The control group received Standard EnteraMeal (Karen Pharma and Food supplement Co., Iran) for 14 days, and the taurine group received daily amount of 30mg/kg with a maximum dose of 3 grams/day of taurine powder (Nutricost, USA) for 14 days in addition to the Standard EnteraMeal (Karen Pharma and Food supplement Co., Iran). Taurine powder was given to patients in two divided doses. Weight of the Patients was measured from the entrance by the scale of hospital bed. Patients’ height was calculated by measuring the knee height and then, by the formula. Body Mass Index (BMI) was calculated by dividing weight by the square of height. Patients required calorie was calculated using the formula of 25kcal/kg/day. Patient’s feeding started from 30 ml/hr, and then, 30 ml/hr was added to it every three hours to reach the calculated energy within 48-72 hours. For determination of nutritional risk of patients, NUTRIC score form was completed. The clinical history and demographic characteristics of patients were evaluated at the time of admission. The Sequential Organ Failure Assessment (SOFA) score was calculated for all patients in the beginning with the study, day 7, day 14 and Acute Physiology And Chronic Health Evaluation II (APACHE II) score at the beginning and end of study to evaluate the severity and outcomes of disease. In order to measure the serum levels of IL-6, IL-10, TNF-a and hs-CRP, at the beginning and end to the study, 10 ml of vein blood was taken from each patient and after centrifugation and serum separation, serum was kept in -70 ° C until analysis. Serum levels of IL-6, IL-10, hs-CRP, and TNF-a were measured by ELISA kit. The length of ICU stay, duration of ventilator dependency and the 30-day mortality rates were investigated. The sample size was calculated based on the averages comparison formula with α= 0.01 and β= 0.1, µ1= – 0.096، S1= 0.3 ،µ2= – 0.5 ،S2= 0.25 based on the previous study for the serum levels of IL-6 variable (29).
The total sample size of 30 patients (15 in each group) was calculated. Based on previous experiences and studies, it was estimated that there would be a 30% dropout after randomization. Thus, the final sample size was considered as 44 patients.
The data were analyzed using the statistical software program SPSS 25 (SPSS Inc., Chicago, IL, USA).
Data distribution was assessed by Kolmogorov-Smirnov test. Comparisons between groups were made with Independent Samples t-test if data distribution was normal. Comparisons of non-normally distributed samples were performed using Mann-Whitney U test to compare differences between the two groups. Two-sided P < 0.05 was considered statistically significant. Comparisons of qualitative data were done by chi-squared test or Fisher’s exact test (30).
During the April to November 2018, 83 patients with traumatic brain injury were assessed for eligibility and 44 were enrolled (Fig. 1) which 32 patients finished the study and others were excluded from the study due to the reasons mentioned in Fig. 1.
Baseline characteristics of patients are shown in Table1. No significant difference existed between two groups in age, sex, weight, and BMI.
Nutrition variables were assessed in each group and are presented in Table 2. Mean daily energy intake was compared with the energy calculated by 25kcal/kg ideal body weight formula. No significant difference existed between the groups for energy intake. Weight loss in the taurine group was significantly lower than the control group (p = 0.050). NUTRIC score showed no significant difference between groups (p = 0.402).
Table 3 shows the levels of serum IL-6, IL-10, TNF-a, and hs-CRP at the beginning and end of study in both groups. As can be observed, a significant difference exists in the serum levels of IL-6 between two groups at the end of the study (p = 0.038). Although the serum levels of hs-CRP and IL-10 showed higher reduction in the taurine group, this differencea were not significant (p = 0.239 and p = 0.802, respectively). TNF-a showed higher increase in the control group but no significant difference was observed between the groups at the end of the study (p = 0.073).
Clinical outcomes are presented in Table 4. At the beginning of the study, no significant difference existed between the groups in GCS, APACHEll, and SOFA scores. At the end of the study, a significant difference was observed in GCS and APACHEll scores in two groups (p = 0.028 and p = 0.049, respectively). Although mortality rate and ventilator dependency duration in the taurine group were less than the control group, this difference was not significant (p = 0.240 and p = 0.215, respectively). Also, no difference was observed between the groups in length of ICU stay (p = 0.963).
The present study was a double-blind randomized clinical trial to determine the effect of taurine on patients with traumatic brain injury fed through enteral route. Generally, patients who received taurine showed better clinical outcomes compared with the patients who did not receive taurine.
About the safety of the of taurine used in the present study, it is reported that 3-6 g/day taurine for one year does not have any harmful effects on the health (31) and about the effectiveness, Elmokadem et al. (29) suggested that in critically ill septic patients, 30 mg/kg/day taurine reduces IL-6 (as an important marker of immune and inflammatory response in the central nervous system). Therefore, based on the evidence, we decided to administer 30 mg/kg/day with the maximum dose of 3 g/day of taurine.
To our best knowledge, this is the first clinical trial that has investigated the effect of taurine on patients with traumatic brain injury.
Taurine has anti-inflammatory effects that can explain the beneficial effects of this amino acid in traumatic brain injury. One of the recommended protective mechanisms for taurine, is it’s reaction with hypochlorous acid to produce taurine chloramine (Tau-Cl) that is a strong anti-inflammatory factor. Hypochlorous acid is a reactive molecule in neutrophils and monocytes of mammalians that is produced through myeloperoxidase pathway (32, 33). Taurine chloramine negatively regulates the production of inflammatory proteins such as TNF-a and IL-6 by phagocytic cells. This process suppresses the inflammatory reaction and protects cells against cytotoxic and cytolytic activity of hypochlorous acid (34).
