Aim
The aim of this study is to investigate the analgesic effect of single shot liposomal bupivacaine versus continuous nerve block (with standard bupivacaine) administered via ISB for patients undergoing proximal humerus fracture fixation.
Study design and setting
This will be a double-blind, single-centre, non-inferiority randomized control trial. A non-inferiority design has been selected because there is no expectation that liposomal bupivacaine will provide superior pain relief compared to a continuous infusion of standard bupivacaine, based on previous studies comparing the two treatments (11-13). Seventy-eight patients will be recruited. The study will be conducted at an academic tertiary hospital in Hong Kong. Patients scheduled for plate fixation of acute proximal humerus fractures will be screened for eligibility. Upon giving written informed consent, patients will be randomised and allocated in a one-to-one ratio to receive either continuous ISB with standard bupivacaine (C-ISB group) or single shot ISB with liposomal bupivacaine (LP-ISB). Patients, investigators and all parties involved in patient management or outcome assessment will remain blinded throughout the study period. The study will be conducted in accordance with Good Clinical Practice guidelines (17). All methods were carried out in accordance with Declaration of Helsinki.
Sample size calculation
Sample size calculation is based on the significance level of 0.05 and a 1-β error of 90%. A noninferiority margin of 1.5 numerical scale rating (NRS) pain score was selected based on historical data on the minimally important clinical difference (18, 19). A pooled standard deviation of 2 NRS points was chosen based on calculations from pilot data. The required sample size is 31 patients per treatment arm, which has been calculated based on the method for non-inferiority randomized controlled trial (20). Accounting for 20% attrition, the 78 patients will be recruited in total (39 per treatment arm).
Recruitment and eligibility criteria
Consecutively admitted patients will be approached preoperatively for enrolment by an investigator with the support of the attending anaesthetists.
The following inclusion criteria will be used to screen for eligibility:
- 18-80 years,
- Isolated proximal humerus fractures (AO Types 31.A1-3 or Neer 2-/3-part or greater tuberosity fracture equivalent)
- Treatment with plate, nail or suture anchor fixation (using a minimally invasive deltoid-splitting approach for nailing)
- American Society of Anaesthesiologists (ASA) classification level I-III
Patients who have one or more of the following exclusion criteria will be excluded:
- Pathological fracture
- 4-part or shaft fracture
- Multiple fractures
- Fracture fixation with implants other than a locking plate or nail
- Revision surgery
- Pre-existing shoulder pathology
- Chronic pain (other than knee)
- Nerve palsy
- Pregnancy
- Impaired renal or hepatic function
- Impaired cognitive function (Abbreviated Mental Test (AMT) score < 8)
- Dependent on others for activities of daily living
- Unwilling, unable, or unlikely to give consent or follow study protocol.
- Chronic use of opioids (3 months or more)
- Alcohol and substance abuse
- Allergy to amide local anaesthetics, paracetamol, non-steroidal anti-inflammatory drugs (NSAID, COX-2 inhibitors, or opioids
Randomisation, allocation and blinding
Each patient will be randomised to either receive ISB with liposomal bupivacaine (LP-ISB group) or continuous ISB with standard bupivacaine (C-ISB group). Randomization will be performed by a research personnel unaware of the nature of the study using a computer-generated permutated block (random size between 4-8) method, with an allocation ratio of 1:1. There will be no stratification. Group allocation will be placed in a sealed, consecutively numbered, opaque envelope by the same research personnel. Each envelope will be opened in sequence by an independent (unblinded) anaesthetist as the patient before the start of anaesthesia. The unblinded anaesthetist will prepare a single 10ml of 1.33% liposomal bupivacaine (LP-ISB group) or 10 ml of 0.25% standard bupivacaine (C-ISB group) according to group allocation. S/he will also prepare an elastomeric pump filled either with 300 ml of normal saline (normal saline for the LP-ISB group) or 300 ml of 0.2% standard bupivacaine (C-ISB group). The unblinded anaesthetist will not be involved in the anaesthetic management or follow up of the study patient. The treatments will be administered by the attending anaesthetist, who will be blinded. To maintain blinding, both the syringe, the pump and pump clamp will be covered by an aluminium foil and remain so until hospital discharge. Outcome assessors will remain blinded throughout the study period. Unblinding will occur only as per clinical need as determined by the principal investigator (PI).
