Trial design and setting
This prospective, two-armed, parallel RCT will be performed at Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, China. The study is developed based on the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statements, Fig.1 (the SPIRIT checklist is available as Additional file 1) [26]. The Consolidated Standards of Reporting Trials (CONSORT) flow diagram will be followed in reporting the final results of this trial. A flowchart of the trial design is shown in Fig.2.
Informed consent
Written informed consent shall be obtained from each patient before enrollment. They will be informed that they are free to withdraw their consent from the study at any time. The procedure, benefits, risks, and data management of this study will be clarified in detail for the participants during the preoperative conversation.
Participants and recruitment
Elderly patients scheduled for open reduction and internal fixation (ORIF) for unilateral with proximal humeral fracture will be recruited and screened for eligibility. An independent researcher (QZ) will finish the recruitment when performing the preoperative interview one day before the surgery.
Inclusion Criteria:
- Written informed consent obtained from the patient or patient’s legal representative
- Age≥ 65 years old
- Body mass index (BMI) < 30kg/m2
- American Society of Anesthesiologists (ASA) classification I-II
- Anterior approach of operative incision
Exclusion Criteria:
- Request for general anesthesia
- Nerve block is unable to be performed due to various reasons (open trauma, hematoma or skin infection at the blocking area)
- Coagulation dysfunction or anticoagulation therapy
- History of upper limb nerve injury or phrenic nerve injury
- Multiple trauma
- Uncontrolled respiratory disease (severe chronic obstructive pulmonary disease, asthma, pulmonary infection, pneumothorax, etc.)
- Uncontrolled hypertension (systolic pressure over 180mmHg or diastolic pressure over 110mmHg)
- Uncontrolled heart disease (moderate and severe coronary heart disease, valvular disease or arrhythmia, etc.)
- Stroke or cognitive dysfunction (unable to communicate or cooperate)
- Hypersensitivity or allergy to anesthetics (ropivacaine or remifentanil)
Randomization and blinding
Random allocation will be performed by a researcher (HZ) before the trial using a randomization sequence (generated on http://www.randomization.com). The allocation concealment strategy is achieved with sequentially numbered, opaque, sealed envelopes until confirming the inclusion/exclusion criteria. After the envelopes opened sequentially, the patients will be randomly assigned in a 1:1 ratio to receive IC block (combined interscalene brachial plexus with superficial cervical plexus block) or ICTP block (combined thoracic paravertebral block with brachial plexus and cervical plexus block). The envelopes will be resealed after confirming the allocation. As the nerve block intervention cannot be blinded from patients and staff implementing the intervention, only the outcome assessor (ZX) will be kept blinded to the randomized allocation and intervention. He will not be present in the operation theatre until the nerve block is finished. Emergency un-blinding rules will be applied for the outcome assessor if a serious adverse event (total spinal block or pneumothorax) occurs during the surgery.
Interventions
All the patients will undergo preoperative fasting for 8 hours and water deprivation for 2 hours. After placement of standard ASA monitors, intravenous access for fluid infusion will be established in the forearm. No sedatives or intravenous narcotics will be given prior to the block. The patient will receive ultrasound-guided IC block or ICTP block according to the allocation. It will be performed following standard skin disinfection with a SonoSite S-NerveTM ultrasound machine (Bothell, WA, USA). Local lidocaine (1%) for skin numbing will be given prior to insertion of block needle. The entire nerve block procedure of all the patients will be performed by the same anesthesiologist, who is skilled in performing ultrasound-guided regional anesthesia (XW).
In the IC group, combined interscalene brachial plexus and superficial plexus block will be performed as follows.
The patient will be placed in the lateral decubitus position with the operative side upwards. A linear array transducer (6-13 MHz) with a sterile cover and a 22 gauge (G) block needle (KDLTM, Kindly group, China) will be used. An in-plane approach, advancing the needle along the longitudinal axis of the transducer and visualizing the entire shaft, will be employed. Twenty milliliters (ml) of 0.375% ropivacaine (NaropinTM, AstraZeneca AB, Sweden) will be injected between superior and middle trunk of brachial plexus at C7 level to reduce phrenic nerve palsy. The transducer will be then moved cephalad until the superficial cervical plexus emerges from the C4 intervertebral foramen. Ten ml of 0.25% ropivacaine will be injected to block the nerve [27–29]. The total dose of ropivacaine for IC group will be 100 milligram (mg).
