Background: Traumatic brain injury (TBI) has become a leading cause of death among young people worldwide. Survivors may live with a long-term TBI-related disability or even develop a disorder of consciousness resulting in poor life quality and shortened life expectancy. Thus far, very few approaches have been found to be effective in the consciousness recovery of these patients. Acupuncture has long been used in the treatment of neurological disorders in China. However, its efficacy and safety in consciousness recovery remain to be proved. Methods: Here, we present a study design and protocol of a randomized, blinded, controlled study to evaluate the efficacy and safety of electro-acupuncture in the consciousness recovery of patients with TBI. A total of 150 patients with initial Glasgow coma scale score of less than 8 points will be recruited in the trial and randomized into acupuncture or control groups. Patients in the control group will receive routine pharmacological treatment alone while patients in the acupuncture group will receive electro-acupuncture treatment for 10 days in addition to routine treatment. The efficacy will be assessed with the changes in Glasgow coma scale score and mismatch negativity of event-related brain potentials before and after treatment. Moreover, Glasgow outcome scale and Barthel index of activities of daily living will be compared between the two groups at 3 months after treatment. The secondary outcome measures are the length of stay in ICU and hospital, expenses in ICU and hospital, as well as the incidence of coma-related complications. The safety of electro-acupuncture will be assessed by monitoring the incidence of adverse events and changes in vital signs during the study. Discussion: Results from this trial will significantly add to the current body of evidence on the role of electro- acupuncture in the consciousness recovery of patients with severe TBI. In addition, a more convenient and consistent electro-acupuncture method can be set up for clinical practice. If found to be effective and safe, electro-acupuncture will be a valuable complementary option for comatose patients with TBI. Trial registration: Chinese Clinical Trial Registry: ChiCTR-INR-17011674. Registered on 16 June 2016. Keywords: Electro-acupuncture, Traumatic brain injury, Consciousness, Mismatch, Negativity * Correspondence: firstname.lastname@example.org Department of Critical Care Medicine, West-China Hospital of Sichuan University, Guoxuexiang 37, Chengdu 610041, Sichuan, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liu et al. Trials (2018) 19:296 Page 2 of 6 Background aims to provide high-quality evidence for the application Traumatic brain injury (TBI) is a major cause of mor- of acupuncture in the management of comatose patients tality and morbidity in young people . Despite the as well as to establish a standard acupuncture procedure continuous advances in neurosurgery, numerous sur- for clinical practice. vivors suffer from TBI-related disabilities. It is esti- mated that 5.2 million and 7.3 million people in the Methods USA and in the European Union, respectively, have Design and setting disabilities due to TBI [2, 3]. Given the rapid develop- This is a single-center, randomized controlled trial. This ment of urban construction and transportation, the study has been approved by the Ethical and Biomedical incidence of TBI in China has increased dramatically Research Committee of West-China Hospital, Sichuan in recent years, with the current mortality rate within University. It is registered on http://www.chictr.org.cn the range of 2.7% to 21.8% . Due to the limited with registration number ChiCTR-INR-17011674. healthcare and rehabilitation sources, TBI survivors The study will be conducted in the West-China depend mainly on their families for their treatment, Hospital of Sichuan University. The legal representa- especially those who fail to recover consciousness. tive of each patient will be asked to sign an informed Therefore, the TBI-related disability of survivors has consent form. To avoid selective bias, all enrolled pa- become a critical public health issue in China. tients will be divided into two equal groups to receive Neurocognitive deficits are common in patients with either acupuncture plus routine treatment (acupunc- severe TBI. Patients who fail to fully recover conscious- ture group) or routine treatment alone (control ness may enter a disorder of consciousness (DOC) such group) using the random scheme generated from as coma, a vegetative state, or a minimally conscious SPSS software. The serial number will be sealed in a state . With the development of diagnostic tools non-transparent envelope by the principal investigator such as functional magnetic resonance and electroen- and given to