Study procedures
Preoperative care
Patients will be fasted 6 hours before surgery and allowed to drink clear fluids up to 2 hours before surgery. Premedication will not be given.
Regional analgesic technique and intervention
Time-out will be performed prior to ISB in accordance with the WHO Surgical Safety Checklist (21) , including confirmation of treatment side. Target controlled infusion of propofol at an effect site concentration of 0-1.5 mcg/ml will be used for sedation during the procedure. Patient will be placed in the lateral position and standard monitoring (ECG, Pulse oximeter, NIBP) will be connected. ISB nerve injection and catheter insertion will be performed with ultrasound (USG) guidance under aseptic technique. All ISB will be administered by specialist anaesthetists experienced with ultrasound guided nerve block injections. The USG linear transducer will be placed at the posterolateral aspect of the neck. The middle and anterior scalene muscles will be identified and the elements of brachial plexus will be located between them. A catheter-over-needle set with 50mm insulated needle will be inserted via an in-plane approach, from lateral to medial towards the nerve roots of brachial plexus. Entrance into the interscalene groove will be appreciated by a pop sensation during advancement. Administration of the injectate will be done under USG guided visualization after testing for negative aspiration. After injection, an indwelling peripheral nerve block catheter will be placed between the C5 and C6 nerve roots. The catheter will be anchored by skin sutures. Good spread of local anaesthetic at the catheter tip around the nerve roots of the cervical plexus should be visualized. Peripheral nerve stimulator can be used at the discretion of anaesthetists.
Patients randomized to the LP-ISB group will receive ISB injection with 10ml of 1.33% liposomal bupivacaine followed by nerve catheter infusion with normal saline. Patients in the C-ISB group will receive ISB injection with 10ml of 0.25% standard bupivacaine, followed by nerve catheter infusion with 0.2% standard bupivacaine. A successful ISB will defined as reduced cold sensation to ice in the C5 dermatome, which will be tested by the attending anaesthetist. Intention to treat analysis would be used (patients with preserved sensation to ice and a failed block will continue to be analysed in their original study group). The presence ISB related complications will also be screened for before induction of general anaesthesia.
Upon arrival in the postoperative anaesthetic care unit (PACU), a nurse will connect the nerve catheter to a fixed-rate portable elastomeric pump (Easypump®, Braun, France). The elastomeric pump will contain normal saline for patients in the LP-ISB group and 0.2% standard bupivacaine for patients in the C-ISB group. The fixed rate of infusion will be 5 mL per hour for both groups. The catheter and pump will be removed on POD 2, at which time the patient may be discharged from hospital. The catheter and pump will be removed before POD 2 if infusion cannot be delivered because of one or more of the following: irreversible kinking/obstruction of the catheter, significant leakage around the catheter site, significant catheter migration, local inflammation/infection.
General anaesthesia
Both groups of patients will receive the same general anaesthetic management after completion of ISB. General anaesthesia will be induced with intravenous propofol (2-4mg/kg), fentanyl (1-2 μg/kg), and 0.6-1mg/kg of rocuronium. Endotracheal intubation will be performed after induction. Maintenance of general anaesthesia will be achieved with desflurane (minimum alveolar concentration 0.7-1), along with a mixture of air and oxygen to obtain an FiO2 of 35-50%. Intravenous morphine 3mg will be given before skin incision. Remifentanil infusion between 0.05-0.3μg/kg/min will be titrated to maintain systolic blood pressure within 20% of baseline value. Vasopressors, anti-hypertensive medications, anti-arrhythmic medications may be given as necessary. Other analgesic drugs such as paracetamol, NSAIDs, ketamine, dexmedetomidine, lidocaine or magnesium will not be given. Local wound infiltration with local anaesthetics will also not be given. All patients will receive intravenous ondansetron 4mg 30 minutes before the end of surgery. Reversal will be achieved with 2.5 mg of neostigmine and 1.2 mg of atropine and patients will be extubated when ventilation and consciousness is adequate.