In the ICTP group, the procedure will be performed as follows.
On the basis of combined brachial plexus and superficial plexus block, additional T2 TPVB will then be performed. The T2-3 intervertebral space should be determined by ultrasound image scanning and palpation counting from C7 spinous process. A curve array transducer (2-5 MHz) will be placed at the T2-3 intercostal level with a slightly oblique scan to visualize the transverse process, costotransverse ligament, internal intercostal membrane and parietal pleura (Fig.3). A 10cm, 22G needle will be introduced into the thoracic paravertebral space beyond the internal intercostal membrane with its tip positioned outside the transverse process. Following negative aspiration of air, blood or cerebrospinal fluid in the needle, 10 ml of 0.25% ropivacaine will be injected into the paravertebral space[30, 31]. The total dose for ICTP group will be 125mg.
Then the patient will be placed in the supine position. Twenty minutes later, after the sensory block at the surgical area is assessed, the patient will be transferred to the operating room and placed in a beach-chair position. One mg midazolam will be given intravenously. Oxygen will be routinely given via a nasal catheter at the flow rate of 3L/min until the end of operation. Remifentanil (50μg/ml), propofol (10mg/ml) and laryngeal mask airway (LMA) will be prepared and given when there will be inadequate analgesia. The anesthetic effects will be assessed since the operation began: 1) if it is successful, the operation will be continued; 2) if it is inadequate, the operation will be paused and remifentanil will be given intravenously at the rate of 0.25μg/kg/min. Two minutes later, the operation will be continued if adequate anesthetic effects achieved. The rate of intravenous remifentanil can be appropriately regulated (no more than 0.25μg/kg/min) in the following operation according to the end-tidal carbon dioxide pressure (PETCO2) and respiratory rate of the patient. On the contrary, the inadequately anesthetized patient will be induced with propofol (1.5-2 mg/kg) for converting to GA with LMA. Inhaled sevoflurane will be used to maintain anesthesia during the operation. The patient who received GA will be transferred to post-anesthesia care unit (PACU) after the operation. If no GA required, the patient will be sent to the ward.
Intraoperative monitoring and management
Blood pressure, heart rate, pulse oxygen saturation (SpO2) will be recorded throughout the operation. Respiratory rate and PETCO2 will be monitored via an intranasal catheter connected to the monitor. Intraoperative mean arterial pressure (MAP) higher (or lower) than 30% from the baseline value will be defined as hypertension (or hypotension). Hypotension will be treated promptly with intravenous (IV) ephedrine 5-10mg or deoxyepinephrine 50-100μg, while hypertension will be treated with urapidil 5-10mg. Bradycardia (defined as heart rate <60 beats/min) will be treated with IV atropine 0.5mg. Other adverse events including dyspnea, pneumothorax will also be recorded. Dyspnea caused by phrenic nerve palsy or remifentanil infusion will be supported with mask ventilation or reducing dose of remifentanil. Absolute risk of pneumothorax under ultrasound-guided TPVB is low as it never happened before in our center. However, it should be one of the most serious potential complication caused by TPVB and the patients must be screened with clinical monitoring. Chest fluoroscopy and ultrasound will be used to eliminate pneumothorax if aggravated hypoxemia happens. Closed thoracic drainage then may be administered according to the severity of pneumothorax.
Outcome definitions
Primary outcome evaluation
The primary outcome is the success rate of regional anesthesia with pain-free surgery, which will be recorded by “successful” and “inadequate”. “Successful” is defined as the ability to finish the operation without rescue anesthesia (intravenous narcotics, general anesthesia or local infiltration by the surgeon, etc). The patient who complains painful during the operation will be defined as “inadequate”.
