Trial design and setting
This prospective, non-inferiority, parallel randomized controlled trial will be carried out at the Third Affiliated Hospital of Sun Yat-sen University, China. It is developed according to the Recommendations for Interventional Trials (SPIRIT) 2013 Statements that came from the Standard Protocol Items (Fig. 1, the SPIRIT Checklist is available as Additional file 1) . Besides, the Consolidated Standards of Reporting Trials (CONSORT) flow diagram will be performed in the design period and completing the study to the end. A detailed flowchart of the trial design is shown in Fig. 2.
Written informed consent will be obtained from each patient before enrollment. The ultrasound-guided IA- or CA-SB-related operation sequence, benefits, risks, and data privacy of this study will be explained in detail for the participants during the preoperative visit. We will emphasize that this study is voluntary, and the participants are free to withdraw from the study at any time. If the patient is not willing to participate in the study, he or she will receive other means of brachial plexus block or general anesthesia depending on the patient’s willingness and discretion of the treating anesthesiologist.
Participants and recruitment
The patients scheduled to undergo surgery of the elbow, forearm, wrist, or hand with ultrasound-guided brachial plexus block will be recruited and screened for eligibility in our medical center. An independent researcher will conduct the recruitment when performing the preoperative visit 1 day before surgery.
Inclusion criteria are as follows:
Signed written informed consent
American Society of Anesthesiologists (ASA) physical status I to III
Age 18 to 75 years old
Operative site at the elbow, forearm, wrist, or hand
Exclusion criteria are as follows:
Patient’s refusal of brachial plexus block
Nerve block cannot be performed due to coagulopathy (defined as any coagulation disorders contraindicated to perform peripheral nerve block), pre-existing neuropathy, infection at the supraclavicular fossa, hypersensitivity, or allergy to LA
Body mass index (BMI) > 35 kg/m2
Pregnancy, severe mental illness, or cognitive dysfunction (unable to communicate or cooperate)
Randomization and blinding
After the enrollment, the participants were randomly allocated to one of the two groups (CA-SB or IA-SB group) in a 1:1 ratio by computer-generated simple randomization. A sealed opaque envelope that contained a card (recorded with a random number and subject number) will be opened by a research assistant who will not be involved in other stages of this study. Ultrasound-guided CA-SB or IA-SB will be carried out by one out of our nerve block team (WF. Y, JQ. G, and HB. X) and supervised by the coauthor (QH. L), in which all have extensive experience with both techniques (over 60 attempts/per technique) before this study. Another anesthesiologist who is blinded to the randomized allocation and intervention will be responsible for recording the research-related variables and anesthesia management based on the conventional scheme. During the study period, research assistants who will be kept blind to the group allocation oversaw postoperative follow-up by face-to-face assessment or telephone. If a serious adverse event (pneumothorax or LA systemic toxicity, etc.) occurs during the nerve block, un-blinding will be permissible, and then emergency measure will be initiated under the supervision of the outcome assessor.
All participants will be seen on 1 day before surgery and demonstrated on the use of a 3-point scale for evaluating sensory-motor blockade. On arrival to the operating room, standard ASA monitors (non-invasive cuff blood pressure, pulse oxygen saturation, and electrocardiogram) and supplemental oxygen (nasal cannula at 4 L/min) will be applied. An intravenous access (20-gauge) for fluid infusion will be established in the contralateral forearm, and the premedication (midazolam 0.05 mg/kg or combined with fentanyl 0.5 μg/kg) will be given prior to nerve block. Drugs that improve the block effect or duration of the sensory-motor blockade will be not allowed to use in the perioperative period, including dexmedetomidine or dexamethasone or magnesium sulfate. All patients will be received EtCO2 in monitoring during procedure and surgery. For the two approaches, the nerve block will be performed following standard skin disinfection with a portable ultrasound machine (Sonosite M-turbo, SonoSite, Inc., Bothell, WA) and 80-mm short-beveled stimulating needle (B. Braun Melsungen AG, Melsungen, Germany).
The ultrasound-guided CA-SB with the DI technique will be performed in accordance with the method described in Tran’s study . After obtaining a satisfactory image of elliptical hypoechoic trunks and divisions at the supraclavicular fossa, the operators initially orientate the needle tip to the “corner pocket” between the subclavian artery and the lower trunk with the in-plane technique. A part of the LA (15 mL) of 1:1 mixture of 2% lidocaine (Shandong Hualu Pharmaceutical Co., Ltd.) and 1% ropivacaine (Astrazeneca Pharmaceutical Co., Ltd.) will be injected after the accurate position is confirmed by the “water separation” technique under ultrasound guidance. Subsequently, the needle will withdraw and targets the center of the main neural cluster floated upward by the former LA. The remaining volume (10 mL) will be carefully administered into that central position.
