Investigation of melatonin effect on the outcome of moderate and severe diffuse axonal injury (DAI) - A randomized, placebo-controlled clinical trial

Investigation of melatonin effect on the outcome of moderate and severe diffuse axonal injury (DAI) - A randomized, placebo-controlled clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Investigation of melatonin effect on the outcome of moderate and severe diffuse axonal injury (DAI) - A randomized, placebo-controlled clinical trial Alireza Ghaedamini, Saeed Karamoozian, Mohammad Khaksari Hadad, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4980173/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective The efficacy of melatonin in improving diffuse axonal injury has not been evaluated. This study investigated the melatonin effect on moderate and severe diffuse axonal injury outcomes. Methods This was a randomized clinical trial. The case group (N = 35) received 3mg of oral melatonin, and the control group (N = 35) received Placebo. extended-Glasgow Outcome Scale (e-GOS) and Functional Independence Measure (FIM) scores at baseline, 1 month, 3 months, and 6 months after injury were defined as primary outcomes, and Glasgow Coma Scale (GCS) at baseline, 24 hours, 48 hours, 1 week, 2week until discharge defined as secondary outcomes. Results A total of 70 patients were enrolled and were randomly allocated into the intervention (n = 35) and placebo (n = 35) groups. The results showed that there was no statistically significant difference between melatonin and placebo in GOS (P > 0.05) and FIM (P > 0.05) at 3 months and 6 months after hospitalization but the mean E-GOS (P = 0.001) and FIM (P = 0.001) at the first month was significantly higher in the melatonin group. Conclusions The use of melatonin as a low-cost and safe medicine complementary treatment in people with DAI can accelerates functional recovery. Diffuse axonal injury Melatonin Outcome Figures Figure 1 INTRODUCTION Diffuse axonal injury (DAI) is a brain injury in which scattered lesions arise over a large area in white and grey matter tracts ( 1 ). It results from shear and tensile forces delivered to axons during rotational acceleration and deceleration. it is a major cause of unconsciousness and persistent vegetative state after TBI ( 2 ). By involvement of different axonal tracts, DAI can cause significant neurological impairment without gross pathologic findings on CT scans and conventional Magnetic Resonance Imaging (MRI) ( 3 ). Although advanced MRI sequences like Diffusion Tensor Imaging (DTI), Gradient-Echo (GRE), and Diffusion-weighted (DWI) can possibly reveal microstructural changes in white matter tracts but their use in clinical settings is limited ( 4 ). So DAI is mostly diagnosed based on clinical evidence combined with conventional imaging. There were more than 64,000 deaths from DAI occured in the United States in 2020 ( 3 ). Patients who recovered from DAI live with sequels in different aspects of life like neurological, psychological, ans social and emotional and physical ( 5 ). The leading cause of DAI is traffic accidents, sports-related incidents, and violence. Clinical manifestations of DAI depend on the severity of brain damage ( 6 ). In mild cases sometimes called concussion, a person experiences vomiting, nausea, fatigue, headache, dizziness, rapid breathing, excessive sweating, and hyperthermia ( 6 ). In moderate and severe cases, they may appear with loss of consciousness with a GCS of 9–12 and 3–8 repectivly ( 7 , 8 ). Treatment of DAI begins with formal trauma ABC (airway, bleeding, circulation) algorithm and continues with conservative and supportive treatment (ICU admission in moderate to severe cases) with no specifically approved available medication ( 8 ). Melatonin is a natural product found in plants and animals. This substance is known as a brain hormone associated with the control of the sleep-wake cycle. Based on available data melatonin has low toxicity ( 10 ), ability to cross the blood-brain barrier ( 11 ), and the ability to regulate the electron transport chain ( 12 ) and phosphorylation ( 13 ). It also has antioxidant and anti-inflammatory effects ( 14 ). It has a hypothermic effect that reduces secondary brain damage ( 15 ). Various studies have evaluated the effect of melatonin in TBI ( 16 – 23 ) but no study has been done regarding its effect on DAI specifically ( 21 – 23 ). Due to the neuroprotective effect ( 8 ) it is possible to consider melatonin in the treatment regimen of DAI to increase awareness and function. Considering havy burden of DAI in truma patients and the lack of appropriate and specific medical treatment for it this study was conducted to evaluate the melatonin effect on patients with moderate and severe DAI. MATERIALS AND METHODS Study design and patients This study was Double-blind, randomized, placebo-controlled were conducted in Kerman, Iran, from march 2022 to actobert 2022 at Shahid Bahonar Referral University Hospital (A trauma center in the southeast of Iran). Eligible patients were Iranian adults between the ages of 18 to 60 referred to the emergency department of Shahid Bahonar Hospital of Kerman. The main inclusion criteria were moderate (Glasgow Coma Scale (GCS): 9-12) to severe (GCS≤8) DAI (according to clinical presentation and imaging) approved by a neurosurgeon who is a faculty member of the university) and less than 4 hours passed from the Truama (FIGURE 1). The exclusion criteria included brain death, sepsis, electrolyte imbalances, use of steroids, need for a non-neurosurgical procedure, high blood pressure, diabetes, metabolic acidosis (bicarbonate less than 12), liver trauma, cancer, history depression, having cardiovascular risk factors, autoimmune diseases, respiratory failure, fracture and other sever truamatic injuries to chestm abdomen and limb, and severe hypothermia (temperature less than 35 degrees Celsius) (24). The Patients were randomized (1:1) to receive 3mg of oral melatonin (Intervention group, N=35 people) made by RAZAK Laboratory or placebo (Control group, N=35). The randomization sequence was generated using the block randomization technique using Stata 9® software (StataCorp LP, College Station, TX, USA). The melatonin was administered at the beginning of hospitalization in emergency department and then once daily for 4 weeks at 10 PM. Then Extended Glascow Outcome Scale (25) (E-GOS) and Functional Independence Measure (26) (FIM) of the patients were measured at the beginning of admission, the first month, the third month and the sixth month after the injury, and the GCS of the patients was measured in the beginning of admission, the first day, the second day, the first week and the second week after the injury. Outcome measures Primary outcomes include Extended-GOS and FIM scores at baseline, 1 month, 3 months and 6 months after injury. Extended GOS classifies patients after traumatic brain injury, in 8 categories as follows: 1- Death 2-Vegetative state: Severe damage with a prolonged state of unresponsiveness and a lack of higher mental functions 3- Lower Severe disability: continuous but dependent at lower spectrum 4- Upper Severe disability. continuous but dependent at the maximum spectrum 5-Lower Moderate disability: independent but disabled at lower spectrum 6- Upper Moderate disability: independent but disabled at the maximum spectrum 7- Lower good recovery: can resume normal activity at the minimum spectrum 8- Upper good recovery: can resume normal activity at the maximum spectrum (25). The FIM is an 18-item measure that assesses the level of independence for basic self-care, mobility, communication, psychosocial adjustment, and cognitive functioning. Each item of FIM scores range from 1 to 7 ( 1 = total assist and 7 = complete independence, with the minimum score of 18 and the maximum score of 126). The measure consists of separate motor and cognitive sub-scales which can be combined for a total FIM score, with higher scores. denoting higher levels of independence (26). Secondary outcome include GCS score as an assessmebt tool for messuring barain injury severity (at baseline, 24 hours, 48 hours, 1 week, 2week until discharge). Three injury severity groups can be identified using GCS score ranges: severe (3–7), moderate (8–12) and mild (13–15) (27). Statistical Analyses The normality of continuous data was evaluated using the Kolmogorov-Smirnov test and Q-Q plot in a subtle way. Independent samples t-test used to compare normally distributed data between groups (The Mann–Whitney U method was used for the non-parametric distribution of the data). All statistical analyses were conducted using SPSS, version 24 (IBM Inc., Chicago, IL, USA) and GraphPad