the researcher. Acupuncture will be per- cephalography, clinicians are able to detect DOC in formed by doctors from the Department of Trad- patients with severe TBI and commence early inter- itional Chinese and Western Medicine. The efficacy vention [6, 7]. Current therapeutic strategies for DOC and safety will be evaluated by doctors from the De- include behavioral, pharmacological, and neurostimu- partment of Critical Care Medicine, Department of latory approaches, among which the latter two have Neurosurgery and Department of Neurology, who will been intensively studied. For example, amantadine and be blind to the allocation of the patients. other dopaminergic agents have shown beneficial ef- fects in promoting recovery after TBI, but warrant fur- Participants ther systemic investigation [8–10]. As a potential A total of 150 patients with TBI being treated at restorative treatment for DOC, neurostimulation has West-China Hospital of Sichuan University will be en- attracted increasing interest. A study of thalamic deep rolled in this study after the legal representative signs brain stimulation demonstrated a remarkable behavioral the informed consent. The inclusion, exclusion, and recovery in patients with TBI . Non-invasive forms of withdrawal criteria are described in Table 1. neurostimulation, such as transcranial magnetic stimula- tion and transcranial direct current stimulation, have Procedure shown some short-term effects on behavioral improve- Figure 1 shows the study procedure flowchart. Poten- ment, but need further study [12–14]. tial participants from the Department of Critical Care Acupuncture therapy is an important component of Medicine, Shangjin clinics, West-China Hospital of traditional Chinese medicine and has long been used Sichuan University, will be enrolled according to the in China to promote the neurological functions in pa- inclusion criteria and randomized into the acupunc- tients with stroke and hemiplegia . Although nu- ture or control groups. In addition to routine treat- merous studies have been conducted to evaluate the ment, patients in the acupuncture group will receive a effects of acupuncture, results from these randomized 10-day electro-acupuncture treatment. Acupuncture controlled trials are controversial due to problems will start 3 days after trauma if the patient’s situation is concerning the study design, including small sample stable. Patients in the control group will receive rou- size, high drop-out rate, lack of proper control, and tine treatment alone, involving the prescription of randomization . coma arousal and neuroprotective agents by the neuro- Herein, we present a study design and protocol of a surgeons. If the patient needs vasoconstrictor or randomized, blinded, controlled study to evaluate the ef- hypothermiatherapy duetoanunstableintracranial ficacy and safety of electro-acupuncture in improving situation, electro-acupuncture will be started 3 days the consciousness level in patients with TBI. This study after the end of such treatments. Liu et al. Trials (2018) 19:296 Page 3 of 6 Table 1 Inclusion and exclusion criteria for electro-acupuncture inserted into the respective acupoints. The needle will in severe traumatic brain injury trial be inserted perpendicularly for PC6 at a depth of Inclusion Patients with severe traumatic brain injury admitted 20 mm. For GV26, the needle will be inserted towards to ICU: the nose at a depth of 5–10 mm. The needle will be ma- � Initial GCS score less than 8 points on admission nipulated using twirling, lifting, thrusting, and mild � Estimated ICU stay longer than 2 weeks � Normal consciousness level before brain injury, reinforcing-reducing methods to promote Qi. Eye mois- no primary disorders in cognitive or motor function ture or the presence of tears will be used as an indicator � Aged from 18 to 75 years of Qi arrival since patients are not able to express their � Agree to participate in the study and sign the informed consent feelings. The electro-acupuncture apparatus electrodes will then be linked onto the needle handles of both sides Exclusion Patients are excluded from the study if any of the following criteria apply: of PC6. The electro-acupuncture apparatus will be set � Vital signs are not stable on admission, die within for disperse-dense waves at a frequency of 10/50 Hz and 24 h current of 1 mA. The needles will be retained for 60 min � Women with pregnancy � Legal representative or immediate family has no after electro-acupuncture for 30 min duration. Due to strong treatment intent, can withdraw from the specific location of GV26, only hand manipulation treatment within 1 week will be applied for 30 min. � Patients with multiple trauma associated with limb fracture or skin defect Electrophysiological methods Withdrawal Patients