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The Effect of Curcumin in the Recovery of Severe Traumatic Brain Injury: A Double-Blind Randomized Controlled Trial

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Introduction

Traumatic Brain Injury (TBI) has affected approximately 50% of the world's population at some stage of life. Trauma is one of the most important causes of death and disability in the active population in developing countries and studies indicate that attention to trauma is less in these countries [1-4]. In 2016, 27.08 million new cases of brain trauma were registered in the world, which has increased the standardized prevalence of sense TBI in the world from 1990 to 2016 [5]. According to a report published by BMJ in 2017, TBI caused 8.1 million years of lost life in the world in 2016, which is a significant increase compared to the total number of years of life lost in 1990.

Traumatic Brain Injury (TBI) is defined as an acquired brain disease caused by an external force in the form of mechanical, chemical, thermal, or electrical energy or a combination of these. According to US statistics, 43% of severe TBI survivors are likely to suffer longterm disability [6,7]. On the other hand, it should be noted that the burden of severe brain trauma extends to the patient's family and the health care system [8]. The direct and indirect economic and social costs caused by trauma to families are relatively high so the estimated cost of brain trauma is approximately 400 billion US dollars per year and about 11% of the years of life lost due to disability. It is caused by trauma [9].

To date, there is no complete and effective treatment for traumatic brain injury, as most injuries occur due to secondary effects through various pathophysiological pathways. In addition, the main approach in the treatment of brain trauma is measures such as damage control, surgery, and post-operative care [10]. In the control of damage caused by severe brain trauma, measures aimed at targeting multiple pathways are needed for more effective treatment of this disease. Previous studies have shown that several natural products and herbal medicines have been tested for their ability to improve disorders such as neuron inflammatory conditions characterized by impaired redox balance and excessive inflammation [11-13]. There is evidence that Curcumin can be traditionally used as a natural treatment for many diseases including diabetes, inflammatory diseases, and neurological disorders. Some pharmacological studies also indicate the effect of Curcumin in the treatment of brain trauma and injuries caused by it, but it seems that these results are not enough and more extensive research should be done in this field [14].

Curcumin is considered a poly phenolic that, in addition to its anti-inflammatory, thrombolytic and anti-cancer effects, can be used in the treatment of several diseases such as Alzheimer's disease and injuries caused by trauma by inhibiting the accumulation of amyloid protein [15]. The effect of Curcumin on endogenous neuron regeneration in rats after TBI has been confirmed, so the apoptotic cells in the damaged area of rats that had TBI and received Curcumin were significantly less than in the control group. In addition to the animal studies that have shown Curcumin's therapeutic effect on brain trauma, they have not shown any toxicity at a dose of 500 mg [16]. On the other hand, the anti-inflammatory effect of Curcumin with low molecular weight has been of interest for centuries, despite various studies on Curcumin in laboratory animals and the lack of studies on humans considering the published literature, this study is aimed to the effect of Curcumin in the treatment of severe brain injuries in patients [17].

Methodology

The current study is a controlled double-blind clinical trial study that was conducted on 128 patients. In this study, the patients were divided into two control groups by a simple randomization method (recipients of Standard care treatment i.e. treatment according to Yeoman's treatment protocol and treatment with prophylactic anticonvulsant drugs and antibiotics if needed and placebo) and intervention group (i.e. recipients of Standard care treatment and oral NanoCurcumin as orally or through a nasogastric tube in the amount of 500 mg every 8 hours and for three weeks). In this study, patients suffering from severe brain trauma referred to the special care department of neurosurgery and specialized and subspecialized in Hamadan Besat hospital, West Iran from 2019 to 2021 were selected.

The included patients were randomized using a computer random number generator to select random permuted blocks with a block size of eight and an equal allocation ratio. Sequentially numbered, opaque, sealed envelopes were used to ensure concealment. Three members of the study team recruited, enrolled, and assigned participants to a computer generated randomization sequence, held by an independent observer.

Inclusion criteria were people between the ages of 18 and 70 years, duration of concussion less than 24 hours, level of consciousness (GCS) 8 or less, not candidates for craniotomy surgery, and pregnant and lactating women. The exclusion criteria were those who had an unstable systemic condition, the presence of multiple and severe organic injuries, lack of brain stem reflexes, kidney failure, and the need for any type of surgery in the early days of hospitalization.