Prism, version 9.3 (GraphPad Software, Inc., San Diego, CA). RESULTS seventy patients entered into the study. One patient expired in the melatonin group due to myocardial infarction (not realative to truma) in second month of fallow up. Sixty-nine patients remained until the completion of the study (Fig. 1 , 34 people in the melatonin and 35 people in the control group). The results of the demographic variables are presented in Table 1 . The mean ± standard deviation of age was 25.09 ± 14.25 in the melatonin group and 24.23 ± 13.98 in the placebo group. There was no statistically significant difference between the age group (P = 0.751), gender (P = 0.836), and etiology (P = 0.194) in the two groups. Table 1 Demographic characteristics of participants Characteristics Subgroups Placebo (N = 35) Melatonin (N = 35) P-value Age < 18 15 (42.9) 12 (34.3) 0.424 18 ≤ age < 65 19 (54.2) 23 (65.7) 65 ≤ 1 (2.9) 0 Gender Male 27 (77.1) 26 (74.3) 0.780 Female 8 (22.9) 9 (25.7) Etiology Accident 32 (91.4) 29 (82.9) 0.194 Fall 1 (2.9) 5 (14.2) Conflict 2 (5.7) 1 (2.9) The results showed no statistically significant difference between GCS, GOS, and FIM within and between groups in different time episodes (Table 2 ). The scores of E-GOS and FIM were shown to be substantially raised within 6 months, although no significant difference was found between groups. but the mean E-GOS (P = 0.001) and FIM (P = 0.001) at the first month was significantly higher in the melatonin group. (Table 2 ). The interaction effect between the FIM and GOS with time in the melatonin group was statistically significant compared to the control gro Table 2 Comparison of changes in two groups of melatonin and placebo character Subgroup Melatonin Placebo P-value* Mean S.D Mean S.D E-GOS Baseline 1.97 1.51 3.00 1.82 .535 Month 1 6.80 1.34 5.52 1.78 .001 Month 3 7.14 .86 5.91 2.071 .087 Month 6 7.29 1.04 6.75 1.481 .160 FIM Baseline 37.58 30.88 53.23 33.09 .027 Month 1 111.77 22.13 87.91 29.40 .001 Month 3 121.31 11.60 98.80 37.27 .176 Month 6 119.54 15.62 112.48 23.15 .317 GCS Baseline 6.85 1.873 7.09 3.04 .686 24 hours 7.90 2.125 7.44 3.48 .120 48 hours 9.20 2.764 8.00 3.31 0.50 * Mann-Whitney U DISCUSSION This was the first double blind randomized controlled study of melatonin effects on FIM, E-GOS and GCS in DAI patients. In total, both melatonin and placebo groups reched the same functional recovery in the third (mid follow-up) and sixth months (late follow-up). The Results showed the mean E-GOS at third and sixth months were not significantly different between two groups. However based on E-GOS results, in the early (one-month) follow-up, the melatonin group had better functional improvement. It was probably caused by the neuroprotective effects of melatonin in damaged tissues ( 28 ), anti-inflammatory impact ( 29 ), reduction of glial cell death ( 30 , 31 ) and better repair of the blood-brain barrier ( 31 ). Litritre review shows that secretion of melatonin in people with lower GOS is impaired ( 32 ). Therefore, it seems logical to use exogenous melatonin in people with TBI to compensate for reduced endogenous melatonin. (Refrence). Due to the fact that no similar study done on this issue, additional research is recommended. Anlysis of FIM results indicates no significant difference different in the two groups at third and sixth months. However, in the early follow-up, the melatonin group had better functional FIM results and functional improvement occurred earlier with the statistical signefecance. paitents who received melatonin had more independence in performing daily activities at first month, which is probably due to the anti-apoptotic effect ( 33 ), energy regulation ( 34 ), reduction of cerebral edema ( 35 ), regulation of autophagy ( 36 ), a broad-spectrum antioxidant (cerebral cortex, cerebellum, hippocampus, hypothalamus, and striatum) and reducing anxiety after trauma ( 37 ). As far as the researchers of this study are aware, no clinical trial studies has been performed to evaluate the association between melatonin and FIM in DAI patients, and it is recommended to conduct additional studies in this field. As a role, it is very important for clinicians to speed up clinical recovery after DAI. Because delayed recovery predisposes patients to various and sometimes catastrophic events like (Deep Vein Thrombosis) DVT, (Pulmonary Thromboembolism) PTE caused by immobility ( 38 ), pulmonary diseases, pneumonia ( 39 ), bedsores, infection, prolonged ICU admission and hospital stay, the increased financial burden for the health system, family and patient (including absence from work) ( 40 – 41 ) increased emotional stress on family and patients sometimes evolving to psychiatry disorders. Although melatonin and control group enentualy reached the same functional recovery level at three and six month but accelerated short term recovery that happened in melatonin group at first month could be apportuanity to prevent the mentioned catastrophic complication of DAI. On the other hand, the reason for the lack of statistical significance in the third and sixth months could be possibly due to errors during data collection, a small sample size, and a limited statistical population. When anlysisng GCS results there wasn't any significant difference between GCS in two groups in any time period (from admission to the end of first week post truma) possibily indicating that melatonin regiment doseant cause and early recovery defect in fact it takes a month for melatonin to reproduce it defect (significant E-GOS at the end of first month). Limited studies have been conducted on the effect of melatonin in improving low consciousness which mostly showed an impaired level of melatonin secration in people with low GCS ( 42 ). Litriture review demonstrated that the use of melatonin in TBI patients improves the quality of sleep, which can increase the quality of life ( 43 ). Melatonin can also reduce Alzheimer's after trauma ( 44 ). Considering that sideeffects of melatonin overlap with some of the comment DAI symptoms like nausea, vomiting, and dizziness, There is a possibility that the use of melatonin could aggravates the symptoms, which must be keept in mind ( 45 ). On the other hand, melatonin improves symptoms such as headache, pain, and anxiety probably through the gamma-aminobutyric acid (GABA) system and opiate receptors ( 46 ). The limitations of this study were small sample size and statistical papulation. In avitable, combination of melatonin with a variety of other drugs wich exist in the priscription regiment of an ICU admitted, limited arms of the intervention groups with only 3 mg daily dose and exclusion of mild DAI (concussion). The advantages of the current research were long-term follow-ups, evaluation on humans (instead of animal models), and incorporating FIM score. It is suggested that future studies should be conducted with larger sample size and in a multicenter system. It is also recommended to conduct meta-analysis research in this field. Considering the effects of melatonin on GOS and FIM, it can accelerates the speed of functional recovery as a low-cost and safe supplement in DAI. CONCLUSION Althogh melatonin and control group reach the same fanctional recovery level at mid-term (3 moth) and longterm (6 month) fallow up, melatonin accelerates the speed of functional recovery in short term (1 month) fallow up after DAI. Thus melatonin as a lowcast and safe medication can be incoroporated in DAI treatment to increase the speed of recovery rate and decrease mortality and morbidity after DAI resulting in an improve quality of life.This study investigated the clinical effects of melatonin. Conducting similar studies that evaluate molecular biomarkers and inflammatory markers after TBI can be helpful. Declarations Availability of data and materials The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. The materials used in this study are available commercially or can be obtained from the authors upon request. Funding Not applicable. Conflicts of Interest The authors declared no conflict of interest Competing interests Not applicable. Acknowledgement Not applicable. Contributions Alireza Ghaedamini: writing and editing manuscript Saeed Karamoozian :supervising Mohammad Khaksari Hadad: data collection Zahra Soltani: data collection Hossein Ghaedamini : editing manuscript Ali Hojati: writing manuscript Amin Soleimani: writing manuscript Reza Karimabadi: writing of the research Masod Mayel: writing of the research Nazanin Sabet: writing of the research Mohammad Mehdi Ahmadinejad: writing of the research Gholamreza Asadikorom: editing of the research Behshad Mofid: editing of the research Nozar Nakheie: statistical analysis Payam Khazaeli: editing of the research Elham Jafari: editing of the research Ethics approval The study protocol was approved by Iranian Registry of Clinical Trials (IRCT Code: IRCT20190717044248N6) and the Medical Ethics Committee of Kerman University of Medical Sciences (Ethical Code: IR.KMU.AH.REC.1400.228). Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests No potential conflict of interest relevant to this article was reported. Conflict of Interest: The authors have no financial conflicts of interest. References Shahhosseini R, Nejad AE, Shahba M, Tajoddini S, Ghaedamini H, Farahbakhsh S, Daneshi S, Hushmandi K, Raei M. Investigation of the changes in CT scan findings in patients with head trauma referred to the emergency department of Shahid Bahonar Hospital in Kerman in 2020. Qom University of Medical Sciences Journal. 2021 Apr 10;15(2):130-9. Jang SH. Diagnostic problems in diffuse axonal injury. Diagnostics. 2020 Feb 21;10(2):117. Graham NS, Jolly A, Zimmerman K, Bourke NJ, Scott G, Cole JH, Schott JM, Sharp DJ. Diffuse axonal injury predicts neurodegeneration after moderate–severe traumatic brain injury. Brain. 2020 Dec;143(12):3685-98. Benjamini D, Iacono D, Komlosh ME, Perl DP, Brody DL, Basser PJ. Diffuse axonal injury has a characteristic multidimensional MRI signature in the human brain. Brain. 2021 Mar;144(3):800-16. van Eijck MM, Sprengers MO, Oldenbeuving AW, de Vries J, Schoonman GG, Roks G. The use of the PSH-AM in patients with diffuse axonal injury and autonomic dysregulation: a cohort study and review. Journal of Critical Care. 2019 Feb 1;49:110-7. Zhong YH, Zheng BE, He RH, Zhou Z, Zhang SQ, Wei Y, Fan JZ. Serum levels of HDL cholesterol are associated with diffuse axonal injury in patients with traumatic brain injury. Neurocritical Care. 2021 Apr;34:465-72. Janas AM, Qin F, Hamilton S, Jiang B, Baier N, Wintermark M, Threlkeld Z, Lee S. Diffuse axonal injury grade on early MRI is associated with worse outcome in children with moderate-severe traumatic brain injury. Neurocritical Care. 2022 Apr;36(2):492-503. Rostami E, Ginstman F, Ljungqvist J, Olivecrona M, Koskinen LO, Bellander BM, Marklund N. Treatment of traumatic brain injury in the acute setting-An overview. Lakartidningen. 2023 Jan 27;120:22067-. Lohani S, Bhandari S, Ranabhat K, Agrawal P. Does diffuse axonal injury MRI grade really correlate with functional outcome?. World Neurosurgery. 2020 Mar 1;135:e424-6. Tomita K, Nakada TA, Oshima T, Motoshima T, Kawaguchi R, Oda S. Tau protein as a diagnostic marker for diffuse axonal injury. PLoS One. 2019 Mar 22;14(3):e0214381. Ramos E, Gil-Martín E, De Los Ríos C, Egea J, López-Muñoz F, Pita R, Juberías A, Torrado JJ, Serrano DR, Reiter RJ, Romero A. Melatonin as Modulator for Sulfur and Nitrogen Mustard-Induced Inflammation, Oxidative Stress and DNA Damage: Molecular Therapeutics. Antioxidants. 2023 Feb 6;12(2):397. Thangwong P, Jearjaroen P, Tocharus C, Govitrapong P, Tocharus J. Melatonin suppresses inflammation and blood‒brain barrier disruption in rats with vascular dementia possibly by activating the SIRT1/PGC-1α/PPARγ signaling pathway. Inflammopharmacology. 2023 Apr 5:1-3. Sun C, Meng S, Wang B, Zhao S, Liu Y, Qi M, Wang Z, Yin Z, Li T. Exogenous melatonin enhances tomato heat resistance by regulating photosynthetic electron flux and maintaining ROS homeostasis. Plant Physiology and Biochemistry. 2023 Mar 1;196:197-209. Yang S, Zeng H, Jiang L, Fu C, Gao L, Zhang L, Zhang Y, Zhang X, Zhu L, Zhang F, Chen J. Melatonin reduces melanogenesis by inhibiting the paracrine effects of keratinocytes. Experimental Dermatology. 2023 Jan 9. Potes Y, Caballero B. Special Issue on “Pleiotropic Benefits of Melatonin: From Basic Mechanisms to Disease”. International Journal of Molecular Sciences. 2023 Mar 9;24(6):5223. Osier N, McGreevy E, Pham L, Puccio A, Ren D, Conley YP, Alexander S, Dixon CE. Melatonin as a Therapy for Traumatic Brain Injury: A Review of Published Evidence. Int J Mol Sci. 2018 May 22;19(5):1539. doi: 10.3390/ijms19051539. PMID: 29786658; PMCID: PMC5983792. Naseem M, Parvez S. Role of melatonin in traumatic brain injury and spinal cord injury. ScientificWorldJournal. 2014;2014:586270. doi: 10.1155/2014/586270. Epub 2014 Dec 21. PMID: 25587567; PMCID: PMC4283270. Bell A, Hewins B, Bishop C, Fortin A, Wang J, Creamer JL, Collen J, Werner Jr JK. Traumatic Brain Injury, Sleep, and Melatonin—Intrinsic Changes with Therapeutic Potential. Clocks & Sleep. 2023 Apr 6;5(2):177-203. Dehghan F, Khaksari Hadad M, Asadikram G, Najafipour H, Shahrokhi N. Effect of melatonin on intracranial pressure and brain edema following traumatic brain injury: role of oxidative stresses. Archives of medical research. 2013;44(4):251-8. Dehghan F, Shahrokhi N, Khaksari M, Soltani Z, Asadikorom G, Najafi A, et al. Does the administration of melatonin during post-traumatic brain injury affect cytokine levels? Inflammopharmacology. 2018;26(4):1017-23. Wang Z, Zhou F, Dou Y, Tian X, Liu C, Li H, et al. Melatonin Alleviates Intracerebral Hemorrhage-Induced Secondary Brain Injury in Rats via Suppressing Apoptosis, Inflammation, Oxidative Stress, DNA Damage, and Mitochondria Injury. Translational stroke research. 2018;9(1):74-91. Wang DL, Ling ZQ, Cao FY, Zhu LQ, Wang JZ. Melatonin attenuates isoproterenol-induced protein kinase A overactivation and tau hyperphosphorylation in rat brain. Journal of pineal research. 2004;37(1):11-6. Kostoglou-Athanassiou I. Therapeutic applications of melatonin. Therapeutic advances in endocrinology and metabolism. 2013;4(1):13-24. Barlow KM, Esser MJ, Veidt M, Boyd R. Melatonin as a treatment after traumatic brain injury: a systematic review and meta-analysis of the pre-clinical and clinical literature. Journal of neurotrauma. 2019 Feb 1;36(4):523-37. Wright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, et al. Very early administration of progesterone for acute traumatic brain injury. The New England journal of medicine. 2014;37(1):2457-2466. Yamal JM, Hannay HJ, Gopinath S, Aisiku IP, Benoit JS, Robertson CS. Glasgow outcome scale measures and impact on analysis and results of a randomized clinical trial of severe traumatic brain injury. Journal of neurotrauma. 2019 Sep 1;36(17):2484-92. Maritz R, Tennant A, Fellinghauer C, Stucki G, Prodinger B. The Functional Independence Measure 18-item version can be reported as a unidimensional interval-scaled metric: Internal construct validity revisited. Journal of Rehabilitation Medicine. 2019 Mar 5;51(3):193-200. Mohamed OM, Mohammad SY, Ameen DA, Abo El-Hoda AH. Validity of Glasgow Coma Scale-Pupil Age Charts in predicting the outcome for patients with traumatic brain injury. Evidence-Based Nursing Research. 2022 Sep 19;4(4):16-32. Lee JG, Woo YS, Park SW, Seog DH, Seo MK, Bahk WM. The neuroprotective effects of melatonin: Possible role in the pathophysiology of neuropsychiatric disease. Brain sciences. 2019 Oct 21;9(10):285. Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, Zagrean AM. Melatonin’s impact on antioxidative and anti-inflammatory reprogramming in homeostasis and disease. Biomolecules. 2020 Aug 20;10(9):1211. Amer ME, Othamn AI, El-Missiry MA. Melatonin ameliorates diabetes-induced brain injury in rats. Acta Histochemica. 2021 Feb 1;123(2):151677. Qin W, Li J, Zhu R, Gao S, Fan J, Xia M, Zhao RC, Zhang J. Melatonin protects blood-brain barrier integrity and permeability by inhibiting matrix metalloproteinase-9 via the NOTCH3/NF-κB pathway. Aging (Albany NY). 2019 Dec 12;11(23):11391. Zhan CP, Zhuge CJ, Yan XJ, Dai WM, Yu GF. Measuring serum melatonin concentrations to predict clinical outcome after aneurysmal subarachnoid hemorrhage. Clinica Chimica Acta. 2021 Feb 1;513:1-5. Farid A, El-Dewak M, Safwat G, Diab A. Anti-apoptotic and antioxidant effects of melatonin protect spleen of whole body γ-irradiated male Sprague-dawley rats. International Journal of Radiation Research. 2021 Oct 1;19(4):861-72. Owino S, Buonfiglio DD, Tchio C, Tosini G. Melatonin signaling a key regulator of glucose homeostasis and energy metabolism. Frontiers in endocrinology. 2019 Jul 17;10:488. Liu L, Cao Q, Gao W, Li B, Xia Z, Zhao B. Melatonin protects against focal cerebral ischemia-reperfusion injury in diabetic mice by ameliorating mitochondrial impairments: involvement of the Akt-SIRT3-SOD2 signaling pathway. Aging (albany NY). 2021 Jun 6;13(12):16105. Luo F, Sandhu AF, Rungratanawanich W, Williams GE, Akbar M, Zhou S, Song BJ, Wang X. Melatonin and autophagy in aging-related neurodegenerative diseases. International Journal of Molecular Sciences. 2020 Sep 28;21(19):7174. Wido A, Bajamal AH, Apriawan T, Parenrengi MA, Al Fauzi A. Deep vein thrombosis prophylaxis use in traumatic brain injury patients in tropical climate. International Journal of Health & Medical Sciences. 