will be withdrawn from the study if any of the following criteria applies: To assess the patients’ consciousness level, event-related � Life-threatening complications potentials (ERP) will be recorded from scalp electrodes � Secondary hydrocephalus placed on sites CZ and FZ according to the international � Uncontrolled intracranial infection � Re-operate due to varieties of causes 10–20 system, using the nose as reference. Mismatch nega- � Massive cerebral infarction tivity (MMN) will be produced using a pitch change in a re- � Unable to follow-up petitive auditory sequence. ERP will be recorded before electro-acupuncture starts, after the 10-day acupuncture is Electro-acupuncture procedure completed, on the day when the patient is discharged from Patients in the acupuncture group will be treated at acu- ICU, and on the day of hospital discharge. MMN will be points PC6 (Neiguan) and GV26 (Shuigou), as described recorded at the same time of day for each measurement. in Table 2. The patient will be placed in a supine pos- ition. After disinfection of skin with 75% alcohol, the Outcome measures acupuncture needles (stainless steel, sterile and dispos- The primary measurements for efficacy assessment will able, 30-guage in thickness, and 45 mm in length, Jiajian be changes in Glasgow Coma Scale (GCS) and MMN. Medical Instrument Co. Std, Jiangsu, China) will be Additionally, Glasgow Outcome Scale and Barthel Index Assessed for eligibility Excluded if meet Enrollment exclusion criteria randomized Allocated to acupuncture Allocated to control group Allocation group Withdrawn if meet withdraw Withdrawn if meet withdraw criteria Follow-up criteria Lost to follow-up Lost to follow-up Analyzed Analyzed Analysis Fig. 1 Flow chart of the study procedure Liu et al. Trials (2018) 19:296 Page 4 of 6 Table 2 Description of acupuncture points the consent form. Any adverse events, including acu- point hematoma, infection, and apostasis, will be re- Acupoints Descriptions corded by the researcher. In case of severe adverse PC6: Neiguan Locations: 2 cun above the transverse crease of the wrist, between the tendons of m. Palmaris events occurring, acupuncture intervention will be longus and m. flexor radialis ceased immediately and proper treatment will be pro- Indications: cardiac pain, mental disorder, epilepsy, vided. All severe adverse events will be reported to the insomnia, vomiting, hiccup, febrile disease Insertion depth: 20 mm principle investigator and the ethics committee within 48 h. Patients will be followed up for 1 month after the GV26: Shuigou Locations: at the junction of the upper and middle third of the philtrum trial. Indications: mental disorders, epilepsy, hysteria, coma, aplexy-faint Sample size calculation Insertion depth: 5–10 mm The purpose of this study is to clarify the role of acu- puncture in the consciousness recovery of patients with of Activities of Daily Living at 3 months after the trauma TBI. Therefore, GCS change will be used as an evalu- will be compared between the two groups. Secondary ation index. Changes in GCS before and after treatment measurements will be the length of stay in ICU and hos- in our pilot study were shown to be 2.27 ± 3.52 (n = 11) pital, expenses in ICU and hospital, and the incidence of in the control group and 3.70 ± 2.16 (n = 12) in the acu- coma-related complications. Safety will be assessed by puncture group. Sample size was calculated using the monitoring adverse events as well as changes in vital following formula: signs during the study (see Fig. 2 and Additional file 1: Standard Protocol Items: Recommendations for Inter- Z þ Z σ 1 1 α=2 β n ¼ þ ventional Trials (SPIRIT) Checklist). δ Q Q 1 2 Safety monitoring where n represents the number of samples required, Patients’ legal representatives will be informed of poten- n = n + n ,Q = n /n,Q n /n with 80% power and 1 2 1 1 2= 2 tial adverse events from acupuncture prior to signing significance level at 5% for a two-sided test. Thus, STUDY PERIOD Enrolment Allocation Post-allocation Close-out TIMEPOINT** -T T T T -T T T T T 1 0 1 2 8 10 11 12 13 ENROLMENT: Eligibility screen Informed consent X Allocation Interventions: Acupuncture/control ASSESSMENTS: X X X X GCS X X X X MMN GOS ADL LOS and expense in ICU LOS and expense in hospital complications SAFETY Fig. 2 Schedule of enrollment, interventions, and assessments Liu et al. Trials (2018) 19:296 Page 5 of 6 allowing for 10% of attrition, we will recruit 150 par- we have introduced strict quality control procedures, in- ticipants, with 75 in each group. cluding randomization, blinding, adequate sample size, and proper control. Allocation concealment will be used Statistical analysis to randomize the enrolled patients into acupuncture or SPSS 17.0 (IBM SPSS, Chicago, IL, USA) will be used