If a complication occurs and is observed by the attending physician, the treatment with Curcumin was stopped. The patients in both groups were subjected to mechanical ventilation if needed, and no patient received barbiturate treatment. Consciousness level, blood pressure, the reaction of pupils to light, movement, and strength of organs were checked daily. Brain CT scan was performed on the first, third, and seventh days based on the patient's condition. To investigate drug side effects, parameters such as serum biochemistry, platelet count, hemoglobin, PT, PTT, serum electrolytes, and liver tests were measured on the first, third, and seventh days after hospitalization. To classify patients at discharge, GOS was used in three-month and six-month follow-ups. Patients with good recovery or moderate disability were included in the favorable outcome group, and those with severe disability or vegetative life, as well as those who died, were included in the unfavorable outcome group. This study was approved and registered by the Research Ethics Committee of the Hamadan University of Medical Sciences at the address IR.UMSHA.REC.1398.010 and the IRCT code is IRCT20120215009014N305. Informed consent was obtained from all participants in this study. Participants' privacy and data confidentiality were guaranteed.

Analysis

We used an intention to treat analysis approach and include all randomly assigned participants. In this study, mean and standard deviation were used to describe quantitative variables, and number and percentage were used to describe qualitative variables. To compare the level of alertness and biochemical factors of patients in two groups of control and intervention from the variance analysis of repeated data, to determine the relationship between the performance of patients after discharge in the two groups using the chi-square test, to compare the frequency of edema in the two groups using the exact-Fisher test. The significance level in this study is less than 0.05 and SPSS version 21 software was used (Figure 1).

Figure 1: Follow-up chart of patients based on Consort 2010 guidelines.

Results

This study was conducted on 128 severe brain trauma patients who were randomized into two intervention and control groups. The number of men in the intervention and control groups was 51 (79.7%) and 49 (76.7%) respectively. The Chi-square test showed that the gender distribution between the two groups was not statistically significant (p=0.669). Patients in the intervention (14.44 ± 31.86) and control (33.34 ± 14.86) groups did not differ in terms of age (p=0.543). The frequency of the cause of severe brain trauma among patients is shown in Table 1. Although Table 1 shows that the performance six months after discharge based on the GOS score was not significantly different between the two intervention and control groups, the frequency of optimal performance in the third month after discharge in the intervention group was significantly higher than in the control group. (p=0.034). Brain CT scan findings on the first and third day showed no difference in terms of edema between the two groups, but on the seventh day, a score of 1 in the intervention group and a score of 3 in the control group were significantly observed (Table 1, p=0.038).

Table 1: Frequency and percentage of the cause of severe brain trauma, function, edema, and other biochemical characteristics of patients in two intervention and control groups.

The findings of the present study showed that although there was no significant difference in the level of consciousness of patients in the two groups on the first day of hospitalization, the level of consciousness of patients in the intervention group was significantly higher than the control group on the third (p=0.004) and seventh (p=0.001) days. Also, the analysis of the variance of the repeated data showed that the changes in the level of consciousness of the patients in the intervention group were significantly different from the control group (Table 2, p=0.003).

Table 2: Comparison of the level of consciousness and biochemical parameters in intervention and control group.

According to the findings in Table 2, there was a significant difference in the PT values of patients in the intervention and control groups on the first (p<0.001), third (p=0.002), and seventh (p<0.001) days of hospitalization. The comparison of PT sizes in two groups showed that this parameter is different between the two groups over time (p=0.021) and the PT of patients in the intervention group is always lower than the control group.

In addition, there is no statistically significant difference in the PTT value between the patients of the two groups. The average INR in the intervention group was lower than the control group in all three stages, i.e. the first, third, and seventh days of hospitalization. Variance analysis of repeated data also showed that there is a significant difference between these averages during the measurements made in the two groups (Table 2, p=0.023). The biggest difference in INR between the two groups was observed on the seventh day of hospitalization.

During the follow-up of the patients, there is a significant difference in sodium changes between the intervention and control groups (p=0.007), so the biggest difference was observed on the third day of follow-up (p=0.019) between the two groups. According to the results of Table 2, no significant difference was observed in the changes in blood urea and creatinine between the two groups. The results of this study showed that although there is no difference in the general trend of urea changes between the patients of the intervention and control groups, that is, they had almost a slight increase (p=0.660), but in the two-by-two comparison of the groups on the first day (p=0.009) and the seventh day (p=0.015) statistically significant difference was evident.

According to the findings, there was no difference between the creatinine levels of the patients in the two groups (p=0.073), while the average white blood cell count was significantly lower in the patients of the intervention group (p=0.016). The findings show that the difference between the white blood cells between the two groups was on the third day (p=0.004) and the seventh day (p=0.009). The average SGOT of patients in the intervention group was about 1.6 times higher than the control group, and this difference was significant (p=0.024). However, there was no difference between the SGOT of control and intervention group patients on the first and third days. In addition, the variance analysis of repeated data also did not show a significant difference between the two groups in terms of SGOT changes in general (0.313). In both intervention and control groups, there was no significant difference between the average SGPT (p=0.600) and ALK (p=0.203) during the hospitalization period of the patients.