In the PACU, NRS pain scores at rest will be evaluated every 5 minutes. If the pain score is greater than 4/10, intravenous morphine 2mg will be given every 5 mins provided the patient has a respiratory rate > 12 breaths/min and a sedation score of <1/4 until NRS pain score < 4/10 is achieved. Patients will be discharged back to the ward after around 30 minutes in the PACU provided their condition is stable.
Postoperative analgesic regime
The following standardised postoperative analgesic regime will be prescribed in the ward:
- Intravenous patient-controlled analgesic (PCA) morphine for 2 days (PCA morphine setting: 1mg bolus, 5-minute lockout interval, no background morphine infusion, maximum 6mg per hour)
- Oral paracetamol (500 mg four times a day) for 2 weeks (including after discharge)
- Oral dihydrocodeine (30 mg four times a day as needed) from POD 3 to POD 7.
- Oral celecoxib (200 mg daily) for 3 days
- Rescue morphine (0.1 mg/kg every four hours as needed) for 3 days
- Intravenous ondansetron (0.1 mg/kg every 8 hours as needed or vomiting) for 3 days
Surgical procedure and rehabilitation
Surgery will be performed by orthopaedic surgeons experienced in plate and nail fixation of proximal humerus fractures. The conventional split deltoid approach will be used for plate fixation and a minimally invasive split deltoid approach will be employed for nail fixation. All patients will be allowed to mobilize their shoulder passively for the first four weeks, then active exercises will be prescribed with occupational therapist supervision.
Outcomes
The primary outcomes are the weighted AUC NRS pain scores in the first 48 hours after surgery (0-10 scale, 0 being no pain and 10 being the worst pain) at rest and with movement (attempted passive forward flexion to 90 degrees). NRS pain scores will be assessed 3 times per day on POD 1 and POD2 (while the patient is in hospital), and then daily from POD 3-5 (by telephone follow up).
The following secondary outcomes will be assessed during the acute postoperative period (up to POD 5)
- Postoperative PCA morphine and rescue morphine consumption (mg) will be assessed daily on POD 1 and POD 2.
- Postoperative dihydrocodeine consumption will be assessed from POD 3-5.
- ISB-related complications will be assessed on the day after ISB injection. The ISB related side effects and complications that will be looked for are shown in Table 1.
- Opioid related adverse effects (nausea, vomiting, dizziness, constipation, pruritus) will be assessed from POD 1-5.
- All other adverse events (AEs) and serious adverse events (SAEs) will be looked for from POD 1-5.
- Total length of stay (days) in hospital
- Overall Benefit of Analgesia Score (OBAS) will be assessed from POD 1-5.
- Quality of recovery (QoR) will be assessed from POD 1-5.
- Vasoactive inotropic scores (VIS) will be calculated for the intraoperative period
Table 1. Interscalene block (ISB) related side effects and complications.
The following secondary outcomes will be assessed at a 2, 6 and 12 weeks after operation:
- Presence of chronic pain (yes/no); severity of chronic pain if present using NRS scale.
- Presence of neuropathic pain measured by physical examination and neuropathic pain questionnaire (22).
- Shortened Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH). QuickDASH is a patient-reported measure of pain and functioning specific to the upper limb (23). The optional work and recreation modules will also be assessed.
- Health-related quality of life (HRQOL) as measured by the Short Form 12-item health survey (SF-12v2). The SF-12v2 is a patient-reported measure of HRQOL consisting of a mental component summary (MCS) and physical component summary (PCS) (24).
In addition to outcome data, the following data will also be collected before surgery.
- Age
- Sex
- ASA status
- Medical and psychological comorbidities
- Smoking status
- Occupational status
- Recreational sports, musical and arts hobbies
- Preoperative NRS pain scores at rest and during attempted active flexion
- Type of proximal humeral fracture (AO classification)
- Baseline function and HRQOL as measured by the QuickDASH (including work and recreation module) and SF-12.