2022;5(1):67-74. Finsterer J. Neurological perspectives of neurogenic pulmonary edema. European neurology. 2019 May 22;81(1-2):94-102. Murphy JM, Bennett JM, de la Piedad Garcia X, Willis ML. Emotion recognition and traumatic brain injury: A systematic review and meta-analysis. Neuropsychology review. 2022 Sep;32(3):520-36. Knott RJ, Harris A, Higgins A, Nichol A, French C, Little L, Haddad S, Presneill J, Arabi Y, Bailey M, Cooper DJ. Cost-effectiveness of erythropoietin in traumatic brain injury: a multinational trial-based economic analysis. Journal of neurotrauma. 2019 Sep 1;36(17):2541-8. Osier N, McGreevy E, Pham L, Puccio A, Ren D, Conley YP, Alexander S, Dixon CE. Melatonin as a Therapy for Traumatic Brain Injury: A Review of Published Evidence. Int J Mol Sci. 2018 May 22;19(5):1539. doi: 10.3390/ijms19051539 Huang Y, Li Y, Leng Z. Melatonin inhibits GABAergic neurons in the hypothalamus consistent with a reduction in wakefulness. Neuroreport. 2020 Jan 27;31(2):92-8. Grima NA, Rajaratnam SM, Mansfield D, Sletten TL, Spitz G, Ponsford JL. Efficacy of melatonin for sleep disturbance following traumatic brain injury: a randomised controlled trial. BMC medicine. 2018 Dec;16(1):1-0. Blum B, Kaushal S, Khan S, Kim JH, Villalba CL. Melatonin in traumatic brain injury and cognition. Cureus. 2021 Sep 6;13(9). Maas MB, Lizza BD, Abbott SM, Liotta EM, Gendy M, Eed J, Naidech AM, Reid KJ, Zee PC. Factors disrupting melatonin secretion rhythms during critical illness. Critical care medicine. 2020 Jun;48(6):854. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4980173","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":349354625,"identity":"5ac4207e-4c27-4679-b576-bcdf0b8bbe67","order_by":0,"name":"Alireza Ghaedamini","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alireza","middleName":"","lastName":"Ghaedamini","suffix":""},{"id":349354626,"identity":"61668bec-02a6-410d-9727-dd7a382bf719","order_by":1,"name":"Saeed Karamoozian","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYBAC/hlAggeEmHkYH4DYfIS0SNxAaGE2ALHZCGkxkIBoASsGsRkIa5FufvjgTc02GXN23mOVX3PsZNgYmB8+uoFPi8wxY8M5x27zWDbzpd2W3ZYMdBibsXEOHi2GNxLMpHnYbvMYHOYxuy25jRmohYdNGp8Wgxvp33/z/INoKZbcVk+MlhwzZt42iBbGj9sOE9YicSOnWHJuH1iLsTTjtuM8bMwE/MI/I33jhzffbtsbnD9j+PHntmp7fvbmh4/xaUEBzOAIYiZWOQgw/iBF9SgYBaNgFIwYAABYFkNyQ5HMFAAAAABJRU5ErkJggg==","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Saeed","middleName":"","lastName":"Karamoozian","suffix":""},{"id":349354629,"identity":"246fe2ea-d5ff-45bd-9f9c-82b4450e3225","order_by":2,"name":"Mohammad Khaksari Hadad","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Khaksari","lastName":"Hadad","suffix":""},{"id":349354630,"identity":"eaad802c-ba09-4670-b393-80d5ac053e0c","order_by":3,"name":"Hossein Ghaedamini","email":"","orcid":"","institution":"Jundishapur University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hossein","middleName":"","lastName":"Ghaedamini","suffix":""},{"id":349354631,"identity":"369802a4-fb75-45e1-b60d-d2700d9b0fcd","order_by":4,"name":"Zahra Soltani","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zahra","middleName":"","lastName":"Soltani","suffix":""},{"id":349354634,"identity":"33820f76-a0a1-4f6e-9593-6d0258369368","order_by":5,"name":"Ali Hojati","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ali","middleName":"","lastName":"Hojati","suffix":""},{"id":349354635,"identity":"5798e5d5-9056-4d2b-bd12-cb21b8583de9","order_by":6,"name":"Amin Soleimani","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Amin","middleName":"","lastName":"Soleimani","suffix":""},{"id":349354636,"identity":"299464e2-4fcc-466a-aa17-1fb0d083fc7a","order_by":7,"name":"Reza Karimabadi","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Reza","middleName":"","lastName":"Karimabadi","suffix":""},{"id":349354637,"identity":"d348abde-f6e1-4ca4-8b5a-b69eb8e18a70","order_by":8,"name":"Masod Mayel","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masod","middleName":"","lastName":"Mayel","suffix":""},{"id":349354638,"identity":"757add04-d121-4217-ada9-15756efb1257","order_by":9,"name":"Nazanin Sabet","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nazanin","middleName":"","lastName":"Sabet","suffix":""},{"id":349354639,"identity":"7ffd6bd2-c9c8-4998-a945-6275a4c16c42","order_by":10,"name":"Mohammad Mehdi Ahmadinejad","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Mehdi","lastName":"Ahmadinejad","suffix":""},{"id":349354640,"identity":"8d14a070-02fd-4709-b3ec-859df8f958ac","order_by":11,"name":"Gholamreza Asadikorom","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gholamreza","middleName":"","lastName":"Asadikorom","suffix":""},{"id":349354641,"identity":"ec0036c8-b8e8-45a7-bfd2-7df9ea80a407","order_by":12,"name":"Behshad Mofid","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Behshad","middleName":"","lastName":"Mofid","suffix":""},{"id":349354642,"identity":"2b22581c-507a-4836-b7c5-f873198afacb","order_by":13,"name":"Nozar Nakheie","email":"","orcid":"","institution":"Professor of Community Medicine, Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nozar","middleName":"","lastName":"Nakheie","suffix":""},{"id":349354643,"identity":"80c9d20d-06b4-44de-b995-46554056eae5","order_by":14,"name":"Payam Khazaeli","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Payam","middleName":"","lastName":"Khazaeli","suffix":""},{"id":349354644,"identity":"c341e6eb-c3f4-43ff-856d-69274808b799","order_by":15,"name":"Elham Jafari","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elham","middleName":"","lastName":"Jafari","suffix":""}],"badges":[],"createdAt":"2024-08-26 20:55:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4980173/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4980173/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66949749,"identity":"b89be52c-cffd-4d28-bdb0-94e16fe30923","added_by":"auto","created_at":"2024-10-18 10:07:46","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":70442,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram summarizing the study in a step-by-step fashion.\u003c/p\u003e\n\u003cp\u003en: number of patients\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e* The paitents was fallowed for 2 moths when he passed away from a sudden cardiac death.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4980173/v1/469f628e657baea7d9e38607.jpeg"},{"id":69553642,"identity":"8acb0195-831c-49ef-a1bf-fad182d7441a","added_by":"auto","created_at":"2024-11-21 14:53:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":603638,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4980173/v1/25900658-51de-468e-ba33-5af3ef011342.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Investigation of melatonin effect on the outcome of moderate and severe diffuse axonal injury (DAI) - A randomized, placebo-controlled clinical trial","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eDiffuse axonal injury (DAI) is a brain injury in which scattered lesions arise over a large area in white and grey matter tracts (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). It results from shear and tensile forces delivered to axons during rotational acceleration and deceleration. it is a major cause of unconsciousness and persistent vegetative state after TBI (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBy involvement of different axonal tracts, DAI can cause significant neurological impairment without gross pathologic findings on CT scans and conventional Magnetic Resonance Imaging (MRI) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough advanced MRI sequences like Diffusion Tensor Imaging (DTI), Gradient-Echo (GRE), and Diffusion-weighted (DWI) can possibly reveal microstructural changes in white matter tracts but their use in clinical settings is limited (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). So DAI is mostly diagnosed based on clinical evidence combined with conventional imaging.