Secondary outcomes evaluation
- Assessment of sensory block at surgical area [It will be evaluated on a 3-point rating scale (0=normal sensation, 1=decreased sensation and 2=no perception) 20mins after nerve block by a pinprick and an alcohol swab, respectively. The testing area will be divided into 4 portions: distal clavicle area, deltoid area, upper medial and upper lateral area of upper extremity]
- Proportion of patients completed the surgery with remifentanil
- Proportion of patients converted to GA with LMA
- Cumulative doses of intraoperative vasoactive medications (urapidil, atropine, ephedrine and deoxyepinephrine, etc.)
- Complications related with anesthesia (local anesthetic systemic toxicity, pneumothorax, epidural block, total spinal block, hematoma, etc.)
- Intraoperative adverse reactions (hypertension, hypotension, bradycardia, tachycardia, dyspnea, etc.)
Participant timeline
For a given participant, enrollment will be performed 1 day prior to surgery and confirmed again on the day of surgery. Then random allocation will be assigned by HZ before intervention. The participant will be followed up for postoperative complications on 1 day after surgery. The accrual period of this trial is expected to be about 1 year. The timeline is shown in Fig.1.
Sample size calculation
Calculation of the sample size is based on the primary outcome. A study included 27 patients underwent shoulder or upper extremity surgery using brachial plexus block showed that the success rate was 85.2% [32]. In our study, only patients undergo anterior approach ORIF for proximal humeral fracture will be included. So we assume the actual success rate of IC group will be lower than that in the previous study. On the other hand, we conducted a pilot study with 10 patients in each group. The success rate achieved 60% in IC group and 90% in ICTP group (unpublished data). Therefore, using the formula of Two Independent Sample Rates (Testing Two Proportions using the Z-Test with Pooled Variance), sample size of 32 for each group will achieve 80% power to detect the difference with a two-tailed 5% significance level. Then the total sample size will be 80 including the possible missing (20%).
Statistical analysis
Statistical data analyses will be performed on an intention-to-treat basis, including all participants as randomized, except whose who withdraw consent for the use of their data [33]. Numerical variables such as patient characteristics and surgery data will be expressed as mean ± standard deviation (SD) or median (interquartile range). The normally distributed numerical data will be compared using Student’s unpaired t-test, whereas non-parametric data will be compared using the Mann-Whitney U-test. Categorical variables such as success rate and sensory block at surgical area will be expressed as frequency (%). A chi-square test or Fisher’s exact test will be used for categorical variables. The statistical analysis will be performed with SPSS V.24.0 (IBM Corporation, Armonk, New York, USA). A two tailed, P<0.05 will be considered statistically significant.
Data collection, monitoring and management
Preoperative, intraoperative and one-day postoperative follow-up data will be collected from electronic medical record, monitor machines and relevant manual records by the research staff ZX. All electronic and handwriting data will be stored on a password-protected computer. Data and safety monitoring will be the responsibility of the principle investigator (XW) and study director (JZ).
Harms
All the severe adverse events related to the study intervention will be recorded in the study database and reported as required to Shanghai Jiao Tong University Affiliated Sixth People’s Hospital Institutional Review Board.
Auditing
No formal auditing process is proposed for this trial.
Participant retention and withdrawal
All reasonable efforts will be made to ensure optimum participant engagement and to reduce study attrition. However, the study involves an intention-to-treat analysis. Therefore, all participants will have the right to withdraw from the study at any stage. If the participant is willing to provide them, any data already collected from that participant will be analyzed.
Data retention
To enable evaluations and audits from regulatory authorities, data obtained from participants will retained confidential and stored securely at the department of anesthesiology of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital for a minimum of 5 years. The investigators shall keep records including the identity of all participants, all original signed informed consents, serious adverse event recordings and case report forms. The data will be kept safely and not revealed to other people without appropriate permission.
Protocol amendments
Any change in the study protocol will require an amendment. Any proposed protocol amendments will be initiated by the principal investigators. All amended versions of the protocol will be signed by the staff in the study and the amendment forms will be submitted to the ethics committee for approval.
Trial dissemination
The outcomes of the study shall be disseminated in a peer-reviewed journal or at scientific conferences.