Randomised, double-blind, placebo-controlled study investigating Safety and efficAcy of MLC901 in post-traUmatic bRAin Injury: the SAMURAI study protocol.

INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of death in young adults globally and 90% of cases are mild TBI. Treatment to facilitate recovery after TBI is needed. Traditional medicine MLC901 (NeuroAiD II) with neuroprotective and neuroproliferative properties in cellular and animal models of brain injury showed TBI-associated cognitive improvement in mild or moderate TBI. METHODS AND ANALYSIS: This is a randomised placebo-controlled trial, with 6-month treatment and 9-month follow-up, to determine the safety and efficacy of MLC901 in improving cognitive function in patients with cognitive impairment following mild TBI. This multicentre trial is conducted at the research centres of six hospitals/institutions in Russia. The primary outcome is to determine the effect of MLC901 on complex attention using the CNS Vital Signs (CNS-VS) online neurological test after 6-month treatment in patients receiving MLC901 compared with placebo. Secondary outcomes include other cognitive domains of CNS-VS and Rivermead Post Concussion Symptoms Questionnaire. The exploratory endpoints include Quality of Life after Brain Injury, Hospital Anxiety and Depression Scale and evaluation of improved neurological parameters 3 months after treatment completion. In addition, treatment compliance, concomitant therapies and adverse events will be collected. Investigators will use a secured online system for data entry. ETHICS AND DISSEMINATION: The study has been approved by the ethic committee of Ministry of Health of the Russian Federation (No: 58074). The results of this study will be published in a peer-review journal and presented at international conferences as poster presentations. TRIAL REGISTRATION NUMBER: NCT04861688.

The Cerebrovascular Resistance in Combined Traumatic Brain Injury with Intracranial Hematomas.

OBJECTIVE: The aim was to evaluate changes in cerebrovascular resistance (CVR) in combined traumatic brain injury (CTBI) in groups with and without intracranial hematomas (IH). MATERIALS AND METHODS: Treatment outcomes in 70 patients with CTBI (42 males and 28 females) were studied. Mean age was 35.5 ± 14.8 years (range, 15-73). The patients were divided into two groups: group 1 included 34 CTBI patients without hematomas; group 2 comprised 36 patients with CTBI and IH. The severity according to the Glasgow Coma Scale averaged 10.4 ± 2.6 in group 1, and 10.6 ± 2.8 in group 2. All patients underwent perfusion computed tomography (CT) and transcranial Doppler of both middle cerebral arteries. Cerebral perfusion pressure and CVR were calculated. RESULTS: The mean CVR values in each group (both with and without hematomas) appeared to be statistically significantly higher than the mean normal value. Intergroup comparison of CVR values showed statistically significant increase in the CVR level in group 2 on the side of the removed hematoma (р = 0.037). CVR in the perifocal zone of the removed hematoma remained significantly higher compared with the symmetrical zone in the contralateral hemisphere (p = 0.0009). CONCLUSION: CVR in patients with CTBI is significantly increased compared to the normal value and remains elevated after evacuation of hematoma in the perifocal zone compared to the symmetrical zone in the contralateral hemisphere. This is indicative of certain correlation between the mechanisms of cerebral blood flow autoregulation and maintaining CVR.

Intrahospital Transfer of Patients with Traumatic Brain Injury: Increase in Intracranial Pressure.

AIM: To assess the dynamic of intracranial pressure (ICP), cerebral perfusion pressure (CPP), and dynamic pressure reactivity index (PRx) during intrahospital transport. MATERIALS AND METHODS: There were 33 comatose patients with severe traumatic brain injury (TBI). The mean age was 36.3 ± 4.8 years (range 19-45 years), and there were 17 men and 16 women. The median Glasgow Coma Scale score at admission was 6.2 ± 0.7. Computed tomography (CT) included native CT, perfusion CT, and CT angiography. RESULTS: The mean CPPs before and after the CT scans were 95.9 ± 10.7 and 81.5 ± 12.5 mmHg respectively. The mean ICP before transport was 19.98 ± 5.3 mmHg (minimum 11.7; maximum 51.7). It was statistically significantly lower (p < 0.001) than during the transfer (26.1 ± 13.5 mmHg). During the period described all patients had increased ICP, especially during vertical movement in an elevator. During horizontal movement on the floor ICP remained higher (p < 0.05). The mean dynamic PRx before and after intrahospital transport was 0.23 ± 0.14 and 0.52 ± 0.04, respectively (p < 0.001). Average duration of the transfer and CT study was 15.3 ± 3.4 min. CONCLUSION: Intrahospital transport of patients with TBI may lead to a significant increase in ICP, dynamic PRx, and decreased CPP. The results suppose that the decision to perform brain CT in comatose patients with TBI should be carefully considered by clinicians.

Comparison of Cerebral Oxygen Saturation and Cerebral Perfusion Computed Tomography in Cerebral Blood Flow in Patients with Brain Injury.

The purpose of this study was to determine the relationship between cerebral tissue oxygen saturation and cerebral blood volume in patients with traumatic brain injury. Perfusion computed tomography of the brain was performed in 25 patients with traumatic brain injury together with simultaneous SctO2 level measurement using cerebral near-infrared oxymetry. The mean age of the injured persons was 34.5±15.6 years (range 15-65); 14 men, 11 women. The Injury Severity Score (ISS) values were 44.4±9.7 (range 25-81). The Glasgow Coma Score (GCS) mean value before the study was 10.6±2.1 (range 5-13). SctO2 ranged from 51 to 89%, mean 62±8.2%. Cerebral blood volume (CBV) values were 2.1±0.67 ml/100 g (min 1.1; max 4.3 ml/100 g). Cerebral blood flow (CBF) was 31.99±13.6 ml/100 g×min. Mean transit time (MTT) values were 5.7±4.5 s (min 2.8; max 34.3 s). The time to peak (TTP) was 22.2±3.1 s. A statistically significant correlation was found between SctO2 level and cerebral blood volume (CBV) level (R=0.9; p<0.000001). No other significant correlations were found between brain tissue oxygenation and other parameters of brain perfusion.

Cerebrovascular Time Constant in Patients with Head Injury.

The cerebrovascular time constant (τ) theoretically estimates how fast the cerebral arterial bed is filled by blood volume after a sudden change in arterial blood pressure during one cardiac cycle. The aim of this study was to assess the time constant of the cerebral arterial bed in patients with traumatic brain injury (TBI) with and without intracranial hematomas (IH). We examined 116 patients with severe TBI (mean 35 ± 15 years, 61 men, 55 women). The first group included 58 patients without IH and the second group included 58 patients with epidural (7), subdural (48), and multiple (3) hematomas. Perfusion computed tomography (PCT) was performed 1-12 days after TBI in the first group and 2-8 days after surgical evacuation of the hematoma in the second group. Arteriovenous amplitude of regional cerebral blood volume oscillation was calculated as the difference between arterial and venous blood volume in the "region of interest" of 1 cm(2). Mean arterial pressure was measured and the flow rate of the middle cerebral artery was recorded with transcranial Doppler ultrasound after PCT. The time constant was calculated by the formula modified by Kasprowicz. The τ was shorter (p = 0.05) in both groups 1 and 2 in comparison with normal data. The time constant in group 2 was shorter than in group 1, both on the side of the former hematoma (р = 0.012) and on the contralateral side (р = 0.044). The results indicate failure of autoregulation of cerebral capillary blood flow in severe TBI, which increases in patients with polytrauma and traumatic IH.