TABLE 1.

Summary of the included studies.

Trial		Patient population	Intervention	Comp.	Outcome(s)	Conclusion
1	Mansour et al. (2021) Egypt	(n = 50) TBI patients, GCS (3–12)	100 mg doxycycline BID for 7 days	Placebo	Difference between tde two study groups in mean NSE serum levels at day 7.	NSE serum levels in tde doxycycline group were significantly lower tdan in tde control group.
2	Mahyudanil et al. (2020) Indonesia	(n = 40) TBI patients, GCS of 4–8	Single dose progesterone 1 mg/kg	Placebo	Difference in serum level of S-100β in 24 h and 96 h between the two arms of the study.	Insignificant change in serum level of S-100β was observed.
3	Koulaeinejad et al. (2019) Iran	(n = 40) TBI patients, GCS ≤12.	100 mg minocycline BID for 7 days	Placebo	Changes in level of NSE and S100 β from day 1 to day 5 after randomization.	The reduction in serum NSE and S100 β levels from baseline to day 5 was statistically significant in the minocycline group but not in the placebo group.
4	(Taheri et al., 2019) Iran	(n = 30) TBI patients, GCS ≤8	1 g metformin/12 h for 5 days.	No drug	5-day post-trauma serum concentration profile (24 h, 48 h, 72 h and 120 h) of S100B and GFAP.	Significantly lower S100b in patients allocated to metformin. GFAP values did not differ between groups at all study time points
5	Mahmoodpoor et al. (2018)	(n = 58) TBI patients, GCS ≤8.	2 g L-carnitine once daily for 7 days	Placebo	Difference between the study groups in mean NSE serum levels at day 3.	L-carnitine failed to reduce serum NSE levels in patients with TBI.
6	Mokhtari et al. (2018) Iran	(n = 68) TBI patient, GCS (9–12)	30 mg memantine BID for 7 days	No drug	Difference in NSE serum levels at days 1, 3, and 7 post randomizations.	Memantine significantly reduced NSE levels by day in patients with moderate TBI.
7	Clark et al. (2017) United States	(n = 14) TBI pediatric patients, GCS ≤8	Combined N-acetylcysteine and probenecid	Placebo	Difference in serum levels of NSE and GFAP, in 24 h and 96 h between the two arms of the study.	Brain injury biomarkers were deemed comparable between the two groups (p = 0.441).
8	Shahrokhi et al. (2016) Iran	(n = 32) DAI patients, GCS ≤12.	1 mg/kg IM BID progesterone for 5 days.	Placebo	Difference between the two study groups in mean NSE serum levels at days 1 and 6.	Progesterone did not change the serum level of NSE between the study groups.
9	Li et al. (2016) China	(n = 159) TBI patients, GCS ≤8.	100 U/kg erythropoietin SC for 12 days	Normal Saline	The difference between groups in S100B and NSE levels	Serum NSE and S-100ß protein levels were lower in patients who received erythropoietin.
10	(Nirula et al., 2010) United States	(n = 16) TBI patients, GCS ≤13.	Erythropoietin (40,000 Units IV) within 6 h of injury.	placebo	Difference between groups in serum concentrations of S100B and NSE at day 1, 2, 3,4 and 5 post resuscitation	Erythropoietin did not impact NSE (p = .89) or S100 B (p = 0.53) levels compared to the placebo.
11	Baker et al. (2009) Canada	(n = 64) TBI patients, GCS ≤8.	250 mL 7.5% hypertonic saline +6% dextran70 (HSD)	0.9% normal saline (NS)	Difference between groups in serum concentrations of S100B and NSE at 12, 24, and 48 h post-resuscitation.	Compared with NS resuscitation, S100B and NSE were two and threefold lower in HSD-treated patients and normalized within 12 h.