\u003c/p\u003e \u003cp\u003eThere were more than 64,000 deaths from DAI occured in the United States in 2020 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Patients who recovered from DAI live with sequels in different aspects of life like neurological, psychological, ans social and emotional and physical (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe leading cause of DAI is traffic accidents, sports-related incidents, and violence. Clinical manifestations of DAI depend on the severity of brain damage (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In mild cases sometimes called concussion, a person experiences vomiting, nausea, fatigue, headache, dizziness, rapid breathing, excessive sweating, and hyperthermia (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In moderate and severe cases, they may appear with loss of consciousness with a GCS of 9\u0026ndash;12 and 3\u0026ndash;8 repectivly (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Treatment of DAI begins with formal trauma ABC (airway, bleeding, circulation) algorithm and continues with conservative and supportive treatment (ICU admission in moderate to severe cases) with no specifically approved available medication (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMelatonin is a natural product found in plants and animals. This substance is known as a brain hormone associated with the control of the sleep-wake cycle. Based on available data melatonin has low toxicity (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), ability to cross the blood-brain barrier (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), and the ability to regulate the electron transport chain (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) and phosphorylation (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). It also has antioxidant and anti-inflammatory effects (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). It has a hypothermic effect that reduces secondary brain damage (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eVarious studies have evaluated the effect of melatonin in TBI (\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21 CR22\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) but no study has been done regarding its effect on DAI specifically (\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDue to the neuroprotective effect (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) it is possible to consider melatonin in the treatment regimen of DAI to increase awareness and function. Considering havy burden of DAI in truma patients and the lack of appropriate and specific medical treatment for it this study was conducted to evaluate the melatonin effect on patients with moderate and severe DAI.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy design and patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was Double-blind, randomized, placebo-controlled were conducted in Kerman, Iran, from march 2022 to actobert 2022 at Shahid Bahonar Referral University Hospital (A trauma center in the southeast of Iran).\u003c/p\u003e\n\u003cp\u003eEligible patients were Iranian adults between the ages of 18 to 60 referred to the emergency department of Shahid Bahonar Hospital of Kerman.\u003c/p\u003e\n\u003cp\u003eThe main inclusion criteria were moderate (Glasgow Coma Scale (GCS): 9-12) \u0026nbsp;to severe (GCS\u0026le;8) DAI (according to clinical presentation and imaging) approved by a neurosurgeon who is a faculty member of the university) and less than 4 hours passed from the Truama (FIGURE 1).\u003c/p\u003e\n\u003cp\u003eThe exclusion criteria included brain death, sepsis, electrolyte imbalances, use of steroids, need for a non-neurosurgical procedure, high blood pressure, diabetes, metabolic acidosis (bicarbonate less than 12), liver trauma, cancer, history depression, having cardiovascular risk factors, autoimmune diseases, \u0026nbsp;respiratory failure, fracture and other sever truamatic injuries to chestm abdomen and limb, \u0026nbsp; and severe hypothermia (temperature less than 35 degrees Celsius)\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(24).\u003c/p\u003e\n\u003cp\u003eThe Patients were randomized (1:1) to receive 3mg of oral melatonin\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e(Intervention group, N=35 people) \u0026nbsp;made by RAZAK Laboratory or placebo (Control group, N=35). The randomization sequence was generated using the block randomization technique using Stata 9\u0026reg; software (StataCorp LP, College Station, TX, USA). The melatonin was administered at the beginning of hospitalization in emergency department and then once daily for 4 weeks at 10 PM. Then Extended Glascow Outcome Scale (25) (E-GOS) and Functional Independence Measure (26) (FIM) of the patients were measured at the beginning of admission, the first month, the third month and the sixth month after the injury, and the GCS of the patients was measured in the beginning of admission, the first day, the second day, the first week and the second week after the injury.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary outcomes include Extended-GOS and FIM scores at baseline, 1 month, 3 months and 6 months after injury. Extended GOS classifies patients after traumatic brain injury, in 8 categories as follows:\u003c/p\u003e\n\u003cp\u003e1- Death\u003c/p\u003e\n\u003cp\u003e2-Vegetative state: Severe damage with a prolonged state of unresponsiveness and a lack of higher mental functions\u003c/p\u003e\n\u003cp\u003e3- \u0026nbsp;Lower Severe disability: continuous but dependent at lower spectrum\u003c/p\u003e\n\u003cp\u003e4- Upper Severe disability. continuous but dependent at the maximum spectrum\u003c/p\u003e\n\u003cp\u003e5-Lower Moderate disability: independent but disabled at lower spectrum\u003c/p\u003e\n\u003cp\u003e6- Upper Moderate disability: independent but disabled at the maximum spectrum\u003c/p\u003e\n\u003cp\u003e7- Lower good recovery: can resume normal activity at the minimum spectrum\u003c/p\u003e\n\u003cp\u003e8- Upper good recovery: can resume normal activity at the maximum spectrum\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;(25).\u003c/p\u003e\n\u003cp\u003eThe FIM is an 18-item measure that assesses the level of independence for basic self-care, mobility, communication, psychosocial adjustment, and cognitive functioning. Each item of FIM scores range from 1 to 7 ( 1 = total assist and 7 = complete independence, with the minimum score of 18 and the maximum score of 126). The measure consists of separate motor and cognitive sub-scales which can be combined for a total FIM score, with higher scores. denoting higher levels of independence (26).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecondary outcome include GCS score as an assessmebt tool for messuring barain injury severity (at baseline, 24 hours, 48 hours, 1 week, 2week until discharge). Three injury severity groups can be identified using GCS score ranges: severe (3\u0026ndash;7), moderate (8\u0026ndash;12) and mild (13\u0026ndash;15)\u003csup\u003e\u0026nbsp;\u003c/sup\u003e(27).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analyses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe normality of continuous data was evaluated using the \u0026nbsp; Kolmogorov-Smirnov test and Q-Q plot in a subtle way. Independent samples t-test used to compare normally distributed data between groups (The Mann\u0026ndash;Whitney U method was used for the non-parametric distribution of the data). All statistical analyses were conducted using SPSS, version 24 (IBM Inc., Chicago, IL, USA) and GraphPad Prism, version 9.3 (GraphPad Software, Inc., San Diego, CA).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eseventy patients entered into the study. One patient expired in the melatonin group due to myocardial infarction (not realative to truma) in second month of fallow up.\u003c/p\u003e\n\u003cp\u003eSixty-nine patients remained until the completion of the study (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, 34 people in the melatonin and 35 people in the control group).\u003c/p\u003e\n\u003cp\u003eThe results of the demographic variables are presented in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation of age was 25.09\u0026thinsp;\u0026plusmn;\u0026thinsp;14.25 in the melatonin group and 24.23\u0026thinsp;\u0026plusmn;\u0026thinsp;13.98 in the placebo group. There was no statistically significant difference between the age group (P\u0026thinsp;=\u0026thinsp;0.751), gender (P\u0026thinsp;=\u0026thinsp;0.836), and etiology (P\u0026thinsp;=\u0026thinsp;0.194) in the two groups.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDemographic characteristics of participants\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSubgroups\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (34.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"3\"\u003e\n \u003cp\u003e0.424\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u0026thinsp;\u0026le;\u0026thinsp;age\u0026thinsp;\u0026lt;\u0026thinsp;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19 (54.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (65.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 \u0026le;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e27 (77.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (74.