For the ultrasound-guided IA-SB, the procedures with the DI technique are replicated from Siddiqui’s study  and the optimal order of injections will be followed according to the suggestion in Endersby’s letter . Using a high-frequency pattern, a consecutive scan will be performed initially at the supraclavicular fossa toward the base of the neck in a coronal oblique plane. Once the three trunks of the plexus (upper, middle, and lower) and its epineurium are well defined, the needle is advanced from the lateral end of the probe, and the first part of LA (15 mL) will be accurately injected into the intertruncal plane between the middle and lower trunks. It is worth noting that each trunk is in a different stage of its trajectory and those divisions have not been fused with each other yet in this area. Then, the second placement of LA (10 mL) is carefully distributed to the other intertruncal plane between the upper and middle trunks.
Outcome definitions and evaluations
The definitions and evaluations of the primary and secondary outcomes of this study are summarized in Table 1.
Sample size calculation and statistical analysis
Our working hypothesis is that ultrasound-guided CA- versus IA-SB yield similar block dynamics. Thus, this study will be designed as a non-inferiority trial. In the previous studies using single or multiple injections in SB, we have observed that the proportion of patients with complete sensory blockade reached a plateau starting at 20 min after injection. It fluctuates between 70% and close to 100% within 30 min [3,4,5,6, 16]. In other words, relative to itself, the variation is very subtle from 20 to 30 min. The primary outcome is considered as the proportion of patients with complete sensory blockade of all 4 terminal nerves at 20 min after injection in this study. Based on a pilot study with 15 patients in each group, the proportion of patients with complete sensory blockade achieved was 73% in the CA-SB group and 87% in the IA-SB group (unpublished data). Therefore, we assume that a difference in proportion between the two groups less than − 5%, measured at 20 min after injection, will be considered non-inferiority. The required sample size per group is calculated to be 55 with a statistical power of 80% and a one-sided 95% confidence interval. To account for a possible 10% dropout rate, the total sample size is inflated to 122 participants (n = 61, per group).
Statistical analysis will be performed using SPSS for Windows 18.0 (SPSS Inc., Chicago, IL). For continuous data, normality will be first assessed with the Kolmogorov-Smirnov test and then analyzed using an independent-samples t test. Categorical variables will be summarized as a frequency, n (%), such as the proportion of complete sensory or motor blockade, success rates, and adverse events, etc. The Pearson χ2 test, Fisher’s exact test, or a Mann-Whitney U test will be used for categorical variables as appropriate. A p < 0.05 will be considered statistically significant for all results.
Data collection and retention
The nerve block-related parameters and postoperative follow-up data will be recorded by a research assistant, and a statistics analysis will be carried out by an independent statistician. To enable examination and re-analysis from regulatory authorities, all electronic data will be desensitized and stored securely at the Department of Anesthesiology of the Third Affiliated Hospital of Sun Yat-sen University for 5 years. Preserved paper materials of this study include the original signed informed consents, study protocol and interventions, and case report forms. The project will be monitored by a data monitoring committee composed of specialists in ethics, anesthesiology, and statistics. These data will be kept in our research database and not revealed to other people without appropriate permission.
All adverse events will be monitored and recorded. Once any serious adverse event occurs, it will be immediately reported to the research group, which will determine the causality and therapeutic measures of the adverse events. The chief investigator will be responsible for reporting all adverse events to the Ethics Committee.
No formal auditing process is proposed for this trial.
In principle, the established study protocol is not to be modified. Any amendments to the study will be first initiated by the principal investigators and then agreed and confirmed by all study participants. Finally, the modified version of the protocol will be submitted to the Ethics Committee for approval.
The research results and findings will be disseminated in a peer-reviewed journal or at scientific conferences.
Patient and public involvement
No patients were involved in the design, recruitment, and conduct of the study and were also directly consulted in the development of the research question or outcome measures. An original article will be prepared to present the trial results at the proper time after the end of the study. Results of the final study will be disseminated to all study participants through E-mail recorded at the time of enrolment. The burden of intervention will not be taken by the participants themselves.