High technical barriers, catheter displacement, leakage, high workload and other problems are not conducive to promotion	Medium
LB single-injection FICB	The analgesia is clear and the duration is sufficient, about 60–72 hours	There is long-term numbness of thighs and decreased exercise ability	Low technical requirements, no additional follow-up is required for a single injection	Ultra-low comfort, low patient acceptance. Need to fully communicate with the patient in advance about thigh numbness after block	Medium

FICB, fascia iliaca compartment block; LB, liposomal bupivacaine; PENG, pericapsular nerve group.

Traditional local anaesthetics, such as ropivacaine, are nowadays limited by a relatively short duration of action, and they fall short of providing prolonged preoperative analgesia for many patients.²⁸ Although LB, the only long-acting local anaesthetic currently available, can achieve extended pain relief when administered via femoral or fascia iliaca blocks, it is frequently accompanied by prolonged lower-limb numbness and motor impairment, which may compromise patient comfort.²⁹ Although continuous nerve block techniques can provide effective analgesia, they are associated with potential complications, including catheter misplacement or dislodgement, leakage and pump malfunction, and they require close and ongoing monitoring, thereby increasing clinical workload.³⁰ In comparison, the single-injection PENG block with LB used in this study provides a practical and effective option for preoperative pain control. Prior work from our group has shown that this approach can deliver analgesia lasting up to 60 hours, and in some cases beyond 72 hours, which is sufficient to cover the preoperative interval for most patients with hip fractures who undergo surgery within 48 hours of admission, as recommended by current clinical guidelines.¹⁸

Another key innovation of this research is the adoption of a function-based evaluation of pain, in line with the multidisciplinary consensus statements of the Society of Anesthesiologists and the British Pain Association. We further customised this model to capture the unique pattern of pain and functional impairment characteristic of hip fracture patients.³¹ Traditional methods of pain assessment often involve passive elevation of the affected limb to 15 degrees to assess pain on movement. This methodology, however, can result in unnecessary strain on patients (particularly those in whom pain control has been inadequate), although it is well established.³² To address these limitations, a novel pain assessment instrument (table 1) was developed by our group, focused on core functional activities that are commonly undertaken in the hospital, for example, sitting upright to eat (hip flexion>70°), moving for personal hygiene (hip rotation) and transferring for diagnostic imaging (lateral hip motion). In contrast to traditional scoring systems, it has clear advantages, such as reduced burden on healthcare workers, a focus on clinically relevant pain episodes and avoidance of unnecessary manipulation of the limb during evaluation. This study will evaluate the clinical utility of this new method, with the aim of laying the groundwork for broader adoption in clinical practice.

Due to the distinct colour and higher injection resistance of LB compared with conventional local anaesthetics, it is difficult for administering personnel to remain blinded to the intervention, a known limitation in the design of blinding protocols.³³ To address this challenge, syringes and connecting tubes with colour-concealing properties will be employed in this study, and a nurse anaesthetist not involved in any other aspects of this trial will be assigned to perform the bolus injection (see figures 2 and 3). In addition, as prolonged preoperative waiting time may influence the primary study outcome, we will incorporate a subgroup analysis stratified by different preoperative waiting times.¹ This approach introduces a novel perspective for investigating the relationship between waiting time and DVT development. Logistic regression analyses have identified age>75 years and time from fracture to admission>24 hours as risk factors for perioperative DVT.¹¹ Other studies have also shown that age>60 years is a significant predictor for new-onset postoperative DVT.³⁴ Based on this evidence, and the findings of retrospective studies indicating that elderly patients with hip fractures are more likely to develop DVT of lower limbs, this study will focus exclusively on elderly patients. To minimise confounding, we will exclude patients whose time from injury to admission exceeds 24 hours^{11 34 35} as well as those already receiving long-term anticoagulation therapy, which is known to reduce the incidence of venous thromboembolism.³⁶

The underlying mechanisms contributing to the high incidence of DVT in hip fracture patients are still unclear. This study will include an exploratory component designed to investigate these mechanisms. Recently, multivariate logistic regression models have suggested that neutrophil/lymphocyte ratio and systemic immune inflammatory index are independent predictors of preoperative DVT in patients with intertrochanteric fractures, showing significant differences from non-DVT cases.³⁷ Mcllroy et al demonstrated, using live-cell fluorescence microscopy and DNA quantitative polymerase chain reaction, that NETs containing mitochondrial DNA were present in patients with major trauma (including hip and pelvic fractures), implicating NETs as key components of the immune-thrombotic response.³⁸ Other relevant studies further support the role of inflammatory activation and immune-mediated thrombosis in the pathogenesis of DVT in hip fracture patients. In this study, we will measure inflammatory markers and immune thrombosis-related indicators (MPO-DNA complex and citrullinated histone H3) to preliminarily explore their roles in DVT formation and provide a clinical basis for future mechanistic studies in cell and animal models.

Our study has several limitations. First, implementing a regional block analgesia protocol immediately after admission in other medical facilities within this region presents certain challenges, such as the lack of an independent preoperative analgesia team to ensure timely regional blockade; thus, this study did not pursue a multicentre trial. Second, ultrasound examination remains the most commonly used method for diagnosing DVT in the lower extremities; however, the possibility of misdiagnosis still exists.³⁹ To address this issue, we have arranged for a senior ultrasound physician to conduct a second review of positive results to minimise the likelihood of errors. Third, this study excluded participants with ASA physical status 4–5 and moderate to severe cognitive impairment (MMSE score≤20) to ensure safety and compliance with informed consent protocols. The side effects of LB in elderly patients with severe underlying conditions remain unclear, which may limit the applicability of the study findings to high-risk populations. Fourth, the first 24 hours after a hip fracture represent the peak of the pain-related stress response, during which early implementation of a PENG block may be critical for modulating thrombotic pathophysiology.^{9 11} Therefore, patients with an injury-to-admission interval exceeding 24 hours were excluded, which may limit the generalisability of the study findings. Additionally, DVT, as the primary observation indicator, is only monitored during the perioperative period, which may lead to concerns regarding the brevity of follow-up duration. Future studies should further investigate its implications on long-term outcomes.

This study is designed to evaluate whether the addition of a regional nerve block technique to preoperative multimodal analgesia in elderly hip fracture patients can influence the incidence of perioperative lower limb DVT. Despite theoretical support for a potential benefit, this single-centre, double-blind, prospective randomised controlled trial is designed to generate empirical evidence to clarify this association and to address a clinically important gap in current knowledge.

Ethics and dissemination

The study protocol was approved by the Ethics Committee of Shunde Hospital of Guangzhou University of Traditional Chinese Medicine (Approval No KY-2025005) and complies with the Declaration of Helsinki. The current protocol version is V.1.2 (25 December 2025); any subsequent amendments will require ethics committee approval and will be communicated to all relevant stakeholders. Previous protocol versions are available online. Written informed consent will be obtained from all participants, as detailed in online supplemental material 5. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2500100799). Data registration and management are conducted via the ResMan raw data–sharing platform of the Chinese Clinical Trial Registry, accessible at www.medresman.org. Participant recruitment is scheduled to begin on 1 March 2026.