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"2\"\u003e\n \u003cp\u003e0.780\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8 (22.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (25.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eEtiology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAccident\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32 (91.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (82.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" rowspan=\"3\"\u003e\n \u003cp\u003e0.194\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConflict\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eThe results showed no statistically significant difference between GCS, GOS, and FIM within and between groups in different time episodes (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe scores of E-GOS and FIM were shown to be substantially raised within 6 months, although no significant difference was found between groups. but the mean E-GOS (P\u0026thinsp;=\u0026thinsp;0.001) and FIM (P\u0026thinsp;=\u0026thinsp;0.001) at the first month was significantly higher in the melatonin group. (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). The interaction effect between the FIM and GOS with time in the melatonin group was statistically significant compared to the control gro\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eComparison of changes in two groups of melatonin and placebo\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003echaracter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eSubgroup\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eP-value*\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eS.D\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eS.D\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003eE-GOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.535\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMonth 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMonth 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.071\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.087\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMonth 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.481\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.160\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003eFIM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.027\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMonth 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e111.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMonth 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e121.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e98.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.176\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMonth 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e119.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e112.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.317\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003eGCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.873\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.686\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e.120\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.764\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003e* Mann-Whitney U\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis was the first double blind randomized controlled study of melatonin effects on FIM, E-GOS and GCS in DAI patients.\u003c/p\u003e \u003cp\u003eIn total, both melatonin and placebo groups reched the same functional recovery in the third (mid follow-up) and sixth months (late follow-up).\u003c/p\u003e \u003cp\u003eThe Results showed the mean E-GOS at third and sixth months were not significantly different between two groups. However based on E-GOS results, in the early (one-month) follow-up, the melatonin group had better functional improvement. It was probably caused by the neuroprotective effects of melatonin in damaged tissues (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), anti-inflammatory impact (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), reduction of glial cell death (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) and better repair of the blood-brain barrier (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Litritre review shows that secretion of melatonin in people with lower GOS is impaired (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Therefore, it seems logical to use exogenous melatonin in people with TBI to compensate for reduced endogenous melatonin. (Refrence). Due to the fact that no similar study done on this issue, additional research is recommended.\u003c/p\u003e \u003cp\u003eAnlysis of FIM results indicates no significant difference different in the two groups at third and sixth months. However, in the early follow-up, the melatonin group had better functional FIM results and functional improvement occurred earlier with the statistical signefecance. paitents who received melatonin had more independence in performing daily activities at first month, which is probably due to the anti-apoptotic effect (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e), energy regulation (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), reduction of cerebral edema (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e), regulation of autophagy (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e), a broad-spectrum antioxidant (cerebral cortex, cerebellum, hippocampus, hypothalamus, and striatum) and reducing anxiety after trauma (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs far as the researchers of this study are aware, no clinical trial studies has been performed to evaluate the association between melatonin and FIM in DAI patients, and it is recommended to conduct additional studies in this field.\u003c/p\u003e \u003cp\u003eAs a role, it is very important for clinicians to speed up clinical recovery after DAI. Because delayed recovery predisposes patients to various and sometimes catastrophic events like (Deep Vein Thrombosis) DVT, (Pulmonary Thromboembolism) PTE caused by immobility (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e), pulmonary diseases, pneumonia (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e), bedsores, infection, prolonged ICU admission and hospital stay, the increased financial burden for the health system, family and patient (including absence from work) (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) increased emotional stress on family and patients sometimes evolving to psychiatry disorders.\u003c/p\u003e \u003cp\u003eAlthough melatonin and control group enentualy reached the same functional recovery level at three and six month but accelerated short term recovery that happened in melatonin group at first month could be apportuanity to prevent the mentioned catastrophic complication of DAI.\u003c/p\u003e \u003cp\u003eOn the other hand, the reason for the lack of statistical significance in the third and sixth months could be possibly due to errors during data collection, a small sample size, and a limited statistical population.\u003c/p\u003e \u003cp\u003eWhen anlysisng GCS results there wasn't any significant difference between GCS in two groups in any time period (from admission to the end of first week post truma) possibily indicating that melatonin regiment doseant cause and early recovery defect in fact it takes a month for melatonin to reproduce it defect (significant E-GOS at the end of first month). Limited studies have been conducted on the effect of melatonin in improving low consciousness which mostly showed an impaired level of melatonin secration in people with low GCS (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Litriture review demonstrated that the use of melatonin in TBI patients improves the quality of sleep, which can increase the quality of life (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). Melatonin can also reduce Alzheimer's after trauma (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eConsidering that sideeffects of melatonin overlap with some of the comment DAI symptoms like nausea, vomiting, and dizziness, There is a possibility that the use of melatonin could aggravates the symptoms, which must be keept in mind (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOn the other hand, melatonin improves symptoms such as headache, pain, and anxiety probably through the gamma-aminobutyric acid (GABA) system and opiate receptors (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe limitations of this study were small sample size and statistical papulation. In avitable, combination of melatonin with a variety of other drugs wich exist in the priscription regiment of an ICU admitted, limited arms of the intervention groups with only 3 mg daily dose and exclusion of mild DAI (concussion).