Data collection and management
Research staff will monitor data inputs and remind appropriate personnel to complete data collection within the same week. Data will be collected using hardcopy forms and transcribed into the Research Electronic Data Capture (REDCap) database system (25). REDCap is a HIPPA compliant medical research database. Within the database, accessible information will be de-identified except for principal investigator and clinicians who also have access to patient medical records. Collected data will be stored in computers that are password-protected and are accessible only to investigators and research staff. Exported data will also be stored in password-protected computers accessible only to investigators and research staff. Any documents containing data from the study will be locked and destroyed five years after the completion of the study. The data will be made available at an online public data repository at the end of the study.
Statistical analysis
Statistical analysis will be performed on both an intention-to-treat and per-protocol basis, as per best practice recommendations (26, 27). Patients with a failed ISB block will be followed up and results included for analysis in their original allocated group. After checking for the population normality and homogeneity of variance, normal data will be presented as means with standard deviations and compared using independent sample t-tests. Data that are not normally distributed will be presented as medians with interquartile ranges and compared using Mann-Whitney U tests. Categorical data will be presented as counts and percentages and compared using Chi-square or Fisher’s exact tests. Benjamini-Hochberg false discovery rates (FDRs) will be used to correct multiple-hypothesis (28). Missing data will not be imputed.
Oversight and monitoring
Oversight will be conducted by the investigator-initiated study group. No formal data monitoring committee will be established due to the relatively small scale of the study. Investigators will follow a checklist for all data entry and accuracy of data will be reassessed prior to analysis. A dedicated electronic communications group will be established for distribution of protocol amendments to members of the research team, if any. Modifications to the protocol will also be communicated to the HKU/HA HKW institutional review board and amendments will be made at clinicaltrials.gov. Regular bimonthly meetings will be held to review trial conduct, recruitment and adverse events (AEs). Adverse events will be monitored via review of patient records, patient self-report and by clinicians. All adverse events and serious adverse events will be reported to the HKU/HA HKW institutional review board.
Safety and potential risks
There are potential risks to study patients, but this is low. Administration of liposomal bupivacaine via ISB was not associated with increased adverse events compared to placebo and standard bupivacaine (15, 16). Possible adverse effects from ISB include the following: phrenic nerve palsy, recurrent laryngeal nerve palsy, Horner’s syndrome, block failure, neurological injury, pneumothorax, vertebral artery puncture/intravascular injection, local anaesthetic toxicity and drug allergy (29). However, the risk of these adverse events is low. Risks associated with ISB nerve catheter include catheter displacement, dislodgement, obstruction and infection (30). Risks associated with general anaesthesia and the use of opioid analgesics will also be present, but is low and not higher than other patients undergoing general anaesthesia. Overall, the risk of serious adverse events in this study is low.
Ethical considerations and patient informed consent
This study has been registered at ClinicalTrials.gov (NCT04928664) prior to patient recruitment. Ethics approval has been obtained from the Hong Kong University/Hospital Authority Hong Kong West Cluster (HKU/HA HKW) Institutional Review Board (reference no: UW 20-247). Written consent will be obtained by the research personnel using the local language from eligible patients before enrolment into the study. This will be performed in the orthopaedic ward and potential study patients will be given sufficient time to ask questions and make an informed decision with regards to participation.
Finance and insurance
This study is supported by internal seed funding contributed by the investigators. Patients are not required to pay any additional fee for participation in the study. No priority on the surgical waiting list will be granted. There is no indemnity for this study, however medical care and treatment will be given for any study-related adverse events. Patients may consult their insurer (if any) for participation in the study.
Status and timeline of study
The clinical trial began in August 2020 and 27 patients have completed the study up to now. We predict that we will finish recruitment after 34 months. Data collection and analysis should be complete by 40 months. The results of the study should be written up and submitted for journal publication by 43 months from now.