This study showed that the rate of blood pressure reduction (p=0.028) and death (p<0.001) was significantly lower in patients who received routine+Curcumin treatment compared to the control Pupil reactions of the right and left eyes were checked on the seventh day of hospitalization in both groups and no difference was observed between the two groups (Table 3).

Table 3: Comparison of the frequency of blood pressure reduction, eye reaction, and mortality in patients with severe brain trauma in the intervention and control groups.

Discussion

In the current study, considering the beneficial properties of Curcumin in relieving inflammation, it was used to treat severe brain trauma patients in comparison to routine treatment in a clinical trial study. We focused on Curcumin because it is a spice with multiple pharmacological properties, very low toxicity, and availability. Cerebral edema and subsequent increase in ICP as well as decreased level of consciousness are serious complications of brain trauma that contribute to increased patient mortality and long-term disability [18].

The present study clearly shows that doses of 500 mg every 8 hours of nano Curcumin reduce cerebral edema and its mortality, especially from the seventh day onwards, reducing the frequency of hypotension, and the level of cerebral function in the first trimester. And secondly, it improves post-discharge, which improper performance can cause death, and improves some biochemical factors.

The therapeutic properties of Curcumin in the intervention group reduced the amount of brain edema caused by severe brain trauma compared to the control group. Such a result with the study of samini et al. [19] which was conducted on rats with traumatic brain injury with doses of 50 and 100 mg/kg and also with the results of the study of Laird MD et al. with three doses of 150-57 300 mg/kg was done. Siahaan et al.'s study [20] in a study on rats with mild brain damage reported that the use of turmeric extract is not effective in improving neurological function caused by repeated mild brain damage in rats. It should be noted that the present study was conducted on humans and the maximum dose was 10 mg/kg. The difference between the results of this study and siahaan may be due to the severity of the trauma.

One of the results of this study was a significant increase in the level of consciousness of patients receiving Curcumin compared to the control on the third day of treatment and at the time of discharge. Such a result is not far from expected, because Smal et al. [21] conducted a clinical trial study and confirmed the effect of Curcumin bioavailability on memory and brain amyloid over 18 months. Previous studies emphasized that Curcumin can relieve inflammation and apoptosis by modulating the involved molecular signaling pathways [22]. On the other hand Shu et al. also showed that Curcumin is effective on endogenous neuron regeneration in an animal model after brain trauma. Therefore, the chemical mechanisms at the level of the brain also confirm the results of this study.

Another important result of this study was a reduction in the death rate among Curcumin recipients compared to controls. This result is also reasonable because Ahmadi et al. [23] showed in a clinical trial that Curcumin as an adjunctive treatment with riluzole can increase the survival of patients with amyotrophic lateral sclerosis. They reported this significant difference with the Kaplan-Meier survival plot. Although the present study was conducted on patients with severe brain trauma, both our study and Ahmadi et al.'s study confirmed the effect of Curcumin on patients' survival.

Another important result we achieved in this study was that we did not observe any difference between severe brain trauma patients who received Curcumin and controls in terms of coagulation factors, electrolytes, liver enzymes, and kidney function. This means that there is no additional risk of liver, coagulation, and electrolyte damage in patients taking Curcumin. Regarding the safety of Curcumin as a treatment or complementary treatment in other diseases, reports have been published [24,25] and in this study, it was also confirmed that it is without complications in severe brain trauma patients. In this study, we used a dose of 500 mg of Curcumin per day, while some studies used doses of 1200 mg per day and did not report any toxicity. Zhu et al. [26] during their study confirmed that Curcumin as a phytochemical compound with anti-inflammatory properties reduces inflammation and accelerates the recovery of brain function.

Conclusion

This study showed that the administration of oral NanoCurcumin supplement at the rate of 500 mg every 8 hours in a three-week treatment period in hospitalized patients with severe brain trauma can have an effective role in improving cerebral edema and increasing the level of consciousness of patients in addition to their routine treatment. and this is without any side effects such as disorders in the coagulation, liver, and kidney systems also it did not any interactions with other drugs drug. Therefore, the chemical mechanisms at the level of the brain also confirm of this study. The present study clearly shows that doses of 500 mg every 8 hours of nano Curcumin reduce cerebral edema and its mortality, especially from the seventh day onwards, reducing the frequency of hypotension, and the level of cerebral function in the first trimester.

Acknowledgments

The authors would like to thank the Clinical Research Development Unit (CRDU) of Besat Hospital, Hamadan University of Medical Sciences, and Hamadan, Iran for their support cooperation and assistance thought the period of study. (Grant number 14001203310086).

Conflict of Interest Statement

The authors declare that they have no conflict of interest

Funding

The Vice-Chancellor of Research and Technology, Hamadan University of Medical Sciences funded this study (Grant number 14001203310086). However, the funder had no role in the study design, data collection, analysis, decision to publish, or manuscript preparation.

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