\u003c/p\u003e \u003cp\u003eThe advantages of the current research were long-term follow-ups, evaluation on humans (instead of animal models), and incorporating FIM score.\u003c/p\u003e \u003cp\u003eIt is suggested that future studies should be conducted with larger sample size and in a multicenter system. It is also recommended to conduct meta-analysis research in this field.\u003c/p\u003e \u003cp\u003eConsidering the effects of melatonin on GOS and FIM, it can accelerates the speed of functional recovery as a low-cost and safe supplement in DAI.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eAlthogh melatonin and control group reach the same fanctional recovery level at mid-term (3 moth) and longterm (6 month) fallow up, melatonin accelerates the speed of functional recovery in short term (1 month) fallow up after DAI. Thus melatonin as a lowcast and safe medication can be incoroporated in DAI treatment to increase the speed of recovery rate and decrease mortality and morbidity after DAI resulting in an improve quality of life.This study investigated the clinical effects of melatonin. Conducting similar studies that evaluate molecular biomarkers and inflammatory markers after TBI can be helpful.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. The materials used in this study are available commercially or can be obtained from the authors upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declared no conflict of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eAlireza Ghaedamini: writing and editing manuscript \u003c/p\u003e\n\u003cp\u003eSaeed Karamoozian :supervising\u003c/p\u003e\n\u003cp\u003eMohammad Khaksari Hadad: data collection\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e \u003c/sup\u003eZahra Soltani: data collection\u003c/p\u003e\n\u003cp\u003eHossein Ghaedamini : editing manuscript\u003c/p\u003e\n\u003cp\u003eAli Hojati: writing manuscript\u003c/p\u003e\n\u003cp\u003eAmin Soleimani: writing manuscript\u003c/p\u003e\n\u003cp\u003eReza Karimabadi: writing of the research\u003c/p\u003e\n\u003cp\u003eMasod Mayel: writing of the research\u003c/p\u003e\n\u003cp\u003eNazanin Sabet: writing of the research\u003c/p\u003e\n\u003cp\u003eMohammad Mehdi Ahmadinejad: writing of the research\u003c/p\u003e\n\u003cp\u003eGholamreza Asadikorom: editing of the research\u003c/p\u003e\n\u003cp\u003eBehshad Mofid: editing of the research \u003c/p\u003e\n\u003cp\u003eNozar Nakheie: statistical analysis\u003c/p\u003e\n\u003cp\u003ePayam Khazaeli: editing of the research \u003c/p\u003e\n\u003cp\u003eElham Jafari: editing of the research\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eEthics approval \u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eThe study protocol was approved by Iranian Registry of Clinical Trials (IRCT Code: IRCT20190717044248N6) and the Medical Ethics Committee of Kerman University of Medical Sciences (Ethical Code: IR.KMU.AH.REC.1400.228). \u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/h3\u003e\n\u003ch3\u003eNo potential conflict of interest relevant to this article was reported.\u003c/h3\u003e\n\n\n\u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003e \u003c/span\u003e\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no financial conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eShahhosseini R, Nejad AE, Shahba M, Tajoddini S, Ghaedamini H, Farahbakhsh S, Daneshi S, Hushmandi K, Raei M. Investigation of the changes in CT scan findings in patients with head trauma referred to the emergency department of Shahid Bahonar Hospital in Kerman in 2020. Qom University of Medical Sciences Journal. 2021 Apr 10;15(2):130-9.\u003c/li\u003e\n \u003cli\u003eJang SH. Diagnostic problems in diffuse axonal injury. Diagnostics. 2020 Feb 21;10(2):117.\u003c/li\u003e\n \u003cli\u003eGraham NS, Jolly A, Zimmerman K, Bourke NJ, Scott G, Cole JH, Schott JM, Sharp DJ. Diffuse axonal injury predicts neurodegeneration after moderate\u0026ndash;severe traumatic brain injury. Brain. 2020 Dec;143(12):3685-98.\u003c/li\u003e\n \u003cli\u003eBenjamini D, Iacono D, Komlosh ME, Perl DP, Brody DL, Basser PJ. Diffuse axonal injury has a characteristic multidimensional MRI signature in the human brain. Brain. 2021 Mar;144(3):800-16.\u003c/li\u003e\n \u003cli\u003evan Eijck MM, Sprengers MO, Oldenbeuving AW, de Vries J, Schoonman GG, Roks G. The use of the PSH-AM in patients with diffuse axonal injury and autonomic dysregulation: a cohort study and review. Journal of Critical Care. 2019 Feb 1;49:110-7.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Zhong YH, Zheng BE, He RH, Zhou Z, Zhang SQ, Wei Y, Fan JZ. Serum levels of HDL cholesterol are associated with diffuse axonal injury in patients with traumatic brain injury. Neurocritical Care. 2021 Apr;34:465-72.\u003c/li\u003e\n \u003cli\u003eJanas AM, Qin F, Hamilton S, Jiang B, Baier N, Wintermark M, Threlkeld Z, Lee S. Diffuse axonal injury grade on early MRI is associated with worse outcome in children with moderate-severe traumatic brain injury. Neurocritical Care. 2022 Apr;36(2):492-503.\u003c/li\u003e\n \u003cli\u003eRostami E, Ginstman F, Ljungqvist J, Olivecrona M, Koskinen LO, Bellander BM, Marklund N. Treatment of traumatic brain injury in the acute setting-An overview. Lakartidningen. 2023 Jan 27;120:22067-.\u003c/li\u003e\n \u003cli\u003eLohani S, Bhandari S, Ranabhat K, Agrawal P. Does diffuse axonal injury MRI grade really correlate with functional outcome?. World Neurosurgery. 2020 Mar 1;135:e424-6.\u003c/li\u003e\n \u003cli\u003eTomita K, Nakada TA, Oshima T, Motoshima T, Kawaguchi R, Oda S. Tau protein as a diagnostic marker for diffuse axonal injury. PLoS One. 2019 Mar 22;14(3):e0214381.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Ramos E, Gil-Mart\u0026iacute;n E, De Los R\u0026iacute;os C, Egea J, L\u0026oacute;pez-Mu\u0026ntilde;oz F, Pita R, Juber\u0026iacute;as A, Torrado JJ, Serrano DR, Reiter RJ, Romero A. Melatonin as Modulator for Sulfur and Nitrogen Mustard-Induced Inflammation, Oxidative Stress and DNA Damage: Molecular Therapeutics. Antioxidants. 2023 Feb 6;12(2):397.\u003c/li\u003e\n \u003cli\u003eThangwong P, Jearjaroen P, Tocharus C, Govitrapong P, Tocharus J. Melatonin suppresses inflammation and blood‒brain barrier disruption in rats with vascular dementia possibly by activating the SIRT1/PGC-1\u0026alpha;/PPAR\u0026gamma; signaling pathway. Inflammopharmacology. 2023 Apr 5:1-3.\u003c/li\u003e\n \u003cli\u003eSun C, Meng S, Wang B, Zhao S, Liu Y, Qi M, Wang Z, Yin Z, Li T. Exogenous melatonin enhances tomato heat resistance by regulating photosynthetic electron flux and maintaining ROS homeostasis. Plant Physiology and Biochemistry. 2023 Mar 1;196:197-209.\u003c/li\u003e\n \u003cli\u003eYang S, Zeng H, Jiang L, Fu C, Gao L, Zhang L, Zhang Y, Zhang X, Zhu L, Zhang F, Chen J. Melatonin reduces melanogenesis by inhibiting the paracrine effects of keratinocytes. Experimental Dermatology. 2023 Jan 9.\u003c/li\u003e\n \u003cli\u003ePotes Y, Caballero B. Special Issue on \u0026ldquo;Pleiotropic Benefits of Melatonin: From Basic Mechanisms to Disease\u0026rdquo;. International Journal of Molecular Sciences. 2023 Mar 9;24(6):5223.\u003c/li\u003e\n \u003cli\u003eOsier N, McGreevy E, Pham L, Puccio A, Ren D, Conley YP, Alexander S, Dixon CE. Melatonin as a Therapy for Traumatic Brain Injury: A Review of Published Evidence. Int J Mol Sci. 2018 May 22;19(5):1539. doi: 10.3390/ijms19051539. PMID: 29786658; PMCID: PMC5983792.\u003c/li\u003e\n \u003cli\u003eNaseem M, Parvez S. Role of melatonin in traumatic brain injury and spinal cord injury. ScientificWorldJournal. 2014;2014:586270. doi: 10.1155/2014/586270. Epub 2014 Dec 21. PMID: 25587567; PMCID: PMC4283270.\u003c/li\u003e\n \u003cli\u003eBell A, Hewins B, Bishop C, Fortin A, Wang J, Creamer JL, Collen J, Werner Jr JK. Traumatic Brain Injury, Sleep, and Melatonin\u0026mdash;Intrinsic Changes with Therapeutic Potential. Clocks \u0026amp; Sleep. 2023 Apr 6;5(2):177-203.\u003c/li\u003e\n \u003cli\u003eDehghan F, Khaksari Hadad M, Asadikram G, Najafipour H, Shahrokhi N. Effect of melatonin on intracranial pressure and brain edema following traumatic brain injury: role of oxidative stresses. Archives of medical research. 2013;44(4):251-8.\u003c/li\u003e\n \u003cli\u003eDehghan F, Shahrokhi N, Khaksari M, Soltani Z, Asadikorom G, Najafi A, et al. Does the administration of melatonin during post-traumatic brain injury affect cytokine levels? Inflammopharmacology. 2018;26(4):1017-23.