IL-6 is an important inflammatory and immune response marker in central nervous system that was assessed in this trial. Early studies have shown that in patients with traumatic brain injury, IL-6 levels in CSF are significantly higher than plasma levels (35). In previous studies, taurine has significantly reduced IL-6 levels (29, 36-40). Similarly, the present study showed that taurine suppresses the elevated levels of IL-6 due to traumatic brain injury. Since astrocytes constitute the main source of IL-6, it is possible that taurine reduces IL-6 levels through reducing the activation of astrocytes.
TNF-a is a pro-inflammatory cytokine that is produced by microglia and astrocytes and is involved in brain trauma pathogenesis. Elevated TNF-a levels were observed in CSF and plasma of patients with TBI (41, 42). Taurine, through reducing TNF-a levels in different models of tissue damage has indicated anti-inflammatory effect (34, 37, 38, 40). In our study, Taurine inhibited TNF-a activity and prevented it’s further increase and this is consistent with Su Y et al. study (37).
Among examined cytokines, IL-10 is an anti-inflammatory cytokine that has an important role in inflammation suppression and prevention of excessive immune response. Elevated IL-10 levels in CSF and serum of patients with excessive TBI have been reported (43). On the other hand, it has been indicated that elevated IL-10 production is related to the subsequent sepsis (44). Also, it has been reported that IL-10 concentration in CSF of patients who experience undesirable outcomes is higher (45) and it was consistent with a study on burn patients in 2015 (46). Taurine supplementation in our study reduced IL-10 serum levels. However, at the end of the study, the comparison of mean changes in IL-10 levels, showed no significant difference between the two groups which can be due to the small sample size.
CRP is an acute-phase protein that at the time of tissue injury or inflammation is produced in the liver and can have pro-inflammatory effects and increases secondary brain damage. Hs-CRP due to the close relationship with inflammation and tissue damage is considered as clinical infection marker and acute inflammatory response (47). Similar to other studies (29, 46, 48), supplementation with taurine reduced serum levels of hs-CRP. However, this difference between the two groups was not significant but further reduction of hs-CRP in taurine group shows faster control of inflammation resulted from brain traumatic injury.
It has been indicated that longer duration of mechanical ventilation and ICU support for critically-ill patients with sepsis is related to low levels of plasma taurine (49). On the other hand, in previous studies, low plasma taurine levels are reported in patients with trauma (22-25). The most commonly used clinical tool for severity of neurological injury in adults is Glasgow Coma Scale (50) that is due to it’s inter-observer reliability and predictive validity (51). In our study, GCS in the taurine group increased significantly that shows improvement of clinical condition.
Acute Physiology and Chronic Health Evaluation II (APACHEII) Score is a tool to measure disease severity in patients hospitalized in ICU (52). High APACHEII score is related to the subsequent risk of many common diseases and hospital mortalities (53, 54). In our study, APACHEII score in the taurine group reduced significantly.
SOFA score is an objective and simple score that allows the estimation of both number and severity of organ dysfucntion and during the first days of hospitalization in ICU, is a suitable prognostic index (55). In the present study, supplementation with taurine could not reduce this score in the taurine group significantly.
The length of ICU stay and dependence on ventilator in the taurine group were not significantly lower than the control group. On the other hand, two patients in the taurine group (9.1%) and six patients in the control group (27.3%) had thirty-day mortality and the percentage of mortality in the control group was almost similar to the study by Kasmaei et al. (56). Although taurine reduced mortality rate, no significant difference was observed between the two groups (p = 0.240). This non-significance can be due to small sample size and in this regard, the clinical importance of this reduction should not be ignored. For this purpose, NNT was estimated for thirty-day mortality. The Number Needed to Treat (NNT) includes the number of patients who should be treated to prevent a bad outcome. NNT estimated from 1/Absolute Risk Reduction. In the present study, NNT is equal to 6, meaning that of every 6 patients who received taurine, 1 death was prevented.
Nutrition Risk in Critically ill (NUTRIC) score is the first nutrition risk instrument that is specifically validated for patients in ICU and can identify patients under malnutrition risk (57). In this scoring system, 0-5 show low nutrition risk and 6-10 show high nutrition risk. Those who are in the high risk group, can take more advantage of nutrition supports (58). Although in this study improvement of nutrition risk in the taurine group was higher, no significant difference existed between the two groups.
Patients’ weight decreased in both groups that in the taurine group, it was significantly lower than the control group and this is consistent with a study by Sun et al. (59).
This trial is the first study that has investigated the effects of taurine on inflammatory markers and clinical outcomes in human models. The limitations of this study included small sample size and short-term period of supplementation. Therefore, future studies with larger sample size and longer supplement periods are needed to provide more evidences to support the use of taurine in patients with TBI for inflammation improvement and clinical outcomes.
The findings of this study suggest that taurine supplementation for patients with TBI is accompanied by clinical advantages compared with the patients in the control group, because this supplement reduced the levels of inflammatory biomarkers and also APACHEII score. Moreover, thirty-day mortality and weigh loss in patients in taurine group was less than the patients in the control group. Also, GCS of patients in taurine group improved significantly. Therefore, taurine can reduce the inflammation of patients with TBI and may be considered as an adjunctive treatment for these patients. However, more studies with larger sample size are necessary to clarify the advantages for this group of patients.
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