to control groups, and only the acupuncture doctors will analyze the data. Quantitative data will be presented as know the patient’s group allocation. All data will be col- mean ± SD. Single factor variance analysis will be used lected and analyzed by researchers aware of group allo- to compare the difference in heart rate, blood pressure, cation only when the trial has been completed. The mean arterial pressure, respiratory rate, and saturation initial GCS of patients will be set at 8 so as to largely re- of pulse oxygen between the two groups. The χ test will duce the placebo effects of acupuncture. be used to compare the incidence of complications and In this study, the acupuncture points of PC6 and adverse events between groups. Measurement of neural GV26 have been selected based on Xingnaokaiqiao the- function recovery, including GCS, Glasgow Outcome ory . PC6 is an acupoint mainly used to improve car- Scale, and activities of daily living, will be analyzed diac function and increase cerebral perfusion. It has using rank sum-test. Longitudinal changes in MMN been proved, in an animal model, that acupuncture at amplitude will be analyzed using a mixed model pro- PC6 can increase cardiac output as well as blood and cedure. P values of less than 0.05 will be considered oxygen supply to the brain, meliorating brain edema statistically significant. . In addition, PC6 acupuncture may induce connec- tions between cerebral cortex regions . In China, Quality control GV26 is widely used in patients with stroke for prompt In order to avoid possible heterogeneity in the measure- restoration of consciousness. ment data and to ensure high-quality data results, the Mechanism studies using animal models have shown study data will be manually recorded on the case report that electro-acupuncture may alleviate cerebral injuries form and uploaded to the database. The trial manage- via upregulation of transforming growth factor beta 1 + + ment team will control data quality through regular . Activation of large-conductance Ca -activated K meetings and strict trainings to ensure that the acupunc- channels is also likely involved in the protective effects turists, intensivists, neurosurgeons, and nurses are fully of GV26 . Herein, in order to avoid variations in the aware of the complete procedure. When the clinical trial acupuncture procedure, electro-acupuncture will be begins, the principle investigator will supervise the trial used to achieve good control of the depth, frequency, to ensure that (1) the recruited patients are within the and duration of treatment. scope of the planned number; (2) all participants meet ERP can provide important information on human the inclusion criteria; and (3) all participants follow the brain functions. Among all the auditory ERP components, clinical trial process. Auditing trial conduct will be per- MMN is an automatic event related to brain response. formed every 3 months by investigators, intensivists, MMN can be recorded in comatose patient and is consid- and surgeons. ered a reliable predictor of awakening from coma, with a specificity of 91% . When patients start to regain con- Discussion sciousness, there might be an enhancement of MMN TBI has become a severe socioeconomic issue due to its amplitude prior to communicating with the environment. high mortality and morbidity. Patients surviving the ori- Herein, longitudinal changes in MMN responses will be ginal insult may remain in a comatose state for a consid- investigated to identify early signs of recovery. erable time. Effective and safe treatments to improve the In conclusion, this study will provide solid evidence of outcome of patients with TBI are necessary. Despite acu- the role of electro-acupuncture in the recovery of con- puncture having long been used in the treatment of sciousness of patients with TBI. neurological diseases in China, its efficacy has attracted the interests of western medicine only in recent years Trial status  and several randomized controlled trials have been Patient recruitment is ongoing. This is protocol version conducted to evaluate its potentials in clinical practice. 20160701, version date is 2016.7.23. Recruitment was However, the results are controversial due to the lack of started in June 2017 and will be completed in June 2018. high-quality studies, limited sample numbers, variation in acupuncture administration, and the possible placebo Additional file effects of acupuncture. This study is designed to evaluate the efficacy and Additional file 1: SPIRIT 2013 checklist for the study protocol. safety of electro- acupuncture in the consciousness re- (DOC 127 kb) covery of patients with TBI. To reduce the possible bias, Liu et al. Trials (2018) 19:296 Page 6 of 6 Abbreviations 8. Monti MM, Rosenberg M, Finoia P, Kamau E, Pickard JD, Owen AM. DOC: Disorder of consciousness; ERP: Event-related potentials; GCS: Glasgow Thalamo-frontal connectivity mediates top-down cognitive functions in Coma Scale; MMN: Mismatch negativity; TBI: Traumatic brain injury disorders of consciousness. Neurology. 