\u003c/li\u003e\n \u003cli\u003eWang Z, Zhou F, Dou Y, Tian X, Liu C, Li H, et al. Melatonin Alleviates Intracerebral Hemorrhage-Induced Secondary Brain Injury in Rats via Suppressing Apoptosis, Inflammation, Oxidative Stress, DNA Damage, and Mitochondria Injury. Translational stroke research. 2018;9(1):74-91.\u003c/li\u003e\n \u003cli\u003eWang DL, Ling ZQ, Cao FY, Zhu LQ, Wang JZ. Melatonin attenuates isoproterenol-induced protein kinase A overactivation and tau hyperphosphorylation in rat brain. Journal of pineal research. 2004;37(1):11-6.\u003c/li\u003e\n \u003cli\u003eKostoglou-Athanassiou I. Therapeutic applications of melatonin. Therapeutic advances in endocrinology and metabolism. 2013;4(1):13-24.\u003c/li\u003e\n \u003cli\u003eBarlow KM, Esser MJ, Veidt M, Boyd R. Melatonin as a treatment after traumatic brain injury: a systematic review and meta-analysis of the pre-clinical and clinical literature. Journal of neurotrauma. 2019 Feb 1;36(4):523-37.\u003c/li\u003e\n \u003cli\u003eWright DW, Yeatts SD, Silbergleit R, Palesch YY, Hertzberg VS, Frankel M, et al. Very early administration of progesterone for acute traumatic brain injury. The New England journal of medicine. 2014;37(1):2457-2466.\u003c/li\u003e\n \u003cli\u003eYamal JM, Hannay HJ, Gopinath S, Aisiku IP, Benoit JS, Robertson CS. Glasgow outcome scale measures and impact on analysis and results of a randomized clinical trial of severe traumatic brain injury. Journal of neurotrauma. 2019 Sep 1;36(17):2484-92.\u003c/li\u003e\n \u003cli\u003eMaritz R, Tennant A, Fellinghauer C, Stucki G, Prodinger B. The Functional Independence Measure 18-item version can be reported as a unidimensional interval-scaled metric: Internal construct validity revisited. Journal of Rehabilitation Medicine. 2019 Mar 5;51(3):193-200.\u003c/li\u003e\n \u003cli\u003eMohamed OM, Mohammad SY, Ameen DA, Abo El-Hoda AH. Validity of Glasgow Coma Scale-Pupil Age Charts in predicting the outcome for patients with traumatic brain injury. Evidence-Based Nursing Research. 2022 Sep 19;4(4):16-32.\u003c/li\u003e\n \u003cli\u003eLee JG, Woo YS, Park SW, Seog DH, Seo MK, Bahk WM. The neuroprotective effects of melatonin: Possible role in the pathophysiology of neuropsychiatric disease. Brain sciences. 2019 Oct 21;9(10):285.\u003c/li\u003e\n \u003cli\u003eChitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, Zagrean AM. Melatonin\u0026rsquo;s impact on antioxidative and anti-inflammatory reprogramming in homeostasis and disease. Biomolecules. 2020 Aug 20;10(9):1211.\u003c/li\u003e\n \u003cli\u003eAmer ME, Othamn AI, El-Missiry MA. Melatonin ameliorates diabetes-induced brain injury in rats. Acta Histochemica. 2021 Feb 1;123(2):151677.\u003c/li\u003e\n \u003cli\u003eQin W, Li J, Zhu R, Gao S, Fan J, Xia M, Zhao RC, Zhang J. Melatonin protects blood-brain barrier integrity and permeability by inhibiting matrix metalloproteinase-9 via the NOTCH3/NF-\u0026kappa;B pathway. Aging (Albany NY). 2019 Dec 12;11(23):11391.\u003c/li\u003e\n \u003cli\u003eZhan CP, Zhuge CJ, Yan XJ, Dai WM, Yu GF. Measuring serum melatonin concentrations to predict clinical outcome after aneurysmal subarachnoid hemorrhage. Clinica Chimica Acta. 2021 Feb 1;513:1-5.\u003c/li\u003e\n \u003cli\u003eFarid A, El-Dewak M, Safwat G, Diab A. Anti-apoptotic and antioxidant effects of melatonin protect spleen of whole body \u0026gamma;-irradiated male Sprague-dawley rats. International Journal of Radiation Research. 2021 Oct 1;19(4):861-72.\u003c/li\u003e\n \u003cli\u003eOwino S, Buonfiglio DD, Tchio C, Tosini G. Melatonin signaling a key regulator of glucose homeostasis and energy metabolism. Frontiers in endocrinology. 2019 Jul 17;10:488.\u003c/li\u003e\n \u003cli\u003eLiu L, Cao Q, Gao W, Li B, Xia Z, Zhao B. Melatonin protects against focal cerebral ischemia-reperfusion injury in diabetic mice by ameliorating mitochondrial impairments: involvement of the Akt-SIRT3-SOD2 signaling pathway. Aging (albany NY). 2021 Jun 6;13(12):16105.\u003c/li\u003e\n \u003cli\u003eLuo F, Sandhu AF, Rungratanawanich W, Williams GE, Akbar M, Zhou S, Song BJ, Wang X. Melatonin and autophagy in aging-related neurodegenerative diseases. International Journal of Molecular Sciences. 2020 Sep 28;21(19):7174.\u003c/li\u003e\n \u003cli\u003eWido A, Bajamal AH, Apriawan T, Parenrengi MA, Al Fauzi A. Deep vein thrombosis prophylaxis use in traumatic brain injury patients in tropical climate. International Journal of Health \u0026amp; Medical Sciences. 2022;5(1):67-74.\u003c/li\u003e\n \u003cli\u003eFinsterer J. Neurological perspectives of neurogenic pulmonary edema. European neurology. 2019 May 22;81(1-2):94-102.\u003c/li\u003e\n \u003cli\u003eMurphy JM, Bennett JM, de la Piedad Garcia X, Willis ML. Emotion recognition and traumatic brain injury: A systematic review and meta-analysis. Neuropsychology review. 2022 Sep;32(3):520-36.\u003c/li\u003e\n \u003cli\u003eKnott RJ, Harris A, Higgins A, Nichol A, French C, Little L, Haddad S, Presneill J, Arabi Y, Bailey M, Cooper DJ. Cost-effectiveness of erythropoietin in traumatic brain injury: a multinational trial-based economic analysis. Journal of neurotrauma. 2019 Sep 1;36(17):2541-8.\u003c/li\u003e\n \u003cli\u003eOsier N, McGreevy E, Pham L, Puccio A, Ren D, Conley YP, Alexander S, Dixon CE. Melatonin as a Therapy for Traumatic Brain Injury: A Review of Published Evidence. Int J Mol Sci. 2018 May 22;19(5):1539. doi: 10.3390/ijms19051539\u003c/li\u003e\n \u003cli\u003eHuang Y, Li Y, Leng Z. Melatonin inhibits GABAergic neurons in the hypothalamus consistent with a reduction in wakefulness. Neuroreport. 2020 Jan 27;31(2):92-8.\u003c/li\u003e\n \u003cli\u003eGrima NA, Rajaratnam SM, Mansfield D, Sletten TL, Spitz G, Ponsford JL. Efficacy of melatonin for sleep disturbance following traumatic brain injury: a randomised controlled trial. BMC medicine. 2018 Dec;16(1):1-0.\u003c/li\u003e\n \u003cli\u003eBlum B, Kaushal S, Khan S, Kim JH, Villalba CL. Melatonin in traumatic brain injury and cognition. Cureus. 2021 Sep 6;13(9).\u003c/li\u003e\n \u003cli\u003eMaas MB, Lizza BD, Abbott SM, Liotta EM, Gendy M, Eed J, Naidech AM, Reid KJ, Zee PC. Factors disrupting melatonin secretion rhythms during critical illness. Critical care medicine. 2020 Jun;48(6):854.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Diffuse axonal injury, Melatonin, Outcome","lastPublishedDoi":"10.21203/rs.3.rs-4980173/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4980173/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThe efficacy of melatonin in improving diffuse axonal injury has not been evaluated. This study investigated the melatonin effect on moderate and severe diffuse axonal injury outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis was a randomized clinical trial. The case group (N\u0026thinsp;=\u0026thinsp;35) received 3mg of oral melatonin, and the control group (N\u0026thinsp;=\u0026thinsp;35) received Placebo. extended-Glasgow Outcome Scale (e-GOS) and Functional Independence Measure (FIM) scores at baseline, 1 month, 3 months, and 6 months after injury were defined as primary outcomes, and Glasgow Coma Scale (GCS) at baseline, 24 hours, 48 hours, 1 week, 2week until discharge defined as secondary outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 70 patients were enrolled and were randomly allocated into the intervention (n\u0026thinsp;=\u0026thinsp;35) and placebo (n\u0026thinsp;=\u0026thinsp;35) groups. The results showed that there was no statistically significant difference between melatonin and placebo in GOS (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and FIM (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) at 3 months and 6 months after hospitalization but the mean E-GOS (P\u0026thinsp;=\u0026thinsp;0.001) and FIM (P\u0026thinsp;=\u0026thinsp;0.001) at the first month was significantly higher in the melatonin group.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe use of melatonin as a low-cost and safe medicine complementary treatment in people with DAI can accelerates functional recovery.\u003c/p\u003e","manuscriptTitle":"Investigation of melatonin effect on the outcome of moderate and severe diffuse axonal injury (DAI) - A randomized, placebo-controlled clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-18 09:59:41","doi":"10.21203/rs.3.rs-4980173/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d95152ab-4775-4d21-b00f-c3d96ca5594f","owner":[],"postedDate":"October 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-21T14:53:43+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-18 09:59:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4980173","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4980173","identity":"rs-4980173","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}