2015;84(2):167–73. 9. Ugoya SO, Akinyemi RO. The place of I-dopa/carbidopa in persistent vegetative state. Clin Neuropharmacol. 2010;33(6):279–84. Funding 10. Fridman EA, Krimchansky BZ, Bonetto M, Galperin T, Gamzu ER, Leiguarda This report is supported by the Administration of Traditional Chinese RC, Zafonte R. Continuous subcutaneous apomorphine for severe disorders Medicine of Sichuan (2016C053), Yongxingxiang 15, Jinjiangqu, Chengdu of consciousness after traumatic brain injury. Brain Inj. 2010;24(4):636–41. City, China, 610016. 11. Yamamoto T, Katayama Y, Kobayashi K, Oshima H, Fukaya C, Tsubokawa T. The funder has no role in the design, data collection, data analysis, Deep brain stimulation for the treatment of vegetative state. Eur J Neurosci. manuscript writing, or submission. 2010;32(7):1145–51. 12. Piccione F, Cavinato M, Manganotti P, Formaggio E, Storti SF, Battistin L, Availability of data and materials Cagnin A, Tonin P, Dam M. Behavioral and neurophysiological effects of The results of this trial will be presented through scientific reports or journals. repetitive transcranial magnetic stimulation on the minimally conscious state: a case study. Neurorehabil Neural Repair. 2011;25(1):98–102. Authors’ contributions 13. Thibaut A, Bruno MA, Ledoux D, Demertzi A, Laureys S. tDCS in patients JL: acupuncture and draft the paper. XSX: consciousness level assessment and with disorders of consciousness: sham-controlled randomized double-blind statistical analysis. YW and CHY: ERP recording and follow-up. NL: acupuncture study. Neurology. 2014;82(13):1112–8. and experimental design. HPL: experimental design and trial organization. 14. Schnakers C, Monti MM. Disorders of consciousness after severe brain injury: All authors approve the final version of the paper. therapeutic options. Curr Opin Neurol. 2017;30(6):573–9. 15. Yang A, Wu HM, Tang JL, Xu L, Yang M, Liu GJ. Acupuncture for stroke rehabilitation. Cochrane Database Syst Rev. 2016;(8):CD004131. Ethics approval and consent to participate 16. Deng S, Zhao X, Du R, He S, Wen Y, Huang L, Tian G, Zhang C, Meng Z, Shi We strictly follow the principles of the medical ethics of the Declaration of X. Is acupuncture no more than a placebo? Extensive discussion required Helsinki with the approval of the Ethics and Research Committee of West-China about possible bias. Experimental Therapeutic Med. 2015;10(4):1247–52. Hospital of Sichuan University (No. 2016–252), China. 17. Marwick C. Acceptance of some acupuncture applications. JAMA. 1997; If there are any protocol modifications, we will report to the Ethics and Research 278(21):1725–7. Committee for approval. 18. Xingnaokaiqiao Method. In: Shi XM. Chief Editor. Shi Xuemin Practical All patients will be recruited from the Department of Critical Care Medicine acupuncture. 1st ed. Beijing: Traditional Chinese Medicine Press; with signed informed consent from their legal representatives. 2009. p. 264–76. Participant information will be protected. All experimental data will be stored 19. Quirico PE, Allais G, Ferrando M, De Lorenzo C, Bergandi F, Rolando S, in a secure storage area with access limited to the researchers alone. Schiaparelli P, Benedetto C. Effects of the acupoints PC6 Neiguan and LR3 Taichong on cerebral blood flow in normal subjects and in migraine Competing interests patients. Neurol Sci. 2014;35(Suppl 1):129–33. The authors declare that they have no competing interests. 20. Yu H, Xu G, Guo L, Fu L, Yang S, Lv H. Magnetic stimulation at Neiguan (PC6) acupoint increases connections between cerebral cortex regions. Neural Regen Res. 2016;11(7):1141–6. Publisher’sNote 21. Wang W, Yang L, He Q, Li T, Ma Y, Zhang P, Cao Y. Mechanisms of Springer Nature remains neutral with regard to jurisdictional claims in electroacupuncture effects on acute cerebral ischemia/reperfusion injury: published maps and institutional affiliations. possible association with upregulation of transforming growth factor beta 1. Neural Regen Res. 2016;11(7):1099–101. Author details 1 22. Wang Y, Shen Y, Lin H, Li Z, Chen Y, Wang S. Large-conductance Ca2+ Department of Traditional Chinese Medicine and Western Medicine, −activated K+ channel involvement in suppression of cerebral ischemia/ West-China Hospital of Sichuan University, Guoxuexiang 37, Chengdu 2 reperfusion injury after electroacupuncture at Shuigou(GV26) acupoint in 610041, Sichuan, China. Department of Critical Care Medicine, West-China rats. 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Published: May 29, 2018